Hematology

From the University of Texas MD Anderson Cancer Center, Houston, TX (Drs. Narayanan, Lopez, Chaoul, Liu, Milbury, and Cohen, and Ms. Mallaiah); the University of Texas Health Science Center at Tyler (Dr. Meegada); and Texas Tech University Health Sciences Center, Lubbock, TX (Ms. Francisco).

Abstract

• Objective: To review the effects of yoga as an adjunct supportive care modality alongside conventional cancer treatment on quality of life (QOL), physical and mental health outcomes, and physiological and biological measures of cancer survivors.
• Methods: Nonsystematic review of the literature.
• Results: Yoga therapy, one of the most frequently used mind-body modalities, has been studied extensively in cancer survivors (from the time of diagnosis through long-term recovery). Yoga affects human physiology on multiple levels, including psychological outcomes, immune and endocrine function, and cardiovascular parameters, as well as multiple areas of QOL. It has been found to reduce psychological stress and fatigue and improve QOL in cancer patients and survivors. Yoga has also been used to manage symptoms such as arthralgia, fatigue, and insomnia. In addition, yoga offers benefits not only for cancer survivors but also for their caregivers.
• Conclusion: As part of an integrative, evidence-informed approach to cancer care, yoga may provide benefits that support the health of cancer survivors and caregivers.

Keywords: fatigue; cancer; proinflammatory cytokines; integrative; mind-body practices; meditation; DNA damage; stress; psychoneuro-immunoendocrine axis; lymphedema; insomnia.

A diagnosis of cancer and adverse effects related to its treatment may have negative effects on quality of life (QOL), contributing to emotional and physical distress in patients and caregivers. Many patients express an interest in pursuing nonpharmacological options, alone or as an adjunct to conventional therapy, to help manage symptoms. The use of complementary medicine approaches to health, including nonpharmacological approaches to symptom management, is highest among individuals with cancer.¹ According to a published expert consensus, integrative oncology is defined as a “patient-centered, evidence-informed field of cancer care that utilizes mind and body practices, natural products, and/or lifestyle modifications from different traditions alongside conventional cancer treatments. Integrative oncology aims to optimize health, QOL, and clinical outcomes across the cancer care continuum and to empower people to prevent cancer and become active participants before, during, and beyond cancer treatment.”² A key component of this definition, often misunderstood in the field of oncology, is that these modalities and treatments are used alongside conventional cancer treatments and not as an alternative. In an attempt to meet patients’ needs and appropriately use these approaches, integrative oncology programs are now part of most cancer centers in the United States.^3-6

Because of their overall safety, mind-body therapies are commonly used by patients and recommended by clinicians. Mind-body therapies include yoga, tai chi, qigong, meditation, and relaxation. Expressive arts such as journaling and music, art, and dance therapies also fall in the mind-body category.⁷ Yoga is a movement-based mind-body practice that focuses on synchronizing body, breath, and mind. Yoga has been increasingly used by patients for health benefits,⁸ and numerous studies have evaluated yoga as a complementary intervention for individuals with cancer.^9-14 Here, we review the physiological basis of yoga in oncology and the effects of yoga on biological processes, QOL, and symptoms during and after cancer treatment.

Physiological Basis

Many patients may use mind-body programs such as yoga to help manage the psychological and physiological consequences of unmanaged chronic stress and improve their overall QOL. The central nervous system, endocrine system, and immune system influence and interact with each other in a complex manner in response to chronic stress.^15,16 In a stressful situation, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) are activated. HPA axis stimulation leads to adrenocorticotrophic hormone production by the pituitary gland, which releases glucocorticoid hormones. SNS axis stimulation leads to epinephrine and norepinephrine production by the adrenal gland.^17,18 Recently, studies have explored modulation of signal transduction between the nervous and immune systems and how that may impact tumor growth and metastasis.¹⁹ Multiple studies, controlled for prognosis, disease stage, and other factors, have shown that patients experiencing more distress or higher levels of depressive symptoms do not live as long as their counterparts with low distress or depression levels.²⁰ Both the meditative and physical components of yoga can lead to enhanced relaxation, reduced SNS activation, and greater parasympathetic tone, countering the negative physiological effects of chronic stress. The effects of yoga on the HPA axis and SNS, proinflammatory cytokines, immune function, and DNA damage are discussed below.

Biological Processes

Nervous System

The effects of yoga and other forms of meditation on brain functions have been established through several studies. Yoga seems to influence basal ganglia function by improving circuits that are involved in complex cognitive functions, motor coordination, and somatosensory and emotional processes.^21,22 Additionally, changes in neurotransmitter levels have been observed after yoga practice. For instance, in a 12-week yoga intervention in healthy subjects, increased levels of thalamic gamma-aminobutyric acid (GABA) in the yoga group were reported to have a positive correlation with improved mood and decreased anxiety compared with a group who did metabolically matched walking exercise.²³ Levels of GABA, an inhibitory neurotransmitter, are decreased in conditions such as anxiety, depression, and epilepsy.²⁴ Yoga therapy has been shown to improve symptoms of mood disorders and epilepsy, which leads to the hypothesis that the mechanism driving the benefits of yoga may work through stimulation of vagal efferents and an increase in GABA-mediated cortical-inhibitory tone.^24,25

 

 

HPA Axis

Stress activates the HPA/SNS axis, which releases hormones such as cortisol and norepinephrine. These hormones may play a role in angiogenesis, inflammation, immune suppression, and other physiological functions, and may even reduce the effect of chemotherapeutic agents.^26,27 Regular yoga practice has been shown to reduce SNS and HPA axis activity, most likely by increasing parasympathetic dominance through vagal stimulation, as demonstrated through increases in heart rate variability.²⁸ One indicator of HPA axis dysregulation, diurnal salivary cortisol rhythm, was shown to predict survival in patients with advanced breast and renal cancer.^29-33 Yoga has been shown to lead to less cortisol dysregulation due to radiotherapy and to reductions in mean cortisol levels and early morning cortisol levels in breast cancer patients undergoing radiotherapy.³⁴ This lends support to the hypothesis that yoga helps restore HPA axis balance.

Proinflammatory Cytokines

Cancer patients tend to have increased levels of inflammatory markers such as interleukin (IL)-4, IL-10, tumor necrosis factor (TNF), interferon-γ, and C-reactive protein. This increase in inflammation is associated with worse outcomes in cancer.³⁵ This association becomes highly relevant because the effect of inflammation on host cells in the tumor microenvironment is connected to disease progression.²⁶ Inflammatory cytokines are also implicated in cancer-related symptoms such as fatigue, cognitive dysfunction, peripheral neuropathy, and sleep disturbances.³⁶

Yoga is known to reduce stress and may directly or indirectly decrease inflammatory cytokines. A randomized clinical trial of a 12-week hatha yoga intervention among breast cancer survivors demonstrated decreases in IL-6, IL-1β, TNF, corticotropin-releasing factor, and cognitive complaints in the yoga group compared with those in the standard care group after 3 months.^37,38 Furthermore, Carlson et al showed that, after mindfulness-based stress reduction involving a combination of gentle yoga, meditation techniques, and relaxation exercises, breast and prostate cancer patients had reduced levels of proinflammatory cytokines and cortisol.³⁹ These reductions translated into patients reporting decreased stress levels and enhanced QOL.

Immune Function

The effects of yoga practice on the immune system have been studied in both healthy individuals and individuals with cancer. The effects on T and B lymphocytes, natural killer (NK) cells, and other immune effector cells demonstrate that meditation and yoga have beneficial effects on immune activity.⁴⁰ Hormones such as catecholamines and glucocorticoids are thought to influence the availability and function of NK cells, and, as noted above, yoga has been shown to modulate stress hormones and lead to reduced immune suppression in patients with early-stage breast cancer undergoing chemotherapy.⁴¹ Additional evidence supports the ability of yoga to reduce immune suppression in the postsurgical setting, with no observed decrease in NK cell percentage after surgery for those in a yoga group compared with a control group.⁴² This finding is relevant to patients undergoing surgical management of their cancer and highlights the impact of yoga on the immune system.

DNA Damage

Radiation damages DNA in the peripheral blood lymphocytes of patients undergoing treatment.^43,44 This damage is significant in breast cancer patients undergoing radiotherapy.⁴⁵ Stress additionally causes DNA damage⁴⁶ and is correlated to impaired DNA repair capacity.^47,48 In a study conducted by Banerjee et al, breast cancer patients were randomly assigned to a yoga group or a supportive therapy group for 6 weeks during radiotherapy.⁴⁹ Prior to the intervention, patients in the study had significant genomic instability. After treatment, patients in the yoga group experienced not only a significant reduction in anxiety and depression levels, but also a reduction in DNA damage due to radiotherapy.

 

 

Yoga in Quality of Life and Symptom Management

There is evidence showing that yoga therapy improves multiple aspects of QOL, including physical functioning, emotional health outcomes, and the symptoms cancer patients may experience, such as sleep disturbances, fatigue, and pain. Danhauer et al systematically reviewed both nonrandomized trials and randomized controlled trials involving yoga during cancer treatment.⁵⁰ They found that yoga improved depression and anxiety as well as sleep and fatigue. Benefits of yoga in cancer based on randomized controlled trials are summarized in the Table. The role of yoga in improving QOL and managing symptoms patients experience during and after treatment is discussed in the following sections.

Quality of Life

Danhauer et al’s systematic review of trials involving yoga during cancer treatment found that yoga improved multiple aspects of QOL.⁵⁰ For example, yoga has been shown to improve QOL in breast cancer patients undergoing radiotherapy. In a study by Chandwani et al, yoga (60-minute sessions twice a week for 6 weeks) was associated with better general health perception and physical functioning scores as well as greater benefit finding, or finding meaning in their experience, after radiotherapy compared with a wait-list group.⁵¹ The yoga group had an increase in intrusive thoughts, believed to be due to a more thorough processing of the cancer experience, which helps to improve patients’ outlook on life.⁵² The benefits of yoga extend beyond psychological measures during radiation treatment. Yoga was found to increase physical functioning compared with stretching in breast cancer patients undergoing radiotherapy.⁵³

Cognitive Function

Cancer-related cognitive impairment commonly occurs during cancer treatments (eg, chemotherapy, radiotherapy, surgery, hormone therapy) and persists for months or years in survivors.⁵⁴ Impairment of memory, executive function, attention, and concentration are commonly reported. In a trial of a combined hatha and restorative yoga program called Yoga for Cancer Survivors (YOCAS), which was designed by researchers at the University of Rochester, patients in the yoga arm had less memory difficulty than did patients in the standard care arm.⁵⁵ However, the primary aim of the trial was to treat insomnia, so this secondary outcome needs to be interpreted with caution. Deficits in attention, memory, and executive function are often seen in cancer-related cognitive impairment, and the meditative aspect of yoga may have behavioral and neurophysical benefits that could improve cognitive functions.⁵⁶ More evidence is needed to understand the role of yoga in improving cognitive functioning.

Emotional Health

Psychosocial stress is high among breast cancer patients and survivors.^57,58 This causes circadian rhythm and cortisol regulation abnormalities, which are reported in women with breast cancer.^59-64 Yoga is known to help stress and psychosocial and physical functioning in patients with cancer.⁶⁵ Yoga was also shown to be equivalent to cognitive behavioral therapy in stress management in a population of patients without cancer.⁶⁶ Daily yoga sessions lasting 60 minutes were shown to reduce reactive anxiety and trait anxiety in early-stage breast cancer patients undergoing conventional radiotherapy and chemotherapy compared with patients receiving supportive therapy, highlighting the role of yoga in managing anxiety related to treatment.⁶⁷ In a study done by Culos-Reed et al, 20 cancer survivors who did 75 minutes of yoga per week for 7 weeks were compared with 18 cancer survivors who served as a control group.⁶⁸ The intervention group reported significant improvement in emotional well-being, depression, concentration, and mood disturbances. In a longitudinal study by Mackenzie et al, 66 cancer survivors completed a 7-week yoga program and were assessed at baseline, immediately after the final yoga session, and at 3 and 6 months after the final session.⁶⁹ Participants had significantly improved energy levels and affect. They also had moderate improvement in mindfulness and a moderate decrease in stress. Breast cancer patients who underwent restorative yoga sessions found improvements in mental health, depression, positive affect, and spirituality (peace/meaning).⁷⁰ This was more pronounced in women with higher negative affect and lower emotional well-being at baseline. In a study of patients with ovarian cancer receiving chemotherapy, patients were instructed to perform up to 15-minute sessions including awareness, body movement, and breathing.⁷¹ Even with just 1 session of yoga intervention, patients experienced decreased anxiety.

Fatigue

Studies on yoga show improvement in fatigue both during and after treatment. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit cognitive fatigue.⁷² Older cancer survivors also seem to benefit from yoga interventions.⁷³ In a trial of a DVD-based yoga program, the benefits of yoga were similar to those of strengthening exercises, and both interventions helped decrease fatigue and improve QOL during the first year after diagnosis in early-stage breast cancer patients with cancer-related fatigue.⁷⁴ Bower et al also showed that, for breast cancer survivors experiencing persistent chronic fatigue, a targeted yoga intervention led to significant improvements in fatigue and vigor over a 3-month follow-up compared with controls.⁷⁵ Fatigue is commonly seen in breast cancer patients who are receiving adjuvant chemotherapy. In a study by Taso et al, women with breast cancer receiving chemotherapy were assigned to 60-minute yoga sessions incorporating Anusara yoga, gentle stretching, and relaxation twice a week for 8 weeks.⁷⁶ By week 4, patients with low pretest fatigue in the yoga group experienced a reduction in fatigue. By week 8, all patients in the yoga group experienced a reduction in fatigue. Four weeks after the yoga intervention, patients in the group maintained the reduction in fatigue. This study shows the feasibility of an 8-week yoga program for women undergoing breast cancer therapy by improving fatigue. Yoga recently was added to National Comprehensive Cancer Network (NCCN) guidelines for management of cancer-related fatigue (level 1 evidence).⁷⁷ However, the evidence was based on studies in women with breast cancer and survivors; therefore, more studies are needed in men and women with other cancers.

 

 

Surgical Setting/Postoperative Distress

Distress surrounding surgery in patients with breast cancer can impact postoperative outcomes. Yoga interventions, including breathing exercises, regulated breathing, and yogic relaxation techniques, improved several postsurgical measures such as length of hospital stay, drain retention, and suture removal.⁷⁸ In this study, patients who practiced yoga also experienced a decrease in plasma TNF and better wound healing. Symptoms of anxiety and distress that occur preoperatively can lead to impaired immune function in addition to decreased QOL. In a study of yoga in early-stage breast cancer patients undergoing surgery, the benefit of yoga was seen not only with stress reduction but also with immune enhancement.⁴²

Yoga has been shown to help alleviate acute pain and distress in women undergoing major surgery for gynecological cancer. A regimen of 3 15-minute sessions of yoga, including awareness meditation, coordination of breath with movement, and relaxation breathing, was shown to reduce acute pain and distress in such patients in an inpatient setting.⁷⁹

Menopausal Symptoms

Breast cancer survivors have more severe menopausal symptoms compared with women without cancer.^80,81 Hot flashes cause sleep disturbances and worsen fatigue and QOL.⁸² Tamoxifen and aromatase inhibitors significantly worsen menopausal symptoms such as hot flashes.⁸¹ Carson et al conducted a study of yoga that included postures, breathing techniques, didactic presentations, and group discussions.⁸³ The yoga awareness regimen consisted of 8 weekly 120-minute group classes. Patients in the yoga arm had statistically significant improvements in the frequency, severity, and number of hot flashes. There were also improvements in arthralgia (joint pain), fatigue, sleep disturbance, vigor, and acceptance.

Arthralgia

Joint pain can be a major side effect that interferes with daily functions and activities in postmenopausal breast cancer survivors who receive aromatase inhibitor therapy.⁸⁴ Arthralgia is reported in up to 50% of patients treated with aromatase inhibitors.^84,85 It can affect functional status and lead to discontinuation of aromatase inhibitor therapy, jeopardizing clinical outcomes.⁸⁶ Yoga as a complementary therapy has been shown to improve conditions such as low back pain⁸⁷ and knee osteoarthritis⁸⁸ in patients who do not have cancer. In a single-arm pilot trial by Galantino et al, breast cancer patients with aromatase inhibitor–related joint pain were provided with twice-weekly yoga sessions for 8 weeks. There were statistically significant improvements in balance, flexibility, pain severity, and health-related QOL.⁸⁹ As noted above, improvement in arthralgia was also found in the study conducted by Carson et al.⁸³

Insomnia

Insomnia is common among cancer patients and survivors^90,91 and leads to increased fatigue and depression, decreased adherence to cancer treatments, and poor physical function and QOL.^90-92 Management of insomnia consists of pharmacologic therapies such as benzodiazepines^93,94 and nonpharmacologic options such as cognitive behavioral therapy.⁹⁵

The first study of yoga found to improve sleep quality was conducted at MD Anderson Cancer Center in lymphoma patients.⁹⁶ The effects of Tibetan yoga practices incorporating controlled breathing and visualization, mindfulness techniques, and low-impact postures were studied. Patients in the Tibetan yoga group had better subjective sleep quality, faster sleep latency, longer sleep duration, and less use of sleep medications. Mustian et al conducted a large yoga study in cancer survivors in which patients reporting chronic sleep disturbances were randomly assigned to the YOCAS program, which consisted of pranayama (breath control), 16 gentle hatha and restorative yoga postures, and meditation, or to usual care.⁹² The study reported improvements in global sleep quality, subjective sleep quality, actigraphy measures (wake after sleep onset, sleep efficiency), daytime dysfunction, and use of sleep medication after the yoga intervention compared with participants who received standard care.

Yoga to Address Other Symptoms

There is preliminary evidence supporting yoga as an integrative therapy for other symptoms unique to cancer survivors. For example, in head and neck cancer survivors, soft tissue damage involving the jaw, neck, shoulders, and chest results in swallowing issues, trismus, and aspiration, which are more pronounced in patients treated with conventional radiotherapy than in those treated with intensity-modulated radiotherapy.⁹⁷ Some late effects of radiotherapy for head and neck cancer—such as pain, anxiety, and impaired shoulder function—were shown to be improved through the practice of hatha yoga in 1 study.⁹⁸ Similarly, in a randomized controlled pilot study of patients with stage I to III breast cancer 6 months after treatment, participants in an 8-week yoga program experienced a reduction in arm induration and improvement in a QOL subscale of lymphedema symptoms. However, more evidence is needed to support the use of yoga as a therapeutic measure for breast cancer lymphedema.^99,100

Yoga for Caregivers

Along with cancer patients, caregivers face psychological and physical burdens as well as deterioration in their QOL. Caregivers tend to report clinical levels of anxiety, depression, sleep disturbance, and fatigue and have similar or in fact higher levels than those of the patients for whom they are caring.^101,102 Yoga has been found to help caregivers of patients with cancer. Recently, MD Anderson researchers conducted a trial in patients with high-grade glioma and their caregivers as dyads.^103,104 Each dyad attended 2 or 3 60-minute weekly Vivekananda yoga sessions involving breathing exercises, physical exercises, relaxation, and meditation. The researchers found that the yoga program was safe, feasible, acceptable, and subjectively useful for patients with high-grade glioma and their caregivers. Preliminary evidence of QOL improvement for both patients and caregivers was noted. An improvement in QOL was also demonstrated in another preliminary study of yoga in patients undergoing thoracic radiotherapy and their caregivers.¹⁰⁵

Another study by the group at MD Anderson evaluated a couple-based Tibetan yoga program that emphasized breathing exercises, gentle movements, guided visualizations, and emotional connectedness during radiotherapy for lung cancer.¹⁰⁶ This study included 10 patient‐caregiver dyads and found the program to be feasible, safe, and acceptable. The researchers also found preliminary evidence of improved QOL by the end of radiotherapy relative to baseline—specifically in the areas of spiritual well‐being for patients, fatigue for caregivers, and sleep disturbances and mental health issues such as anxiety and depressive symptoms for both patients and caregivers. This is noteworthy, as QOL typically deteriorates during the course of radiotherapy, and the yoga program was able to buffer these changes.

Conclusion

Yoga therapy has been used successfully as an adjunct modality to improve QOL and cancer-related symptoms. As a part of an integrative medicine approach, yoga is commonly recommended for patients undergoing cancer treatment. Danhauer et al reviewed randomized controlled trials during and after treatment and concluded that the evidence is clearly positive for QOL, fatigue, and perceived stress.¹⁰⁷ Results are less consistent but supportive for psychosocial outcomes such as benefit finding and spirituality. Evidence is mixed for sleep, anxiety, and depression. Post-treatment studies demonstrate improvements in fatigue, sleep, and multiple QOL domains. Yoga has been included in NCCN guidelines for fatigue management. Yoga, if approved by a physician, is also included among the behavioral therapies for anticipatory emesis and prevention and treatment of nausea in the recent update of the NCCN guidelines.¹⁰⁸ The Society for Integrative Oncology guidelines include yoga for anxiety/stress reduction as a part of integrative treatment in breast cancer patients during and after therapy, which was endorsed by the American Society of Clinical Oncology.¹⁰⁹

Because of the strong evidence for its benefits and a low side-effect profile, yoga is offered in group-class settings for patients during and after treatment and/or for caregivers in our institution. We often prescribe yoga as a therapeutic modality for selected groups of patients in our clinical practice. However, some patients may have restrictions after surgery that must be considered. In general, yoga has an excellent safety profile, the evidence base is strong, and we recommend that yoga therapy should be part of the standard of care as an integrative approach for patients with cancer undergoing active treatment as well as for cancer survivors and caregivers.

Acknowledgement: The authors thank Bryan Tutt for providing editorial assistance.

Corresponding author: Santhosshi Narayanan, MD, Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030; snarayanan2@mdanderson.org.

Financial disclosures: None.

From the University of Texas MD Anderson Cancer Center, Houston, TX (Drs. Narayanan, Lopez, Chaoul, Liu, Milbury, and Cohen, and Ms. Mallaiah); the University of Texas Health Science Center at Tyler (Dr. Meegada); and Texas Tech University Health Sciences Center, Lubbock, TX (Ms. Francisco).

Abstract

• Objective: To review the effects of yoga as an adjunct supportive care modality alongside conventional cancer treatment on quality of life (QOL), physical and mental health outcomes, and physiological and biological measures of cancer survivors.
• Methods: Nonsystematic review of the literature.
• Results: Yoga therapy, one of the most frequently used mind-body modalities, has been studied extensively in cancer survivors (from the time of diagnosis through long-term recovery). Yoga affects human physiology on multiple levels, including psychological outcomes, immune and endocrine function, and cardiovascular parameters, as well as multiple areas of QOL. It has been found to reduce psychological stress and fatigue and improve QOL in cancer patients and survivors. Yoga has also been used to manage symptoms such as arthralgia, fatigue, and insomnia. In addition, yoga offers benefits not only for cancer survivors but also for their caregivers.
• Conclusion: As part of an integrative, evidence-informed approach to cancer care, yoga may provide benefits that support the health of cancer survivors and caregivers.

Keywords: fatigue; cancer; proinflammatory cytokines; integrative; mind-body practices; meditation; DNA damage; stress; psychoneuro-immunoendocrine axis; lymphedema; insomnia.

A diagnosis of cancer and adverse effects related to its treatment may have negative effects on quality of life (QOL), contributing to emotional and physical distress in patients and caregivers. Many patients express an interest in pursuing nonpharmacological options, alone or as an adjunct to conventional therapy, to help manage symptoms. The use of complementary medicine approaches to health, including nonpharmacological approaches to symptom management, is highest among individuals with cancer.¹ According to a published expert consensus, integrative oncology is defined as a “patient-centered, evidence-informed field of cancer care that utilizes mind and body practices, natural products, and/or lifestyle modifications from different traditions alongside conventional cancer treatments. Integrative oncology aims to optimize health, QOL, and clinical outcomes across the cancer care continuum and to empower people to prevent cancer and become active participants before, during, and beyond cancer treatment.”² A key component of this definition, often misunderstood in the field of oncology, is that these modalities and treatments are used alongside conventional cancer treatments and not as an alternative. In an attempt to meet patients’ needs and appropriately use these approaches, integrative oncology programs are now part of most cancer centers in the United States.^3-6

Because of their overall safety, mind-body therapies are commonly used by patients and recommended by clinicians. Mind-body therapies include yoga, tai chi, qigong, meditation, and relaxation. Expressive arts such as journaling and music, art, and dance therapies also fall in the mind-body category.⁷ Yoga is a movement-based mind-body practice that focuses on synchronizing body, breath, and mind. Yoga has been increasingly used by patients for health benefits,⁸ and numerous studies have evaluated yoga as a complementary intervention for individuals with cancer.^9-14 Here, we review the physiological basis of yoga in oncology and the effects of yoga on biological processes, QOL, and symptoms during and after cancer treatment.

Physiological Basis

Many patients may use mind-body programs such as yoga to help manage the psychological and physiological consequences of unmanaged chronic stress and improve their overall QOL. The central nervous system, endocrine system, and immune system influence and interact with each other in a complex manner in response to chronic stress.^15,16 In a stressful situation, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) are activated. HPA axis stimulation leads to adrenocorticotrophic hormone production by the pituitary gland, which releases glucocorticoid hormones. SNS axis stimulation leads to epinephrine and norepinephrine production by the adrenal gland.^17,18 Recently, studies have explored modulation of signal transduction between the nervous and immune systems and how that may impact tumor growth and metastasis.¹⁹ Multiple studies, controlled for prognosis, disease stage, and other factors, have shown that patients experiencing more distress or higher levels of depressive symptoms do not live as long as their counterparts with low distress or depression levels.²⁰ Both the meditative and physical components of yoga can lead to enhanced relaxation, reduced SNS activation, and greater parasympathetic tone, countering the negative physiological effects of chronic stress. The effects of yoga on the HPA axis and SNS, proinflammatory cytokines, immune function, and DNA damage are discussed below.

Biological Processes

Nervous System

The effects of yoga and other forms of meditation on brain functions have been established through several studies. Yoga seems to influence basal ganglia function by improving circuits that are involved in complex cognitive functions, motor coordination, and somatosensory and emotional processes.^21,22 Additionally, changes in neurotransmitter levels have been observed after yoga practice. For instance, in a 12-week yoga intervention in healthy subjects, increased levels of thalamic gamma-aminobutyric acid (GABA) in the yoga group were reported to have a positive correlation with improved mood and decreased anxiety compared with a group who did metabolically matched walking exercise.²³ Levels of GABA, an inhibitory neurotransmitter, are decreased in conditions such as anxiety, depression, and epilepsy.²⁴ Yoga therapy has been shown to improve symptoms of mood disorders and epilepsy, which leads to the hypothesis that the mechanism driving the benefits of yoga may work through stimulation of vagal efferents and an increase in GABA-mediated cortical-inhibitory tone.^24,25

 

 

HPA Axis

Stress activates the HPA/SNS axis, which releases hormones such as cortisol and norepinephrine. These hormones may play a role in angiogenesis, inflammation, immune suppression, and other physiological functions, and may even reduce the effect of chemotherapeutic agents.^26,27 Regular yoga practice has been shown to reduce SNS and HPA axis activity, most likely by increasing parasympathetic dominance through vagal stimulation, as demonstrated through increases in heart rate variability.²⁸ One indicator of HPA axis dysregulation, diurnal salivary cortisol rhythm, was shown to predict survival in patients with advanced breast and renal cancer.^29-33 Yoga has been shown to lead to less cortisol dysregulation due to radiotherapy and to reductions in mean cortisol levels and early morning cortisol levels in breast cancer patients undergoing radiotherapy.³⁴ This lends support to the hypothesis that yoga helps restore HPA axis balance.

Proinflammatory Cytokines

Cancer patients tend to have increased levels of inflammatory markers such as interleukin (IL)-4, IL-10, tumor necrosis factor (TNF), interferon-γ, and C-reactive protein. This increase in inflammation is associated with worse outcomes in cancer.³⁵ This association becomes highly relevant because the effect of inflammation on host cells in the tumor microenvironment is connected to disease progression.²⁶ Inflammatory cytokines are also implicated in cancer-related symptoms such as fatigue, cognitive dysfunction, peripheral neuropathy, and sleep disturbances.³⁶

Yoga is known to reduce stress and may directly or indirectly decrease inflammatory cytokines. A randomized clinical trial of a 12-week hatha yoga intervention among breast cancer survivors demonstrated decreases in IL-6, IL-1β, TNF, corticotropin-releasing factor, and cognitive complaints in the yoga group compared with those in the standard care group after 3 months.^37,38 Furthermore, Carlson et al showed that, after mindfulness-based stress reduction involving a combination of gentle yoga, meditation techniques, and relaxation exercises, breast and prostate cancer patients had reduced levels of proinflammatory cytokines and cortisol.³⁹ These reductions translated into patients reporting decreased stress levels and enhanced QOL.

Immune Function

The effects of yoga practice on the immune system have been studied in both healthy individuals and individuals with cancer. The effects on T and B lymphocytes, natural killer (NK) cells, and other immune effector cells demonstrate that meditation and yoga have beneficial effects on immune activity.⁴⁰ Hormones such as catecholamines and glucocorticoids are thought to influence the availability and function of NK cells, and, as noted above, yoga has been shown to modulate stress hormones and lead to reduced immune suppression in patients with early-stage breast cancer undergoing chemotherapy.⁴¹ Additional evidence supports the ability of yoga to reduce immune suppression in the postsurgical setting, with no observed decrease in NK cell percentage after surgery for those in a yoga group compared with a control group.⁴² This finding is relevant to patients undergoing surgical management of their cancer and highlights the impact of yoga on the immune system.

DNA Damage

Radiation damages DNA in the peripheral blood lymphocytes of patients undergoing treatment.^43,44 This damage is significant in breast cancer patients undergoing radiotherapy.⁴⁵ Stress additionally causes DNA damage⁴⁶ and is correlated to impaired DNA repair capacity.^47,48 In a study conducted by Banerjee et al, breast cancer patients were randomly assigned to a yoga group or a supportive therapy group for 6 weeks during radiotherapy.⁴⁹ Prior to the intervention, patients in the study had significant genomic instability. After treatment, patients in the yoga group experienced not only a significant reduction in anxiety and depression levels, but also a reduction in DNA damage due to radiotherapy.

 

 

Yoga in Quality of Life and Symptom Management

There is evidence showing that yoga therapy improves multiple aspects of QOL, including physical functioning, emotional health outcomes, and the symptoms cancer patients may experience, such as sleep disturbances, fatigue, and pain. Danhauer et al systematically reviewed both nonrandomized trials and randomized controlled trials involving yoga during cancer treatment.⁵⁰ They found that yoga improved depression and anxiety as well as sleep and fatigue. Benefits of yoga in cancer based on randomized controlled trials are summarized in the Table. The role of yoga in improving QOL and managing symptoms patients experience during and after treatment is discussed in the following sections.

Quality of Life

Danhauer et al’s systematic review of trials involving yoga during cancer treatment found that yoga improved multiple aspects of QOL.⁵⁰ For example, yoga has been shown to improve QOL in breast cancer patients undergoing radiotherapy. In a study by Chandwani et al, yoga (60-minute sessions twice a week for 6 weeks) was associated with better general health perception and physical functioning scores as well as greater benefit finding, or finding meaning in their experience, after radiotherapy compared with a wait-list group.⁵¹ The yoga group had an increase in intrusive thoughts, believed to be due to a more thorough processing of the cancer experience, which helps to improve patients’ outlook on life.⁵² The benefits of yoga extend beyond psychological measures during radiation treatment. Yoga was found to increase physical functioning compared with stretching in breast cancer patients undergoing radiotherapy.⁵³

Cognitive Function

Cancer-related cognitive impairment commonly occurs during cancer treatments (eg, chemotherapy, radiotherapy, surgery, hormone therapy) and persists for months or years in survivors.⁵⁴ Impairment of memory, executive function, attention, and concentration are commonly reported. In a trial of a combined hatha and restorative yoga program called Yoga for Cancer Survivors (YOCAS), which was designed by researchers at the University of Rochester, patients in the yoga arm had less memory difficulty than did patients in the standard care arm.⁵⁵ However, the primary aim of the trial was to treat insomnia, so this secondary outcome needs to be interpreted with caution. Deficits in attention, memory, and executive function are often seen in cancer-related cognitive impairment, and the meditative aspect of yoga may have behavioral and neurophysical benefits that could improve cognitive functions.⁵⁶ More evidence is needed to understand the role of yoga in improving cognitive functioning.

Emotional Health

Psychosocial stress is high among breast cancer patients and survivors.^57,58 This causes circadian rhythm and cortisol regulation abnormalities, which are reported in women with breast cancer.^59-64 Yoga is known to help stress and psychosocial and physical functioning in patients with cancer.⁶⁵ Yoga was also shown to be equivalent to cognitive behavioral therapy in stress management in a population of patients without cancer.⁶⁶ Daily yoga sessions lasting 60 minutes were shown to reduce reactive anxiety and trait anxiety in early-stage breast cancer patients undergoing conventional radiotherapy and chemotherapy compared with patients receiving supportive therapy, highlighting the role of yoga in managing anxiety related to treatment.⁶⁷ In a study done by Culos-Reed et al, 20 cancer survivors who did 75 minutes of yoga per week for 7 weeks were compared with 18 cancer survivors who served as a control group.⁶⁸ The intervention group reported significant improvement in emotional well-being, depression, concentration, and mood disturbances. In a longitudinal study by Mackenzie et al, 66 cancer survivors completed a 7-week yoga program and were assessed at baseline, immediately after the final yoga session, and at 3 and 6 months after the final session.⁶⁹ Participants had significantly improved energy levels and affect. They also had moderate improvement in mindfulness and a moderate decrease in stress. Breast cancer patients who underwent restorative yoga sessions found improvements in mental health, depression, positive affect, and spirituality (peace/meaning).⁷⁰ This was more pronounced in women with higher negative affect and lower emotional well-being at baseline. In a study of patients with ovarian cancer receiving chemotherapy, patients were instructed to perform up to 15-minute sessions including awareness, body movement, and breathing.⁷¹ Even with just 1 session of yoga intervention, patients experienced decreased anxiety.

Fatigue

Studies on yoga show improvement in fatigue both during and after treatment. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit cognitive fatigue.⁷² Older cancer survivors also seem to benefit from yoga interventions.⁷³ In a trial of a DVD-based yoga program, the benefits of yoga were similar to those of strengthening exercises, and both interventions helped decrease fatigue and improve QOL during the first year after diagnosis in early-stage breast cancer patients with cancer-related fatigue.⁷⁴ Bower et al also showed that, for breast cancer survivors experiencing persistent chronic fatigue, a targeted yoga intervention led to significant improvements in fatigue and vigor over a 3-month follow-up compared with controls.⁷⁵ Fatigue is commonly seen in breast cancer patients who are receiving adjuvant chemotherapy. In a study by Taso et al, women with breast cancer receiving chemotherapy were assigned to 60-minute yoga sessions incorporating Anusara yoga, gentle stretching, and relaxation twice a week for 8 weeks.⁷⁶ By week 4, patients with low pretest fatigue in the yoga group experienced a reduction in fatigue. By week 8, all patients in the yoga group experienced a reduction in fatigue. Four weeks after the yoga intervention, patients in the group maintained the reduction in fatigue. This study shows the feasibility of an 8-week yoga program for women undergoing breast cancer therapy by improving fatigue. Yoga recently was added to National Comprehensive Cancer Network (NCCN) guidelines for management of cancer-related fatigue (level 1 evidence).⁷⁷ However, the evidence was based on studies in women with breast cancer and survivors; therefore, more studies are needed in men and women with other cancers.

 

 

Surgical Setting/Postoperative Distress

Distress surrounding surgery in patients with breast cancer can impact postoperative outcomes. Yoga interventions, including breathing exercises, regulated breathing, and yogic relaxation techniques, improved several postsurgical measures such as length of hospital stay, drain retention, and suture removal.⁷⁸ In this study, patients who practiced yoga also experienced a decrease in plasma TNF and better wound healing. Symptoms of anxiety and distress that occur preoperatively can lead to impaired immune function in addition to decreased QOL. In a study of yoga in early-stage breast cancer patients undergoing surgery, the benefit of yoga was seen not only with stress reduction but also with immune enhancement.⁴²

Yoga has been shown to help alleviate acute pain and distress in women undergoing major surgery for gynecological cancer. A regimen of 3 15-minute sessions of yoga, including awareness meditation, coordination of breath with movement, and relaxation breathing, was shown to reduce acute pain and distress in such patients in an inpatient setting.⁷⁹

Menopausal Symptoms

Breast cancer survivors have more severe menopausal symptoms compared with women without cancer.^80,81 Hot flashes cause sleep disturbances and worsen fatigue and QOL.⁸² Tamoxifen and aromatase inhibitors significantly worsen menopausal symptoms such as hot flashes.⁸¹ Carson et al conducted a study of yoga that included postures, breathing techniques, didactic presentations, and group discussions.⁸³ The yoga awareness regimen consisted of 8 weekly 120-minute group classes. Patients in the yoga arm had statistically significant improvements in the frequency, severity, and number of hot flashes. There were also improvements in arthralgia (joint pain), fatigue, sleep disturbance, vigor, and acceptance.

Arthralgia

Joint pain can be a major side effect that interferes with daily functions and activities in postmenopausal breast cancer survivors who receive aromatase inhibitor therapy.⁸⁴ Arthralgia is reported in up to 50% of patients treated with aromatase inhibitors.^84,85 It can affect functional status and lead to discontinuation of aromatase inhibitor therapy, jeopardizing clinical outcomes.⁸⁶ Yoga as a complementary therapy has been shown to improve conditions such as low back pain⁸⁷ and knee osteoarthritis⁸⁸ in patients who do not have cancer. In a single-arm pilot trial by Galantino et al, breast cancer patients with aromatase inhibitor–related joint pain were provided with twice-weekly yoga sessions for 8 weeks. There were statistically significant improvements in balance, flexibility, pain severity, and health-related QOL.⁸⁹ As noted above, improvement in arthralgia was also found in the study conducted by Carson et al.⁸³

Insomnia

Insomnia is common among cancer patients and survivors^90,91 and leads to increased fatigue and depression, decreased adherence to cancer treatments, and poor physical function and QOL.^90-92 Management of insomnia consists of pharmacologic therapies such as benzodiazepines^93,94 and nonpharmacologic options such as cognitive behavioral therapy.⁹⁵

The first study of yoga found to improve sleep quality was conducted at MD Anderson Cancer Center in lymphoma patients.⁹⁶ The effects of Tibetan yoga practices incorporating controlled breathing and visualization, mindfulness techniques, and low-impact postures were studied. Patients in the Tibetan yoga group had better subjective sleep quality, faster sleep latency, longer sleep duration, and less use of sleep medications. Mustian et al conducted a large yoga study in cancer survivors in which patients reporting chronic sleep disturbances were randomly assigned to the YOCAS program, which consisted of pranayama (breath control), 16 gentle hatha and restorative yoga postures, and meditation, or to usual care.⁹² The study reported improvements in global sleep quality, subjective sleep quality, actigraphy measures (wake after sleep onset, sleep efficiency), daytime dysfunction, and use of sleep medication after the yoga intervention compared with participants who received standard care.

Yoga to Address Other Symptoms

There is preliminary evidence supporting yoga as an integrative therapy for other symptoms unique to cancer survivors. For example, in head and neck cancer survivors, soft tissue damage involving the jaw, neck, shoulders, and chest results in swallowing issues, trismus, and aspiration, which are more pronounced in patients treated with conventional radiotherapy than in those treated with intensity-modulated radiotherapy.⁹⁷ Some late effects of radiotherapy for head and neck cancer—such as pain, anxiety, and impaired shoulder function—were shown to be improved through the practice of hatha yoga in 1 study.⁹⁸ Similarly, in a randomized controlled pilot study of patients with stage I to III breast cancer 6 months after treatment, participants in an 8-week yoga program experienced a reduction in arm induration and improvement in a QOL subscale of lymphedema symptoms. However, more evidence is needed to support the use of yoga as a therapeutic measure for breast cancer lymphedema.^99,100

Yoga for Caregivers

Along with cancer patients, caregivers face psychological and physical burdens as well as deterioration in their QOL. Caregivers tend to report clinical levels of anxiety, depression, sleep disturbance, and fatigue and have similar or in fact higher levels than those of the patients for whom they are caring.^101,102 Yoga has been found to help caregivers of patients with cancer. Recently, MD Anderson researchers conducted a trial in patients with high-grade glioma and their caregivers as dyads.^103,104 Each dyad attended 2 or 3 60-minute weekly Vivekananda yoga sessions involving breathing exercises, physical exercises, relaxation, and meditation. The researchers found that the yoga program was safe, feasible, acceptable, and subjectively useful for patients with high-grade glioma and their caregivers. Preliminary evidence of QOL improvement for both patients and caregivers was noted. An improvement in QOL was also demonstrated in another preliminary study of yoga in patients undergoing thoracic radiotherapy and their caregivers.¹⁰⁵

Another study by the group at MD Anderson evaluated a couple-based Tibetan yoga program that emphasized breathing exercises, gentle movements, guided visualizations, and emotional connectedness during radiotherapy for lung cancer.¹⁰⁶ This study included 10 patient‐caregiver dyads and found the program to be feasible, safe, and acceptable. The researchers also found preliminary evidence of improved QOL by the end of radiotherapy relative to baseline—specifically in the areas of spiritual well‐being for patients, fatigue for caregivers, and sleep disturbances and mental health issues such as anxiety and depressive symptoms for both patients and caregivers. This is noteworthy, as QOL typically deteriorates during the course of radiotherapy, and the yoga program was able to buffer these changes.

Conclusion

Yoga therapy has been used successfully as an adjunct modality to improve QOL and cancer-related symptoms. As a part of an integrative medicine approach, yoga is commonly recommended for patients undergoing cancer treatment. Danhauer et al reviewed randomized controlled trials during and after treatment and concluded that the evidence is clearly positive for QOL, fatigue, and perceived stress.¹⁰⁷ Results are less consistent but supportive for psychosocial outcomes such as benefit finding and spirituality. Evidence is mixed for sleep, anxiety, and depression. Post-treatment studies demonstrate improvements in fatigue, sleep, and multiple QOL domains. Yoga has been included in NCCN guidelines for fatigue management. Yoga, if approved by a physician, is also included among the behavioral therapies for anticipatory emesis and prevention and treatment of nausea in the recent update of the NCCN guidelines.¹⁰⁸ The Society for Integrative Oncology guidelines include yoga for anxiety/stress reduction as a part of integrative treatment in breast cancer patients during and after therapy, which was endorsed by the American Society of Clinical Oncology.¹⁰⁹

Because of the strong evidence for its benefits and a low side-effect profile, yoga is offered in group-class settings for patients during and after treatment and/or for caregivers in our institution. We often prescribe yoga as a therapeutic modality for selected groups of patients in our clinical practice. However, some patients may have restrictions after surgery that must be considered. In general, yoga has an excellent safety profile, the evidence base is strong, and we recommend that yoga therapy should be part of the standard of care as an integrative approach for patients with cancer undergoing active treatment as well as for cancer survivors and caregivers.

Acknowledgement: The authors thank Bryan Tutt for providing editorial assistance.

Corresponding author: Santhosshi Narayanan, MD, Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030; snarayanan2@mdanderson.org.

Financial disclosures: None.

From the University of Texas MD Anderson Cancer Center, Houston, TX (Drs. Narayanan, Lopez, Chaoul, Liu, Milbury, and Cohen, and Ms. Mallaiah); the University of Texas Health Science Center at Tyler (Dr. Meegada); and Texas Tech University Health Sciences Center, Lubbock, TX (Ms. Francisco).

Abstract

• Objective: To review the effects of yoga as an adjunct supportive care modality alongside conventional cancer treatment on quality of life (QOL), physical and mental health outcomes, and physiological and biological measures of cancer survivors.
• Methods: Nonsystematic review of the literature.
• Results: Yoga therapy, one of the most frequently used mind-body modalities, has been studied extensively in cancer survivors (from the time of diagnosis through long-term recovery). Yoga affects human physiology on multiple levels, including psychological outcomes, immune and endocrine function, and cardiovascular parameters, as well as multiple areas of QOL. It has been found to reduce psychological stress and fatigue and improve QOL in cancer patients and survivors. Yoga has also been used to manage symptoms such as arthralgia, fatigue, and insomnia. In addition, yoga offers benefits not only for cancer survivors but also for their caregivers.
• Conclusion: As part of an integrative, evidence-informed approach to cancer care, yoga may provide benefits that support the health of cancer survivors and caregivers.

Keywords: fatigue; cancer; proinflammatory cytokines; integrative; mind-body practices; meditation; DNA damage; stress; psychoneuro-immunoendocrine axis; lymphedema; insomnia.

A diagnosis of cancer and adverse effects related to its treatment may have negative effects on quality of life (QOL), contributing to emotional and physical distress in patients and caregivers. Many patients express an interest in pursuing nonpharmacological options, alone or as an adjunct to conventional therapy, to help manage symptoms. The use of complementary medicine approaches to health, including nonpharmacological approaches to symptom management, is highest among individuals with cancer.¹ According to a published expert consensus, integrative oncology is defined as a “patient-centered, evidence-informed field of cancer care that utilizes mind and body practices, natural products, and/or lifestyle modifications from different traditions alongside conventional cancer treatments. Integrative oncology aims to optimize health, QOL, and clinical outcomes across the cancer care continuum and to empower people to prevent cancer and become active participants before, during, and beyond cancer treatment.”² A key component of this definition, often misunderstood in the field of oncology, is that these modalities and treatments are used alongside conventional cancer treatments and not as an alternative. In an attempt to meet patients’ needs and appropriately use these approaches, integrative oncology programs are now part of most cancer centers in the United States.^3-6

Because of their overall safety, mind-body therapies are commonly used by patients and recommended by clinicians. Mind-body therapies include yoga, tai chi, qigong, meditation, and relaxation. Expressive arts such as journaling and music, art, and dance therapies also fall in the mind-body category.⁷ Yoga is a movement-based mind-body practice that focuses on synchronizing body, breath, and mind. Yoga has been increasingly used by patients for health benefits,⁸ and numerous studies have evaluated yoga as a complementary intervention for individuals with cancer.^9-14 Here, we review the physiological basis of yoga in oncology and the effects of yoga on biological processes, QOL, and symptoms during and after cancer treatment.

Physiological Basis

Many patients may use mind-body programs such as yoga to help manage the psychological and physiological consequences of unmanaged chronic stress and improve their overall QOL. The central nervous system, endocrine system, and immune system influence and interact with each other in a complex manner in response to chronic stress.^15,16 In a stressful situation, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) are activated. HPA axis stimulation leads to adrenocorticotrophic hormone production by the pituitary gland, which releases glucocorticoid hormones. SNS axis stimulation leads to epinephrine and norepinephrine production by the adrenal gland.^17,18 Recently, studies have explored modulation of signal transduction between the nervous and immune systems and how that may impact tumor growth and metastasis.¹⁹ Multiple studies, controlled for prognosis, disease stage, and other factors, have shown that patients experiencing more distress or higher levels of depressive symptoms do not live as long as their counterparts with low distress or depression levels.²⁰ Both the meditative and physical components of yoga can lead to enhanced relaxation, reduced SNS activation, and greater parasympathetic tone, countering the negative physiological effects of chronic stress. The effects of yoga on the HPA axis and SNS, proinflammatory cytokines, immune function, and DNA damage are discussed below.

Biological Processes

Nervous System

The effects of yoga and other forms of meditation on brain functions have been established through several studies. Yoga seems to influence basal ganglia function by improving circuits that are involved in complex cognitive functions, motor coordination, and somatosensory and emotional processes.^21,22 Additionally, changes in neurotransmitter levels have been observed after yoga practice. For instance, in a 12-week yoga intervention in healthy subjects, increased levels of thalamic gamma-aminobutyric acid (GABA) in the yoga group were reported to have a positive correlation with improved mood and decreased anxiety compared with a group who did metabolically matched walking exercise.²³ Levels of GABA, an inhibitory neurotransmitter, are decreased in conditions such as anxiety, depression, and epilepsy.²⁴ Yoga therapy has been shown to improve symptoms of mood disorders and epilepsy, which leads to the hypothesis that the mechanism driving the benefits of yoga may work through stimulation of vagal efferents and an increase in GABA-mediated cortical-inhibitory tone.^24,25

 

 

HPA Axis

Stress activates the HPA/SNS axis, which releases hormones such as cortisol and norepinephrine. These hormones may play a role in angiogenesis, inflammation, immune suppression, and other physiological functions, and may even reduce the effect of chemotherapeutic agents.^26,27 Regular yoga practice has been shown to reduce SNS and HPA axis activity, most likely by increasing parasympathetic dominance through vagal stimulation, as demonstrated through increases in heart rate variability.²⁸ One indicator of HPA axis dysregulation, diurnal salivary cortisol rhythm, was shown to predict survival in patients with advanced breast and renal cancer.^29-33 Yoga has been shown to lead to less cortisol dysregulation due to radiotherapy and to reductions in mean cortisol levels and early morning cortisol levels in breast cancer patients undergoing radiotherapy.³⁴ This lends support to the hypothesis that yoga helps restore HPA axis balance.

Proinflammatory Cytokines

Cancer patients tend to have increased levels of inflammatory markers such as interleukin (IL)-4, IL-10, tumor necrosis factor (TNF), interferon-γ, and C-reactive protein. This increase in inflammation is associated with worse outcomes in cancer.³⁵ This association becomes highly relevant because the effect of inflammation on host cells in the tumor microenvironment is connected to disease progression.²⁶ Inflammatory cytokines are also implicated in cancer-related symptoms such as fatigue, cognitive dysfunction, peripheral neuropathy, and sleep disturbances.³⁶

Yoga is known to reduce stress and may directly or indirectly decrease inflammatory cytokines. A randomized clinical trial of a 12-week hatha yoga intervention among breast cancer survivors demonstrated decreases in IL-6, IL-1β, TNF, corticotropin-releasing factor, and cognitive complaints in the yoga group compared with those in the standard care group after 3 months.^37,38 Furthermore, Carlson et al showed that, after mindfulness-based stress reduction involving a combination of gentle yoga, meditation techniques, and relaxation exercises, breast and prostate cancer patients had reduced levels of proinflammatory cytokines and cortisol.³⁹ These reductions translated into patients reporting decreased stress levels and enhanced QOL.

Immune Function

The effects of yoga practice on the immune system have been studied in both healthy individuals and individuals with cancer. The effects on T and B lymphocytes, natural killer (NK) cells, and other immune effector cells demonstrate that meditation and yoga have beneficial effects on immune activity.⁴⁰ Hormones such as catecholamines and glucocorticoids are thought to influence the availability and function of NK cells, and, as noted above, yoga has been shown to modulate stress hormones and lead to reduced immune suppression in patients with early-stage breast cancer undergoing chemotherapy.⁴¹ Additional evidence supports the ability of yoga to reduce immune suppression in the postsurgical setting, with no observed decrease in NK cell percentage after surgery for those in a yoga group compared with a control group.⁴² This finding is relevant to patients undergoing surgical management of their cancer and highlights the impact of yoga on the immune system.

DNA Damage

Radiation damages DNA in the peripheral blood lymphocytes of patients undergoing treatment.^43,44 This damage is significant in breast cancer patients undergoing radiotherapy.⁴⁵ Stress additionally causes DNA damage⁴⁶ and is correlated to impaired DNA repair capacity.^47,48 In a study conducted by Banerjee et al, breast cancer patients were randomly assigned to a yoga group or a supportive therapy group for 6 weeks during radiotherapy.⁴⁹ Prior to the intervention, patients in the study had significant genomic instability. After treatment, patients in the yoga group experienced not only a significant reduction in anxiety and depression levels, but also a reduction in DNA damage due to radiotherapy.

 

 

Yoga in Quality of Life and Symptom Management

There is evidence showing that yoga therapy improves multiple aspects of QOL, including physical functioning, emotional health outcomes, and the symptoms cancer patients may experience, such as sleep disturbances, fatigue, and pain. Danhauer et al systematically reviewed both nonrandomized trials and randomized controlled trials involving yoga during cancer treatment.⁵⁰ They found that yoga improved depression and anxiety as well as sleep and fatigue. Benefits of yoga in cancer based on randomized controlled trials are summarized in the Table. The role of yoga in improving QOL and managing symptoms patients experience during and after treatment is discussed in the following sections.

Quality of Life

Danhauer et al’s systematic review of trials involving yoga during cancer treatment found that yoga improved multiple aspects of QOL.⁵⁰ For example, yoga has been shown to improve QOL in breast cancer patients undergoing radiotherapy. In a study by Chandwani et al, yoga (60-minute sessions twice a week for 6 weeks) was associated with better general health perception and physical functioning scores as well as greater benefit finding, or finding meaning in their experience, after radiotherapy compared with a wait-list group.⁵¹ The yoga group had an increase in intrusive thoughts, believed to be due to a more thorough processing of the cancer experience, which helps to improve patients’ outlook on life.⁵² The benefits of yoga extend beyond psychological measures during radiation treatment. Yoga was found to increase physical functioning compared with stretching in breast cancer patients undergoing radiotherapy.⁵³

Cognitive Function

Cancer-related cognitive impairment commonly occurs during cancer treatments (eg, chemotherapy, radiotherapy, surgery, hormone therapy) and persists for months or years in survivors.⁵⁴ Impairment of memory, executive function, attention, and concentration are commonly reported. In a trial of a combined hatha and restorative yoga program called Yoga for Cancer Survivors (YOCAS), which was designed by researchers at the University of Rochester, patients in the yoga arm had less memory difficulty than did patients in the standard care arm.⁵⁵ However, the primary aim of the trial was to treat insomnia, so this secondary outcome needs to be interpreted with caution. Deficits in attention, memory, and executive function are often seen in cancer-related cognitive impairment, and the meditative aspect of yoga may have behavioral and neurophysical benefits that could improve cognitive functions.⁵⁶ More evidence is needed to understand the role of yoga in improving cognitive functioning.

Emotional Health

Psychosocial stress is high among breast cancer patients and survivors.^57,58 This causes circadian rhythm and cortisol regulation abnormalities, which are reported in women with breast cancer.^59-64 Yoga is known to help stress and psychosocial and physical functioning in patients with cancer.⁶⁵ Yoga was also shown to be equivalent to cognitive behavioral therapy in stress management in a population of patients without cancer.⁶⁶ Daily yoga sessions lasting 60 minutes were shown to reduce reactive anxiety and trait anxiety in early-stage breast cancer patients undergoing conventional radiotherapy and chemotherapy compared with patients receiving supportive therapy, highlighting the role of yoga in managing anxiety related to treatment.⁶⁷ In a study done by Culos-Reed et al, 20 cancer survivors who did 75 minutes of yoga per week for 7 weeks were compared with 18 cancer survivors who served as a control group.⁶⁸ The intervention group reported significant improvement in emotional well-being, depression, concentration, and mood disturbances. In a longitudinal study by Mackenzie et al, 66 cancer survivors completed a 7-week yoga program and were assessed at baseline, immediately after the final yoga session, and at 3 and 6 months after the final session.⁶⁹ Participants had significantly improved energy levels and affect. They also had moderate improvement in mindfulness and a moderate decrease in stress. Breast cancer patients who underwent restorative yoga sessions found improvements in mental health, depression, positive affect, and spirituality (peace/meaning).⁷⁰ This was more pronounced in women with higher negative affect and lower emotional well-being at baseline. In a study of patients with ovarian cancer receiving chemotherapy, patients were instructed to perform up to 15-minute sessions including awareness, body movement, and breathing.⁷¹ Even with just 1 session of yoga intervention, patients experienced decreased anxiety.

Fatigue

Studies on yoga show improvement in fatigue both during and after treatment. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit cognitive fatigue.⁷² Older cancer survivors also seem to benefit from yoga interventions.⁷³ In a trial of a DVD-based yoga program, the benefits of yoga were similar to those of strengthening exercises, and both interventions helped decrease fatigue and improve QOL during the first year after diagnosis in early-stage breast cancer patients with cancer-related fatigue.⁷⁴ Bower et al also showed that, for breast cancer survivors experiencing persistent chronic fatigue, a targeted yoga intervention led to significant improvements in fatigue and vigor over a 3-month follow-up compared with controls.⁷⁵ Fatigue is commonly seen in breast cancer patients who are receiving adjuvant chemotherapy. In a study by Taso et al, women with breast cancer receiving chemotherapy were assigned to 60-minute yoga sessions incorporating Anusara yoga, gentle stretching, and relaxation twice a week for 8 weeks.⁷⁶ By week 4, patients with low pretest fatigue in the yoga group experienced a reduction in fatigue. By week 8, all patients in the yoga group experienced a reduction in fatigue. Four weeks after the yoga intervention, patients in the group maintained the reduction in fatigue. This study shows the feasibility of an 8-week yoga program for women undergoing breast cancer therapy by improving fatigue. Yoga recently was added to National Comprehensive Cancer Network (NCCN) guidelines for management of cancer-related fatigue (level 1 evidence).⁷⁷ However, the evidence was based on studies in women with breast cancer and survivors; therefore, more studies are needed in men and women with other cancers.

 

 

Surgical Setting/Postoperative Distress

Distress surrounding surgery in patients with breast cancer can impact postoperative outcomes. Yoga interventions, including breathing exercises, regulated breathing, and yogic relaxation techniques, improved several postsurgical measures such as length of hospital stay, drain retention, and suture removal.⁷⁸ In this study, patients who practiced yoga also experienced a decrease in plasma TNF and better wound healing. Symptoms of anxiety and distress that occur preoperatively can lead to impaired immune function in addition to decreased QOL. In a study of yoga in early-stage breast cancer patients undergoing surgery, the benefit of yoga was seen not only with stress reduction but also with immune enhancement.⁴²

Yoga has been shown to help alleviate acute pain and distress in women undergoing major surgery for gynecological cancer. A regimen of 3 15-minute sessions of yoga, including awareness meditation, coordination of breath with movement, and relaxation breathing, was shown to reduce acute pain and distress in such patients in an inpatient setting.⁷⁹

Menopausal Symptoms

Breast cancer survivors have more severe menopausal symptoms compared with women without cancer.^80,81 Hot flashes cause sleep disturbances and worsen fatigue and QOL.⁸² Tamoxifen and aromatase inhibitors significantly worsen menopausal symptoms such as hot flashes.⁸¹ Carson et al conducted a study of yoga that included postures, breathing techniques, didactic presentations, and group discussions.⁸³ The yoga awareness regimen consisted of 8 weekly 120-minute group classes. Patients in the yoga arm had statistically significant improvements in the frequency, severity, and number of hot flashes. There were also improvements in arthralgia (joint pain), fatigue, sleep disturbance, vigor, and acceptance.

Arthralgia

Joint pain can be a major side effect that interferes with daily functions and activities in postmenopausal breast cancer survivors who receive aromatase inhibitor therapy.⁸⁴ Arthralgia is reported in up to 50% of patients treated with aromatase inhibitors.^84,85 It can affect functional status and lead to discontinuation of aromatase inhibitor therapy, jeopardizing clinical outcomes.⁸⁶ Yoga as a complementary therapy has been shown to improve conditions such as low back pain⁸⁷ and knee osteoarthritis⁸⁸ in patients who do not have cancer. In a single-arm pilot trial by Galantino et al, breast cancer patients with aromatase inhibitor–related joint pain were provided with twice-weekly yoga sessions for 8 weeks. There were statistically significant improvements in balance, flexibility, pain severity, and health-related QOL.⁸⁹ As noted above, improvement in arthralgia was also found in the study conducted by Carson et al.⁸³

Insomnia

Insomnia is common among cancer patients and survivors^90,91 and leads to increased fatigue and depression, decreased adherence to cancer treatments, and poor physical function and QOL.^90-92 Management of insomnia consists of pharmacologic therapies such as benzodiazepines^93,94 and nonpharmacologic options such as cognitive behavioral therapy.⁹⁵

The first study of yoga found to improve sleep quality was conducted at MD Anderson Cancer Center in lymphoma patients.⁹⁶ The effects of Tibetan yoga practices incorporating controlled breathing and visualization, mindfulness techniques, and low-impact postures were studied. Patients in the Tibetan yoga group had better subjective sleep quality, faster sleep latency, longer sleep duration, and less use of sleep medications. Mustian et al conducted a large yoga study in cancer survivors in which patients reporting chronic sleep disturbances were randomly assigned to the YOCAS program, which consisted of pranayama (breath control), 16 gentle hatha and restorative yoga postures, and meditation, or to usual care.⁹² The study reported improvements in global sleep quality, subjective sleep quality, actigraphy measures (wake after sleep onset, sleep efficiency), daytime dysfunction, and use of sleep medication after the yoga intervention compared with participants who received standard care.

Yoga to Address Other Symptoms

There is preliminary evidence supporting yoga as an integrative therapy for other symptoms unique to cancer survivors. For example, in head and neck cancer survivors, soft tissue damage involving the jaw, neck, shoulders, and chest results in swallowing issues, trismus, and aspiration, which are more pronounced in patients treated with conventional radiotherapy than in those treated with intensity-modulated radiotherapy.⁹⁷ Some late effects of radiotherapy for head and neck cancer—such as pain, anxiety, and impaired shoulder function—were shown to be improved through the practice of hatha yoga in 1 study.⁹⁸ Similarly, in a randomized controlled pilot study of patients with stage I to III breast cancer 6 months after treatment, participants in an 8-week yoga program experienced a reduction in arm induration and improvement in a QOL subscale of lymphedema symptoms. However, more evidence is needed to support the use of yoga as a therapeutic measure for breast cancer lymphedema.^99,100

Yoga for Caregivers

Along with cancer patients, caregivers face psychological and physical burdens as well as deterioration in their QOL. Caregivers tend to report clinical levels of anxiety, depression, sleep disturbance, and fatigue and have similar or in fact higher levels than those of the patients for whom they are caring.^101,102 Yoga has been found to help caregivers of patients with cancer. Recently, MD Anderson researchers conducted a trial in patients with high-grade glioma and their caregivers as dyads.^103,104 Each dyad attended 2 or 3 60-minute weekly Vivekananda yoga sessions involving breathing exercises, physical exercises, relaxation, and meditation. The researchers found that the yoga program was safe, feasible, acceptable, and subjectively useful for patients with high-grade glioma and their caregivers. Preliminary evidence of QOL improvement for both patients and caregivers was noted. An improvement in QOL was also demonstrated in another preliminary study of yoga in patients undergoing thoracic radiotherapy and their caregivers.¹⁰⁵

Another study by the group at MD Anderson evaluated a couple-based Tibetan yoga program that emphasized breathing exercises, gentle movements, guided visualizations, and emotional connectedness during radiotherapy for lung cancer.¹⁰⁶ This study included 10 patient‐caregiver dyads and found the program to be feasible, safe, and acceptable. The researchers also found preliminary evidence of improved QOL by the end of radiotherapy relative to baseline—specifically in the areas of spiritual well‐being for patients, fatigue for caregivers, and sleep disturbances and mental health issues such as anxiety and depressive symptoms for both patients and caregivers. This is noteworthy, as QOL typically deteriorates during the course of radiotherapy, and the yoga program was able to buffer these changes.

Conclusion

Yoga therapy has been used successfully as an adjunct modality to improve QOL and cancer-related symptoms. As a part of an integrative medicine approach, yoga is commonly recommended for patients undergoing cancer treatment. Danhauer et al reviewed randomized controlled trials during and after treatment and concluded that the evidence is clearly positive for QOL, fatigue, and perceived stress.¹⁰⁷ Results are less consistent but supportive for psychosocial outcomes such as benefit finding and spirituality. Evidence is mixed for sleep, anxiety, and depression. Post-treatment studies demonstrate improvements in fatigue, sleep, and multiple QOL domains. Yoga has been included in NCCN guidelines for fatigue management. Yoga, if approved by a physician, is also included among the behavioral therapies for anticipatory emesis and prevention and treatment of nausea in the recent update of the NCCN guidelines.¹⁰⁸ The Society for Integrative Oncology guidelines include yoga for anxiety/stress reduction as a part of integrative treatment in breast cancer patients during and after therapy, which was endorsed by the American Society of Clinical Oncology.¹⁰⁹

Because of the strong evidence for its benefits and a low side-effect profile, yoga is offered in group-class settings for patients during and after treatment and/or for caregivers in our institution. We often prescribe yoga as a therapeutic modality for selected groups of patients in our clinical practice. However, some patients may have restrictions after surgery that must be considered. In general, yoga has an excellent safety profile, the evidence base is strong, and we recommend that yoga therapy should be part of the standard of care as an integrative approach for patients with cancer undergoing active treatment as well as for cancer survivors and caregivers.

Acknowledgement: The authors thank Bryan Tutt for providing editorial assistance.

Corresponding author: Santhosshi Narayanan, MD, Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030; snarayanan2@mdanderson.org.

Financial disclosures: None.

Study Overview

Objective. To compare the efficacy and safety of lenalidomide in combination with rituximab (known as the R² regimen) to rituximab plus placebo in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma (MZL).

Design. Phase 3, multicenter, international, placebo controlled randomized trial.

Setting and participants. 358 patients with rituximab-sensitive relapsed or refractory grade 1-3a follicular lymphoma or MZL.

Intervention. Patients were randomly assigned 1:1 to receive lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5.

Main outcome measures. The primary endpoint was progression-free survival (PFS) as determined by independent radiology reviewers using intent-to-treat analysis. Secondary end points included overall response rate, complete response rate, duration of response, overall survival, event-free survival, and time to next anti-lymphoma therapy. Time to next chemotherapy treatment and histologic transformation were exploratory endpoints. Responses were assessed by participating investigators and independent reviewers. Computed tomography or magnetic resonance imaging was used to obtain tumor measurements. Positron emission tomography was not used. Complete remissions were confirmed by bone marrow biopsy, as bone marrow involvement is exceedingly common in these lymphomas. Gastrointestinal endoscopy was performed to obtain disease status if there was involvement by lymphoma initially.

Improvement in primary and secondary endpoints as well as extrapolatory endpoints were reported in the R² group. Primary efficacy analyses were conducted in the intention-to-treat population primary endpoint of PFS at 1-sided α = 0.025 level.

Main results. PFS was significantly improved for patients treated with the R² regimen compared to those who recieved placebo plus rituximab, with a hazard ratio of 0.46 (95% confidence interval [CI], 0.34-0.62; P < 0.001). Median duration of PFS in the R² group was 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months) in the rituximab/placebo group. Overall response in the R² group was 78% (95% CI, 71%-83%) versus 53% (95% CI, 46%-61%; P < 0.0001) in the rituximab/placebo group, with 34% (95% CI, 27%-41%) versus 18% (95% CI, 13%-25%) of patients achieving complete remission (P = 0.001). There were 15 deaths in the R² group versus 26 deaths in the rituximab/placebo group. Overall survival data is not mature yet.

Conclusion. The R² regimen was superior to rituximab and placebo in relapsed or recurrent follicular lymphomas. The regimen’s safety profile was acceptable, with higher events of usual and expected but manageable toxicities in the R² regimen compared to rituximab/placebo.

Commentary

Nearly half of non-Hodgkins lymphomas (NHLs) diagnosed in the United States are classified as indolent B-cell lymphomas.¹ Follicular lymphomas constitute about 50% of all indolent NHLs, while MZLs comprise less than 15%.¹ These slowly progressive B-cell lymphomas are currently considered treatable but have very low cure rates. Cure is primarily limited to early stage I/II disease and may be possible in less than half of patients by applying involved-field radiation therapy with curative intent.

More than two thirds of indolent lymphomas present in advanced stages (III-IV). Despite an advanced stage at presentation, initial chemoimmunotherapy can induce complete remission in nearly 60% of patients. Unfortunately, nearly all patients relapse over the next 10 years.² The wait-and-watch approach is a common strategy, and most patients are administered initial therapy or subsequent lines of therapy if they are symptomatic.² As such, for the majority of these patients, the goal of therapy is to minimize toxicities, preserve quality of life, treat symptoms, and achieve a long PFS without an attempt to cure. Following each line of therapy, patients often revert to watchful surveillance, sometimes for more than a decade. With additional subsequent lines of therapy, lymphoma tends to get more refractory to treatment.

A median survival of nearly 2 decades has been achieved in advanced follicular lymphomas^2,3 and MZL.⁴ However, wide variation in overall response, duration of response, and survival is reported based on the individual risk profile.

The drug of interest in the present study by Leonard and colleagues, lenalidomide, has immunomodulatory properties and antiproliferative effects, possibly related to its binding of the E3 ligase protein cereblon and subsequent ubiquitination of the transcription factors Aiolos and Ikaros.⁵ The benefits of combination lenalidomide/rituximab against follicular lymphoma in preclinical settings have been attributed to mechanisms mediated by tumor-infiltrating lymphocytes, natural killer cells, monocytes, and antibody-dependent cell-mediated toxicity.⁵ The combination has now been studied in first-line and subsequent lines of therapy for follicular lymphoma and MZL.⁶

RELEVANCE, a phase 3 trial, compared the R² regimen in the upfront setting in advanced follicular lymphoma with rituximab and chemotherapy combination (including CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], CVP [cyclophosphamide, vincristine, prednisone], and bendamustine).⁷ Efficacy outcomes were similar between the comparators and R² was noninferior. MAGNIFY, a phase 3b trial involving rituximab-sensitive and rituximab-refractory patients with previously treated follicular lymphoma and MZL, demonstrated an overall response rate of 73%, complete response rate of 45%, and median PFS of 36 months in patients who received the R² regimen and who entered a plan to receive maintenance with rituximab.⁸

The AUGMENT trial was conducted at 97 centers in the United States and 14 Asian and European countries; it enrolled 358 patients, 82% of whom had a follicular lymphoma, between February 13, 2014 and January 26, 2017. The study was well conducted. The R² regimen was compared to the often used second-line therapy of rituximab alone, and 1:1 randomization was done with stratification factors of prior rituximab use, marginal versus follicular histology, and time lapse of less than or greater than 2 years since last therapy. A limitation of this study is that it selected individuals with a better prognosis, as the study patients were not rituximab refractory and 57% had received only a single prior therapy.

As observed in other R² regimen trials in follicular or marginal zone lymphomas, the most common adverse reactions (occurring in at least 20% of patients) were neutropenia, fatigue, and constipation. These were manageable with dose adjustments and interruptions, and, in the opinion of authors, did not take away from the overall benefits seen.

The authors acknowledge that a limitation of this study was a lower assessment of median PFS in both arms by investigators than by independent reviewers. The independent review committee assessed PFS for R² at 39.4 months, whereas investigators assessed it at 25.4 months. The median PFS benefit remained at 14.1 months by both methods of assessment. This may highlight the differences of radiographic measurements in a central setting versus at individual centers.

Histologic transformation to a higher-grade aggressive lymphoma occurred in 2 patients in the R² arm and 10 patients in the placebo/rituximab arm. After transformation, 1 patient in the R² arm and 6 in the placebo plus rituximab arm died. A plausible mechanism for this variation has not been provided. If confirmed across a wider population, this may be one of the most significant benefits of the R² regimen.

Applications for Clinical Practice

Therapy for relapsed and refractory indolent B-cell lymphomas continues to evolve. While chemotherapy remains an effective option, immunomodulation using non-chemotherapeutic intervention has emerged as an attractive strategy. The AUGMENT trial further solidifies adoption of the non-chemotherapy doublet option of rituximab/lenalidomide based on the premise of immunomodulation. Both the agents have been commercially available for more than a decade and are being used for other indications beyond the study population for this trial.

Based on the AUGMENT and MAGNIFY trials, lenalidomide combined with rituximab was approved by the Food and Drug Administration for use in relapsed and refractory follicular or marginal zone lymphomas soon after the AUGMENT study results were published. The recommended lenalidomide dose for both lymphomas is 20 mg once daily orally on days 1 to 21 of repeated 28-day cycles for up to 12 cycles.

The evidence from this trial has yielded what is likely to be a practice changing regimen, with R² replacing single-agent rituximab for treating follicular lymphoma in the second line or beyond. The response rates and PFS periods were slightly lower in MZL. R² offers advantages associated with a chemotherapy-free regimen and improved PFS. Also, in the AUGEMENT trial the secondary and exploratory endpoints of time to next therapy, overall response rates, and overall survival rates were improved in patients treated with R².

Practitioners may choose lenalidomide plus rituximab over rituximab alone based on the AUGMENT study. When considering this regimen, several points should be kept in mind. A very careful selection of patients would be prudent, considering that the study’s follow-up of less than 4 years is short for a disease with long overall survival rates. The study was not powered to compare overall survival benefit. Also, practitioners are reminded to limit the use of lenalidomide to a maximum of 12 months, with planned interruptions and 8 doses of rituximab, replicating the trial schema. Additionally, as per the clinical trial design, the regimen is not intended for rituximab-refractory patients. Patients with MZL constituted only 18% of the study, and conclusions of superiority in this subgroup were not statistically significant. Lenalidomide is not approved for other indolent B cell lymphoproliferative malignancies, such as small lymphocytic lymphoma and chronic lymphocytic leukemia. The conclusion of the published study abstract suggests acceptable use in recurrent indolent lymphomas, but no such conclusion can be made due to lack of inclusion of all indolent lymphoma subtypes in this study.

Longer-term use of lenalidomide has been associated with a marginally increased risk of secondary hematologic malignancies in patients with multiple myeloma who were prescribed lenalidomide maintenance therapy for up to 2 years following high-dose chemotherapy and autologous hematopoietic stem cell transplant.⁹ Interestingly, in the AUGMENT study and other trials using lenalidomide/rituximab, no significant increase in secondary hematologic malignancies has been reported. The absence of prior myeloablative chemotherapy and a shorter duration of use (1 year) in this group of patients may be factors in why no additional risk of secondary hematologic malignancies was observed. Longer-term follow-up may be needed to evaluate this risk.

In the R² arm of this study, 55% patients experienced grades 3 and 4 neutropenia. With a median age of presentation for both follicular lymphoma and MZL of over 60 years, oncologists should remain aware of this potentially fatal complication, especially in the frail, the elderly, and previously treated individuals who may have a high risk of myelosuppression. Clinicians should be prepared to rapidly adopt strategies of dose interruption, dose reduction, and growth factor use, as implemented in the trial. Of note, despite the high rates of severe neutropenia, only 3% of the participants experienced febrile neutropenia, and 71% patients in R² group and 61% in rituximab group completed planned protocol therapy. Growth factor use was high at 36% in the R² group, which may have been responsible for a lower incidence of febrile neutropenia.

Increased toxicities of tumor flare, rash, and constipation were observed in the R² arm. Patients with greater than grade 1 neuropathy were excluded. For those at risk of thromboembolism, prophylactic anticoagulation or antiplatelet therapy was recommended in the trial. Lenalidomide dose was reduced to 10 mg for those with creatinine clearance of 30 to 59 mL/min.

The cost-effectiveness of lenalidomide/rituximab combination has not been fully studied against a sequential approach of using rituximab and lenalidomide for a limited number of cycles. The cost of a Revlimid 10-mg pill may be over $700.¹⁰ Costs associated with supportive care due to additional toxicities have not been quantified. For those with cost concerns or lack of insurance coverage, the R² regimen may be cost prohibitive without financial assistance from charities.

Indolent NHL remains mostly incurable. The R² approach is still not a curative one, and resources should be directed to investigate a cure for this population. Whenever feasible, participation in a clinical trial should be encouraged. Parameters have not been reported based on prognostic groups, and the study did not identify any biomarkers that may correlate with improved outcome. Perhaps a biomarker-based trial design may be most suitable in explaining the heterogeneity in follicular and marginal zone lymphomas.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

Study Overview

Objective. To compare the efficacy and safety of lenalidomide in combination with rituximab (known as the R² regimen) to rituximab plus placebo in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma (MZL).

Design. Phase 3, multicenter, international, placebo controlled randomized trial.

Setting and participants. 358 patients with rituximab-sensitive relapsed or refractory grade 1-3a follicular lymphoma or MZL.

Intervention. Patients were randomly assigned 1:1 to receive lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5.

Main outcome measures. The primary endpoint was progression-free survival (PFS) as determined by independent radiology reviewers using intent-to-treat analysis. Secondary end points included overall response rate, complete response rate, duration of response, overall survival, event-free survival, and time to next anti-lymphoma therapy. Time to next chemotherapy treatment and histologic transformation were exploratory endpoints. Responses were assessed by participating investigators and independent reviewers. Computed tomography or magnetic resonance imaging was used to obtain tumor measurements. Positron emission tomography was not used. Complete remissions were confirmed by bone marrow biopsy, as bone marrow involvement is exceedingly common in these lymphomas. Gastrointestinal endoscopy was performed to obtain disease status if there was involvement by lymphoma initially.

Improvement in primary and secondary endpoints as well as extrapolatory endpoints were reported in the R² group. Primary efficacy analyses were conducted in the intention-to-treat population primary endpoint of PFS at 1-sided α = 0.025 level.

Main results. PFS was significantly improved for patients treated with the R² regimen compared to those who recieved placebo plus rituximab, with a hazard ratio of 0.46 (95% confidence interval [CI], 0.34-0.62; P < 0.001). Median duration of PFS in the R² group was 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months) in the rituximab/placebo group. Overall response in the R² group was 78% (95% CI, 71%-83%) versus 53% (95% CI, 46%-61%; P < 0.0001) in the rituximab/placebo group, with 34% (95% CI, 27%-41%) versus 18% (95% CI, 13%-25%) of patients achieving complete remission (P = 0.001). There were 15 deaths in the R² group versus 26 deaths in the rituximab/placebo group. Overall survival data is not mature yet.

Conclusion. The R² regimen was superior to rituximab and placebo in relapsed or recurrent follicular lymphomas. The regimen’s safety profile was acceptable, with higher events of usual and expected but manageable toxicities in the R² regimen compared to rituximab/placebo.

Commentary

Nearly half of non-Hodgkins lymphomas (NHLs) diagnosed in the United States are classified as indolent B-cell lymphomas.¹ Follicular lymphomas constitute about 50% of all indolent NHLs, while MZLs comprise less than 15%.¹ These slowly progressive B-cell lymphomas are currently considered treatable but have very low cure rates. Cure is primarily limited to early stage I/II disease and may be possible in less than half of patients by applying involved-field radiation therapy with curative intent.

More than two thirds of indolent lymphomas present in advanced stages (III-IV). Despite an advanced stage at presentation, initial chemoimmunotherapy can induce complete remission in nearly 60% of patients. Unfortunately, nearly all patients relapse over the next 10 years.² The wait-and-watch approach is a common strategy, and most patients are administered initial therapy or subsequent lines of therapy if they are symptomatic.² As such, for the majority of these patients, the goal of therapy is to minimize toxicities, preserve quality of life, treat symptoms, and achieve a long PFS without an attempt to cure. Following each line of therapy, patients often revert to watchful surveillance, sometimes for more than a decade. With additional subsequent lines of therapy, lymphoma tends to get more refractory to treatment.

A median survival of nearly 2 decades has been achieved in advanced follicular lymphomas^2,3 and MZL.⁴ However, wide variation in overall response, duration of response, and survival is reported based on the individual risk profile.

The drug of interest in the present study by Leonard and colleagues, lenalidomide, has immunomodulatory properties and antiproliferative effects, possibly related to its binding of the E3 ligase protein cereblon and subsequent ubiquitination of the transcription factors Aiolos and Ikaros.⁵ The benefits of combination lenalidomide/rituximab against follicular lymphoma in preclinical settings have been attributed to mechanisms mediated by tumor-infiltrating lymphocytes, natural killer cells, monocytes, and antibody-dependent cell-mediated toxicity.⁵ The combination has now been studied in first-line and subsequent lines of therapy for follicular lymphoma and MZL.⁶

RELEVANCE, a phase 3 trial, compared the R² regimen in the upfront setting in advanced follicular lymphoma with rituximab and chemotherapy combination (including CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], CVP [cyclophosphamide, vincristine, prednisone], and bendamustine).⁷ Efficacy outcomes were similar between the comparators and R² was noninferior. MAGNIFY, a phase 3b trial involving rituximab-sensitive and rituximab-refractory patients with previously treated follicular lymphoma and MZL, demonstrated an overall response rate of 73%, complete response rate of 45%, and median PFS of 36 months in patients who received the R² regimen and who entered a plan to receive maintenance with rituximab.⁸

The AUGMENT trial was conducted at 97 centers in the United States and 14 Asian and European countries; it enrolled 358 patients, 82% of whom had a follicular lymphoma, between February 13, 2014 and January 26, 2017. The study was well conducted. The R² regimen was compared to the often used second-line therapy of rituximab alone, and 1:1 randomization was done with stratification factors of prior rituximab use, marginal versus follicular histology, and time lapse of less than or greater than 2 years since last therapy. A limitation of this study is that it selected individuals with a better prognosis, as the study patients were not rituximab refractory and 57% had received only a single prior therapy.

As observed in other R² regimen trials in follicular or marginal zone lymphomas, the most common adverse reactions (occurring in at least 20% of patients) were neutropenia, fatigue, and constipation. These were manageable with dose adjustments and interruptions, and, in the opinion of authors, did not take away from the overall benefits seen.

The authors acknowledge that a limitation of this study was a lower assessment of median PFS in both arms by investigators than by independent reviewers. The independent review committee assessed PFS for R² at 39.4 months, whereas investigators assessed it at 25.4 months. The median PFS benefit remained at 14.1 months by both methods of assessment. This may highlight the differences of radiographic measurements in a central setting versus at individual centers.

Histologic transformation to a higher-grade aggressive lymphoma occurred in 2 patients in the R² arm and 10 patients in the placebo/rituximab arm. After transformation, 1 patient in the R² arm and 6 in the placebo plus rituximab arm died. A plausible mechanism for this variation has not been provided. If confirmed across a wider population, this may be one of the most significant benefits of the R² regimen.

Applications for Clinical Practice

Therapy for relapsed and refractory indolent B-cell lymphomas continues to evolve. While chemotherapy remains an effective option, immunomodulation using non-chemotherapeutic intervention has emerged as an attractive strategy. The AUGMENT trial further solidifies adoption of the non-chemotherapy doublet option of rituximab/lenalidomide based on the premise of immunomodulation. Both the agents have been commercially available for more than a decade and are being used for other indications beyond the study population for this trial.

Based on the AUGMENT and MAGNIFY trials, lenalidomide combined with rituximab was approved by the Food and Drug Administration for use in relapsed and refractory follicular or marginal zone lymphomas soon after the AUGMENT study results were published. The recommended lenalidomide dose for both lymphomas is 20 mg once daily orally on days 1 to 21 of repeated 28-day cycles for up to 12 cycles.

The evidence from this trial has yielded what is likely to be a practice changing regimen, with R² replacing single-agent rituximab for treating follicular lymphoma in the second line or beyond. The response rates and PFS periods were slightly lower in MZL. R² offers advantages associated with a chemotherapy-free regimen and improved PFS. Also, in the AUGEMENT trial the secondary and exploratory endpoints of time to next therapy, overall response rates, and overall survival rates were improved in patients treated with R².

Practitioners may choose lenalidomide plus rituximab over rituximab alone based on the AUGMENT study. When considering this regimen, several points should be kept in mind. A very careful selection of patients would be prudent, considering that the study’s follow-up of less than 4 years is short for a disease with long overall survival rates. The study was not powered to compare overall survival benefit. Also, practitioners are reminded to limit the use of lenalidomide to a maximum of 12 months, with planned interruptions and 8 doses of rituximab, replicating the trial schema. Additionally, as per the clinical trial design, the regimen is not intended for rituximab-refractory patients. Patients with MZL constituted only 18% of the study, and conclusions of superiority in this subgroup were not statistically significant. Lenalidomide is not approved for other indolent B cell lymphoproliferative malignancies, such as small lymphocytic lymphoma and chronic lymphocytic leukemia. The conclusion of the published study abstract suggests acceptable use in recurrent indolent lymphomas, but no such conclusion can be made due to lack of inclusion of all indolent lymphoma subtypes in this study.

Longer-term use of lenalidomide has been associated with a marginally increased risk of secondary hematologic malignancies in patients with multiple myeloma who were prescribed lenalidomide maintenance therapy for up to 2 years following high-dose chemotherapy and autologous hematopoietic stem cell transplant.⁹ Interestingly, in the AUGMENT study and other trials using lenalidomide/rituximab, no significant increase in secondary hematologic malignancies has been reported. The absence of prior myeloablative chemotherapy and a shorter duration of use (1 year) in this group of patients may be factors in why no additional risk of secondary hematologic malignancies was observed. Longer-term follow-up may be needed to evaluate this risk.

In the R² arm of this study, 55% patients experienced grades 3 and 4 neutropenia. With a median age of presentation for both follicular lymphoma and MZL of over 60 years, oncologists should remain aware of this potentially fatal complication, especially in the frail, the elderly, and previously treated individuals who may have a high risk of myelosuppression. Clinicians should be prepared to rapidly adopt strategies of dose interruption, dose reduction, and growth factor use, as implemented in the trial. Of note, despite the high rates of severe neutropenia, only 3% of the participants experienced febrile neutropenia, and 71% patients in R² group and 61% in rituximab group completed planned protocol therapy. Growth factor use was high at 36% in the R² group, which may have been responsible for a lower incidence of febrile neutropenia.

Increased toxicities of tumor flare, rash, and constipation were observed in the R² arm. Patients with greater than grade 1 neuropathy were excluded. For those at risk of thromboembolism, prophylactic anticoagulation or antiplatelet therapy was recommended in the trial. Lenalidomide dose was reduced to 10 mg for those with creatinine clearance of 30 to 59 mL/min.

The cost-effectiveness of lenalidomide/rituximab combination has not been fully studied against a sequential approach of using rituximab and lenalidomide for a limited number of cycles. The cost of a Revlimid 10-mg pill may be over $700.¹⁰ Costs associated with supportive care due to additional toxicities have not been quantified. For those with cost concerns or lack of insurance coverage, the R² regimen may be cost prohibitive without financial assistance from charities.

Indolent NHL remains mostly incurable. The R² approach is still not a curative one, and resources should be directed to investigate a cure for this population. Whenever feasible, participation in a clinical trial should be encouraged. Parameters have not been reported based on prognostic groups, and the study did not identify any biomarkers that may correlate with improved outcome. Perhaps a biomarker-based trial design may be most suitable in explaining the heterogeneity in follicular and marginal zone lymphomas.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

Study Overview

Objective. To compare the efficacy and safety of lenalidomide in combination with rituximab (known as the R² regimen) to rituximab plus placebo in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma (MZL).

Design. Phase 3, multicenter, international, placebo controlled randomized trial.

Setting and participants. 358 patients with rituximab-sensitive relapsed or refractory grade 1-3a follicular lymphoma or MZL.

Intervention. Patients were randomly assigned 1:1 to receive lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5.

Main outcome measures. The primary endpoint was progression-free survival (PFS) as determined by independent radiology reviewers using intent-to-treat analysis. Secondary end points included overall response rate, complete response rate, duration of response, overall survival, event-free survival, and time to next anti-lymphoma therapy. Time to next chemotherapy treatment and histologic transformation were exploratory endpoints. Responses were assessed by participating investigators and independent reviewers. Computed tomography or magnetic resonance imaging was used to obtain tumor measurements. Positron emission tomography was not used. Complete remissions were confirmed by bone marrow biopsy, as bone marrow involvement is exceedingly common in these lymphomas. Gastrointestinal endoscopy was performed to obtain disease status if there was involvement by lymphoma initially.

Improvement in primary and secondary endpoints as well as extrapolatory endpoints were reported in the R² group. Primary efficacy analyses were conducted in the intention-to-treat population primary endpoint of PFS at 1-sided α = 0.025 level.

Main results. PFS was significantly improved for patients treated with the R² regimen compared to those who recieved placebo plus rituximab, with a hazard ratio of 0.46 (95% confidence interval [CI], 0.34-0.62; P < 0.001). Median duration of PFS in the R² group was 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months) in the rituximab/placebo group. Overall response in the R² group was 78% (95% CI, 71%-83%) versus 53% (95% CI, 46%-61%; P < 0.0001) in the rituximab/placebo group, with 34% (95% CI, 27%-41%) versus 18% (95% CI, 13%-25%) of patients achieving complete remission (P = 0.001). There were 15 deaths in the R² group versus 26 deaths in the rituximab/placebo group. Overall survival data is not mature yet.

Conclusion. The R² regimen was superior to rituximab and placebo in relapsed or recurrent follicular lymphomas. The regimen’s safety profile was acceptable, with higher events of usual and expected but manageable toxicities in the R² regimen compared to rituximab/placebo.

Commentary

Nearly half of non-Hodgkins lymphomas (NHLs) diagnosed in the United States are classified as indolent B-cell lymphomas.¹ Follicular lymphomas constitute about 50% of all indolent NHLs, while MZLs comprise less than 15%.¹ These slowly progressive B-cell lymphomas are currently considered treatable but have very low cure rates. Cure is primarily limited to early stage I/II disease and may be possible in less than half of patients by applying involved-field radiation therapy with curative intent.

More than two thirds of indolent lymphomas present in advanced stages (III-IV). Despite an advanced stage at presentation, initial chemoimmunotherapy can induce complete remission in nearly 60% of patients. Unfortunately, nearly all patients relapse over the next 10 years.² The wait-and-watch approach is a common strategy, and most patients are administered initial therapy or subsequent lines of therapy if they are symptomatic.² As such, for the majority of these patients, the goal of therapy is to minimize toxicities, preserve quality of life, treat symptoms, and achieve a long PFS without an attempt to cure. Following each line of therapy, patients often revert to watchful surveillance, sometimes for more than a decade. With additional subsequent lines of therapy, lymphoma tends to get more refractory to treatment.

A median survival of nearly 2 decades has been achieved in advanced follicular lymphomas^2,3 and MZL.⁴ However, wide variation in overall response, duration of response, and survival is reported based on the individual risk profile.

The drug of interest in the present study by Leonard and colleagues, lenalidomide, has immunomodulatory properties and antiproliferative effects, possibly related to its binding of the E3 ligase protein cereblon and subsequent ubiquitination of the transcription factors Aiolos and Ikaros.⁵ The benefits of combination lenalidomide/rituximab against follicular lymphoma in preclinical settings have been attributed to mechanisms mediated by tumor-infiltrating lymphocytes, natural killer cells, monocytes, and antibody-dependent cell-mediated toxicity.⁵ The combination has now been studied in first-line and subsequent lines of therapy for follicular lymphoma and MZL.⁶

RELEVANCE, a phase 3 trial, compared the R² regimen in the upfront setting in advanced follicular lymphoma with rituximab and chemotherapy combination (including CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], CVP [cyclophosphamide, vincristine, prednisone], and bendamustine).⁷ Efficacy outcomes were similar between the comparators and R² was noninferior. MAGNIFY, a phase 3b trial involving rituximab-sensitive and rituximab-refractory patients with previously treated follicular lymphoma and MZL, demonstrated an overall response rate of 73%, complete response rate of 45%, and median PFS of 36 months in patients who received the R² regimen and who entered a plan to receive maintenance with rituximab.⁸

The AUGMENT trial was conducted at 97 centers in the United States and 14 Asian and European countries; it enrolled 358 patients, 82% of whom had a follicular lymphoma, between February 13, 2014 and January 26, 2017. The study was well conducted. The R² regimen was compared to the often used second-line therapy of rituximab alone, and 1:1 randomization was done with stratification factors of prior rituximab use, marginal versus follicular histology, and time lapse of less than or greater than 2 years since last therapy. A limitation of this study is that it selected individuals with a better prognosis, as the study patients were not rituximab refractory and 57% had received only a single prior therapy.

As observed in other R² regimen trials in follicular or marginal zone lymphomas, the most common adverse reactions (occurring in at least 20% of patients) were neutropenia, fatigue, and constipation. These were manageable with dose adjustments and interruptions, and, in the opinion of authors, did not take away from the overall benefits seen.

The authors acknowledge that a limitation of this study was a lower assessment of median PFS in both arms by investigators than by independent reviewers. The independent review committee assessed PFS for R² at 39.4 months, whereas investigators assessed it at 25.4 months. The median PFS benefit remained at 14.1 months by both methods of assessment. This may highlight the differences of radiographic measurements in a central setting versus at individual centers.

Histologic transformation to a higher-grade aggressive lymphoma occurred in 2 patients in the R² arm and 10 patients in the placebo/rituximab arm. After transformation, 1 patient in the R² arm and 6 in the placebo plus rituximab arm died. A plausible mechanism for this variation has not been provided. If confirmed across a wider population, this may be one of the most significant benefits of the R² regimen.

Applications for Clinical Practice

Therapy for relapsed and refractory indolent B-cell lymphomas continues to evolve. While chemotherapy remains an effective option, immunomodulation using non-chemotherapeutic intervention has emerged as an attractive strategy. The AUGMENT trial further solidifies adoption of the non-chemotherapy doublet option of rituximab/lenalidomide based on the premise of immunomodulation. Both the agents have been commercially available for more than a decade and are being used for other indications beyond the study population for this trial.

Based on the AUGMENT and MAGNIFY trials, lenalidomide combined with rituximab was approved by the Food and Drug Administration for use in relapsed and refractory follicular or marginal zone lymphomas soon after the AUGMENT study results were published. The recommended lenalidomide dose for both lymphomas is 20 mg once daily orally on days 1 to 21 of repeated 28-day cycles for up to 12 cycles.

The evidence from this trial has yielded what is likely to be a practice changing regimen, with R² replacing single-agent rituximab for treating follicular lymphoma in the second line or beyond. The response rates and PFS periods were slightly lower in MZL. R² offers advantages associated with a chemotherapy-free regimen and improved PFS. Also, in the AUGEMENT trial the secondary and exploratory endpoints of time to next therapy, overall response rates, and overall survival rates were improved in patients treated with R².

Practitioners may choose lenalidomide plus rituximab over rituximab alone based on the AUGMENT study. When considering this regimen, several points should be kept in mind. A very careful selection of patients would be prudent, considering that the study’s follow-up of less than 4 years is short for a disease with long overall survival rates. The study was not powered to compare overall survival benefit. Also, practitioners are reminded to limit the use of lenalidomide to a maximum of 12 months, with planned interruptions and 8 doses of rituximab, replicating the trial schema. Additionally, as per the clinical trial design, the regimen is not intended for rituximab-refractory patients. Patients with MZL constituted only 18% of the study, and conclusions of superiority in this subgroup were not statistically significant. Lenalidomide is not approved for other indolent B cell lymphoproliferative malignancies, such as small lymphocytic lymphoma and chronic lymphocytic leukemia. The conclusion of the published study abstract suggests acceptable use in recurrent indolent lymphomas, but no such conclusion can be made due to lack of inclusion of all indolent lymphoma subtypes in this study.

Longer-term use of lenalidomide has been associated with a marginally increased risk of secondary hematologic malignancies in patients with multiple myeloma who were prescribed lenalidomide maintenance therapy for up to 2 years following high-dose chemotherapy and autologous hematopoietic stem cell transplant.⁹ Interestingly, in the AUGMENT study and other trials using lenalidomide/rituximab, no significant increase in secondary hematologic malignancies has been reported. The absence of prior myeloablative chemotherapy and a shorter duration of use (1 year) in this group of patients may be factors in why no additional risk of secondary hematologic malignancies was observed. Longer-term follow-up may be needed to evaluate this risk.

In the R² arm of this study, 55% patients experienced grades 3 and 4 neutropenia. With a median age of presentation for both follicular lymphoma and MZL of over 60 years, oncologists should remain aware of this potentially fatal complication, especially in the frail, the elderly, and previously treated individuals who may have a high risk of myelosuppression. Clinicians should be prepared to rapidly adopt strategies of dose interruption, dose reduction, and growth factor use, as implemented in the trial. Of note, despite the high rates of severe neutropenia, only 3% of the participants experienced febrile neutropenia, and 71% patients in R² group and 61% in rituximab group completed planned protocol therapy. Growth factor use was high at 36% in the R² group, which may have been responsible for a lower incidence of febrile neutropenia.

Increased toxicities of tumor flare, rash, and constipation were observed in the R² arm. Patients with greater than grade 1 neuropathy were excluded. For those at risk of thromboembolism, prophylactic anticoagulation or antiplatelet therapy was recommended in the trial. Lenalidomide dose was reduced to 10 mg for those with creatinine clearance of 30 to 59 mL/min.

The cost-effectiveness of lenalidomide/rituximab combination has not been fully studied against a sequential approach of using rituximab and lenalidomide for a limited number of cycles. The cost of a Revlimid 10-mg pill may be over $700.¹⁰ Costs associated with supportive care due to additional toxicities have not been quantified. For those with cost concerns or lack of insurance coverage, the R² regimen may be cost prohibitive without financial assistance from charities.

Indolent NHL remains mostly incurable. The R² approach is still not a curative one, and resources should be directed to investigate a cure for this population. Whenever feasible, participation in a clinical trial should be encouraged. Parameters have not been reported based on prognostic groups, and the study did not identify any biomarkers that may correlate with improved outcome. Perhaps a biomarker-based trial design may be most suitable in explaining the heterogeneity in follicular and marginal zone lymphomas.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

SAN FRANCISCO – Should targeted agents replace chemoimmunotherapy (CIT) as first-line treatment for chronic lymphocytic leukemia (CLL)? A recent debate suggests there’s no consensus.

Jennifer Smith/MDedge News

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, debated the topic at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Dr. Wierda argued that CLL patients should receive a BTK inhibitor or BCL2 inhibitor, with or without obinutuzumab, as first-line therapy because these targeted agents have been shown to provide better progression-free survival (PFS) than CIT, and the targeted therapies may prolong overall survival (OS) as well.

Dr. Brown countered that targeted agents don’t improve PFS for all CLL patients, improved PFS doesn’t always translate to improved OS, and targeted agents cost more than CIT.
 

No role for CIT as first-line treatment

“We have two approaches right now, with nonchemoimmunotherapy-based treatment,” Dr. Wierda said. “One approach, with small-molecule inhibitors, is to have a sustained and durable period of disease control, particularly with BTK inhibitors. The other strategy that has emerged is deep remissions with fixed-duration treatment with BCL2 small-molecule inhibitor-based therapy, which, I would argue, is better than being exposed to genotoxic chemoimmunotherapy.”

Dr. Wierda went on to explain that the BTK inhibitor ibrutinib has been shown to improve PFS, compared with CIT, in phase 3 trials.

In the iLLUMINATE trial, researchers compared ibrutinib plus obinutuzumab to chlorambucil plus obinutuzumab as first-line treatment in CLL. At a median follow-up of 31.3 months, the median PFS was not reached in the ibrutinib arm and was 19 months in the chlorambucil arm (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:43-56).

In the A041202 study, researchers compared ibrutinib alone (Ib) or in combination with rituximab (Ib-R) to bendamustine plus rituximab (BR) in untreated, older patients with CLL. The 2-year PFS estimates were 74% in the BR arm, 87% in the Ib arm, and 88% in the Ib-R arm (P less than .001 for BR vs. Ib or Ib-R; N Engl J Med. 2018; 379:2517-28).

In the E1912 trial, researchers compared Ib-R to fludarabine, cyclophosphamide, and rituximab (FCR) in younger, untreated CLL patients. The 3-year PFS was 89.4% with Ib-R and 72.9% with FCR (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43).

Dr. Wierda noted that the E1912 trial also showed superior OS with Ib-R. The 3-year OS rate was 98.8% with Ib-R and 91.5% with FCR (P less than .001). However, there was no significant difference in OS between the treatment arms in the A041202 trial or the iLLUMINATE trial.

“But I would argue that is, in part, because of short follow-up,” Dr. Wierda said. “The trials were all designed to look at progression-free survival, not overall survival. With longer follow-up, we may see differences in overall survival emerging.”

Dr. Wierda went on to say that fixed‐duration treatment with the BCL2 inhibitor venetoclax can improve PFS over CIT.

In the phase 3 CLL14 trial, researchers compared fixed-duration treatment with venetoclax plus obinutuzumab to chlorambucil plus obinutuzumab in previously untreated CLL patients with comorbidities. The estimated PFS at 2 years was 88.2% in the venetoclax group and 64.1% in the chlorambucil group (P less than .001; N Engl J Med. 2019; 380:2225-36).

“[There was] no difference in overall survival,” Dr. Wierda noted. “But, again, I would argue ... that follow-up is relatively limited. We may ultimately see a difference in overall survival.”

Based on these findings, Dr. Wierda made the following treatment recommendations:

• Any CLL patient with del(17p) or TP53 mutation, and older, unfit patients with unmutated IGHV should receive a BTK inhibitor, with or without obinutuzumab.
• All young, fit patients, and older, unfit patients with mutated IGHV should receive a BCL2 inhibitor plus obinutuzumab.

Dr. Wierda also noted that ibrutinib and venetoclax in combination have shown early promise for patients with previously untreated CLL (N Engl J Med. 2019; 380:2095-2103).
 

CIT still has a role as first-line treatment

Dr. Brown suggested that a PFS benefit may not be enough to recommend targeted agents over CIT. For one thing, the PFS benefit doesn’t apply to all patients, as the IGHV-mutated subgroup does equally well with CIT and targeted agents.

Jennifer Smith/MDedge News

In the IGHV-mutated group from the E1912 trial, the 3-year PFS was 88% for patients who received Ib-R and those who received FCR (N Engl J Med. 2019 Aug 1;381:432-43). In the A041202 study, the 2-year PFS among IGHV-mutated patients was 87% in the BR arm, 86% in the Ib arm, and 88% in the Ib-R arm (N Engl J Med. 2018; 379:2517-28).

In the CLL14 trial, PFS rates were similar among IGHV-mutated patients who received chlorambucil plus obinutuzumab and IGHV-mutated or unmutated patients who received venetoclax and obinutuzumab (N Engl J Med. 2019; 380:2225-36).

Dr. Brown also noted that the overall improvement in PFS observed with ibrutinib and venetoclax doesn’t always translate to improved OS.

In the A041202 study, there was no significant difference in OS between the Ib, Ib-R, and BR arms (N Engl J Med. 2018; 379:2517-28). There was no significant difference in OS between the ibrutinib and chlorambucil arms in the iLLUMINATE trial (Lancet Oncol. 2019 Jan;20[1]:43-56). And there was no significant difference in OS between the venetoclax and chlorambucil arms in the CLL14 trial (N Engl J Med. 2019; 380:2225-36).

However, in the RESONATE-2 trial, ibrutinib provided an OS benefit over chlorambucil. The 2-year OS was 95% and 84%, respectively (P = .0145; Haematologica. Sept 2018;103:1502-10). Dr. Brown said the OS advantage in this study was due to the “very poor comparator of chlorambucil and very limited crossover.”

As Dr. Wierda mentioned, the OS rate was higher with Ib-R than with FCR in the E1912 trial. The 3-year OS rate was 98.8% and 91.5%, respectively (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43). Dr. Brown noted, however, that there were few deaths in this study, and many of them “were not clearly related to the disease or its treatment.”

Dr. Brown also pointed out that FCR has been shown to have curative potential in IGHV-mutated CLL in both the FCR300 trial (Blood. 2016 127:303-9) and the CLL8 trial (Blood. 2016 127:208-15).

Another factor to consider is the greater cost of targeted agents. One analysis suggested the per-patient lifetime cost of CLL treatment in the United States will increase from $147,000 to $604,000 as targeted therapies overtake CIT as first-line treatment (J Clin Oncol. 2017 Jan 10;35[2]:166-174).

“Given all of the above, chemoimmunotherapy is going to remain part of the treatment repertoire for CLL,” Dr. Brown said. “It’s our only known potential cure for the fit, mutated patients ... and can also result in prolonged treatment-free intervals for patients who are older. As we manage CLL as a chronic disease over a lifetime, we need to continue to have this in our armamentarium.”

Specifically, Dr. Brown said CIT is appropriate for patients who don’t have del(17p) or mutated TP53. FCR should be given to young, fit patients with IGHV-mutated CLL, and FCR or BR should be given to older patients and young, fit patients with IGHV-unmutated CLL.

Dr. Brown and Dr. Wierda reported financial ties to multiple pharmaceutical companies, including makers of CLL treatments.

jensmith@mdedge.com

SAN FRANCISCO – Should targeted agents replace chemoimmunotherapy (CIT) as first-line treatment for chronic lymphocytic leukemia (CLL)? A recent debate suggests there’s no consensus.

Jennifer Smith/MDedge News

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, debated the topic at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Dr. Wierda argued that CLL patients should receive a BTK inhibitor or BCL2 inhibitor, with or without obinutuzumab, as first-line therapy because these targeted agents have been shown to provide better progression-free survival (PFS) than CIT, and the targeted therapies may prolong overall survival (OS) as well.

Dr. Brown countered that targeted agents don’t improve PFS for all CLL patients, improved PFS doesn’t always translate to improved OS, and targeted agents cost more than CIT.
 

No role for CIT as first-line treatment

“We have two approaches right now, with nonchemoimmunotherapy-based treatment,” Dr. Wierda said. “One approach, with small-molecule inhibitors, is to have a sustained and durable period of disease control, particularly with BTK inhibitors. The other strategy that has emerged is deep remissions with fixed-duration treatment with BCL2 small-molecule inhibitor-based therapy, which, I would argue, is better than being exposed to genotoxic chemoimmunotherapy.”

Dr. Wierda went on to explain that the BTK inhibitor ibrutinib has been shown to improve PFS, compared with CIT, in phase 3 trials.

In the iLLUMINATE trial, researchers compared ibrutinib plus obinutuzumab to chlorambucil plus obinutuzumab as first-line treatment in CLL. At a median follow-up of 31.3 months, the median PFS was not reached in the ibrutinib arm and was 19 months in the chlorambucil arm (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:43-56).

In the A041202 study, researchers compared ibrutinib alone (Ib) or in combination with rituximab (Ib-R) to bendamustine plus rituximab (BR) in untreated, older patients with CLL. The 2-year PFS estimates were 74% in the BR arm, 87% in the Ib arm, and 88% in the Ib-R arm (P less than .001 for BR vs. Ib or Ib-R; N Engl J Med. 2018; 379:2517-28).

In the E1912 trial, researchers compared Ib-R to fludarabine, cyclophosphamide, and rituximab (FCR) in younger, untreated CLL patients. The 3-year PFS was 89.4% with Ib-R and 72.9% with FCR (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43).

Dr. Wierda noted that the E1912 trial also showed superior OS with Ib-R. The 3-year OS rate was 98.8% with Ib-R and 91.5% with FCR (P less than .001). However, there was no significant difference in OS between the treatment arms in the A041202 trial or the iLLUMINATE trial.

“But I would argue that is, in part, because of short follow-up,” Dr. Wierda said. “The trials were all designed to look at progression-free survival, not overall survival. With longer follow-up, we may see differences in overall survival emerging.”

Dr. Wierda went on to say that fixed‐duration treatment with the BCL2 inhibitor venetoclax can improve PFS over CIT.

In the phase 3 CLL14 trial, researchers compared fixed-duration treatment with venetoclax plus obinutuzumab to chlorambucil plus obinutuzumab in previously untreated CLL patients with comorbidities. The estimated PFS at 2 years was 88.2% in the venetoclax group and 64.1% in the chlorambucil group (P less than .001; N Engl J Med. 2019; 380:2225-36).

“[There was] no difference in overall survival,” Dr. Wierda noted. “But, again, I would argue ... that follow-up is relatively limited. We may ultimately see a difference in overall survival.”

Based on these findings, Dr. Wierda made the following treatment recommendations:

• Any CLL patient with del(17p) or TP53 mutation, and older, unfit patients with unmutated IGHV should receive a BTK inhibitor, with or without obinutuzumab.
• All young, fit patients, and older, unfit patients with mutated IGHV should receive a BCL2 inhibitor plus obinutuzumab.

Dr. Wierda also noted that ibrutinib and venetoclax in combination have shown early promise for patients with previously untreated CLL (N Engl J Med. 2019; 380:2095-2103).
 

CIT still has a role as first-line treatment

Dr. Brown suggested that a PFS benefit may not be enough to recommend targeted agents over CIT. For one thing, the PFS benefit doesn’t apply to all patients, as the IGHV-mutated subgroup does equally well with CIT and targeted agents.

Jennifer Smith/MDedge News

In the IGHV-mutated group from the E1912 trial, the 3-year PFS was 88% for patients who received Ib-R and those who received FCR (N Engl J Med. 2019 Aug 1;381:432-43). In the A041202 study, the 2-year PFS among IGHV-mutated patients was 87% in the BR arm, 86% in the Ib arm, and 88% in the Ib-R arm (N Engl J Med. 2018; 379:2517-28).

In the CLL14 trial, PFS rates were similar among IGHV-mutated patients who received chlorambucil plus obinutuzumab and IGHV-mutated or unmutated patients who received venetoclax and obinutuzumab (N Engl J Med. 2019; 380:2225-36).

Dr. Brown also noted that the overall improvement in PFS observed with ibrutinib and venetoclax doesn’t always translate to improved OS.

In the A041202 study, there was no significant difference in OS between the Ib, Ib-R, and BR arms (N Engl J Med. 2018; 379:2517-28). There was no significant difference in OS between the ibrutinib and chlorambucil arms in the iLLUMINATE trial (Lancet Oncol. 2019 Jan;20[1]:43-56). And there was no significant difference in OS between the venetoclax and chlorambucil arms in the CLL14 trial (N Engl J Med. 2019; 380:2225-36).

However, in the RESONATE-2 trial, ibrutinib provided an OS benefit over chlorambucil. The 2-year OS was 95% and 84%, respectively (P = .0145; Haematologica. Sept 2018;103:1502-10). Dr. Brown said the OS advantage in this study was due to the “very poor comparator of chlorambucil and very limited crossover.”

As Dr. Wierda mentioned, the OS rate was higher with Ib-R than with FCR in the E1912 trial. The 3-year OS rate was 98.8% and 91.5%, respectively (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43). Dr. Brown noted, however, that there were few deaths in this study, and many of them “were not clearly related to the disease or its treatment.”

Dr. Brown also pointed out that FCR has been shown to have curative potential in IGHV-mutated CLL in both the FCR300 trial (Blood. 2016 127:303-9) and the CLL8 trial (Blood. 2016 127:208-15).

Another factor to consider is the greater cost of targeted agents. One analysis suggested the per-patient lifetime cost of CLL treatment in the United States will increase from $147,000 to $604,000 as targeted therapies overtake CIT as first-line treatment (J Clin Oncol. 2017 Jan 10;35[2]:166-174).

“Given all of the above, chemoimmunotherapy is going to remain part of the treatment repertoire for CLL,” Dr. Brown said. “It’s our only known potential cure for the fit, mutated patients ... and can also result in prolonged treatment-free intervals for patients who are older. As we manage CLL as a chronic disease over a lifetime, we need to continue to have this in our armamentarium.”

Specifically, Dr. Brown said CIT is appropriate for patients who don’t have del(17p) or mutated TP53. FCR should be given to young, fit patients with IGHV-mutated CLL, and FCR or BR should be given to older patients and young, fit patients with IGHV-unmutated CLL.

Dr. Brown and Dr. Wierda reported financial ties to multiple pharmaceutical companies, including makers of CLL treatments.

jensmith@mdedge.com

SAN FRANCISCO – Should targeted agents replace chemoimmunotherapy (CIT) as first-line treatment for chronic lymphocytic leukemia (CLL)? A recent debate suggests there’s no consensus.

Jennifer Smith/MDedge News

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, debated the topic at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Dr. Wierda argued that CLL patients should receive a BTK inhibitor or BCL2 inhibitor, with or without obinutuzumab, as first-line therapy because these targeted agents have been shown to provide better progression-free survival (PFS) than CIT, and the targeted therapies may prolong overall survival (OS) as well.

Dr. Brown countered that targeted agents don’t improve PFS for all CLL patients, improved PFS doesn’t always translate to improved OS, and targeted agents cost more than CIT.
 

No role for CIT as first-line treatment

“We have two approaches right now, with nonchemoimmunotherapy-based treatment,” Dr. Wierda said. “One approach, with small-molecule inhibitors, is to have a sustained and durable period of disease control, particularly with BTK inhibitors. The other strategy that has emerged is deep remissions with fixed-duration treatment with BCL2 small-molecule inhibitor-based therapy, which, I would argue, is better than being exposed to genotoxic chemoimmunotherapy.”

Dr. Wierda went on to explain that the BTK inhibitor ibrutinib has been shown to improve PFS, compared with CIT, in phase 3 trials.

In the iLLUMINATE trial, researchers compared ibrutinib plus obinutuzumab to chlorambucil plus obinutuzumab as first-line treatment in CLL. At a median follow-up of 31.3 months, the median PFS was not reached in the ibrutinib arm and was 19 months in the chlorambucil arm (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:43-56).

In the A041202 study, researchers compared ibrutinib alone (Ib) or in combination with rituximab (Ib-R) to bendamustine plus rituximab (BR) in untreated, older patients with CLL. The 2-year PFS estimates were 74% in the BR arm, 87% in the Ib arm, and 88% in the Ib-R arm (P less than .001 for BR vs. Ib or Ib-R; N Engl J Med. 2018; 379:2517-28).

In the E1912 trial, researchers compared Ib-R to fludarabine, cyclophosphamide, and rituximab (FCR) in younger, untreated CLL patients. The 3-year PFS was 89.4% with Ib-R and 72.9% with FCR (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43).

Dr. Wierda noted that the E1912 trial also showed superior OS with Ib-R. The 3-year OS rate was 98.8% with Ib-R and 91.5% with FCR (P less than .001). However, there was no significant difference in OS between the treatment arms in the A041202 trial or the iLLUMINATE trial.

“But I would argue that is, in part, because of short follow-up,” Dr. Wierda said. “The trials were all designed to look at progression-free survival, not overall survival. With longer follow-up, we may see differences in overall survival emerging.”

Dr. Wierda went on to say that fixed‐duration treatment with the BCL2 inhibitor venetoclax can improve PFS over CIT.

In the phase 3 CLL14 trial, researchers compared fixed-duration treatment with venetoclax plus obinutuzumab to chlorambucil plus obinutuzumab in previously untreated CLL patients with comorbidities. The estimated PFS at 2 years was 88.2% in the venetoclax group and 64.1% in the chlorambucil group (P less than .001; N Engl J Med. 2019; 380:2225-36).

“[There was] no difference in overall survival,” Dr. Wierda noted. “But, again, I would argue ... that follow-up is relatively limited. We may ultimately see a difference in overall survival.”

Based on these findings, Dr. Wierda made the following treatment recommendations:

• Any CLL patient with del(17p) or TP53 mutation, and older, unfit patients with unmutated IGHV should receive a BTK inhibitor, with or without obinutuzumab.
• All young, fit patients, and older, unfit patients with mutated IGHV should receive a BCL2 inhibitor plus obinutuzumab.

Dr. Wierda also noted that ibrutinib and venetoclax in combination have shown early promise for patients with previously untreated CLL (N Engl J Med. 2019; 380:2095-2103).
 

CIT still has a role as first-line treatment

Dr. Brown suggested that a PFS benefit may not be enough to recommend targeted agents over CIT. For one thing, the PFS benefit doesn’t apply to all patients, as the IGHV-mutated subgroup does equally well with CIT and targeted agents.

Jennifer Smith/MDedge News

In the IGHV-mutated group from the E1912 trial, the 3-year PFS was 88% for patients who received Ib-R and those who received FCR (N Engl J Med. 2019 Aug 1;381:432-43). In the A041202 study, the 2-year PFS among IGHV-mutated patients was 87% in the BR arm, 86% in the Ib arm, and 88% in the Ib-R arm (N Engl J Med. 2018; 379:2517-28).

In the CLL14 trial, PFS rates were similar among IGHV-mutated patients who received chlorambucil plus obinutuzumab and IGHV-mutated or unmutated patients who received venetoclax and obinutuzumab (N Engl J Med. 2019; 380:2225-36).

Dr. Brown also noted that the overall improvement in PFS observed with ibrutinib and venetoclax doesn’t always translate to improved OS.

In the A041202 study, there was no significant difference in OS between the Ib, Ib-R, and BR arms (N Engl J Med. 2018; 379:2517-28). There was no significant difference in OS between the ibrutinib and chlorambucil arms in the iLLUMINATE trial (Lancet Oncol. 2019 Jan;20[1]:43-56). And there was no significant difference in OS between the venetoclax and chlorambucil arms in the CLL14 trial (N Engl J Med. 2019; 380:2225-36).

However, in the RESONATE-2 trial, ibrutinib provided an OS benefit over chlorambucil. The 2-year OS was 95% and 84%, respectively (P = .0145; Haematologica. Sept 2018;103:1502-10). Dr. Brown said the OS advantage in this study was due to the “very poor comparator of chlorambucil and very limited crossover.”

As Dr. Wierda mentioned, the OS rate was higher with Ib-R than with FCR in the E1912 trial. The 3-year OS rate was 98.8% and 91.5%, respectively (P less than .001; N Engl J Med. 2019 Aug 1;381:432-43). Dr. Brown noted, however, that there were few deaths in this study, and many of them “were not clearly related to the disease or its treatment.”

Dr. Brown also pointed out that FCR has been shown to have curative potential in IGHV-mutated CLL in both the FCR300 trial (Blood. 2016 127:303-9) and the CLL8 trial (Blood. 2016 127:208-15).

Another factor to consider is the greater cost of targeted agents. One analysis suggested the per-patient lifetime cost of CLL treatment in the United States will increase from $147,000 to $604,000 as targeted therapies overtake CIT as first-line treatment (J Clin Oncol. 2017 Jan 10;35[2]:166-174).

“Given all of the above, chemoimmunotherapy is going to remain part of the treatment repertoire for CLL,” Dr. Brown said. “It’s our only known potential cure for the fit, mutated patients ... and can also result in prolonged treatment-free intervals for patients who are older. As we manage CLL as a chronic disease over a lifetime, we need to continue to have this in our armamentarium.”

Specifically, Dr. Brown said CIT is appropriate for patients who don’t have del(17p) or mutated TP53. FCR should be given to young, fit patients with IGHV-mutated CLL, and FCR or BR should be given to older patients and young, fit patients with IGHV-unmutated CLL.

Dr. Brown and Dr. Wierda reported financial ties to multiple pharmaceutical companies, including makers of CLL treatments.

jensmith@mdedge.com

Several initiatives are in the works to improve the management of patients with sickle cell disease in the ED, experts said at a recent webinar held by the National Heart, Lung, and Blood Institute.

JazzIRT/Getty Images

In 2014, the NHLBI released evidence-based guidelines for the management of patients with sickle cell disease. The expert panel provided recommendations on the treatment of acute complications of sickle cell disease, many of which are common reasons for ED visits.

Optimizing the treatment of acute complications, namely vasoocclusive crisis, is essential to ensure improved long-term outcomes, explained Paula Tanabe, PhD, of Duke University, Durham, N.C.

Pain management

While the majority of pain-related ED visits in sickle cell are the result of vasoocclusive crisis, other causes, such as acute chest syndrome, abdominal catastrophes, and splenic sequestration, are also important.

The hallmark of pain management in this population is rapid and aggressive treatment with intravenous opioids. The use of individualized doses is also important, but if not available, an sickle cell disease–specific pain protocol can be used, she explained.

Recent evidence has confirmed the benefit of using an individualized (patient-specific) dosing protocol. Dr. Tanabe reported the results of a randomized pilot study that compared two pain protocols for patients undergoing a vasoocclusive episode in the ED.

“The reason we pursued this project is to generate additional evidence beyond the expert panel,” she said.

The primary outcome of the study was the difference in pain scores from arrival to discharge between patients receiving an individualized or weight-based dosing protocol. Secondary outcomes included safety, pain experience, and side effects, among others.

The researchers found that patients who received an individualized protocol had significantly lower pain scores, compared with a standard weight-based protocol (between-protocol pain score difference, 15.6 plus or minus 5.0; P = .002).

Additionally, patients in the individualized dosing arm were admitted less often than those in the weight-based arm (P = .03), Dr. Tanabe reported.

The findings from the previous study formed the basis for an ongoing study that is further examining the impact of patient-specific dosing in patients who present with a vasoocclusive episode. The COMPARE VOE study is currently enrolling patients and is being funded by NHLBI.

The NHLBI also provides funding to eight Sickle Cell Disease Implementation Consortium sites throughout the United States. The objective of this grant funding is to help implement NHLBI recommendations in the emergency setting.

Quality improvement

“One area [that] we want to improve is how quickly we administer [analgesic therapy] to patients when they are experiencing a vasoocclusive episode,” said Caroline Freiermuth, MD, of the University of Cincinnati.

Some common barriers to delivering rapid analgesia in this setting include difficulties in obtaining intravenous access, high patient volumes, lack of education, and provider biases, she explained.

With respect to high patient volumes, one strategy that may help overcome this barrier is to triage patients as Emergency Severity Index level 2, allowing for accelerated room placement.

Sickle cell patients undergoing vasoocclusive crisis meet the criteria for level 2 based on morbidity, degree of pain, and the level of resources often required.

Another important strategy is improving education related to sickle cell disease, particularly the high morbidity and mortality seen in these patients, Dr. Freiermuth said.

“The median lifespan for patients with HbSS disease is in the 40s, basically half of the lifespan of a typical American,” she said.

At present, acute chest syndrome is the principal cause of death in patients with sickle cell disease, and most frequently occurs during a vasoocclusive episode. As a result, screening for this complication is essential to reduce mortality in the emergency setting.

Dr. Freiermuth explained that one of the best ways to prevent acute chest syndrome is to encourage the use of incentive spirometry in patients undergoing a vasoocclusive episode.

In order to increase the likelihood of obtaining intravenous access, the use of ultrasound may help guide placement. Educating nurses on the proper use of ultrasound-guided placement of intravenous catheters is one practical approach, she said.

Alternatively, opioid analgesia can be administered subcutaneously. Benefits of subcutaneous delivery include comparable pharmacokinetics, less pain, and a reduced likelihood of sterile abscesses that are often seen with intramuscular administration.

Dr. Freiermuth outlined the quality-improvement initiative being tested at her institution, which involves the administration of parenteral opioid therapy during triage for sickle cell patients undergoing a suspected vasoocclusive crisis. The initiative was developed with input from both the emergency and hematology departments at the site.

Early results have shown no significant changes using this approach, but the data is still preliminary. Initial feedback has revealed that time to room placement has been the greatest barrier, she reported.

Dr. Tanabe reported grant/research support from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Freiermuth reported research support from Pfizer.

Several initiatives are in the works to improve the management of patients with sickle cell disease in the ED, experts said at a recent webinar held by the National Heart, Lung, and Blood Institute.

JazzIRT/Getty Images

In 2014, the NHLBI released evidence-based guidelines for the management of patients with sickle cell disease. The expert panel provided recommendations on the treatment of acute complications of sickle cell disease, many of which are common reasons for ED visits.

Optimizing the treatment of acute complications, namely vasoocclusive crisis, is essential to ensure improved long-term outcomes, explained Paula Tanabe, PhD, of Duke University, Durham, N.C.

Pain management

While the majority of pain-related ED visits in sickle cell are the result of vasoocclusive crisis, other causes, such as acute chest syndrome, abdominal catastrophes, and splenic sequestration, are also important.

The hallmark of pain management in this population is rapid and aggressive treatment with intravenous opioids. The use of individualized doses is also important, but if not available, an sickle cell disease–specific pain protocol can be used, she explained.

Recent evidence has confirmed the benefit of using an individualized (patient-specific) dosing protocol. Dr. Tanabe reported the results of a randomized pilot study that compared two pain protocols for patients undergoing a vasoocclusive episode in the ED.

“The reason we pursued this project is to generate additional evidence beyond the expert panel,” she said.

The primary outcome of the study was the difference in pain scores from arrival to discharge between patients receiving an individualized or weight-based dosing protocol. Secondary outcomes included safety, pain experience, and side effects, among others.

The researchers found that patients who received an individualized protocol had significantly lower pain scores, compared with a standard weight-based protocol (between-protocol pain score difference, 15.6 plus or minus 5.0; P = .002).

Additionally, patients in the individualized dosing arm were admitted less often than those in the weight-based arm (P = .03), Dr. Tanabe reported.

The findings from the previous study formed the basis for an ongoing study that is further examining the impact of patient-specific dosing in patients who present with a vasoocclusive episode. The COMPARE VOE study is currently enrolling patients and is being funded by NHLBI.

The NHLBI also provides funding to eight Sickle Cell Disease Implementation Consortium sites throughout the United States. The objective of this grant funding is to help implement NHLBI recommendations in the emergency setting.

Quality improvement

“One area [that] we want to improve is how quickly we administer [analgesic therapy] to patients when they are experiencing a vasoocclusive episode,” said Caroline Freiermuth, MD, of the University of Cincinnati.

Some common barriers to delivering rapid analgesia in this setting include difficulties in obtaining intravenous access, high patient volumes, lack of education, and provider biases, she explained.

With respect to high patient volumes, one strategy that may help overcome this barrier is to triage patients as Emergency Severity Index level 2, allowing for accelerated room placement.

Sickle cell patients undergoing vasoocclusive crisis meet the criteria for level 2 based on morbidity, degree of pain, and the level of resources often required.

Another important strategy is improving education related to sickle cell disease, particularly the high morbidity and mortality seen in these patients, Dr. Freiermuth said.

“The median lifespan for patients with HbSS disease is in the 40s, basically half of the lifespan of a typical American,” she said.

At present, acute chest syndrome is the principal cause of death in patients with sickle cell disease, and most frequently occurs during a vasoocclusive episode. As a result, screening for this complication is essential to reduce mortality in the emergency setting.

Dr. Freiermuth explained that one of the best ways to prevent acute chest syndrome is to encourage the use of incentive spirometry in patients undergoing a vasoocclusive episode.

In order to increase the likelihood of obtaining intravenous access, the use of ultrasound may help guide placement. Educating nurses on the proper use of ultrasound-guided placement of intravenous catheters is one practical approach, she said.

Alternatively, opioid analgesia can be administered subcutaneously. Benefits of subcutaneous delivery include comparable pharmacokinetics, less pain, and a reduced likelihood of sterile abscesses that are often seen with intramuscular administration.

Dr. Freiermuth outlined the quality-improvement initiative being tested at her institution, which involves the administration of parenteral opioid therapy during triage for sickle cell patients undergoing a suspected vasoocclusive crisis. The initiative was developed with input from both the emergency and hematology departments at the site.

Early results have shown no significant changes using this approach, but the data is still preliminary. Initial feedback has revealed that time to room placement has been the greatest barrier, she reported.

Dr. Tanabe reported grant/research support from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Freiermuth reported research support from Pfizer.

Several initiatives are in the works to improve the management of patients with sickle cell disease in the ED, experts said at a recent webinar held by the National Heart, Lung, and Blood Institute.

JazzIRT/Getty Images

In 2014, the NHLBI released evidence-based guidelines for the management of patients with sickle cell disease. The expert panel provided recommendations on the treatment of acute complications of sickle cell disease, many of which are common reasons for ED visits.

Optimizing the treatment of acute complications, namely vasoocclusive crisis, is essential to ensure improved long-term outcomes, explained Paula Tanabe, PhD, of Duke University, Durham, N.C.

Pain management

While the majority of pain-related ED visits in sickle cell are the result of vasoocclusive crisis, other causes, such as acute chest syndrome, abdominal catastrophes, and splenic sequestration, are also important.

The hallmark of pain management in this population is rapid and aggressive treatment with intravenous opioids. The use of individualized doses is also important, but if not available, an sickle cell disease–specific pain protocol can be used, she explained.

Recent evidence has confirmed the benefit of using an individualized (patient-specific) dosing protocol. Dr. Tanabe reported the results of a randomized pilot study that compared two pain protocols for patients undergoing a vasoocclusive episode in the ED.

“The reason we pursued this project is to generate additional evidence beyond the expert panel,” she said.

The primary outcome of the study was the difference in pain scores from arrival to discharge between patients receiving an individualized or weight-based dosing protocol. Secondary outcomes included safety, pain experience, and side effects, among others.

The researchers found that patients who received an individualized protocol had significantly lower pain scores, compared with a standard weight-based protocol (between-protocol pain score difference, 15.6 plus or minus 5.0; P = .002).

Additionally, patients in the individualized dosing arm were admitted less often than those in the weight-based arm (P = .03), Dr. Tanabe reported.

The findings from the previous study formed the basis for an ongoing study that is further examining the impact of patient-specific dosing in patients who present with a vasoocclusive episode. The COMPARE VOE study is currently enrolling patients and is being funded by NHLBI.

The NHLBI also provides funding to eight Sickle Cell Disease Implementation Consortium sites throughout the United States. The objective of this grant funding is to help implement NHLBI recommendations in the emergency setting.

Quality improvement

“One area [that] we want to improve is how quickly we administer [analgesic therapy] to patients when they are experiencing a vasoocclusive episode,” said Caroline Freiermuth, MD, of the University of Cincinnati.

Some common barriers to delivering rapid analgesia in this setting include difficulties in obtaining intravenous access, high patient volumes, lack of education, and provider biases, she explained.

With respect to high patient volumes, one strategy that may help overcome this barrier is to triage patients as Emergency Severity Index level 2, allowing for accelerated room placement.

Sickle cell patients undergoing vasoocclusive crisis meet the criteria for level 2 based on morbidity, degree of pain, and the level of resources often required.

Another important strategy is improving education related to sickle cell disease, particularly the high morbidity and mortality seen in these patients, Dr. Freiermuth said.

“The median lifespan for patients with HbSS disease is in the 40s, basically half of the lifespan of a typical American,” she said.

At present, acute chest syndrome is the principal cause of death in patients with sickle cell disease, and most frequently occurs during a vasoocclusive episode. As a result, screening for this complication is essential to reduce mortality in the emergency setting.

Dr. Freiermuth explained that one of the best ways to prevent acute chest syndrome is to encourage the use of incentive spirometry in patients undergoing a vasoocclusive episode.

In order to increase the likelihood of obtaining intravenous access, the use of ultrasound may help guide placement. Educating nurses on the proper use of ultrasound-guided placement of intravenous catheters is one practical approach, she said.

Alternatively, opioid analgesia can be administered subcutaneously. Benefits of subcutaneous delivery include comparable pharmacokinetics, less pain, and a reduced likelihood of sterile abscesses that are often seen with intramuscular administration.

Dr. Freiermuth outlined the quality-improvement initiative being tested at her institution, which involves the administration of parenteral opioid therapy during triage for sickle cell patients undergoing a suspected vasoocclusive crisis. The initiative was developed with input from both the emergency and hematology departments at the site.

Early results have shown no significant changes using this approach, but the data is still preliminary. Initial feedback has revealed that time to room placement has been the greatest barrier, she reported.

Dr. Tanabe reported grant/research support from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Freiermuth reported research support from Pfizer.

A 78-year-old woman presented to the emergency department with shortness of breath and palpitations and was found to have atrial fibrillation with rapid ventricular response. Medical therapy with drug therapy and cardioversion proved ineffective. She then underwent atrioventricular node ablation and placement of a pacemaker.

At the time of admission, anticoagulation was started with full-dose enoxaparin, injected subcutaneously on the left side of the abdominal wall, as her CHA₂DS₂-VASc score (http://chadvasc.org) was 5, due to age, female sex, and history of heart failure and hypertension.

Four days after admission, she reported lower abdominal pain, and her urine output was minimal. A bladder scan showed more than 500 mL of residual urine. She was hemodynamically stable, but physical examination revealed mild abdominal distention and tenderness in the suprapubic region. Laboratory testing showed a sharp rise in serum creatinine and a drop in hematocrit.

The patient was initially managed conservatively with serial physical examinations, monitoring of the hematocrit, serial imaging studies, and discontinuation of anticoagulation, but the pain and anuria persisted. Repeat computed tomography 15 days after admission showed that the hematoma had expanded, and she now had hydronephrosis on the right side as well, requiring urologic intervention with bilateral nephrostomy tube placement.

The size of the hematoma was evaluated with serial abdominal and pelvic examinations. After several days, her urine output had improved, the nephrostomy tubes were removed, and she was discharged.

RECTUS SHEATH HEMATOMA

Our patient had a giant pelvic hematoma, probably arising from the rectus sheath. This uncommon problem can arise from trauma, anticoagulation, or increased intra-abdominal pressure, but it can also occur spontaneously.¹

In rectus sheath hematoma, a branch of the inferior epigastric artery is injured at its insertion into the rectus abdominis muscle. Symptoms arise if bleeding does not stop spontaneously from a tamponade effect.²

We speculate that in our patient, deep injection of enoxaparin into the abdominal wall injured the inferior epigastric artery, which started the hematoma, and the bleeding was exacerbated by the anticoagulation effect of the enoxaparin.

Another form of pelvic hematoma is retro­peritoneal. It is most commonly caused by trauma but can occur due to rupture of the aorta, compression from tumors, or, infrequently, anticoagulation therapy.³

The role of anticoagulation

Spontaneous pelvic hematoma is usually missed as a cause of abdominal pain in patients on anticoagulation therapy and is mistaken for common acute conditions such as ulcer, diverticulitis, appendicitis, ovarian cyst torsion, and tumor.⁴ It usually develops within 5 days of starting anticoagulation therapy. Symptoms vary depending on the location of the hematoma and are best diagnosed with abdominal computed tomography, with sensitivity as high as 100%.

MANAGEMENT

Conservative management, reserved for patients in stable condition, includes temporarily stopping and reevaluating the risks and benefits of anticoagulation and antiplatelet agents, giving blood transfusions, and controlling pain. If conservative measures fail, options are arterial embolization, stent grafting, and blood vessel ligation.⁵ If these measures fail, patients should undergo surgical evacuation of the hematoma and ligation of bleeding vessels.⁶

TAKE-HOME MESSAGE

Subcutaneous injections, especially of anticoagulants, into the abdominal wall can increase the risk of hematoma. Other risk factors are older age, female sex, and thin body habitus with less abdominal fat.⁷ Healthcare professionals should avoid deep injections into the abdomen and should counsel patients and their caregivers about this, as well. The deltoid region could be a safer alternative.

A 78-year-old woman presented to the emergency department with shortness of breath and palpitations and was found to have atrial fibrillation with rapid ventricular response. Medical therapy with drug therapy and cardioversion proved ineffective. She then underwent atrioventricular node ablation and placement of a pacemaker.

At the time of admission, anticoagulation was started with full-dose enoxaparin, injected subcutaneously on the left side of the abdominal wall, as her CHA₂DS₂-VASc score (http://chadvasc.org) was 5, due to age, female sex, and history of heart failure and hypertension.

Four days after admission, she reported lower abdominal pain, and her urine output was minimal. A bladder scan showed more than 500 mL of residual urine. She was hemodynamically stable, but physical examination revealed mild abdominal distention and tenderness in the suprapubic region. Laboratory testing showed a sharp rise in serum creatinine and a drop in hematocrit.

The patient was initially managed conservatively with serial physical examinations, monitoring of the hematocrit, serial imaging studies, and discontinuation of anticoagulation, but the pain and anuria persisted. Repeat computed tomography 15 days after admission showed that the hematoma had expanded, and she now had hydronephrosis on the right side as well, requiring urologic intervention with bilateral nephrostomy tube placement.

The size of the hematoma was evaluated with serial abdominal and pelvic examinations. After several days, her urine output had improved, the nephrostomy tubes were removed, and she was discharged.

RECTUS SHEATH HEMATOMA

Our patient had a giant pelvic hematoma, probably arising from the rectus sheath. This uncommon problem can arise from trauma, anticoagulation, or increased intra-abdominal pressure, but it can also occur spontaneously.¹

In rectus sheath hematoma, a branch of the inferior epigastric artery is injured at its insertion into the rectus abdominis muscle. Symptoms arise if bleeding does not stop spontaneously from a tamponade effect.²

We speculate that in our patient, deep injection of enoxaparin into the abdominal wall injured the inferior epigastric artery, which started the hematoma, and the bleeding was exacerbated by the anticoagulation effect of the enoxaparin.

Another form of pelvic hematoma is retro­peritoneal. It is most commonly caused by trauma but can occur due to rupture of the aorta, compression from tumors, or, infrequently, anticoagulation therapy.³

The role of anticoagulation

Spontaneous pelvic hematoma is usually missed as a cause of abdominal pain in patients on anticoagulation therapy and is mistaken for common acute conditions such as ulcer, diverticulitis, appendicitis, ovarian cyst torsion, and tumor.⁴ It usually develops within 5 days of starting anticoagulation therapy. Symptoms vary depending on the location of the hematoma and are best diagnosed with abdominal computed tomography, with sensitivity as high as 100%.

MANAGEMENT

Conservative management, reserved for patients in stable condition, includes temporarily stopping and reevaluating the risks and benefits of anticoagulation and antiplatelet agents, giving blood transfusions, and controlling pain. If conservative measures fail, options are arterial embolization, stent grafting, and blood vessel ligation.⁵ If these measures fail, patients should undergo surgical evacuation of the hematoma and ligation of bleeding vessels.⁶

TAKE-HOME MESSAGE

Subcutaneous injections, especially of anticoagulants, into the abdominal wall can increase the risk of hematoma. Other risk factors are older age, female sex, and thin body habitus with less abdominal fat.⁷ Healthcare professionals should avoid deep injections into the abdomen and should counsel patients and their caregivers about this, as well. The deltoid region could be a safer alternative.

A 78-year-old woman presented to the emergency department with shortness of breath and palpitations and was found to have atrial fibrillation with rapid ventricular response. Medical therapy with drug therapy and cardioversion proved ineffective. She then underwent atrioventricular node ablation and placement of a pacemaker.

At the time of admission, anticoagulation was started with full-dose enoxaparin, injected subcutaneously on the left side of the abdominal wall, as her CHA₂DS₂-VASc score (http://chadvasc.org) was 5, due to age, female sex, and history of heart failure and hypertension.

Four days after admission, she reported lower abdominal pain, and her urine output was minimal. A bladder scan showed more than 500 mL of residual urine. She was hemodynamically stable, but physical examination revealed mild abdominal distention and tenderness in the suprapubic region. Laboratory testing showed a sharp rise in serum creatinine and a drop in hematocrit.

The patient was initially managed conservatively with serial physical examinations, monitoring of the hematocrit, serial imaging studies, and discontinuation of anticoagulation, but the pain and anuria persisted. Repeat computed tomography 15 days after admission showed that the hematoma had expanded, and she now had hydronephrosis on the right side as well, requiring urologic intervention with bilateral nephrostomy tube placement.

The size of the hematoma was evaluated with serial abdominal and pelvic examinations. After several days, her urine output had improved, the nephrostomy tubes were removed, and she was discharged.

RECTUS SHEATH HEMATOMA

Our patient had a giant pelvic hematoma, probably arising from the rectus sheath. This uncommon problem can arise from trauma, anticoagulation, or increased intra-abdominal pressure, but it can also occur spontaneously.¹

In rectus sheath hematoma, a branch of the inferior epigastric artery is injured at its insertion into the rectus abdominis muscle. Symptoms arise if bleeding does not stop spontaneously from a tamponade effect.²

We speculate that in our patient, deep injection of enoxaparin into the abdominal wall injured the inferior epigastric artery, which started the hematoma, and the bleeding was exacerbated by the anticoagulation effect of the enoxaparin.

Another form of pelvic hematoma is retro­peritoneal. It is most commonly caused by trauma but can occur due to rupture of the aorta, compression from tumors, or, infrequently, anticoagulation therapy.³

The role of anticoagulation

Spontaneous pelvic hematoma is usually missed as a cause of abdominal pain in patients on anticoagulation therapy and is mistaken for common acute conditions such as ulcer, diverticulitis, appendicitis, ovarian cyst torsion, and tumor.⁴ It usually develops within 5 days of starting anticoagulation therapy. Symptoms vary depending on the location of the hematoma and are best diagnosed with abdominal computed tomography, with sensitivity as high as 100%.

MANAGEMENT

Conservative management, reserved for patients in stable condition, includes temporarily stopping and reevaluating the risks and benefits of anticoagulation and antiplatelet agents, giving blood transfusions, and controlling pain. If conservative measures fail, options are arterial embolization, stent grafting, and blood vessel ligation.⁵ If these measures fail, patients should undergo surgical evacuation of the hematoma and ligation of bleeding vessels.⁶

TAKE-HOME MESSAGE

Subcutaneous injections, especially of anticoagulants, into the abdominal wall can increase the risk of hematoma. Other risk factors are older age, female sex, and thin body habitus with less abdominal fat.⁷ Healthcare professionals should avoid deep injections into the abdomen and should counsel patients and their caregivers about this, as well. The deltoid region could be a safer alternative.

Skyrocketing drug costs are a key issue facing physicians, patients, and policymakers, but an even thornier problem may be determining a drug’s value.

In this Q&A, Richard L. Schilsky, MD, senior vice president and chief medical officer at the American Society of Clinical Oncology (ASCO), weighs in on the value proposition for cancer drugs and the implications for physicians.
 

Q: What tools exist for determining a drug’s value?

A: A number of organizations have developed tools to try to determine the value of cancer drug treatments. ASCO, the European Society for Medical Oncology (ESMO), the Institute for Clinical and Economic Review, Memorial Sloan Kettering Cancer Center, and the National Comprehensive Cancer Network have all developed tools for this purpose.

Our tool, the ASCO Value Framework, assesses the value of new cancer drug treatments based on clinical benefit, side effects, and improvements in patient symptoms or quality of life in the context of cost. While it’s hard to directly compare frameworks – given differences in methodology and the many nuances of evaluating clinical trial results – in 2018, ASCO and ESMO published a joint analysis of our value frameworks in the Journal of Clinical Oncology (2018; 37[4]:336-49).

The analysis found that the frameworks produce comparable measures of the clinical benefits of new therapies in approximately two-thirds of the more than 100 treatment comparisons that were examined. It also identified a number of factors that may contribute to the discordant scores, revealing potential ways for both of our organizations to refine our frameworks in the future.

That said, ASCO’s Value Framework is just one part of our broader, multifaceted effort to achieve high-quality, high-value care for all patients with cancer. Other efforts include ASCO’s proposed Patient-Centered Oncology Payment model, the Choosing Wisely campaign to identify low-value clinical strategies, and CancerLinQ and the Quality Oncology Practice Initiative to implement quality measurement and improvement.
 

Q: How can the issues around drug price and value be addressed earlier in the context of clinical trials?

A: The definition of value ultimately comes down to the price that must be paid to achieve meaningfully improved health outcomes for individual patients or the broader population of affected individuals. Optimizing the value of a new cancer drug treatment begins with an innovation to address an unmet medical need, followed by defining and achieving clinically meaningful improvements in health outcomes through well-designed and efficiently conducted clinical trials. Effectiveness research is also essential to determining how well new treatments perform compared with available alternatives and how they perform in more diverse populations than those typically included in the clinical trials used to establish efficacy.

Patient goals, preferences, and choices shape the real-world experience of a new product, and the direct and indirect costs of a treatment to patients and their families significantly affect whether it is adopted widely. Until their value is clearly established, new and costly products should be deployed judiciously and after careful consideration of the goals of treatment, available options, and the unique needs, preferences, and goals of individual patients.

More research is needed to improve how we assess the value of new cancer drug treatments. New clinical efficacy endpoints – both provider- and patient-reported ones – that accurately describe how a patient feels and functions must be developed and should reflect outcomes of value to patients other than survival, particularly in noncurative settings.

Better predictive biomarkers can transform a drug of modest efficacy in an unselected population to one of high efficacy in a biomarker-defined subgroup and thereby contribute to improving the value of a treatment.

Regulatory and policy initiatives such as adaptive licensing, value-based insurance, and indication-specific pricing that affect marketing approval, reimbursement, or price, respectively, based on treatment effectiveness, also deserve careful consideration and further research to determine their effects on aligning cost with benefit while ensuring patient access to potentially life-extending therapies and continued innovation in drug development.
 

Q: Aside from the policy options, what’s the role of the oncologist in discussing the value of drugs with patients when determining a treatment plan?

A: Since oncologists don’t control drug prices, our role in improving the value of cancer care involves appropriately managing how resources are used and guiding patients during discussions around the right treatment plan for their particular diagnosis, prognosis, and treatment goals.

Adopting and adhering to high-quality oncology clinical pathways is an important way to improve the quality, efficiency, and value of cancer care. High-quality oncology pathways are detailed, evidence-based treatment protocols for delivering cancer care to patients with specific disease types and stages. When properly designed and implemented, oncology pathways serve as an important tool in appropriately managing cancer care resources and improving the quality of care that patients with cancer receive, while also reducing costs.
 

Dr. Schilsky is the senior vice president and chief medical officer of ASCO. Formerly the chief of hematology/oncology in the department of medicine and deputy director of the University of Chicago Comprehensive Cancer Center, he is a leader in the field of clinical oncology, specializing in new drug development and the treatment of gastrointestinal cancers. Dr. Schilsky reported research funding from several pharmaceutical companies to ASCO for the Targeted Agent and Profiling Utilization Registry (TAPUR) clinical trial. He also reported travel/accommodation/expense support from Varian.

Skyrocketing drug costs are a key issue facing physicians, patients, and policymakers, but an even thornier problem may be determining a drug’s value.

In this Q&A, Richard L. Schilsky, MD, senior vice president and chief medical officer at the American Society of Clinical Oncology (ASCO), weighs in on the value proposition for cancer drugs and the implications for physicians.
 

Q: What tools exist for determining a drug’s value?

A: A number of organizations have developed tools to try to determine the value of cancer drug treatments. ASCO, the European Society for Medical Oncology (ESMO), the Institute for Clinical and Economic Review, Memorial Sloan Kettering Cancer Center, and the National Comprehensive Cancer Network have all developed tools for this purpose.

Our tool, the ASCO Value Framework, assesses the value of new cancer drug treatments based on clinical benefit, side effects, and improvements in patient symptoms or quality of life in the context of cost. While it’s hard to directly compare frameworks – given differences in methodology and the many nuances of evaluating clinical trial results – in 2018, ASCO and ESMO published a joint analysis of our value frameworks in the Journal of Clinical Oncology (2018; 37[4]:336-49).

The analysis found that the frameworks produce comparable measures of the clinical benefits of new therapies in approximately two-thirds of the more than 100 treatment comparisons that were examined. It also identified a number of factors that may contribute to the discordant scores, revealing potential ways for both of our organizations to refine our frameworks in the future.

That said, ASCO’s Value Framework is just one part of our broader, multifaceted effort to achieve high-quality, high-value care for all patients with cancer. Other efforts include ASCO’s proposed Patient-Centered Oncology Payment model, the Choosing Wisely campaign to identify low-value clinical strategies, and CancerLinQ and the Quality Oncology Practice Initiative to implement quality measurement and improvement.
 

Q: How can the issues around drug price and value be addressed earlier in the context of clinical trials?

A: The definition of value ultimately comes down to the price that must be paid to achieve meaningfully improved health outcomes for individual patients or the broader population of affected individuals. Optimizing the value of a new cancer drug treatment begins with an innovation to address an unmet medical need, followed by defining and achieving clinically meaningful improvements in health outcomes through well-designed and efficiently conducted clinical trials. Effectiveness research is also essential to determining how well new treatments perform compared with available alternatives and how they perform in more diverse populations than those typically included in the clinical trials used to establish efficacy.

Patient goals, preferences, and choices shape the real-world experience of a new product, and the direct and indirect costs of a treatment to patients and their families significantly affect whether it is adopted widely. Until their value is clearly established, new and costly products should be deployed judiciously and after careful consideration of the goals of treatment, available options, and the unique needs, preferences, and goals of individual patients.

More research is needed to improve how we assess the value of new cancer drug treatments. New clinical efficacy endpoints – both provider- and patient-reported ones – that accurately describe how a patient feels and functions must be developed and should reflect outcomes of value to patients other than survival, particularly in noncurative settings.

Better predictive biomarkers can transform a drug of modest efficacy in an unselected population to one of high efficacy in a biomarker-defined subgroup and thereby contribute to improving the value of a treatment.

Regulatory and policy initiatives such as adaptive licensing, value-based insurance, and indication-specific pricing that affect marketing approval, reimbursement, or price, respectively, based on treatment effectiveness, also deserve careful consideration and further research to determine their effects on aligning cost with benefit while ensuring patient access to potentially life-extending therapies and continued innovation in drug development.
 

Q: Aside from the policy options, what’s the role of the oncologist in discussing the value of drugs with patients when determining a treatment plan?

A: Since oncologists don’t control drug prices, our role in improving the value of cancer care involves appropriately managing how resources are used and guiding patients during discussions around the right treatment plan for their particular diagnosis, prognosis, and treatment goals.

Adopting and adhering to high-quality oncology clinical pathways is an important way to improve the quality, efficiency, and value of cancer care. High-quality oncology pathways are detailed, evidence-based treatment protocols for delivering cancer care to patients with specific disease types and stages. When properly designed and implemented, oncology pathways serve as an important tool in appropriately managing cancer care resources and improving the quality of care that patients with cancer receive, while also reducing costs.
 

Dr. Schilsky is the senior vice president and chief medical officer of ASCO. Formerly the chief of hematology/oncology in the department of medicine and deputy director of the University of Chicago Comprehensive Cancer Center, he is a leader in the field of clinical oncology, specializing in new drug development and the treatment of gastrointestinal cancers. Dr. Schilsky reported research funding from several pharmaceutical companies to ASCO for the Targeted Agent and Profiling Utilization Registry (TAPUR) clinical trial. He also reported travel/accommodation/expense support from Varian.

Skyrocketing drug costs are a key issue facing physicians, patients, and policymakers, but an even thornier problem may be determining a drug’s value.

In this Q&A, Richard L. Schilsky, MD, senior vice president and chief medical officer at the American Society of Clinical Oncology (ASCO), weighs in on the value proposition for cancer drugs and the implications for physicians.
 

Q: What tools exist for determining a drug’s value?

A: A number of organizations have developed tools to try to determine the value of cancer drug treatments. ASCO, the European Society for Medical Oncology (ESMO), the Institute for Clinical and Economic Review, Memorial Sloan Kettering Cancer Center, and the National Comprehensive Cancer Network have all developed tools for this purpose.

Our tool, the ASCO Value Framework, assesses the value of new cancer drug treatments based on clinical benefit, side effects, and improvements in patient symptoms or quality of life in the context of cost. While it’s hard to directly compare frameworks – given differences in methodology and the many nuances of evaluating clinical trial results – in 2018, ASCO and ESMO published a joint analysis of our value frameworks in the Journal of Clinical Oncology (2018; 37[4]:336-49).

The analysis found that the frameworks produce comparable measures of the clinical benefits of new therapies in approximately two-thirds of the more than 100 treatment comparisons that were examined. It also identified a number of factors that may contribute to the discordant scores, revealing potential ways for both of our organizations to refine our frameworks in the future.

That said, ASCO’s Value Framework is just one part of our broader, multifaceted effort to achieve high-quality, high-value care for all patients with cancer. Other efforts include ASCO’s proposed Patient-Centered Oncology Payment model, the Choosing Wisely campaign to identify low-value clinical strategies, and CancerLinQ and the Quality Oncology Practice Initiative to implement quality measurement and improvement.
 

Q: How can the issues around drug price and value be addressed earlier in the context of clinical trials?

A: The definition of value ultimately comes down to the price that must be paid to achieve meaningfully improved health outcomes for individual patients or the broader population of affected individuals. Optimizing the value of a new cancer drug treatment begins with an innovation to address an unmet medical need, followed by defining and achieving clinically meaningful improvements in health outcomes through well-designed and efficiently conducted clinical trials. Effectiveness research is also essential to determining how well new treatments perform compared with available alternatives and how they perform in more diverse populations than those typically included in the clinical trials used to establish efficacy.

Patient goals, preferences, and choices shape the real-world experience of a new product, and the direct and indirect costs of a treatment to patients and their families significantly affect whether it is adopted widely. Until their value is clearly established, new and costly products should be deployed judiciously and after careful consideration of the goals of treatment, available options, and the unique needs, preferences, and goals of individual patients.

More research is needed to improve how we assess the value of new cancer drug treatments. New clinical efficacy endpoints – both provider- and patient-reported ones – that accurately describe how a patient feels and functions must be developed and should reflect outcomes of value to patients other than survival, particularly in noncurative settings.

Better predictive biomarkers can transform a drug of modest efficacy in an unselected population to one of high efficacy in a biomarker-defined subgroup and thereby contribute to improving the value of a treatment.

Regulatory and policy initiatives such as adaptive licensing, value-based insurance, and indication-specific pricing that affect marketing approval, reimbursement, or price, respectively, based on treatment effectiveness, also deserve careful consideration and further research to determine their effects on aligning cost with benefit while ensuring patient access to potentially life-extending therapies and continued innovation in drug development.
 

Q: Aside from the policy options, what’s the role of the oncologist in discussing the value of drugs with patients when determining a treatment plan?

A: Since oncologists don’t control drug prices, our role in improving the value of cancer care involves appropriately managing how resources are used and guiding patients during discussions around the right treatment plan for their particular diagnosis, prognosis, and treatment goals.

Adopting and adhering to high-quality oncology clinical pathways is an important way to improve the quality, efficiency, and value of cancer care. High-quality oncology pathways are detailed, evidence-based treatment protocols for delivering cancer care to patients with specific disease types and stages. When properly designed and implemented, oncology pathways serve as an important tool in appropriately managing cancer care resources and improving the quality of care that patients with cancer receive, while also reducing costs.
 

Dr. Schilsky is the senior vice president and chief medical officer of ASCO. Formerly the chief of hematology/oncology in the department of medicine and deputy director of the University of Chicago Comprehensive Cancer Center, he is a leader in the field of clinical oncology, specializing in new drug development and the treatment of gastrointestinal cancers. Dr. Schilsky reported research funding from several pharmaceutical companies to ASCO for the Targeted Agent and Profiling Utilization Registry (TAPUR) clinical trial. He also reported travel/accommodation/expense support from Varian.

Researchers are leading several studies designed to improve hematopoietic stem cell transplantation (HSCT) for patients with sickle cell disease (SCD), experts at the National Heart, Lung, and Blood Institute reported during a recent webinar.

bubaone/DigitalVision Vectors

“HSCT offers a potential cure [for SCD], which may improve quantity and quality of life [for patients],” said Courtney D. Fitzhugh, MD, a Lasker Clinical Research Scholar in the Laboratory of Early Sickle Mortality Prevention at NHLBI.

Currently, HLA-matched sibling and matched unrelated donor sources provide the best outcomes for sickle cell patients undergoing allogeneic HSCT, she explained. Alternative stem cell sources include umbilical cord blood and haploidentical donors.

Over the past 2 years, the majority of novel transplant techniques have been primarily aimed at improving conditioning regimens and lowering rates of graft-versus-host disease (GVHD).
 

Recent evidence

A recent international survey found high survival rates in patients with SCD who underwent HLA-matched sibling HSCT during 1986-2013. At 5-years, overall- and event-free survival rates were 92.9% and 91.4%, respectively, with even higher rates (95% and 93%) seen in children aged younger than 16 years.

With respect to safety, the cumulative incidence rates of acute and chronic GVHD were 14.8% and 14.3%, Dr. Fitzhugh reported.

Much of the success seen with HLA-matched sibling donors is attributable to recent data demonstrating that complete transformation of patient’s bone marrow is unnecessary to illicit a curative effect.

With donor myeloid chimerism levels of at least 20%, the sickle disease phenotype can be reversed, and there’s a reduced risk of GVHD, she said.

In mouse models, researchers have found that inclusion of sirolimus in HLA-matched pretransplant conditioning regimens leads to higher levels of donor cell engraftment. As a result, some conditioning regimens now administer sirolimus (target 10-15 ng/dL) one-day prior to transplantation.

In 55 patients transplanted using this technique, overall- and event-free survival rates of 93% and 87% have been reported, with no transplant-related mortality or evidence of GVHD. Other institutions have also begun to adopt this technique, and have reported similar findings, Dr. Fitzhugh reported.

“When you [administer high-dose] chemotherapy, you don’t expect that patients are able to have children, but we are excited to report that 8 of our patients have had 13 healthy babies post transplant,” Dr. Fitzhugh said.

As a whole, several recent studies have emphasized the importance of the conditioning regimen in successful transplantation for patients with SCD.

With HLA-matched sibling donors, myeloablative regimens that include antithymocyte globulin have demonstrated greater efficacy, she said.

In patients receiving a transplant from a matched unrelated donor, early use of alemtuzumab is linked to higher rates of GVHD, while ongoing studies are exploring whether abatacept reduces the risk of GVHD, she further explained.

With respect to haploidentical and unrelated umbilical cord donors, T-cell depletion and higher-intensity conditioning have been shown to reduce graft rejection rates, she said.

Dr. Fitzhugh acknowledged that long-term efficacy and safety of these novel conditioning regimens is largely unknown. Thus, ongoing follow-up is essential to monitor for potential late effects.
 

NHLBI-funded trials

Nancy L. DiFronzo, PhD, program director at NHLBI, explained that the agency has funded specific clinical studies evaluating allogeneic HSCT in patients with severe SCD.

“[Surprisingly], this treatment modality is [actually] quite rare, with [only] approximately 9,000 allogeneic transplants occurring in the United States each year,” she said.

One of the primary barriers to HSCT for SCD is a lack of compatible donors. Currently, fewer than 20% of sickle cell patients have a matched unrelated donor or HLA-matched sibling donor, she reported.

Another common barrier are the risks associated with the procedure, including treatment-related toxicities and death. Active participation in a clinical trial is one strategy that can mitigate these risks, she said.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is a group of transplant centers that are recognized experts in HSCT. Dr. DiFronzo explained that the consortium is cosponsored by the National Cancer Institute and NHLBI, with the goal of improving outcomes for both pediatric and adult patients with SCD undergoing HSCT.

At present, the BMT CTN has directly funded three multicenter clinical studies for SCD, including the SCURT study, which has now been completed, as well as the STRIDE2 and Haploidentical HCT trials, both of which are currently enrolling patients.

“The goal of these new approaches [being studied in these 3 trials] is cure, where individuals can live longer with a better quality of life,” Dr. DiFronzo said. “We’ve [specifically] adjusted regimens with [this goal] in mind.”

Dr. Fitzhugh and Dr. DiFronzo did not provide information on financial disclosures.

Researchers are leading several studies designed to improve hematopoietic stem cell transplantation (HSCT) for patients with sickle cell disease (SCD), experts at the National Heart, Lung, and Blood Institute reported during a recent webinar.

bubaone/DigitalVision Vectors

“HSCT offers a potential cure [for SCD], which may improve quantity and quality of life [for patients],” said Courtney D. Fitzhugh, MD, a Lasker Clinical Research Scholar in the Laboratory of Early Sickle Mortality Prevention at NHLBI.

Currently, HLA-matched sibling and matched unrelated donor sources provide the best outcomes for sickle cell patients undergoing allogeneic HSCT, she explained. Alternative stem cell sources include umbilical cord blood and haploidentical donors.

Over the past 2 years, the majority of novel transplant techniques have been primarily aimed at improving conditioning regimens and lowering rates of graft-versus-host disease (GVHD).
 

Recent evidence

A recent international survey found high survival rates in patients with SCD who underwent HLA-matched sibling HSCT during 1986-2013. At 5-years, overall- and event-free survival rates were 92.9% and 91.4%, respectively, with even higher rates (95% and 93%) seen in children aged younger than 16 years.

With respect to safety, the cumulative incidence rates of acute and chronic GVHD were 14.8% and 14.3%, Dr. Fitzhugh reported.

Much of the success seen with HLA-matched sibling donors is attributable to recent data demonstrating that complete transformation of patient’s bone marrow is unnecessary to illicit a curative effect.

With donor myeloid chimerism levels of at least 20%, the sickle disease phenotype can be reversed, and there’s a reduced risk of GVHD, she said.

In mouse models, researchers have found that inclusion of sirolimus in HLA-matched pretransplant conditioning regimens leads to higher levels of donor cell engraftment. As a result, some conditioning regimens now administer sirolimus (target 10-15 ng/dL) one-day prior to transplantation.

In 55 patients transplanted using this technique, overall- and event-free survival rates of 93% and 87% have been reported, with no transplant-related mortality or evidence of GVHD. Other institutions have also begun to adopt this technique, and have reported similar findings, Dr. Fitzhugh reported.

“When you [administer high-dose] chemotherapy, you don’t expect that patients are able to have children, but we are excited to report that 8 of our patients have had 13 healthy babies post transplant,” Dr. Fitzhugh said.

As a whole, several recent studies have emphasized the importance of the conditioning regimen in successful transplantation for patients with SCD.

With HLA-matched sibling donors, myeloablative regimens that include antithymocyte globulin have demonstrated greater efficacy, she said.

In patients receiving a transplant from a matched unrelated donor, early use of alemtuzumab is linked to higher rates of GVHD, while ongoing studies are exploring whether abatacept reduces the risk of GVHD, she further explained.

With respect to haploidentical and unrelated umbilical cord donors, T-cell depletion and higher-intensity conditioning have been shown to reduce graft rejection rates, she said.

Dr. Fitzhugh acknowledged that long-term efficacy and safety of these novel conditioning regimens is largely unknown. Thus, ongoing follow-up is essential to monitor for potential late effects.
 

NHLBI-funded trials

Nancy L. DiFronzo, PhD, program director at NHLBI, explained that the agency has funded specific clinical studies evaluating allogeneic HSCT in patients with severe SCD.

“[Surprisingly], this treatment modality is [actually] quite rare, with [only] approximately 9,000 allogeneic transplants occurring in the United States each year,” she said.

One of the primary barriers to HSCT for SCD is a lack of compatible donors. Currently, fewer than 20% of sickle cell patients have a matched unrelated donor or HLA-matched sibling donor, she reported.

Another common barrier are the risks associated with the procedure, including treatment-related toxicities and death. Active participation in a clinical trial is one strategy that can mitigate these risks, she said.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is a group of transplant centers that are recognized experts in HSCT. Dr. DiFronzo explained that the consortium is cosponsored by the National Cancer Institute and NHLBI, with the goal of improving outcomes for both pediatric and adult patients with SCD undergoing HSCT.

At present, the BMT CTN has directly funded three multicenter clinical studies for SCD, including the SCURT study, which has now been completed, as well as the STRIDE2 and Haploidentical HCT trials, both of which are currently enrolling patients.

“The goal of these new approaches [being studied in these 3 trials] is cure, where individuals can live longer with a better quality of life,” Dr. DiFronzo said. “We’ve [specifically] adjusted regimens with [this goal] in mind.”

Dr. Fitzhugh and Dr. DiFronzo did not provide information on financial disclosures.

Researchers are leading several studies designed to improve hematopoietic stem cell transplantation (HSCT) for patients with sickle cell disease (SCD), experts at the National Heart, Lung, and Blood Institute reported during a recent webinar.

bubaone/DigitalVision Vectors

“HSCT offers a potential cure [for SCD], which may improve quantity and quality of life [for patients],” said Courtney D. Fitzhugh, MD, a Lasker Clinical Research Scholar in the Laboratory of Early Sickle Mortality Prevention at NHLBI.

Currently, HLA-matched sibling and matched unrelated donor sources provide the best outcomes for sickle cell patients undergoing allogeneic HSCT, she explained. Alternative stem cell sources include umbilical cord blood and haploidentical donors.

Over the past 2 years, the majority of novel transplant techniques have been primarily aimed at improving conditioning regimens and lowering rates of graft-versus-host disease (GVHD).
 

Recent evidence

A recent international survey found high survival rates in patients with SCD who underwent HLA-matched sibling HSCT during 1986-2013. At 5-years, overall- and event-free survival rates were 92.9% and 91.4%, respectively, with even higher rates (95% and 93%) seen in children aged younger than 16 years.

With respect to safety, the cumulative incidence rates of acute and chronic GVHD were 14.8% and 14.3%, Dr. Fitzhugh reported.

Much of the success seen with HLA-matched sibling donors is attributable to recent data demonstrating that complete transformation of patient’s bone marrow is unnecessary to illicit a curative effect.

With donor myeloid chimerism levels of at least 20%, the sickle disease phenotype can be reversed, and there’s a reduced risk of GVHD, she said.

In mouse models, researchers have found that inclusion of sirolimus in HLA-matched pretransplant conditioning regimens leads to higher levels of donor cell engraftment. As a result, some conditioning regimens now administer sirolimus (target 10-15 ng/dL) one-day prior to transplantation.

In 55 patients transplanted using this technique, overall- and event-free survival rates of 93% and 87% have been reported, with no transplant-related mortality or evidence of GVHD. Other institutions have also begun to adopt this technique, and have reported similar findings, Dr. Fitzhugh reported.

“When you [administer high-dose] chemotherapy, you don’t expect that patients are able to have children, but we are excited to report that 8 of our patients have had 13 healthy babies post transplant,” Dr. Fitzhugh said.

As a whole, several recent studies have emphasized the importance of the conditioning regimen in successful transplantation for patients with SCD.

With HLA-matched sibling donors, myeloablative regimens that include antithymocyte globulin have demonstrated greater efficacy, she said.

In patients receiving a transplant from a matched unrelated donor, early use of alemtuzumab is linked to higher rates of GVHD, while ongoing studies are exploring whether abatacept reduces the risk of GVHD, she further explained.

With respect to haploidentical and unrelated umbilical cord donors, T-cell depletion and higher-intensity conditioning have been shown to reduce graft rejection rates, she said.

Dr. Fitzhugh acknowledged that long-term efficacy and safety of these novel conditioning regimens is largely unknown. Thus, ongoing follow-up is essential to monitor for potential late effects.
 

NHLBI-funded trials

Nancy L. DiFronzo, PhD, program director at NHLBI, explained that the agency has funded specific clinical studies evaluating allogeneic HSCT in patients with severe SCD.

“[Surprisingly], this treatment modality is [actually] quite rare, with [only] approximately 9,000 allogeneic transplants occurring in the United States each year,” she said.

One of the primary barriers to HSCT for SCD is a lack of compatible donors. Currently, fewer than 20% of sickle cell patients have a matched unrelated donor or HLA-matched sibling donor, she reported.

Another common barrier are the risks associated with the procedure, including treatment-related toxicities and death. Active participation in a clinical trial is one strategy that can mitigate these risks, she said.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is a group of transplant centers that are recognized experts in HSCT. Dr. DiFronzo explained that the consortium is cosponsored by the National Cancer Institute and NHLBI, with the goal of improving outcomes for both pediatric and adult patients with SCD undergoing HSCT.

At present, the BMT CTN has directly funded three multicenter clinical studies for SCD, including the SCURT study, which has now been completed, as well as the STRIDE2 and Haploidentical HCT trials, both of which are currently enrolling patients.

“The goal of these new approaches [being studied in these 3 trials] is cure, where individuals can live longer with a better quality of life,” Dr. DiFronzo said. “We’ve [specifically] adjusted regimens with [this goal] in mind.”

Dr. Fitzhugh and Dr. DiFronzo did not provide information on financial disclosures.

Background: Anemia is common in hospitalized patients and is associated with short- and long-term morbidity and mortality. Current evidence shows that reduced red blood cell (RBC) use and more restrictive transfusion practices do not increase short-term mortality; however, few data exist on the long-term outcomes of anemia.

Given the retrospective design of this study, data must be interpreted with caution in determining a causal relationship. The authors also acknowledge that there may be unmeasured confounding variables not accounted for in the study results.

Bottom line: Despite higher rates of moderate anemia at discharge, there was not an associated rise in subsequent RBC transfusions, readmissions, or mortality in the 6 months after hospital discharge.

Citation: Roubinian NH et al. Long-term outcomes among patients discharged from the hospital with moderate anemia: A retrospective cohort study. Ann Intern Med. 2019 Jan 14. doi: 10.7326/M17-3253.

Dr. Schmit is an associate professor of medicine in the division of general and hospital medicine at UT Health San Antonio and a hospitalist at South Texas Veterans Health Care System, also in San Antonio.

Background: Anemia is common in hospitalized patients and is associated with short- and long-term morbidity and mortality. Current evidence shows that reduced red blood cell (RBC) use and more restrictive transfusion practices do not increase short-term mortality; however, few data exist on the long-term outcomes of anemia.

Given the retrospective design of this study, data must be interpreted with caution in determining a causal relationship. The authors also acknowledge that there may be unmeasured confounding variables not accounted for in the study results.

Bottom line: Despite higher rates of moderate anemia at discharge, there was not an associated rise in subsequent RBC transfusions, readmissions, or mortality in the 6 months after hospital discharge.

Citation: Roubinian NH et al. Long-term outcomes among patients discharged from the hospital with moderate anemia: A retrospective cohort study. Ann Intern Med. 2019 Jan 14. doi: 10.7326/M17-3253.

Dr. Schmit is an associate professor of medicine in the division of general and hospital medicine at UT Health San Antonio and a hospitalist at South Texas Veterans Health Care System, also in San Antonio.

Background: Anemia is common in hospitalized patients and is associated with short- and long-term morbidity and mortality. Current evidence shows that reduced red blood cell (RBC) use and more restrictive transfusion practices do not increase short-term mortality; however, few data exist on the long-term outcomes of anemia.

Given the retrospective design of this study, data must be interpreted with caution in determining a causal relationship. The authors also acknowledge that there may be unmeasured confounding variables not accounted for in the study results.

Bottom line: Despite higher rates of moderate anemia at discharge, there was not an associated rise in subsequent RBC transfusions, readmissions, or mortality in the 6 months after hospital discharge.

Citation: Roubinian NH et al. Long-term outcomes among patients discharged from the hospital with moderate anemia: A retrospective cohort study. Ann Intern Med. 2019 Jan 14. doi: 10.7326/M17-3253.

Dr. Schmit is an associate professor of medicine in the division of general and hospital medicine at UT Health San Antonio and a hospitalist at South Texas Veterans Health Care System, also in San Antonio.

HIV positivity does not preclude chimeric antigen receptor (CAR) T-cell therapy for patients with aggressive lymphoma, a report of two cases suggests. Both of the HIV-positive patients, one of whom had long-term psychiatric comorbidity, achieved durable remission on axicabtagene ciloleucel (Yescarta) without undue toxicity.

Cynthia Goldsmith, CDC

“To our knowledge, these are the first reported cases of CAR T-cell therapy administered to HIV-infected patients with lymphoma,” Jeremy S. Abramson, MD, of Massachusetts General Hospital, Boston and his colleagues wrote in Cancer. “Patients with HIV and AIDS, as well as those with preexisting mental illness, should not be considered disqualified from CAR T-cell therapy and deserve ongoing studies to optimize efficacy and safety in this population.”

The Food and Drug Administration has approved two CAR T-cell products that target the B-cell antigen CD19 for the treatment of refractory lymphoma. But their efficacy and safety in HIV-positive patients are unknown because this group has been excluded from pivotal clinical trials.

Dr. Abramson and coauthors detail the two cases of successful anti-CD19 CAR T-cell therapy with axicabtagene ciloleucel in patients with HIV-associated, refractory, high-grade B-cell lymphoma.

The first patient was an HIV-positive man with diffuse large B-cell lymphoma (DLBCL) of germinal center B-cell subtype who was intermittently adherent to antiretroviral therapy. His comorbidities included posttraumatic stress disorder and schizoaffective disorder.

Previous treatments for DLBCL included dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), and rituximab, ifosfamide, carboplatin, and etoposide (RICE). A recurrence precluded high-dose chemotherapy with autologous stem cell support.

With close multidisciplinary management, including psychiatric consultation, the patient became a candidate for CAR T-cell therapy and received axicabtagene ciloleucel. He experienced grade 2 cytokine release syndrome and grade 3 neurologic toxicity, both of which resolved with treatment. Imaging showed complete remission at approximately 3 months that was sustained at 1 year. Additionally, he had an undetectable HIV viral load and was psychiatrically stable.

The second patient was a man with AIDS-associated, non–germinal center B-cell, Epstein-Barr virus–positive DLBCL who was adherent to antiretroviral therapy. His lymphoma had recurred rapidly after initially responding to dose-adjusted EPOCH-R and then was refractory to combination rituximab and lenalidomide. He previously had hepatitis B virus, cytomegalovirus, and Mycobacterium avium complex infections.

Because of prolonged cytopenias and infectious complications after the previous lymphoma treatments, the patient was considered a poor candidate for high-dose chemotherapy. He underwent CAR T-cell therapy with axicabtagene ciloleucel and had a complete remission on day 28. Additionally, his HIV infection remained well controlled.

“Although much remains to be learned regarding CAR T-cell therapy in patients with refractory hematologic malignancies, with or without HIV infection, the cases presented herein demonstrate that patients with chemotherapy-refractory, high-grade B-cell lymphoma can successfully undergo autologous CAR T-cell manufacturing, and subsequently can safely tolerate CAR T-cell therapy and achieve a durable complete remission,” the researchers wrote. “These cases have further demonstrated the proactive, multidisciplinary care required to navigate a patient with high-risk lymphoma through CAR T-cell therapy with attention to significant medical and psychiatric comorbidities.”

Dr. Abramson reported that he has acted as a paid member of the scientific advisory board and as a paid consultant for Kite Pharma, which markets Yescarta, and several other companies.

SOURCE: Abramson JS et al. Cancer. 2019 Sep 10. doi: 10.1002/cncr.32411.

HIV positivity does not preclude chimeric antigen receptor (CAR) T-cell therapy for patients with aggressive lymphoma, a report of two cases suggests. Both of the HIV-positive patients, one of whom had long-term psychiatric comorbidity, achieved durable remission on axicabtagene ciloleucel (Yescarta) without undue toxicity.

Cynthia Goldsmith, CDC

“To our knowledge, these are the first reported cases of CAR T-cell therapy administered to HIV-infected patients with lymphoma,” Jeremy S. Abramson, MD, of Massachusetts General Hospital, Boston and his colleagues wrote in Cancer. “Patients with HIV and AIDS, as well as those with preexisting mental illness, should not be considered disqualified from CAR T-cell therapy and deserve ongoing studies to optimize efficacy and safety in this population.”

The Food and Drug Administration has approved two CAR T-cell products that target the B-cell antigen CD19 for the treatment of refractory lymphoma. But their efficacy and safety in HIV-positive patients are unknown because this group has been excluded from pivotal clinical trials.

Dr. Abramson and coauthors detail the two cases of successful anti-CD19 CAR T-cell therapy with axicabtagene ciloleucel in patients with HIV-associated, refractory, high-grade B-cell lymphoma.

The first patient was an HIV-positive man with diffuse large B-cell lymphoma (DLBCL) of germinal center B-cell subtype who was intermittently adherent to antiretroviral therapy. His comorbidities included posttraumatic stress disorder and schizoaffective disorder.

Previous treatments for DLBCL included dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), and rituximab, ifosfamide, carboplatin, and etoposide (RICE). A recurrence precluded high-dose chemotherapy with autologous stem cell support.

With close multidisciplinary management, including psychiatric consultation, the patient became a candidate for CAR T-cell therapy and received axicabtagene ciloleucel. He experienced grade 2 cytokine release syndrome and grade 3 neurologic toxicity, both of which resolved with treatment. Imaging showed complete remission at approximately 3 months that was sustained at 1 year. Additionally, he had an undetectable HIV viral load and was psychiatrically stable.

The second patient was a man with AIDS-associated, non–germinal center B-cell, Epstein-Barr virus–positive DLBCL who was adherent to antiretroviral therapy. His lymphoma had recurred rapidly after initially responding to dose-adjusted EPOCH-R and then was refractory to combination rituximab and lenalidomide. He previously had hepatitis B virus, cytomegalovirus, and Mycobacterium avium complex infections.

Because of prolonged cytopenias and infectious complications after the previous lymphoma treatments, the patient was considered a poor candidate for high-dose chemotherapy. He underwent CAR T-cell therapy with axicabtagene ciloleucel and had a complete remission on day 28. Additionally, his HIV infection remained well controlled.

“Although much remains to be learned regarding CAR T-cell therapy in patients with refractory hematologic malignancies, with or without HIV infection, the cases presented herein demonstrate that patients with chemotherapy-refractory, high-grade B-cell lymphoma can successfully undergo autologous CAR T-cell manufacturing, and subsequently can safely tolerate CAR T-cell therapy and achieve a durable complete remission,” the researchers wrote. “These cases have further demonstrated the proactive, multidisciplinary care required to navigate a patient with high-risk lymphoma through CAR T-cell therapy with attention to significant medical and psychiatric comorbidities.”

Dr. Abramson reported that he has acted as a paid member of the scientific advisory board and as a paid consultant for Kite Pharma, which markets Yescarta, and several other companies.

SOURCE: Abramson JS et al. Cancer. 2019 Sep 10. doi: 10.1002/cncr.32411.

HIV positivity does not preclude chimeric antigen receptor (CAR) T-cell therapy for patients with aggressive lymphoma, a report of two cases suggests. Both of the HIV-positive patients, one of whom had long-term psychiatric comorbidity, achieved durable remission on axicabtagene ciloleucel (Yescarta) without undue toxicity.

Cynthia Goldsmith, CDC

“To our knowledge, these are the first reported cases of CAR T-cell therapy administered to HIV-infected patients with lymphoma,” Jeremy S. Abramson, MD, of Massachusetts General Hospital, Boston and his colleagues wrote in Cancer. “Patients with HIV and AIDS, as well as those with preexisting mental illness, should not be considered disqualified from CAR T-cell therapy and deserve ongoing studies to optimize efficacy and safety in this population.”

The Food and Drug Administration has approved two CAR T-cell products that target the B-cell antigen CD19 for the treatment of refractory lymphoma. But their efficacy and safety in HIV-positive patients are unknown because this group has been excluded from pivotal clinical trials.

Dr. Abramson and coauthors detail the two cases of successful anti-CD19 CAR T-cell therapy with axicabtagene ciloleucel in patients with HIV-associated, refractory, high-grade B-cell lymphoma.

The first patient was an HIV-positive man with diffuse large B-cell lymphoma (DLBCL) of germinal center B-cell subtype who was intermittently adherent to antiretroviral therapy. His comorbidities included posttraumatic stress disorder and schizoaffective disorder.

Previous treatments for DLBCL included dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), and rituximab, ifosfamide, carboplatin, and etoposide (RICE). A recurrence precluded high-dose chemotherapy with autologous stem cell support.

With close multidisciplinary management, including psychiatric consultation, the patient became a candidate for CAR T-cell therapy and received axicabtagene ciloleucel. He experienced grade 2 cytokine release syndrome and grade 3 neurologic toxicity, both of which resolved with treatment. Imaging showed complete remission at approximately 3 months that was sustained at 1 year. Additionally, he had an undetectable HIV viral load and was psychiatrically stable.

The second patient was a man with AIDS-associated, non–germinal center B-cell, Epstein-Barr virus–positive DLBCL who was adherent to antiretroviral therapy. His lymphoma had recurred rapidly after initially responding to dose-adjusted EPOCH-R and then was refractory to combination rituximab and lenalidomide. He previously had hepatitis B virus, cytomegalovirus, and Mycobacterium avium complex infections.

Because of prolonged cytopenias and infectious complications after the previous lymphoma treatments, the patient was considered a poor candidate for high-dose chemotherapy. He underwent CAR T-cell therapy with axicabtagene ciloleucel and had a complete remission on day 28. Additionally, his HIV infection remained well controlled.

“Although much remains to be learned regarding CAR T-cell therapy in patients with refractory hematologic malignancies, with or without HIV infection, the cases presented herein demonstrate that patients with chemotherapy-refractory, high-grade B-cell lymphoma can successfully undergo autologous CAR T-cell manufacturing, and subsequently can safely tolerate CAR T-cell therapy and achieve a durable complete remission,” the researchers wrote. “These cases have further demonstrated the proactive, multidisciplinary care required to navigate a patient with high-risk lymphoma through CAR T-cell therapy with attention to significant medical and psychiatric comorbidities.”

Dr. Abramson reported that he has acted as a paid member of the scientific advisory board and as a paid consultant for Kite Pharma, which markets Yescarta, and several other companies.

SOURCE: Abramson JS et al. Cancer. 2019 Sep 10. doi: 10.1002/cncr.32411.

When on call for admissions, a hospitalist receives a request from a colleague to admit an octogenarian man with an acute uncomplicated deep vein thrombosis to start heparin, bridging to warfarin. The patient has no evidence of postphlebitic syndrome, pulmonary embolism, or right-sided heart strain. The hospitalist asks her colleague if he had considered treating the patient in the ambulatory setting using a direct-acting oral anticoagulant (DOAC). After all, this would save the patient an unnecessary hospitalization, weekly international normalized ratio checks, and other important lifestyle changes. In response, the colleague voices concern that the “new drugs don’t have antidotes.”

DOACs have several benefits over vitamin K antagonists (VKAs) and heparins. DOACs have quicker onset of action, can be taken by mouth, in general do not require dosage adjustment, and have fewer dietary and lifestyle modifications, compared with VKAs and heparins. In atrial fibrillation, DOACs have been shown to have lower all-cause and bleeding-related mortality than warfarin (see Table 1).¹ Observational studies also suggest less risk of major bleeding with DOACs over warfarin but no difference in overall mortality when used to treat venous thromboembolism (see Table 2).² Because of these combined advantages, DOACs are increasingly prescribed, accounting for approximately half of all oral anticoagulant prescriptions in 2014.³

Although DOACs have been shown to be as good if not superior to VKAs and heparins in these circumstances, there are situations where a DOAC should not be used. There is limited data on the safety of DOACs in patients with mechanical heart valves, liver failure, and chronic kidney disease with a creatinine clearance less than 30 mL/min.⁴ Therefore, warfarin is still the preferred agent in these settings. There is some data that apixaban may be safe in patients with a creatinine clearance of greater than 10 mL/min, but long-term safety studies have not been performed in patients with end-stage renal disease on hemodialysis.⁵ Finally, in patients requiring concomitant inducers or inhibitors of the P-glycoprotein or cytochrome P450 enzymes like antiepileptics and protease inhibitors, VKAs and heparins are favored.⁴

Notwithstanding their advantages, when DOACs first hit the market there were concerns that reversal agents were not available. In the August issue of the Journal of Hospital Medicine’s Clinical Guideline Highlights for the Hospitalist, Emily Gottenborg, MD, and Gregory Misky, MD, summarized guideline recommendations for reversal of the newer agents.⁶ This includes use of idarucizumab for patients on dabigatran and use of prothrombin complex concentrate (PCC) or recombinant coagulation factor Xa (andexanet alfa) for patients on apixaban or rivaroxaban for the treatment of life-threatening bleeding.

Idarucizumab is a monoclonal antibody developed to reverse the effects of dabigatran, the only DOAC that directly inhibits thrombin. In 2017, researchers reported on a cohort of subjects receiving idarucizumab for uncontrolled bleeding or who were on dabigatran and about to undergo an urgent procedure.⁷ Of those with uncontrolled bleeding, two-thirds had confirmed bleeding cessation within 24 hours. Periprocedural hemostasis was achieved in 93.4% of patients undergoing urgent procedures. However, it should be noted that use of idarucizumab conferred an increase risk (6.3%) of thrombosis within 90 days. Based on these findings, guidelines recommend use of idarucizumab in patients experiencing life-threatening bleeding, balanced against the risk of thrombosis.⁸

In 2018, the Food and Drug Administration approved recombinant coagulation factor Xa for treatment of life-threatening or uncontrolled bleeding in patients on apixaban or rivaroxaban.⁹ The approval came after a study by the ANNEXA-4 investigators showed that recombinant coagulation factor Xa quickly and effectively achieved hemostasis.¹⁰ Full study results were published in April 2019, demonstrating 82% of patients receiving the drug attained clinical hemostasis.¹¹ However, as with idarucizumab, up to 10% of patients had a thrombotic event in the follow-up period. Use of recombinant coagulation factor Xa for treatment of life-threatening bleeding related to betrixaban and edoxaban is considered off label but is recommended by guidelines.⁸ Studies on investigational reversal agents for betrixaban and edoxaban are ongoing.

Both unactivated and activated PCC contain clotting factor X. Their use to control bleeding related to DOAC use is based on observational studies. In a systematic review of the nonrandomized studies, the efficacy of PCC to stem major bleeding was 69% and the risk for thromboembolism was 4%.¹² There are no head-to-head studies comparing use of recombinant coagulation factor Xa and PCC. Therefore, guidelines are to use either recombinant factor Xa or PCC for the treatment of life-threatening bleeding related to DOAC use.⁷

As thrombosis risk heightens after use of any reversal agent, the recommendations are to resume anticoagulation within 90 days if the patient is at moderate or high risk for recurrent thromboembolism.⁸

After discussion with the hospitalist about the new agents available to reverse anticoagulation, the colleague decided to place the patient on a DOAC and keep the patient in his nursing home. Thankfully, the patient did not thereafter experience sustained bleeding necessitating use of these reversal agents. More importantly for the patient, he was able to stay in the comfort of his home.

Dr. Tuck is associate section chief for hospital medicine at the Veterans Affairs Medical Center in Washington, D.C.

References

1. Gómez-Outes A et al. Causes of death in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2016;68:2508-21.

2. Jun M et al. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population-based, observational study. BMJ. 2017;359:j4323.

3. Barnes GD et al. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128:(1300-5).e2.

4. Reddy P et al. Practical approach to VTE management in hospitalized patients. Am J Ther. 2017;24(4):e442-67.

5. Kimachi M et al. Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease. Cochrane Database Syst Rev. 2017 Nov 6;11:CD011373.

6. Gottenborg E et al. Clinical guideline highlights for the hospitalist: The management of anticoagulation in the hospitalized adult. J Hosp Med. 2019; 14(8):499-500.

7. Pollack CV Jr et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med. 2017;377(5):431-41.

8. Witt DM et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood Adv. 2018;2(22):3257-91.

9. Malarky M et al. FDA accelerated approval letter. Retrieved July 15, 2019. https://www.fda.gov/media/113285/download

10. Connolly SJ et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-41.

11. Connolly SJ et al. Full study report of andexanet alfa for bleeding associated with factor xa inhibitors. N Engl J Med. 2019;380(14):1326-35.

12. Piran S et al. Management of direct factor Xa inhibitor–related major bleeding with prothrombin complex concentrate: A meta-analysis. Blood Adv. 2019;3(2):158-67.

When on call for admissions, a hospitalist receives a request from a colleague to admit an octogenarian man with an acute uncomplicated deep vein thrombosis to start heparin, bridging to warfarin. The patient has no evidence of postphlebitic syndrome, pulmonary embolism, or right-sided heart strain. The hospitalist asks her colleague if he had considered treating the patient in the ambulatory setting using a direct-acting oral anticoagulant (DOAC). After all, this would save the patient an unnecessary hospitalization, weekly international normalized ratio checks, and other important lifestyle changes. In response, the colleague voices concern that the “new drugs don’t have antidotes.”

DOACs have several benefits over vitamin K antagonists (VKAs) and heparins. DOACs have quicker onset of action, can be taken by mouth, in general do not require dosage adjustment, and have fewer dietary and lifestyle modifications, compared with VKAs and heparins. In atrial fibrillation, DOACs have been shown to have lower all-cause and bleeding-related mortality than warfarin (see Table 1).¹ Observational studies also suggest less risk of major bleeding with DOACs over warfarin but no difference in overall mortality when used to treat venous thromboembolism (see Table 2).² Because of these combined advantages, DOACs are increasingly prescribed, accounting for approximately half of all oral anticoagulant prescriptions in 2014.³

Although DOACs have been shown to be as good if not superior to VKAs and heparins in these circumstances, there are situations where a DOAC should not be used. There is limited data on the safety of DOACs in patients with mechanical heart valves, liver failure, and chronic kidney disease with a creatinine clearance less than 30 mL/min.⁴ Therefore, warfarin is still the preferred agent in these settings. There is some data that apixaban may be safe in patients with a creatinine clearance of greater than 10 mL/min, but long-term safety studies have not been performed in patients with end-stage renal disease on hemodialysis.⁵ Finally, in patients requiring concomitant inducers or inhibitors of the P-glycoprotein or cytochrome P450 enzymes like antiepileptics and protease inhibitors, VKAs and heparins are favored.⁴

Notwithstanding their advantages, when DOACs first hit the market there were concerns that reversal agents were not available. In the August issue of the Journal of Hospital Medicine’s Clinical Guideline Highlights for the Hospitalist, Emily Gottenborg, MD, and Gregory Misky, MD, summarized guideline recommendations for reversal of the newer agents.⁶ This includes use of idarucizumab for patients on dabigatran and use of prothrombin complex concentrate (PCC) or recombinant coagulation factor Xa (andexanet alfa) for patients on apixaban or rivaroxaban for the treatment of life-threatening bleeding.

Idarucizumab is a monoclonal antibody developed to reverse the effects of dabigatran, the only DOAC that directly inhibits thrombin. In 2017, researchers reported on a cohort of subjects receiving idarucizumab for uncontrolled bleeding or who were on dabigatran and about to undergo an urgent procedure.⁷ Of those with uncontrolled bleeding, two-thirds had confirmed bleeding cessation within 24 hours. Periprocedural hemostasis was achieved in 93.4% of patients undergoing urgent procedures. However, it should be noted that use of idarucizumab conferred an increase risk (6.3%) of thrombosis within 90 days. Based on these findings, guidelines recommend use of idarucizumab in patients experiencing life-threatening bleeding, balanced against the risk of thrombosis.⁸

In 2018, the Food and Drug Administration approved recombinant coagulation factor Xa for treatment of life-threatening or uncontrolled bleeding in patients on apixaban or rivaroxaban.⁹ The approval came after a study by the ANNEXA-4 investigators showed that recombinant coagulation factor Xa quickly and effectively achieved hemostasis.¹⁰ Full study results were published in April 2019, demonstrating 82% of patients receiving the drug attained clinical hemostasis.¹¹ However, as with idarucizumab, up to 10% of patients had a thrombotic event in the follow-up period. Use of recombinant coagulation factor Xa for treatment of life-threatening bleeding related to betrixaban and edoxaban is considered off label but is recommended by guidelines.⁸ Studies on investigational reversal agents for betrixaban and edoxaban are ongoing.

Both unactivated and activated PCC contain clotting factor X. Their use to control bleeding related to DOAC use is based on observational studies. In a systematic review of the nonrandomized studies, the efficacy of PCC to stem major bleeding was 69% and the risk for thromboembolism was 4%.¹² There are no head-to-head studies comparing use of recombinant coagulation factor Xa and PCC. Therefore, guidelines are to use either recombinant factor Xa or PCC for the treatment of life-threatening bleeding related to DOAC use.⁷

As thrombosis risk heightens after use of any reversal agent, the recommendations are to resume anticoagulation within 90 days if the patient is at moderate or high risk for recurrent thromboembolism.⁸

After discussion with the hospitalist about the new agents available to reverse anticoagulation, the colleague decided to place the patient on a DOAC and keep the patient in his nursing home. Thankfully, the patient did not thereafter experience sustained bleeding necessitating use of these reversal agents. More importantly for the patient, he was able to stay in the comfort of his home.

Dr. Tuck is associate section chief for hospital medicine at the Veterans Affairs Medical Center in Washington, D.C.

References

1. Gómez-Outes A et al. Causes of death in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2016;68:2508-21.

2. Jun M et al. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population-based, observational study. BMJ. 2017;359:j4323.

3. Barnes GD et al. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128:(1300-5).e2.

4. Reddy P et al. Practical approach to VTE management in hospitalized patients. Am J Ther. 2017;24(4):e442-67.

5. Kimachi M et al. Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease. Cochrane Database Syst Rev. 2017 Nov 6;11:CD011373.

6. Gottenborg E et al. Clinical guideline highlights for the hospitalist: The management of anticoagulation in the hospitalized adult. J Hosp Med. 2019; 14(8):499-500.

7. Pollack CV Jr et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med. 2017;377(5):431-41.

8. Witt DM et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood Adv. 2018;2(22):3257-91.

9. Malarky M et al. FDA accelerated approval letter. Retrieved July 15, 2019. https://www.fda.gov/media/113285/download

10. Connolly SJ et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-41.

11. Connolly SJ et al. Full study report of andexanet alfa for bleeding associated with factor xa inhibitors. N Engl J Med. 2019;380(14):1326-35.

12. Piran S et al. Management of direct factor Xa inhibitor–related major bleeding with prothrombin complex concentrate: A meta-analysis. Blood Adv. 2019;3(2):158-67.

When on call for admissions, a hospitalist receives a request from a colleague to admit an octogenarian man with an acute uncomplicated deep vein thrombosis to start heparin, bridging to warfarin. The patient has no evidence of postphlebitic syndrome, pulmonary embolism, or right-sided heart strain. The hospitalist asks her colleague if he had considered treating the patient in the ambulatory setting using a direct-acting oral anticoagulant (DOAC). After all, this would save the patient an unnecessary hospitalization, weekly international normalized ratio checks, and other important lifestyle changes. In response, the colleague voices concern that the “new drugs don’t have antidotes.”

DOACs have several benefits over vitamin K antagonists (VKAs) and heparins. DOACs have quicker onset of action, can be taken by mouth, in general do not require dosage adjustment, and have fewer dietary and lifestyle modifications, compared with VKAs and heparins. In atrial fibrillation, DOACs have been shown to have lower all-cause and bleeding-related mortality than warfarin (see Table 1).¹ Observational studies also suggest less risk of major bleeding with DOACs over warfarin but no difference in overall mortality when used to treat venous thromboembolism (see Table 2).² Because of these combined advantages, DOACs are increasingly prescribed, accounting for approximately half of all oral anticoagulant prescriptions in 2014.³

Although DOACs have been shown to be as good if not superior to VKAs and heparins in these circumstances, there are situations where a DOAC should not be used. There is limited data on the safety of DOACs in patients with mechanical heart valves, liver failure, and chronic kidney disease with a creatinine clearance less than 30 mL/min.⁴ Therefore, warfarin is still the preferred agent in these settings. There is some data that apixaban may be safe in patients with a creatinine clearance of greater than 10 mL/min, but long-term safety studies have not been performed in patients with end-stage renal disease on hemodialysis.⁵ Finally, in patients requiring concomitant inducers or inhibitors of the P-glycoprotein or cytochrome P450 enzymes like antiepileptics and protease inhibitors, VKAs and heparins are favored.⁴

Notwithstanding their advantages, when DOACs first hit the market there were concerns that reversal agents were not available. In the August issue of the Journal of Hospital Medicine’s Clinical Guideline Highlights for the Hospitalist, Emily Gottenborg, MD, and Gregory Misky, MD, summarized guideline recommendations for reversal of the newer agents.⁶ This includes use of idarucizumab for patients on dabigatran and use of prothrombin complex concentrate (PCC) or recombinant coagulation factor Xa (andexanet alfa) for patients on apixaban or rivaroxaban for the treatment of life-threatening bleeding.

Idarucizumab is a monoclonal antibody developed to reverse the effects of dabigatran, the only DOAC that directly inhibits thrombin. In 2017, researchers reported on a cohort of subjects receiving idarucizumab for uncontrolled bleeding or who were on dabigatran and about to undergo an urgent procedure.⁷ Of those with uncontrolled bleeding, two-thirds had confirmed bleeding cessation within 24 hours. Periprocedural hemostasis was achieved in 93.4% of patients undergoing urgent procedures. However, it should be noted that use of idarucizumab conferred an increase risk (6.3%) of thrombosis within 90 days. Based on these findings, guidelines recommend use of idarucizumab in patients experiencing life-threatening bleeding, balanced against the risk of thrombosis.⁸

In 2018, the Food and Drug Administration approved recombinant coagulation factor Xa for treatment of life-threatening or uncontrolled bleeding in patients on apixaban or rivaroxaban.⁹ The approval came after a study by the ANNEXA-4 investigators showed that recombinant coagulation factor Xa quickly and effectively achieved hemostasis.¹⁰ Full study results were published in April 2019, demonstrating 82% of patients receiving the drug attained clinical hemostasis.¹¹ However, as with idarucizumab, up to 10% of patients had a thrombotic event in the follow-up period. Use of recombinant coagulation factor Xa for treatment of life-threatening bleeding related to betrixaban and edoxaban is considered off label but is recommended by guidelines.⁸ Studies on investigational reversal agents for betrixaban and edoxaban are ongoing.

Both unactivated and activated PCC contain clotting factor X. Their use to control bleeding related to DOAC use is based on observational studies. In a systematic review of the nonrandomized studies, the efficacy of PCC to stem major bleeding was 69% and the risk for thromboembolism was 4%.¹² There are no head-to-head studies comparing use of recombinant coagulation factor Xa and PCC. Therefore, guidelines are to use either recombinant factor Xa or PCC for the treatment of life-threatening bleeding related to DOAC use.⁷

As thrombosis risk heightens after use of any reversal agent, the recommendations are to resume anticoagulation within 90 days if the patient is at moderate or high risk for recurrent thromboembolism.⁸

After discussion with the hospitalist about the new agents available to reverse anticoagulation, the colleague decided to place the patient on a DOAC and keep the patient in his nursing home. Thankfully, the patient did not thereafter experience sustained bleeding necessitating use of these reversal agents. More importantly for the patient, he was able to stay in the comfort of his home.

Dr. Tuck is associate section chief for hospital medicine at the Veterans Affairs Medical Center in Washington, D.C.

References

1. Gómez-Outes A et al. Causes of death in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2016;68:2508-21.

2. Jun M et al. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population-based, observational study. BMJ. 2017;359:j4323.

3. Barnes GD et al. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128:(1300-5).e2.

4. Reddy P et al. Practical approach to VTE management in hospitalized patients. Am J Ther. 2017;24(4):e442-67.

5. Kimachi M et al. Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease. Cochrane Database Syst Rev. 2017 Nov 6;11:CD011373.

6. Gottenborg E et al. Clinical guideline highlights for the hospitalist: The management of anticoagulation in the hospitalized adult. J Hosp Med. 2019; 14(8):499-500.

7. Pollack CV Jr et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med. 2017;377(5):431-41.

8. Witt DM et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood Adv. 2018;2(22):3257-91.

9. Malarky M et al. FDA accelerated approval letter. Retrieved July 15, 2019. https://www.fda.gov/media/113285/download

10. Connolly SJ et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-41.

11. Connolly SJ et al. Full study report of andexanet alfa for bleeding associated with factor xa inhibitors. N Engl J Med. 2019;380(14):1326-35.

12. Piran S et al. Management of direct factor Xa inhibitor–related major bleeding with prothrombin complex concentrate: A meta-analysis. Blood Adv. 2019;3(2):158-67.