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A toddler with a fever and desquamating perineal rash
Kawasaki disease
Given (KD). An echocardiogram revealed diffuse dilation of the left anterior descending artery without evidence of an aneurysm. The patient was promptly started on 2 g/kg IVIG and high-dose aspirin. She was later transitioned to low-dose aspirin. Long-term follow-up thus far has revealed no cardiac sequelae.
KD, or mucocutaneous lymph node syndrome, is a multisystem vasculitis with predilection for the coronary arteries that most commonly affects children between 6 months and 5 years of age.1 While the etiology remains unclear, the pathogenesis is thought to be the result of an immune response to an infection in the setting of genetic susceptibility.1 Approximately 90% of patients have mucocutaneous manifestations, highlighting the important role dermatologists play in the diagnosis and early intervention to prevent cardiovascular morbidity.
The diagnostic criteria include fever for at least 5 days accompanied by at least four of the following:
- Bilateral bulbar conjunctival injection without exudate that is classically limbal sparing.
- Oral mucosal changes with cracked fissured lips, “strawberry tongue,” or erythema of the lips and mucosa.
- Changes in the extremities: erythema, swelling, or periungual peeling.
- Polymorphous exanthem.
- Cervical lymphadenopathy, often unilateral (greater than 1.5 cm).
Although nonspecific for diagnosis, laboratory abnormalities are common, including anemia, thrombocytosis, leukocytosis, elevated inflammatory markers, elevated alanine aminotransferase (ALT), hypoalbuminemia, and sterile pyuria on urine analysis.1
Notably, a classic finding of KD is perineal dermatitis with desquamation occurring in the acute phase of disease in 80%-90% of patients.2-5 In a retrospective review, up to 67% of patients with KD developed a perineal rash in the first week, most often beginning in the diaper area.2 The perineal rash classically desquamates early during the acute phase of the disease.1
While most individuals with KD follow a benign disease course, it is the most common cause of acquired heart disease in the United States.1 Treatment is aimed at decreasing the risk of developing coronary abnormalities through the prompt administration of IVIG and high-dose aspirin initiated early in the acute phase.6 A second dose of IVIG may be given to patients who remain febrile within 24-48 hours after treatment.6 Infliximab has been used safely and effectively in patients with refractory KD.7 Long-term cardiac follow-up of KD patients is recommended.
Recently, there has been an emerging association between COVID-19 and pediatric multi-system inflammatory syndrome, which shares features with KD. Patients with pediatric multi-system inflammatory syndrome who meet clinical criteria for KD should be promptly treated with IVIG and aspirin to avoid long-term cardiac sequelae.
This case and the photos were submitted by Dr. Elizabeth H. Cusick and Dr. Molly E. Plovanich, both with the department of dermatology at the University of Rochester (N.Y.). Dr. Donna Bilu Martin edited the case.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.
References
1. Bayers S et al. (2013). J Am Acad Dermatol. 2013 Oct;69(4):501.e1-11.
2. Friter BS and Lucky AW. Arch Dermatol. 1988 Dec;124(12):1805-10.
3. Urbach AH et al. Am J Dis Child. 1988 Nov;142(11):1174-6.
4. Fink CW. Pediatr Infect Dis. 1983 Mar-Apr; 2(2):140-1.
5. Aballi A J and Bisken LC. Pediatr Infect Dis. 1984 Mar-Apr;3(2):187.
6. McCrindle BW et al. Circulation. 2017 Apr 25;135(17):e927-e99.
7.Sauvaget E et al. J Pediatr. 2012 May; 160(5),875-6.
Kawasaki disease
Given (KD). An echocardiogram revealed diffuse dilation of the left anterior descending artery without evidence of an aneurysm. The patient was promptly started on 2 g/kg IVIG and high-dose aspirin. She was later transitioned to low-dose aspirin. Long-term follow-up thus far has revealed no cardiac sequelae.
KD, or mucocutaneous lymph node syndrome, is a multisystem vasculitis with predilection for the coronary arteries that most commonly affects children between 6 months and 5 years of age.1 While the etiology remains unclear, the pathogenesis is thought to be the result of an immune response to an infection in the setting of genetic susceptibility.1 Approximately 90% of patients have mucocutaneous manifestations, highlighting the important role dermatologists play in the diagnosis and early intervention to prevent cardiovascular morbidity.
The diagnostic criteria include fever for at least 5 days accompanied by at least four of the following:
- Bilateral bulbar conjunctival injection without exudate that is classically limbal sparing.
- Oral mucosal changes with cracked fissured lips, “strawberry tongue,” or erythema of the lips and mucosa.
- Changes in the extremities: erythema, swelling, or periungual peeling.
- Polymorphous exanthem.
- Cervical lymphadenopathy, often unilateral (greater than 1.5 cm).
Although nonspecific for diagnosis, laboratory abnormalities are common, including anemia, thrombocytosis, leukocytosis, elevated inflammatory markers, elevated alanine aminotransferase (ALT), hypoalbuminemia, and sterile pyuria on urine analysis.1
Notably, a classic finding of KD is perineal dermatitis with desquamation occurring in the acute phase of disease in 80%-90% of patients.2-5 In a retrospective review, up to 67% of patients with KD developed a perineal rash in the first week, most often beginning in the diaper area.2 The perineal rash classically desquamates early during the acute phase of the disease.1
While most individuals with KD follow a benign disease course, it is the most common cause of acquired heart disease in the United States.1 Treatment is aimed at decreasing the risk of developing coronary abnormalities through the prompt administration of IVIG and high-dose aspirin initiated early in the acute phase.6 A second dose of IVIG may be given to patients who remain febrile within 24-48 hours after treatment.6 Infliximab has been used safely and effectively in patients with refractory KD.7 Long-term cardiac follow-up of KD patients is recommended.
Recently, there has been an emerging association between COVID-19 and pediatric multi-system inflammatory syndrome, which shares features with KD. Patients with pediatric multi-system inflammatory syndrome who meet clinical criteria for KD should be promptly treated with IVIG and aspirin to avoid long-term cardiac sequelae.
This case and the photos were submitted by Dr. Elizabeth H. Cusick and Dr. Molly E. Plovanich, both with the department of dermatology at the University of Rochester (N.Y.). Dr. Donna Bilu Martin edited the case.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.
References
1. Bayers S et al. (2013). J Am Acad Dermatol. 2013 Oct;69(4):501.e1-11.
2. Friter BS and Lucky AW. Arch Dermatol. 1988 Dec;124(12):1805-10.
3. Urbach AH et al. Am J Dis Child. 1988 Nov;142(11):1174-6.
4. Fink CW. Pediatr Infect Dis. 1983 Mar-Apr; 2(2):140-1.
5. Aballi A J and Bisken LC. Pediatr Infect Dis. 1984 Mar-Apr;3(2):187.
6. McCrindle BW et al. Circulation. 2017 Apr 25;135(17):e927-e99.
7.Sauvaget E et al. J Pediatr. 2012 May; 160(5),875-6.
Kawasaki disease
Given (KD). An echocardiogram revealed diffuse dilation of the left anterior descending artery without evidence of an aneurysm. The patient was promptly started on 2 g/kg IVIG and high-dose aspirin. She was later transitioned to low-dose aspirin. Long-term follow-up thus far has revealed no cardiac sequelae.
KD, or mucocutaneous lymph node syndrome, is a multisystem vasculitis with predilection for the coronary arteries that most commonly affects children between 6 months and 5 years of age.1 While the etiology remains unclear, the pathogenesis is thought to be the result of an immune response to an infection in the setting of genetic susceptibility.1 Approximately 90% of patients have mucocutaneous manifestations, highlighting the important role dermatologists play in the diagnosis and early intervention to prevent cardiovascular morbidity.
The diagnostic criteria include fever for at least 5 days accompanied by at least four of the following:
- Bilateral bulbar conjunctival injection without exudate that is classically limbal sparing.
- Oral mucosal changes with cracked fissured lips, “strawberry tongue,” or erythema of the lips and mucosa.
- Changes in the extremities: erythema, swelling, or periungual peeling.
- Polymorphous exanthem.
- Cervical lymphadenopathy, often unilateral (greater than 1.5 cm).
Although nonspecific for diagnosis, laboratory abnormalities are common, including anemia, thrombocytosis, leukocytosis, elevated inflammatory markers, elevated alanine aminotransferase (ALT), hypoalbuminemia, and sterile pyuria on urine analysis.1
Notably, a classic finding of KD is perineal dermatitis with desquamation occurring in the acute phase of disease in 80%-90% of patients.2-5 In a retrospective review, up to 67% of patients with KD developed a perineal rash in the first week, most often beginning in the diaper area.2 The perineal rash classically desquamates early during the acute phase of the disease.1
While most individuals with KD follow a benign disease course, it is the most common cause of acquired heart disease in the United States.1 Treatment is aimed at decreasing the risk of developing coronary abnormalities through the prompt administration of IVIG and high-dose aspirin initiated early in the acute phase.6 A second dose of IVIG may be given to patients who remain febrile within 24-48 hours after treatment.6 Infliximab has been used safely and effectively in patients with refractory KD.7 Long-term cardiac follow-up of KD patients is recommended.
Recently, there has been an emerging association between COVID-19 and pediatric multi-system inflammatory syndrome, which shares features with KD. Patients with pediatric multi-system inflammatory syndrome who meet clinical criteria for KD should be promptly treated with IVIG and aspirin to avoid long-term cardiac sequelae.
This case and the photos were submitted by Dr. Elizabeth H. Cusick and Dr. Molly E. Plovanich, both with the department of dermatology at the University of Rochester (N.Y.). Dr. Donna Bilu Martin edited the case.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.
References
1. Bayers S et al. (2013). J Am Acad Dermatol. 2013 Oct;69(4):501.e1-11.
2. Friter BS and Lucky AW. Arch Dermatol. 1988 Dec;124(12):1805-10.
3. Urbach AH et al. Am J Dis Child. 1988 Nov;142(11):1174-6.
4. Fink CW. Pediatr Infect Dis. 1983 Mar-Apr; 2(2):140-1.
5. Aballi A J and Bisken LC. Pediatr Infect Dis. 1984 Mar-Apr;3(2):187.
6. McCrindle BW et al. Circulation. 2017 Apr 25;135(17):e927-e99.
7.Sauvaget E et al. J Pediatr. 2012 May; 160(5),875-6.
An otherwise healthy 18-month-old female presented to the emergency department with 5 days of fever, erythema, fissuring of the lips, conjunctival injection, and a desquamating perineal rash. In addition, she had nasal congestion and cough for which she was started on amoxicillin 2 days prior to presentation given concern for pneumonia.
On exam, she was also noted to have several palpable cervical lymph nodes and edematous hands with overlying erythema. Laboratory evaluation was notable for respiratory syncytial virus positivity by polymerase chain reaction assay, leukocytosis, and elevated inflammatory markers (erythrocyte sedimentation rate and C-reactive protein).
Yoga is a good adjunct to migraine therapy
in Neurology.
The structured yoga program resulted in “remarkably improved” outcomes at 3 months of follow-up in CONTAIN, with both headache frequency and use of medications cut in half, compared with baseline, according to the investigators.
Compared with the control group on standard antimigraine medications alone, the yoga group demonstrated significantly greater reductions in pain intensity, headache frequency, pill counts, and validated measures of disability and headache impact on daily life (see graphic).
“The good news is that practicing something as simple and accessible as yoga may help much more than medications alone. And all you need is a mat,” observed Dr. Bhatia, professor of neurology at the All India Institute of Medical Sciences in New Delhi.
The single-center, open-label, blinded-assessment CONTAIN trial included 160 adult episodic migraine patients ages 18-50 years experiencing 4-14 headaches per month. They were randomized to prophylactic and acute rescue medications alone or in combination with yoga instruction by a qualified yoga therapist in a class that met at the medical center 3 days per week for 1 month. This was followed by practice of the hour-long yoga program at home 5 days per week for the next 2 months, with twice-monthly telephone calls from the yoga center to encourage adherence and encouragement to call if questions arose. Both groups received counseling about the importance of lifestyle changes that may help with migraine, including diet, physical activity, adequate sleep, and stress reduction. Outcomes were assessed in an intent-to-treat analysis.
The yoga program included specific relaxation exercises, breathing techniques, meditation, and yoga postures, or asanas. The migraine-tailored program was vetted by yoga experts at five renowned Indian yoga centers.
No safety issues arose with the yoga program.
The investigators noted that the 47% reduction in migraine medication pill count and 49% decrease in headache frequency over the course of 3 months in the adjunctive yoga group have important implications, not only in a limited-resource country such as India, but also in the United States, where Americans spend an estimated $3.2 billion annually on prescription and over the counter headache medications, and the indirect cost associated with lost productivity due to migraine has been put at $13 billion per year.
Dr. Bhatia and colleagues speculated that the observed benefits of add-on yoga in migraineurs may involve previously described improved vagal tone and parasympathetic drive coupled with decreased sympathetic tone, increased nitric oxide levels, and loosening of stiff muscles, which can trigger headaches.
Real-life goals
Commenting on the research, neurologist Holly Yancy, DO, a headache specialist at the Banner Health - University Medicine Neuroscience Institute in Phoenix, said she was impressed by the high quality of this well-designed, adequately powered study of a complementary and alternative therapy.
“The primary and secondary endpoints were real-life goals of migraine treatment that we strive to achieve in clinical practice – and they were met in the study,” she observed. “To start with a month of in-house yoga classes to instill a baseline competence in yoga prior to transitioning to home practice and to provide resources for ongoing assistance for questions were nice touches.”
She noted that the control group also experienced reductions in migraine frequency, severity, and disability scores, albeit of significantly lesser magnitude than in the yoga group. This underscores how important it is in clinical practice to spend time counseling migraine patients on lifestyle choices.
“A trial such as this provides neurologists and other health care providers with an accessible, evidence-based treatment for migraines that can be used with other preventive treatments to decrease the frequency and the amount of medication their patients are taking. In addition, it is a behavioral therapy that can decrease triggers and potentially help patients cope with pain,” Dr. Yancy said.
“I suspect I’ll not hesitate to recommend yoga as an adjunctive treatment for patients in my clinic that are physically capable. I think it would be logical to try to extrapolate the concept to a chronic migraine population as well, though it would be ideal to base that recommendation on another study conducted with a chronic migraine population.”
Dr. Bhatia and his coinvestigators reported having no financial conflicts regarding their study, funded by the Government of India and the All India Institute of Medical Sciences.
SOURCE: Kumar A et al. Neurology. 2020 May 6. doi: 10.1212/WNL.0000000000009473.
in Neurology.
The structured yoga program resulted in “remarkably improved” outcomes at 3 months of follow-up in CONTAIN, with both headache frequency and use of medications cut in half, compared with baseline, according to the investigators.
Compared with the control group on standard antimigraine medications alone, the yoga group demonstrated significantly greater reductions in pain intensity, headache frequency, pill counts, and validated measures of disability and headache impact on daily life (see graphic).
“The good news is that practicing something as simple and accessible as yoga may help much more than medications alone. And all you need is a mat,” observed Dr. Bhatia, professor of neurology at the All India Institute of Medical Sciences in New Delhi.
The single-center, open-label, blinded-assessment CONTAIN trial included 160 adult episodic migraine patients ages 18-50 years experiencing 4-14 headaches per month. They were randomized to prophylactic and acute rescue medications alone or in combination with yoga instruction by a qualified yoga therapist in a class that met at the medical center 3 days per week for 1 month. This was followed by practice of the hour-long yoga program at home 5 days per week for the next 2 months, with twice-monthly telephone calls from the yoga center to encourage adherence and encouragement to call if questions arose. Both groups received counseling about the importance of lifestyle changes that may help with migraine, including diet, physical activity, adequate sleep, and stress reduction. Outcomes were assessed in an intent-to-treat analysis.
The yoga program included specific relaxation exercises, breathing techniques, meditation, and yoga postures, or asanas. The migraine-tailored program was vetted by yoga experts at five renowned Indian yoga centers.
No safety issues arose with the yoga program.
The investigators noted that the 47% reduction in migraine medication pill count and 49% decrease in headache frequency over the course of 3 months in the adjunctive yoga group have important implications, not only in a limited-resource country such as India, but also in the United States, where Americans spend an estimated $3.2 billion annually on prescription and over the counter headache medications, and the indirect cost associated with lost productivity due to migraine has been put at $13 billion per year.
Dr. Bhatia and colleagues speculated that the observed benefits of add-on yoga in migraineurs may involve previously described improved vagal tone and parasympathetic drive coupled with decreased sympathetic tone, increased nitric oxide levels, and loosening of stiff muscles, which can trigger headaches.
Real-life goals
Commenting on the research, neurologist Holly Yancy, DO, a headache specialist at the Banner Health - University Medicine Neuroscience Institute in Phoenix, said she was impressed by the high quality of this well-designed, adequately powered study of a complementary and alternative therapy.
“The primary and secondary endpoints were real-life goals of migraine treatment that we strive to achieve in clinical practice – and they were met in the study,” she observed. “To start with a month of in-house yoga classes to instill a baseline competence in yoga prior to transitioning to home practice and to provide resources for ongoing assistance for questions were nice touches.”
She noted that the control group also experienced reductions in migraine frequency, severity, and disability scores, albeit of significantly lesser magnitude than in the yoga group. This underscores how important it is in clinical practice to spend time counseling migraine patients on lifestyle choices.
“A trial such as this provides neurologists and other health care providers with an accessible, evidence-based treatment for migraines that can be used with other preventive treatments to decrease the frequency and the amount of medication their patients are taking. In addition, it is a behavioral therapy that can decrease triggers and potentially help patients cope with pain,” Dr. Yancy said.
“I suspect I’ll not hesitate to recommend yoga as an adjunctive treatment for patients in my clinic that are physically capable. I think it would be logical to try to extrapolate the concept to a chronic migraine population as well, though it would be ideal to base that recommendation on another study conducted with a chronic migraine population.”
Dr. Bhatia and his coinvestigators reported having no financial conflicts regarding their study, funded by the Government of India and the All India Institute of Medical Sciences.
SOURCE: Kumar A et al. Neurology. 2020 May 6. doi: 10.1212/WNL.0000000000009473.
in Neurology.
The structured yoga program resulted in “remarkably improved” outcomes at 3 months of follow-up in CONTAIN, with both headache frequency and use of medications cut in half, compared with baseline, according to the investigators.
Compared with the control group on standard antimigraine medications alone, the yoga group demonstrated significantly greater reductions in pain intensity, headache frequency, pill counts, and validated measures of disability and headache impact on daily life (see graphic).
“The good news is that practicing something as simple and accessible as yoga may help much more than medications alone. And all you need is a mat,” observed Dr. Bhatia, professor of neurology at the All India Institute of Medical Sciences in New Delhi.
The single-center, open-label, blinded-assessment CONTAIN trial included 160 adult episodic migraine patients ages 18-50 years experiencing 4-14 headaches per month. They were randomized to prophylactic and acute rescue medications alone or in combination with yoga instruction by a qualified yoga therapist in a class that met at the medical center 3 days per week for 1 month. This was followed by practice of the hour-long yoga program at home 5 days per week for the next 2 months, with twice-monthly telephone calls from the yoga center to encourage adherence and encouragement to call if questions arose. Both groups received counseling about the importance of lifestyle changes that may help with migraine, including diet, physical activity, adequate sleep, and stress reduction. Outcomes were assessed in an intent-to-treat analysis.
The yoga program included specific relaxation exercises, breathing techniques, meditation, and yoga postures, or asanas. The migraine-tailored program was vetted by yoga experts at five renowned Indian yoga centers.
No safety issues arose with the yoga program.
The investigators noted that the 47% reduction in migraine medication pill count and 49% decrease in headache frequency over the course of 3 months in the adjunctive yoga group have important implications, not only in a limited-resource country such as India, but also in the United States, where Americans spend an estimated $3.2 billion annually on prescription and over the counter headache medications, and the indirect cost associated with lost productivity due to migraine has been put at $13 billion per year.
Dr. Bhatia and colleagues speculated that the observed benefits of add-on yoga in migraineurs may involve previously described improved vagal tone and parasympathetic drive coupled with decreased sympathetic tone, increased nitric oxide levels, and loosening of stiff muscles, which can trigger headaches.
Real-life goals
Commenting on the research, neurologist Holly Yancy, DO, a headache specialist at the Banner Health - University Medicine Neuroscience Institute in Phoenix, said she was impressed by the high quality of this well-designed, adequately powered study of a complementary and alternative therapy.
“The primary and secondary endpoints were real-life goals of migraine treatment that we strive to achieve in clinical practice – and they were met in the study,” she observed. “To start with a month of in-house yoga classes to instill a baseline competence in yoga prior to transitioning to home practice and to provide resources for ongoing assistance for questions were nice touches.”
She noted that the control group also experienced reductions in migraine frequency, severity, and disability scores, albeit of significantly lesser magnitude than in the yoga group. This underscores how important it is in clinical practice to spend time counseling migraine patients on lifestyle choices.
“A trial such as this provides neurologists and other health care providers with an accessible, evidence-based treatment for migraines that can be used with other preventive treatments to decrease the frequency and the amount of medication their patients are taking. In addition, it is a behavioral therapy that can decrease triggers and potentially help patients cope with pain,” Dr. Yancy said.
“I suspect I’ll not hesitate to recommend yoga as an adjunctive treatment for patients in my clinic that are physically capable. I think it would be logical to try to extrapolate the concept to a chronic migraine population as well, though it would be ideal to base that recommendation on another study conducted with a chronic migraine population.”
Dr. Bhatia and his coinvestigators reported having no financial conflicts regarding their study, funded by the Government of India and the All India Institute of Medical Sciences.
SOURCE: Kumar A et al. Neurology. 2020 May 6. doi: 10.1212/WNL.0000000000009473.
FROM NEUROLOGY
‘Momentous’ data for first-line combo in liver cancer
New clinical data are set to change the treatment landscape for advanced liver cancer.
The data showed that atezolizumab plus bevacizumab improved survival, when compared with sorafenib, in patients with unresectable hepatocellular carcinoma (HCC).
The advanced liver cancer space has been dominated for a more than a decade by sorafenib (Nexavar, Bayer), which was the first systemic therapy to confer “a meaningful survival benefit in the treatment of advanced hepatocellular carcinoma,” notes Robin K. Kelley, MD, from the University of California, San Francisco.
“Since then, no treatment had surpassed the effect of sorafenib in the first line until the regimen of atezolizumab and bevacizumab” that is now being reported, she notes.
The new data come from the IMbrave150 study, published on May 14 in the New England Journal of Medicine.
“The combination of atezolizumab plus bevacizumab has become the new benchmark for first-line therapy in advanced hepatocellular carcinoma,” Kelley writes in an accompanying editorial.
“These data are momentous, since they identify not only the first therapy to improve survival beyond sorafenib, but also the first successful combination regimen and the first positive randomized, phase 3 trial of immune checkpoint inhibition in this challenging cancer,” she added.
The IMbrave 150 study was sponsored by Roche, manufacturer of both the checkpoint inhibitor atezolizumab (Tecentriq, Genentech/Roche) and the antiangiogenic agent bevacizumab (Avastin, Genentech/Roche); the company has submitted an FDA approval application for use of this combination for inoperable liver cancer.
'Results represent a breakthrough'
“These results represent a breakthrough in the management of advanced HCC,” said Josep M. Llovet, MD, PhD, director of the Mount Sinai Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, and professor of medicine in hepatic oncology at the University of Barcelona, Spain.
The combination has already been acknowledged as a milestone in the management of HCC, he said.
Llovet was approached for comment by Medscape Medical News. He was not involved with IMbrave150 but was the lead author on the SHARP study, which led to the first-line approval of sorafenib.
He explained that, since the approval of sorafenib in 2008, lenvatinib (Lenvima, Eisai) has been the only other agent approved for the front-line treatment of HCC after hitting the noninferiority endpoint for survival in comparison with sorafenib. “Up to now, there was no agent superior to sorafenib, the standard of care,” he said.
Now, the combination of atezolizumab-bevacizumab has shown superior efficacy compared with sorafenib, Llovet noted. It is not only the first combination to show efficacy but is also the first checkpoint inhibitor that has demonstrated efficacy in HCC. “Previous studies of checkpoint inhibitors used as single agents in the front-line or second-line setting of advanced liver cancer were negative,” he said.
'Game-changer' in liver cancer
“The atezolizumab-bevacizumab combination is a game-changer in liver cancer,” the lead author of the IMbrave 150 trial, Richard S. Finn, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, told Medscape Medical News.
“The combination has established a new standard of care that is predicated on the gold standard of overall survival [OS] and is underscored by prolonged progression-free survival [PFS] and high response rates that are durable,” Finn said.
In the IMbrave150 trial, treatment-naive patients who had unresectable liver cancer received either atezolizumab-bevacizumab (n = 336) or sorafenib (n = 165).
After a median follow-up of 8.6 months, median survival was significantly longer for the patients who received atezolizumab-bevacizumab: 13.2 months. For the patients who did not receive the combination, median survival was not reached (hazard ratio [HR], 0.58; P < .001). Six-month OS was 84.8% with the combination versus 72.2% with sorafenib.
Median PFS was also significantly longer for patients who received combination therapy: 6.8 months with the combination versus 4.3 months with sorafenib (HR, 0.59; P < .001). Six-month PFS was 54.4% with the combination versus 37.3% with sorafenib.
The objective response rate was 27.3% (complete response, 5.5%) with the combination versus 11.9% (complete response, 0%) with sorafenib
Median time to deterioration of quality of life was also longer for patients who received combination therapy: 11.2 months with atezolizumab-bevacizumab and 3.6 months for sorafenib.
Incidence of grade 3 or 4 adverse events was similar in both arms of the study: 56.5% for the combination versus 55.1% with sorafenib. Adverse events leading to withdrawal from any study drug was not significantly different: 15.5% versus 10.3% for sorafenib.
The percentage of patients who experienced bleeding of any grade (attributed to bevacizumab) was 25.2% with the combination versus 17.3% with sorafenib. In addition, six incidents of fatal bleeding or perforated ulcer were recorded in the combination group, compared with one for the sorafenib group.
Appropriate for all patients?
Llovet told Medscape Medical News that the combination of atezolizumab and bevacizumab, although still awaiting approval for use in liver cancer, will be adopted by guidelines in the management of HCC as first-line therapy.
It has been accepted as the new front-line standard of care in a soon-to-be-published consensus on trial design and endpoints in HCC that he has authored.
Llovet said that the intravenous (IV) dosing of the combination was not likely to be a problem (sorafenib is administered orally). For patients with untreated advanced HCC, median survival is 8 months; it is 11-13 months with sorafenib. With this combination, the median was not reached, but it is expected to be beyond 17 months. “In this scenario, IV versus oral dosing will only have implications if the treatments had similar efficacy but not significantly better performance,” he said.
In her editorial, Kelley suggests caution when considering use of the combination in a patient population broader than that defined by the IMbrave150 study.
She points out that patients in IMbrave150 were required to have well-compensated liver disease (Child-Pugh class A liver function), and patients with untreated or incompletely treated esophageal or gastric varices with bleeding or those who were at high risk of bleeding were excluded from the study.
“Safety has not been established for persons in the Childs-Pugh class B population, and alternative therapies should be considered for patients at high risk for bleeding,” Kelley writes in her editorial.
Bleeding events, including fatal bleeding and perforated ulcers, “underscore important considerations for the application of the atezolizumab-bevacizumab regimen to a broader population beyond the clinical trial setting,” Kelley noted.
She recommends that all patients at risk for varices undergo “appropriate endoscopic evaluation and management before treatment is initiated.”
Llovet agreed and noted that upper endoscopy is not currently practiced in the management of advanced HCC. “One important issue in the clinical practice will be that all patients require an upper endoscopy to rule out esophageal varices, which are at risk of bleeding with bevacizumab,” he said.
Trial investigator Finn explained that IMbrave 150 is not unique and that every phase 3 study has included patients with Child-Pugh class A liver function.
“Patients with Child-Pugh class B are a heterogeneous group of patients,” Finn said. Physicians should use their judgment in providing this combination to patients with Child-Pugh scores of 7–9, he added. “All patients with advanced liver cancer need an endoscopy,” Finn said.
Kelley and Llovet also observed that several ongoing trials, some of which have been completed, are evaluating combinations of immunotherapy and other antiangiogenic agents or combinations of immunotherapies. The results from these trials will inform how such combinations will be used in the future.
Kelley predicted that, if some of these trials are positive, in the absence of a predictive biomarker, physicians will be guided by “the safety profiles of the combinations as well as the inference of synergy on the basis of depth and durability of responses.”
“Results of these trials will be known within the next 12-18 months and might further improve the current standards for patients with inoperable HCC,” Llovet said.
IMbrave150 was sponsored by F. Hoffmann–La Roche/Genentech. Finn has consulted for AtraZeneca, Bayer, Bristol-Myers Squibb, CStone, Eisai, Eli Lilly, Exelixis, Roche, Genentech, Merck & Co, Novartis, and Pfizer. Finn’s coauthors also report relationships with pharmaceutical companies. Kelley reports institutional research support from many pharmaceutical companies and served on the independent data monitoring committee for the IMbrave150 trial. Llovet has received research support from Bayer HealthCare Pharmaceuticals, Eisai, Bristol-Myers Squibb, Boehringer Ingelheim, and Ipsen and consulting fees from Bayer HealthCare Pharmaceuticals, Merck, Eisai Inc, Bristol-Myers Squibb, Celsion Corporation, Eli Lilly, Roche, Genentech, Glycotest, Nucleix, Can-Fite Biopharma, AstraZeneca, and Exelixis.
This article first appeared on Medscape.com.
New clinical data are set to change the treatment landscape for advanced liver cancer.
The data showed that atezolizumab plus bevacizumab improved survival, when compared with sorafenib, in patients with unresectable hepatocellular carcinoma (HCC).
The advanced liver cancer space has been dominated for a more than a decade by sorafenib (Nexavar, Bayer), which was the first systemic therapy to confer “a meaningful survival benefit in the treatment of advanced hepatocellular carcinoma,” notes Robin K. Kelley, MD, from the University of California, San Francisco.
“Since then, no treatment had surpassed the effect of sorafenib in the first line until the regimen of atezolizumab and bevacizumab” that is now being reported, she notes.
The new data come from the IMbrave150 study, published on May 14 in the New England Journal of Medicine.
“The combination of atezolizumab plus bevacizumab has become the new benchmark for first-line therapy in advanced hepatocellular carcinoma,” Kelley writes in an accompanying editorial.
“These data are momentous, since they identify not only the first therapy to improve survival beyond sorafenib, but also the first successful combination regimen and the first positive randomized, phase 3 trial of immune checkpoint inhibition in this challenging cancer,” she added.
The IMbrave 150 study was sponsored by Roche, manufacturer of both the checkpoint inhibitor atezolizumab (Tecentriq, Genentech/Roche) and the antiangiogenic agent bevacizumab (Avastin, Genentech/Roche); the company has submitted an FDA approval application for use of this combination for inoperable liver cancer.
'Results represent a breakthrough'
“These results represent a breakthrough in the management of advanced HCC,” said Josep M. Llovet, MD, PhD, director of the Mount Sinai Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, and professor of medicine in hepatic oncology at the University of Barcelona, Spain.
The combination has already been acknowledged as a milestone in the management of HCC, he said.
Llovet was approached for comment by Medscape Medical News. He was not involved with IMbrave150 but was the lead author on the SHARP study, which led to the first-line approval of sorafenib.
He explained that, since the approval of sorafenib in 2008, lenvatinib (Lenvima, Eisai) has been the only other agent approved for the front-line treatment of HCC after hitting the noninferiority endpoint for survival in comparison with sorafenib. “Up to now, there was no agent superior to sorafenib, the standard of care,” he said.
Now, the combination of atezolizumab-bevacizumab has shown superior efficacy compared with sorafenib, Llovet noted. It is not only the first combination to show efficacy but is also the first checkpoint inhibitor that has demonstrated efficacy in HCC. “Previous studies of checkpoint inhibitors used as single agents in the front-line or second-line setting of advanced liver cancer were negative,” he said.
'Game-changer' in liver cancer
“The atezolizumab-bevacizumab combination is a game-changer in liver cancer,” the lead author of the IMbrave 150 trial, Richard S. Finn, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, told Medscape Medical News.
“The combination has established a new standard of care that is predicated on the gold standard of overall survival [OS] and is underscored by prolonged progression-free survival [PFS] and high response rates that are durable,” Finn said.
In the IMbrave150 trial, treatment-naive patients who had unresectable liver cancer received either atezolizumab-bevacizumab (n = 336) or sorafenib (n = 165).
After a median follow-up of 8.6 months, median survival was significantly longer for the patients who received atezolizumab-bevacizumab: 13.2 months. For the patients who did not receive the combination, median survival was not reached (hazard ratio [HR], 0.58; P < .001). Six-month OS was 84.8% with the combination versus 72.2% with sorafenib.
Median PFS was also significantly longer for patients who received combination therapy: 6.8 months with the combination versus 4.3 months with sorafenib (HR, 0.59; P < .001). Six-month PFS was 54.4% with the combination versus 37.3% with sorafenib.
The objective response rate was 27.3% (complete response, 5.5%) with the combination versus 11.9% (complete response, 0%) with sorafenib
Median time to deterioration of quality of life was also longer for patients who received combination therapy: 11.2 months with atezolizumab-bevacizumab and 3.6 months for sorafenib.
Incidence of grade 3 or 4 adverse events was similar in both arms of the study: 56.5% for the combination versus 55.1% with sorafenib. Adverse events leading to withdrawal from any study drug was not significantly different: 15.5% versus 10.3% for sorafenib.
The percentage of patients who experienced bleeding of any grade (attributed to bevacizumab) was 25.2% with the combination versus 17.3% with sorafenib. In addition, six incidents of fatal bleeding or perforated ulcer were recorded in the combination group, compared with one for the sorafenib group.
Appropriate for all patients?
Llovet told Medscape Medical News that the combination of atezolizumab and bevacizumab, although still awaiting approval for use in liver cancer, will be adopted by guidelines in the management of HCC as first-line therapy.
It has been accepted as the new front-line standard of care in a soon-to-be-published consensus on trial design and endpoints in HCC that he has authored.
Llovet said that the intravenous (IV) dosing of the combination was not likely to be a problem (sorafenib is administered orally). For patients with untreated advanced HCC, median survival is 8 months; it is 11-13 months with sorafenib. With this combination, the median was not reached, but it is expected to be beyond 17 months. “In this scenario, IV versus oral dosing will only have implications if the treatments had similar efficacy but not significantly better performance,” he said.
In her editorial, Kelley suggests caution when considering use of the combination in a patient population broader than that defined by the IMbrave150 study.
She points out that patients in IMbrave150 were required to have well-compensated liver disease (Child-Pugh class A liver function), and patients with untreated or incompletely treated esophageal or gastric varices with bleeding or those who were at high risk of bleeding were excluded from the study.
“Safety has not been established for persons in the Childs-Pugh class B population, and alternative therapies should be considered for patients at high risk for bleeding,” Kelley writes in her editorial.
Bleeding events, including fatal bleeding and perforated ulcers, “underscore important considerations for the application of the atezolizumab-bevacizumab regimen to a broader population beyond the clinical trial setting,” Kelley noted.
She recommends that all patients at risk for varices undergo “appropriate endoscopic evaluation and management before treatment is initiated.”
Llovet agreed and noted that upper endoscopy is not currently practiced in the management of advanced HCC. “One important issue in the clinical practice will be that all patients require an upper endoscopy to rule out esophageal varices, which are at risk of bleeding with bevacizumab,” he said.
Trial investigator Finn explained that IMbrave 150 is not unique and that every phase 3 study has included patients with Child-Pugh class A liver function.
“Patients with Child-Pugh class B are a heterogeneous group of patients,” Finn said. Physicians should use their judgment in providing this combination to patients with Child-Pugh scores of 7–9, he added. “All patients with advanced liver cancer need an endoscopy,” Finn said.
Kelley and Llovet also observed that several ongoing trials, some of which have been completed, are evaluating combinations of immunotherapy and other antiangiogenic agents or combinations of immunotherapies. The results from these trials will inform how such combinations will be used in the future.
Kelley predicted that, if some of these trials are positive, in the absence of a predictive biomarker, physicians will be guided by “the safety profiles of the combinations as well as the inference of synergy on the basis of depth and durability of responses.”
“Results of these trials will be known within the next 12-18 months and might further improve the current standards for patients with inoperable HCC,” Llovet said.
IMbrave150 was sponsored by F. Hoffmann–La Roche/Genentech. Finn has consulted for AtraZeneca, Bayer, Bristol-Myers Squibb, CStone, Eisai, Eli Lilly, Exelixis, Roche, Genentech, Merck & Co, Novartis, and Pfizer. Finn’s coauthors also report relationships with pharmaceutical companies. Kelley reports institutional research support from many pharmaceutical companies and served on the independent data monitoring committee for the IMbrave150 trial. Llovet has received research support from Bayer HealthCare Pharmaceuticals, Eisai, Bristol-Myers Squibb, Boehringer Ingelheim, and Ipsen and consulting fees from Bayer HealthCare Pharmaceuticals, Merck, Eisai Inc, Bristol-Myers Squibb, Celsion Corporation, Eli Lilly, Roche, Genentech, Glycotest, Nucleix, Can-Fite Biopharma, AstraZeneca, and Exelixis.
This article first appeared on Medscape.com.
New clinical data are set to change the treatment landscape for advanced liver cancer.
The data showed that atezolizumab plus bevacizumab improved survival, when compared with sorafenib, in patients with unresectable hepatocellular carcinoma (HCC).
The advanced liver cancer space has been dominated for a more than a decade by sorafenib (Nexavar, Bayer), which was the first systemic therapy to confer “a meaningful survival benefit in the treatment of advanced hepatocellular carcinoma,” notes Robin K. Kelley, MD, from the University of California, San Francisco.
“Since then, no treatment had surpassed the effect of sorafenib in the first line until the regimen of atezolizumab and bevacizumab” that is now being reported, she notes.
The new data come from the IMbrave150 study, published on May 14 in the New England Journal of Medicine.
“The combination of atezolizumab plus bevacizumab has become the new benchmark for first-line therapy in advanced hepatocellular carcinoma,” Kelley writes in an accompanying editorial.
“These data are momentous, since they identify not only the first therapy to improve survival beyond sorafenib, but also the first successful combination regimen and the first positive randomized, phase 3 trial of immune checkpoint inhibition in this challenging cancer,” she added.
The IMbrave 150 study was sponsored by Roche, manufacturer of both the checkpoint inhibitor atezolizumab (Tecentriq, Genentech/Roche) and the antiangiogenic agent bevacizumab (Avastin, Genentech/Roche); the company has submitted an FDA approval application for use of this combination for inoperable liver cancer.
'Results represent a breakthrough'
“These results represent a breakthrough in the management of advanced HCC,” said Josep M. Llovet, MD, PhD, director of the Mount Sinai Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, and professor of medicine in hepatic oncology at the University of Barcelona, Spain.
The combination has already been acknowledged as a milestone in the management of HCC, he said.
Llovet was approached for comment by Medscape Medical News. He was not involved with IMbrave150 but was the lead author on the SHARP study, which led to the first-line approval of sorafenib.
He explained that, since the approval of sorafenib in 2008, lenvatinib (Lenvima, Eisai) has been the only other agent approved for the front-line treatment of HCC after hitting the noninferiority endpoint for survival in comparison with sorafenib. “Up to now, there was no agent superior to sorafenib, the standard of care,” he said.
Now, the combination of atezolizumab-bevacizumab has shown superior efficacy compared with sorafenib, Llovet noted. It is not only the first combination to show efficacy but is also the first checkpoint inhibitor that has demonstrated efficacy in HCC. “Previous studies of checkpoint inhibitors used as single agents in the front-line or second-line setting of advanced liver cancer were negative,” he said.
'Game-changer' in liver cancer
“The atezolizumab-bevacizumab combination is a game-changer in liver cancer,” the lead author of the IMbrave 150 trial, Richard S. Finn, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, told Medscape Medical News.
“The combination has established a new standard of care that is predicated on the gold standard of overall survival [OS] and is underscored by prolonged progression-free survival [PFS] and high response rates that are durable,” Finn said.
In the IMbrave150 trial, treatment-naive patients who had unresectable liver cancer received either atezolizumab-bevacizumab (n = 336) or sorafenib (n = 165).
After a median follow-up of 8.6 months, median survival was significantly longer for the patients who received atezolizumab-bevacizumab: 13.2 months. For the patients who did not receive the combination, median survival was not reached (hazard ratio [HR], 0.58; P < .001). Six-month OS was 84.8% with the combination versus 72.2% with sorafenib.
Median PFS was also significantly longer for patients who received combination therapy: 6.8 months with the combination versus 4.3 months with sorafenib (HR, 0.59; P < .001). Six-month PFS was 54.4% with the combination versus 37.3% with sorafenib.
The objective response rate was 27.3% (complete response, 5.5%) with the combination versus 11.9% (complete response, 0%) with sorafenib
Median time to deterioration of quality of life was also longer for patients who received combination therapy: 11.2 months with atezolizumab-bevacizumab and 3.6 months for sorafenib.
Incidence of grade 3 or 4 adverse events was similar in both arms of the study: 56.5% for the combination versus 55.1% with sorafenib. Adverse events leading to withdrawal from any study drug was not significantly different: 15.5% versus 10.3% for sorafenib.
The percentage of patients who experienced bleeding of any grade (attributed to bevacizumab) was 25.2% with the combination versus 17.3% with sorafenib. In addition, six incidents of fatal bleeding or perforated ulcer were recorded in the combination group, compared with one for the sorafenib group.
Appropriate for all patients?
Llovet told Medscape Medical News that the combination of atezolizumab and bevacizumab, although still awaiting approval for use in liver cancer, will be adopted by guidelines in the management of HCC as first-line therapy.
It has been accepted as the new front-line standard of care in a soon-to-be-published consensus on trial design and endpoints in HCC that he has authored.
Llovet said that the intravenous (IV) dosing of the combination was not likely to be a problem (sorafenib is administered orally). For patients with untreated advanced HCC, median survival is 8 months; it is 11-13 months with sorafenib. With this combination, the median was not reached, but it is expected to be beyond 17 months. “In this scenario, IV versus oral dosing will only have implications if the treatments had similar efficacy but not significantly better performance,” he said.
In her editorial, Kelley suggests caution when considering use of the combination in a patient population broader than that defined by the IMbrave150 study.
She points out that patients in IMbrave150 were required to have well-compensated liver disease (Child-Pugh class A liver function), and patients with untreated or incompletely treated esophageal or gastric varices with bleeding or those who were at high risk of bleeding were excluded from the study.
“Safety has not been established for persons in the Childs-Pugh class B population, and alternative therapies should be considered for patients at high risk for bleeding,” Kelley writes in her editorial.
Bleeding events, including fatal bleeding and perforated ulcers, “underscore important considerations for the application of the atezolizumab-bevacizumab regimen to a broader population beyond the clinical trial setting,” Kelley noted.
She recommends that all patients at risk for varices undergo “appropriate endoscopic evaluation and management before treatment is initiated.”
Llovet agreed and noted that upper endoscopy is not currently practiced in the management of advanced HCC. “One important issue in the clinical practice will be that all patients require an upper endoscopy to rule out esophageal varices, which are at risk of bleeding with bevacizumab,” he said.
Trial investigator Finn explained that IMbrave 150 is not unique and that every phase 3 study has included patients with Child-Pugh class A liver function.
“Patients with Child-Pugh class B are a heterogeneous group of patients,” Finn said. Physicians should use their judgment in providing this combination to patients with Child-Pugh scores of 7–9, he added. “All patients with advanced liver cancer need an endoscopy,” Finn said.
Kelley and Llovet also observed that several ongoing trials, some of which have been completed, are evaluating combinations of immunotherapy and other antiangiogenic agents or combinations of immunotherapies. The results from these trials will inform how such combinations will be used in the future.
Kelley predicted that, if some of these trials are positive, in the absence of a predictive biomarker, physicians will be guided by “the safety profiles of the combinations as well as the inference of synergy on the basis of depth and durability of responses.”
“Results of these trials will be known within the next 12-18 months and might further improve the current standards for patients with inoperable HCC,” Llovet said.
IMbrave150 was sponsored by F. Hoffmann–La Roche/Genentech. Finn has consulted for AtraZeneca, Bayer, Bristol-Myers Squibb, CStone, Eisai, Eli Lilly, Exelixis, Roche, Genentech, Merck & Co, Novartis, and Pfizer. Finn’s coauthors also report relationships with pharmaceutical companies. Kelley reports institutional research support from many pharmaceutical companies and served on the independent data monitoring committee for the IMbrave150 trial. Llovet has received research support from Bayer HealthCare Pharmaceuticals, Eisai, Bristol-Myers Squibb, Boehringer Ingelheim, and Ipsen and consulting fees from Bayer HealthCare Pharmaceuticals, Merck, Eisai Inc, Bristol-Myers Squibb, Celsion Corporation, Eli Lilly, Roche, Genentech, Glycotest, Nucleix, Can-Fite Biopharma, AstraZeneca, and Exelixis.
This article first appeared on Medscape.com.
New OS data with olaparib support ‘new era’ for ovarian cancer
Women with platinum-sensitive relapsed ovarian cancer and a BRCA mutation could see their survival extended by over a year by maintenance therapy with the PARP inhibitor olaparib (Lynparza, AstraZeneca).
The new overall survival (OS) data come from the SOLO2 study and were described as “a significant advance” in a cancer “that has a historically poor prognosis” by Richard Schilsky, MD, senior vice president and chief medical officer of the American Society of Clinical Oncology.
The results were highlighted at a presscast prior to being presented during the virtual scientific program of the 2020 ASCO annual meeting (abstract 6002).
The SOLO2 study randomly assigned almost 300 women with relapsed BRCA-related ovarian cancer that was responding to platinum-based chemotherapy to maintenance therapy with either olaparib or placebo.
Earlier results from this study showed that olaparib was associated with an investigator-assessed progression-free survival (PFS) of 19.1 months, versus just 5.5 months with placebo, as previously reported by Medscape Medical News.
New data from this trial, presented by Andrés Poveda, MD, Initia Oncology, Hospital Quironsalud, in Valencia, Spain, show that olaparib improved median OS by 12.9 months compared to placebo (51.7 months with olaparib vs. 38.8 months with placebo; hazard ratio, 0.74; P = .054).
At 5 years’ follow-up, 42.1% of women taking olaparib were alive, versus 33.2% taking placebo.
In an ASCO press release, Poveda described the improvement in median OS with olaparib as “impressive” and that it offers a “substantial benefit to our patients.
“This study helps usher in a new era of personalized medicine for women with this difficult-to-treat cancer,” he added.
Poveda told reporters that this study is “the first randomized phase 3 trial to provide overall survival data for maintenance PARP inhibitors.
“The finding that 22% of patient in the olaparib group received the study treatment for more than 5 years is unprecedented in the setting of relapsed ovarian cancer,” he added.
The new OS data were welcomed by Konstantin Zakashansky, MD, director of gynecologic oncology at Mount Sinai West, New York, who was not involved in the study.
“PARP inhibitor trials have revolutionized therapy for ovarian cancer in the front line, as well as in the recurrent setting, [with] all of the recently presented trials showing significant improvement in progression free survival,” he said.
“Overall survival data, however, which is considered the most clinically relevant endpoint in oncology trials and remains the ‘gold standard’ because of its relevance and objectivity, have been limited,” he continued.
Zakashansky recalled that when the earlier PFS data from SOLO2 were presented, “questions were raised regarding the clinical uncertainty of the benefit associated with olaparib maintenance, primarily whether the PFS benefit...would translate to a long-term overall survival benefit.”
For him, the current results “answer that question” and offer the “largest improvement in overall survival of any recurrent ovarian cancer patient trial reported to date.”
Schilsky added that the new data confirm that olaparib “should be the standard maintenance therapy for patients with BRCA-related relapsed ovarian cancer responding to platinum-based chemotherapy.”
The drug is already approved for this indication, but the new data showing a significant survival benefit are “comforting” and “good news,” he said.
Adverse events with olaparib
Treatment-emergent adverse events seen in the study were “consistent with the known tolerability profile of olaparib,” Poveda commented.
The most common events of any grade were nausea, fatigue/asthenia, and anemia. The most common event of grade ≥3 was anemia.
Adverse events leading to dose interruptions occurred in 50% of patients who received olaparib and 19% of patients who took placebo. Adverse events leading to dose reductions occurred in 28% and 3%, respectively.
Treatment discontinuation because of adverse events was reported in 17% of patients given olaparib and 3% of those in the placebo arm.
The study was funded by AstraZeneca and Merck Sharp & Dohme. Poveda reports a consulting or advisory role with AstraZeneca, Clovis Oncology, PharmaMar, Roche, and Tesaro and receiving expenses from PharmaMar. Many coauthors also report relationships with pharmaceutical companies.
This article first appeared on Medscape.com.
Women with platinum-sensitive relapsed ovarian cancer and a BRCA mutation could see their survival extended by over a year by maintenance therapy with the PARP inhibitor olaparib (Lynparza, AstraZeneca).
The new overall survival (OS) data come from the SOLO2 study and were described as “a significant advance” in a cancer “that has a historically poor prognosis” by Richard Schilsky, MD, senior vice president and chief medical officer of the American Society of Clinical Oncology.
The results were highlighted at a presscast prior to being presented during the virtual scientific program of the 2020 ASCO annual meeting (abstract 6002).
The SOLO2 study randomly assigned almost 300 women with relapsed BRCA-related ovarian cancer that was responding to platinum-based chemotherapy to maintenance therapy with either olaparib or placebo.
Earlier results from this study showed that olaparib was associated with an investigator-assessed progression-free survival (PFS) of 19.1 months, versus just 5.5 months with placebo, as previously reported by Medscape Medical News.
New data from this trial, presented by Andrés Poveda, MD, Initia Oncology, Hospital Quironsalud, in Valencia, Spain, show that olaparib improved median OS by 12.9 months compared to placebo (51.7 months with olaparib vs. 38.8 months with placebo; hazard ratio, 0.74; P = .054).
At 5 years’ follow-up, 42.1% of women taking olaparib were alive, versus 33.2% taking placebo.
In an ASCO press release, Poveda described the improvement in median OS with olaparib as “impressive” and that it offers a “substantial benefit to our patients.
“This study helps usher in a new era of personalized medicine for women with this difficult-to-treat cancer,” he added.
Poveda told reporters that this study is “the first randomized phase 3 trial to provide overall survival data for maintenance PARP inhibitors.
“The finding that 22% of patient in the olaparib group received the study treatment for more than 5 years is unprecedented in the setting of relapsed ovarian cancer,” he added.
The new OS data were welcomed by Konstantin Zakashansky, MD, director of gynecologic oncology at Mount Sinai West, New York, who was not involved in the study.
“PARP inhibitor trials have revolutionized therapy for ovarian cancer in the front line, as well as in the recurrent setting, [with] all of the recently presented trials showing significant improvement in progression free survival,” he said.
“Overall survival data, however, which is considered the most clinically relevant endpoint in oncology trials and remains the ‘gold standard’ because of its relevance and objectivity, have been limited,” he continued.
Zakashansky recalled that when the earlier PFS data from SOLO2 were presented, “questions were raised regarding the clinical uncertainty of the benefit associated with olaparib maintenance, primarily whether the PFS benefit...would translate to a long-term overall survival benefit.”
For him, the current results “answer that question” and offer the “largest improvement in overall survival of any recurrent ovarian cancer patient trial reported to date.”
Schilsky added that the new data confirm that olaparib “should be the standard maintenance therapy for patients with BRCA-related relapsed ovarian cancer responding to platinum-based chemotherapy.”
The drug is already approved for this indication, but the new data showing a significant survival benefit are “comforting” and “good news,” he said.
Adverse events with olaparib
Treatment-emergent adverse events seen in the study were “consistent with the known tolerability profile of olaparib,” Poveda commented.
The most common events of any grade were nausea, fatigue/asthenia, and anemia. The most common event of grade ≥3 was anemia.
Adverse events leading to dose interruptions occurred in 50% of patients who received olaparib and 19% of patients who took placebo. Adverse events leading to dose reductions occurred in 28% and 3%, respectively.
Treatment discontinuation because of adverse events was reported in 17% of patients given olaparib and 3% of those in the placebo arm.
The study was funded by AstraZeneca and Merck Sharp & Dohme. Poveda reports a consulting or advisory role with AstraZeneca, Clovis Oncology, PharmaMar, Roche, and Tesaro and receiving expenses from PharmaMar. Many coauthors also report relationships with pharmaceutical companies.
This article first appeared on Medscape.com.
Women with platinum-sensitive relapsed ovarian cancer and a BRCA mutation could see their survival extended by over a year by maintenance therapy with the PARP inhibitor olaparib (Lynparza, AstraZeneca).
The new overall survival (OS) data come from the SOLO2 study and were described as “a significant advance” in a cancer “that has a historically poor prognosis” by Richard Schilsky, MD, senior vice president and chief medical officer of the American Society of Clinical Oncology.
The results were highlighted at a presscast prior to being presented during the virtual scientific program of the 2020 ASCO annual meeting (abstract 6002).
The SOLO2 study randomly assigned almost 300 women with relapsed BRCA-related ovarian cancer that was responding to platinum-based chemotherapy to maintenance therapy with either olaparib or placebo.
Earlier results from this study showed that olaparib was associated with an investigator-assessed progression-free survival (PFS) of 19.1 months, versus just 5.5 months with placebo, as previously reported by Medscape Medical News.
New data from this trial, presented by Andrés Poveda, MD, Initia Oncology, Hospital Quironsalud, in Valencia, Spain, show that olaparib improved median OS by 12.9 months compared to placebo (51.7 months with olaparib vs. 38.8 months with placebo; hazard ratio, 0.74; P = .054).
At 5 years’ follow-up, 42.1% of women taking olaparib were alive, versus 33.2% taking placebo.
In an ASCO press release, Poveda described the improvement in median OS with olaparib as “impressive” and that it offers a “substantial benefit to our patients.
“This study helps usher in a new era of personalized medicine for women with this difficult-to-treat cancer,” he added.
Poveda told reporters that this study is “the first randomized phase 3 trial to provide overall survival data for maintenance PARP inhibitors.
“The finding that 22% of patient in the olaparib group received the study treatment for more than 5 years is unprecedented in the setting of relapsed ovarian cancer,” he added.
The new OS data were welcomed by Konstantin Zakashansky, MD, director of gynecologic oncology at Mount Sinai West, New York, who was not involved in the study.
“PARP inhibitor trials have revolutionized therapy for ovarian cancer in the front line, as well as in the recurrent setting, [with] all of the recently presented trials showing significant improvement in progression free survival,” he said.
“Overall survival data, however, which is considered the most clinically relevant endpoint in oncology trials and remains the ‘gold standard’ because of its relevance and objectivity, have been limited,” he continued.
Zakashansky recalled that when the earlier PFS data from SOLO2 were presented, “questions were raised regarding the clinical uncertainty of the benefit associated with olaparib maintenance, primarily whether the PFS benefit...would translate to a long-term overall survival benefit.”
For him, the current results “answer that question” and offer the “largest improvement in overall survival of any recurrent ovarian cancer patient trial reported to date.”
Schilsky added that the new data confirm that olaparib “should be the standard maintenance therapy for patients with BRCA-related relapsed ovarian cancer responding to platinum-based chemotherapy.”
The drug is already approved for this indication, but the new data showing a significant survival benefit are “comforting” and “good news,” he said.
Adverse events with olaparib
Treatment-emergent adverse events seen in the study were “consistent with the known tolerability profile of olaparib,” Poveda commented.
The most common events of any grade were nausea, fatigue/asthenia, and anemia. The most common event of grade ≥3 was anemia.
Adverse events leading to dose interruptions occurred in 50% of patients who received olaparib and 19% of patients who took placebo. Adverse events leading to dose reductions occurred in 28% and 3%, respectively.
Treatment discontinuation because of adverse events was reported in 17% of patients given olaparib and 3% of those in the placebo arm.
The study was funded by AstraZeneca and Merck Sharp & Dohme. Poveda reports a consulting or advisory role with AstraZeneca, Clovis Oncology, PharmaMar, Roche, and Tesaro and receiving expenses from PharmaMar. Many coauthors also report relationships with pharmaceutical companies.
This article first appeared on Medscape.com.
FROM ASCO 2020
Satralizumab monotherapy reduces NMOSD relapse rate
according to trial results published in the Lancet Neurology.
The findings help confirm the role of interleukin-6 in the pathobiology of aquaporin-4 autoantibody (AQP4-IgG)–seropositive disease. For patients who are AQP4-IgG seronegative, however, “there is insufficient evidence to indicate a risk reduction” with this drug, the investigators wrote. In addition, satralizumab did not significantly affect pain or fatigue.
“The limitations of the study include the relatively small group sizes and low number of relapses. Despite these limitations, a significant treatment benefit was observed with satralizumab, compared with placebo in the study population, with efficacy and safety comparable to satralizumab used in combination with immunosuppressants,” reported lead author Anthony Traboulsee, MD, professor of neurology at the University of British Columbia, Vancouver, and colleagues.
Satralizumab is a humanized monoclonal antibody targeting the IL-6 receptor. A prior phase 3 study, SakuraSky, found that the drug reduces the risk of NMOSD relapse when added to immunosuppressant therapy. To assess the safety and efficacy of satralizumab monotherapy, Dr. Traboulsee and colleagues conducted SakuraStar, a randomized, double-blind, placebo-controlled trial.
Evaluating drug as monotherapy
The phase 3 trial enrolled 95 patients aged 18-74 years at 44 sites in 13 countries. The investigators included patients with AQP4-IgG–seropositive or –seronegative neuromyelitis optica using the 2006 Wingerchuk criteria or with AQP4-IgG–seropositive NMOSD with at least one event of longitudinally extensive myelitis or optic neuritis. The researchers limited the number of AQP4-IgG–seronegative patients to about 30% of the study population. Eligible participants had at least one NMOSD attack or relapse in the past 12 months and a score of 6.5 or less on the Expanded Disability Status Scale (EDSS). The investigators excluded patients with a clinical relapse in the 30 days before study baseline. Participants were randomly assigned 2:1 to receive satralizumab 120 mg or placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Concomitant immunosuppressant use was prohibited, although corticosteroids and intravenous immunoglobulin were permitted as rescue therapy for the treatment of relapse.
The primary endpoint was time to first relapse, and the trial was designed to continue until 44 relapses occurred or for 1.5 years after the last patient entered the trial, whichever occurred first.
“Because even one NMOSD attack can have serious neurological consequences, this design allowed patients who had an attack on placebo to enter the open-label phase and receive the active drug,” the researchers wrote. “The trial design used unequal randomization to minimize exposure to placebo; because patients were not permitted to receive concomitant immunosuppressant treatment in this trial, the design limited the number of patients not receiving any treatment for the disorder. Placebo was selected with the consideration that no drugs were approved for the treatment of NMOSD when the trial was designed.” Recent trials of eculizumab, inebilizumab, and satralizumab have found that the agents are effective treatments for NMOSD. In 2019, the Food and Drug Administration approved eculizumab, a complement inhibitor, for the treatment of AQP4-IgG–seropositive NMOSD.
For the primary endpoint of SakuraStar, the researchers defined relapses as new or worsening objective neurologic symptoms with at least one of the following:
- Increase of 1 or more EDSS points from a baseline EDSS score of more than 0, or increase of 2 or more EDSS points from a baseline EDSS score of 0
- Increase of 2 or more points on at least one appropriate symptom-specific functional system score for pyramidal, cerebellar, brain stem, sensory, bowel or bladder, or a single eye
- Increase of 1 or more points on more than one symptom-specific functional system score with a baseline of at least 1
- Increase of 1 or more points on a single-eye symptom-specific functional system score with a baseline score of at least 1
In addition, symptoms had to be attributable to NMOSD; persist for more than 24 hours; and not be attributable to confounding clinical factors such as fever, infection, injury, change in mood, or adverse reactions to medications. Researchers assessed EDSS and functional system scores within 7 days of a patient reporting symptoms.
The double-blind treatment period ended 1.5 years after the last enrolled patient was assigned to satralizumab or placebo. More than 80% of the participants were women, including 73% of the satralizumab group and 97% of the placebo group. In all, 95 participants were assigned to a treatment between 2014 and 2017 – 63 to satralizumab and 32 to placebo. Relapses occurred in 19 patients receiving satralizumab (30%) and 16 receiving placebo (50%). The hazard ratio was 0.45.
“Patients treated with placebo showed a shorter time to relapse and a higher withdrawal rate than did patients treated with satralizumab,” wrote Dr. Traboulsee and colleagues. The Kaplan-Meier method suggested that 76% of patients on satralizumab had not relapsed at 48 weeks, compared with 62% of patients on placebo. And at 96 weeks, 72% of patients on satralizumab had not relapsed, compared with 51% of patients on placebo.
Among patients who were AQP4-IgG seropositive, the proportion with protocol-defined relapse was 22% in the satralizumab group versus 57% in the placebo group. Among patients who were AQP4-IgG seronegative, the proportion with a protocol-defined relapse was 46% in the satralizumab group versus 33% in the placebo group.
The most common adverse events were urinary tract infection and upper respiratory tract infection, and most adverse events were mild to moderate. A higher rate of severe adverse events was reported in the satralizumab group than in the placebo group (32.1 vs. 9.9 events per 100 patient-years). The investigators considered most of the severe adverse events unrelated to the study treatment. “None of the severe adverse events led to discontinuation of the study drug except one severe event of pneumonia in the satralizumab group,” the researchers wrote.
Data confirm efficacy of IL-6 blockade
“Satralizumab was well tolerated and no meaningful adverse effects from the drug were reported and no deaths occurred,” said Michael Levy, MD, PhD, director of the NMO clinic and research laboratory at Massachusetts General Hospital, Boston, in an accompanying editorial. “This trial of satralizumab was done shortly after the completion of a parallel trial of satralizumab in patients with NMOSD in which the same dose of satralizumab reduced the risk of relapse by 62%, compared with placebo. The main difference between these two trials is that, in the first published study, participants were permitted to use background immunotherapy; otherwise, the trial designs were nearly identical, and the enrolled participants are comparable. Together, the findings from these studies suggest that background therapy seems to provide only a small additional benefit to satralizumab alone.”
Dr. Levy also discussed findings from a phase 2 study of tocilizumab for the prevention of relapse in patients with NMOSD published in the same issue of the Lancet Neurology. The satralizumab and tocilizumab data have “confirmed that IL-6 blockade reduces the risk of relapse in patients with NMOSD,” Dr. Levy said. “IL-6 is a crucial component of the immune system, but when IL-6 production is altered during autoimmune attacks and sepsis, there can be severe consequences.”
The phase 2 trial of tocilizumab, which was described at the 2019 annual congress of the European Committee for Treatment and Research in Multiple Sclerosis, included 118 patients, 87% of whom were AQP4-IgG seropositive. Patients received intravenous tocilizumab or oral azathioprine for up to 60 weeks. Overall, 14% of patients in the tocilizumab group relapsed, compared with 47% of patients in the azathioprine group.
“The main differences between this trial of tocilizumab and the two satralizumab trials are that the tocilizumab was administered intravenously, rather than subcutaneously, the study duration was approximately 1 year, and the investigators were not masked to the treatment allocation,” Dr. Levy said. “Similar to satralizumab, adverse effects with tocilizumab were mild, including asymptomatic elevations in liver enzymes and an increased incidence of respiratory and urinary infections, with no significant differences identified between the tocilizumab and azathioprine groups.”
Various immunopathologic mechanisms may influence outcomes in NMOSD. While satralizumab and tocilizumab target IL-6, eculizumab is a C5 complement inhibitor and inebilizumab is a CD19 B-cell depleting monoclonal antibody, Dr. Levy said. “The safety concerns regarding these approaches are all substantially outweighed by the benefit of preventing NMOSD relapses.”
A need to understand AQP4-IgG–seronegative disease
SakuraStar “provides convincing data for the efficacy of satralizumab monotherapy in NMOSD with subgroup analysis showing that the benefit was seen in AQP4-IgG seropositive patients,” commented Dean M. Wingerchuk, MD, director of the division of multiple sclerosis and autoimmune neurology at the Mayo Clinic in Phoenix. “The results help confirm the key role of IL-6 in the pathobiology of AQP4-IgG–seropositive disease.”
Questions about AQP4-IgG seronegative disease remain. “The results are quite similar to the SakuraSky trial, in which satralizumab was used in conjunction with other background immunosuppressive therapies, suggesting that the primary benefit may be derived primarily from satralizumab. Both trials also showed that satralizumab did not benefit the NMOSD without AQP4-IgG subgroup though the subject numbers are rather small. We need to know more about the clinical and laboratory characteristics of the seronegative patients as they likely comprise a heterogeneous group. For example, did any of them have other autoantibodies such as MOG-IgG? Depending on the results, those details may help us understand the relative role of IL-6 in AQP4-IgG–seronegative subgroups, an important area of further study.”
SakuraStar was funded by Chugai Pharmaceutical, a member of the Roche group. Dr. Traboulsee reported grants, personal fees, and nonfinancial support from Chugai Pharmaceutical during the study, and several coauthors were employees of Chugai Pharmaceutical. Additional coauthors reported personal fees from Chugai, Roche, and other companies. Dr. Levy has received consulting fees from Alexion, Viela Bio, Chugai Pharmaceutical, Quest Diagnostics, and UCB Pharmaceuticals.
SOURCE: Traboulsee A et al. Lancet Neurol. 2020;19(5):402-12.
according to trial results published in the Lancet Neurology.
The findings help confirm the role of interleukin-6 in the pathobiology of aquaporin-4 autoantibody (AQP4-IgG)–seropositive disease. For patients who are AQP4-IgG seronegative, however, “there is insufficient evidence to indicate a risk reduction” with this drug, the investigators wrote. In addition, satralizumab did not significantly affect pain or fatigue.
“The limitations of the study include the relatively small group sizes and low number of relapses. Despite these limitations, a significant treatment benefit was observed with satralizumab, compared with placebo in the study population, with efficacy and safety comparable to satralizumab used in combination with immunosuppressants,” reported lead author Anthony Traboulsee, MD, professor of neurology at the University of British Columbia, Vancouver, and colleagues.
Satralizumab is a humanized monoclonal antibody targeting the IL-6 receptor. A prior phase 3 study, SakuraSky, found that the drug reduces the risk of NMOSD relapse when added to immunosuppressant therapy. To assess the safety and efficacy of satralizumab monotherapy, Dr. Traboulsee and colleagues conducted SakuraStar, a randomized, double-blind, placebo-controlled trial.
Evaluating drug as monotherapy
The phase 3 trial enrolled 95 patients aged 18-74 years at 44 sites in 13 countries. The investigators included patients with AQP4-IgG–seropositive or –seronegative neuromyelitis optica using the 2006 Wingerchuk criteria or with AQP4-IgG–seropositive NMOSD with at least one event of longitudinally extensive myelitis or optic neuritis. The researchers limited the number of AQP4-IgG–seronegative patients to about 30% of the study population. Eligible participants had at least one NMOSD attack or relapse in the past 12 months and a score of 6.5 or less on the Expanded Disability Status Scale (EDSS). The investigators excluded patients with a clinical relapse in the 30 days before study baseline. Participants were randomly assigned 2:1 to receive satralizumab 120 mg or placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Concomitant immunosuppressant use was prohibited, although corticosteroids and intravenous immunoglobulin were permitted as rescue therapy for the treatment of relapse.
The primary endpoint was time to first relapse, and the trial was designed to continue until 44 relapses occurred or for 1.5 years after the last patient entered the trial, whichever occurred first.
“Because even one NMOSD attack can have serious neurological consequences, this design allowed patients who had an attack on placebo to enter the open-label phase and receive the active drug,” the researchers wrote. “The trial design used unequal randomization to minimize exposure to placebo; because patients were not permitted to receive concomitant immunosuppressant treatment in this trial, the design limited the number of patients not receiving any treatment for the disorder. Placebo was selected with the consideration that no drugs were approved for the treatment of NMOSD when the trial was designed.” Recent trials of eculizumab, inebilizumab, and satralizumab have found that the agents are effective treatments for NMOSD. In 2019, the Food and Drug Administration approved eculizumab, a complement inhibitor, for the treatment of AQP4-IgG–seropositive NMOSD.
For the primary endpoint of SakuraStar, the researchers defined relapses as new or worsening objective neurologic symptoms with at least one of the following:
- Increase of 1 or more EDSS points from a baseline EDSS score of more than 0, or increase of 2 or more EDSS points from a baseline EDSS score of 0
- Increase of 2 or more points on at least one appropriate symptom-specific functional system score for pyramidal, cerebellar, brain stem, sensory, bowel or bladder, or a single eye
- Increase of 1 or more points on more than one symptom-specific functional system score with a baseline of at least 1
- Increase of 1 or more points on a single-eye symptom-specific functional system score with a baseline score of at least 1
In addition, symptoms had to be attributable to NMOSD; persist for more than 24 hours; and not be attributable to confounding clinical factors such as fever, infection, injury, change in mood, or adverse reactions to medications. Researchers assessed EDSS and functional system scores within 7 days of a patient reporting symptoms.
The double-blind treatment period ended 1.5 years after the last enrolled patient was assigned to satralizumab or placebo. More than 80% of the participants were women, including 73% of the satralizumab group and 97% of the placebo group. In all, 95 participants were assigned to a treatment between 2014 and 2017 – 63 to satralizumab and 32 to placebo. Relapses occurred in 19 patients receiving satralizumab (30%) and 16 receiving placebo (50%). The hazard ratio was 0.45.
“Patients treated with placebo showed a shorter time to relapse and a higher withdrawal rate than did patients treated with satralizumab,” wrote Dr. Traboulsee and colleagues. The Kaplan-Meier method suggested that 76% of patients on satralizumab had not relapsed at 48 weeks, compared with 62% of patients on placebo. And at 96 weeks, 72% of patients on satralizumab had not relapsed, compared with 51% of patients on placebo.
Among patients who were AQP4-IgG seropositive, the proportion with protocol-defined relapse was 22% in the satralizumab group versus 57% in the placebo group. Among patients who were AQP4-IgG seronegative, the proportion with a protocol-defined relapse was 46% in the satralizumab group versus 33% in the placebo group.
The most common adverse events were urinary tract infection and upper respiratory tract infection, and most adverse events were mild to moderate. A higher rate of severe adverse events was reported in the satralizumab group than in the placebo group (32.1 vs. 9.9 events per 100 patient-years). The investigators considered most of the severe adverse events unrelated to the study treatment. “None of the severe adverse events led to discontinuation of the study drug except one severe event of pneumonia in the satralizumab group,” the researchers wrote.
Data confirm efficacy of IL-6 blockade
“Satralizumab was well tolerated and no meaningful adverse effects from the drug were reported and no deaths occurred,” said Michael Levy, MD, PhD, director of the NMO clinic and research laboratory at Massachusetts General Hospital, Boston, in an accompanying editorial. “This trial of satralizumab was done shortly after the completion of a parallel trial of satralizumab in patients with NMOSD in which the same dose of satralizumab reduced the risk of relapse by 62%, compared with placebo. The main difference between these two trials is that, in the first published study, participants were permitted to use background immunotherapy; otherwise, the trial designs were nearly identical, and the enrolled participants are comparable. Together, the findings from these studies suggest that background therapy seems to provide only a small additional benefit to satralizumab alone.”
Dr. Levy also discussed findings from a phase 2 study of tocilizumab for the prevention of relapse in patients with NMOSD published in the same issue of the Lancet Neurology. The satralizumab and tocilizumab data have “confirmed that IL-6 blockade reduces the risk of relapse in patients with NMOSD,” Dr. Levy said. “IL-6 is a crucial component of the immune system, but when IL-6 production is altered during autoimmune attacks and sepsis, there can be severe consequences.”
The phase 2 trial of tocilizumab, which was described at the 2019 annual congress of the European Committee for Treatment and Research in Multiple Sclerosis, included 118 patients, 87% of whom were AQP4-IgG seropositive. Patients received intravenous tocilizumab or oral azathioprine for up to 60 weeks. Overall, 14% of patients in the tocilizumab group relapsed, compared with 47% of patients in the azathioprine group.
“The main differences between this trial of tocilizumab and the two satralizumab trials are that the tocilizumab was administered intravenously, rather than subcutaneously, the study duration was approximately 1 year, and the investigators were not masked to the treatment allocation,” Dr. Levy said. “Similar to satralizumab, adverse effects with tocilizumab were mild, including asymptomatic elevations in liver enzymes and an increased incidence of respiratory and urinary infections, with no significant differences identified between the tocilizumab and azathioprine groups.”
Various immunopathologic mechanisms may influence outcomes in NMOSD. While satralizumab and tocilizumab target IL-6, eculizumab is a C5 complement inhibitor and inebilizumab is a CD19 B-cell depleting monoclonal antibody, Dr. Levy said. “The safety concerns regarding these approaches are all substantially outweighed by the benefit of preventing NMOSD relapses.”
A need to understand AQP4-IgG–seronegative disease
SakuraStar “provides convincing data for the efficacy of satralizumab monotherapy in NMOSD with subgroup analysis showing that the benefit was seen in AQP4-IgG seropositive patients,” commented Dean M. Wingerchuk, MD, director of the division of multiple sclerosis and autoimmune neurology at the Mayo Clinic in Phoenix. “The results help confirm the key role of IL-6 in the pathobiology of AQP4-IgG–seropositive disease.”
Questions about AQP4-IgG seronegative disease remain. “The results are quite similar to the SakuraSky trial, in which satralizumab was used in conjunction with other background immunosuppressive therapies, suggesting that the primary benefit may be derived primarily from satralizumab. Both trials also showed that satralizumab did not benefit the NMOSD without AQP4-IgG subgroup though the subject numbers are rather small. We need to know more about the clinical and laboratory characteristics of the seronegative patients as they likely comprise a heterogeneous group. For example, did any of them have other autoantibodies such as MOG-IgG? Depending on the results, those details may help us understand the relative role of IL-6 in AQP4-IgG–seronegative subgroups, an important area of further study.”
SakuraStar was funded by Chugai Pharmaceutical, a member of the Roche group. Dr. Traboulsee reported grants, personal fees, and nonfinancial support from Chugai Pharmaceutical during the study, and several coauthors were employees of Chugai Pharmaceutical. Additional coauthors reported personal fees from Chugai, Roche, and other companies. Dr. Levy has received consulting fees from Alexion, Viela Bio, Chugai Pharmaceutical, Quest Diagnostics, and UCB Pharmaceuticals.
SOURCE: Traboulsee A et al. Lancet Neurol. 2020;19(5):402-12.
according to trial results published in the Lancet Neurology.
The findings help confirm the role of interleukin-6 in the pathobiology of aquaporin-4 autoantibody (AQP4-IgG)–seropositive disease. For patients who are AQP4-IgG seronegative, however, “there is insufficient evidence to indicate a risk reduction” with this drug, the investigators wrote. In addition, satralizumab did not significantly affect pain or fatigue.
“The limitations of the study include the relatively small group sizes and low number of relapses. Despite these limitations, a significant treatment benefit was observed with satralizumab, compared with placebo in the study population, with efficacy and safety comparable to satralizumab used in combination with immunosuppressants,” reported lead author Anthony Traboulsee, MD, professor of neurology at the University of British Columbia, Vancouver, and colleagues.
Satralizumab is a humanized monoclonal antibody targeting the IL-6 receptor. A prior phase 3 study, SakuraSky, found that the drug reduces the risk of NMOSD relapse when added to immunosuppressant therapy. To assess the safety and efficacy of satralizumab monotherapy, Dr. Traboulsee and colleagues conducted SakuraStar, a randomized, double-blind, placebo-controlled trial.
Evaluating drug as monotherapy
The phase 3 trial enrolled 95 patients aged 18-74 years at 44 sites in 13 countries. The investigators included patients with AQP4-IgG–seropositive or –seronegative neuromyelitis optica using the 2006 Wingerchuk criteria or with AQP4-IgG–seropositive NMOSD with at least one event of longitudinally extensive myelitis or optic neuritis. The researchers limited the number of AQP4-IgG–seronegative patients to about 30% of the study population. Eligible participants had at least one NMOSD attack or relapse in the past 12 months and a score of 6.5 or less on the Expanded Disability Status Scale (EDSS). The investigators excluded patients with a clinical relapse in the 30 days before study baseline. Participants were randomly assigned 2:1 to receive satralizumab 120 mg or placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Concomitant immunosuppressant use was prohibited, although corticosteroids and intravenous immunoglobulin were permitted as rescue therapy for the treatment of relapse.
The primary endpoint was time to first relapse, and the trial was designed to continue until 44 relapses occurred or for 1.5 years after the last patient entered the trial, whichever occurred first.
“Because even one NMOSD attack can have serious neurological consequences, this design allowed patients who had an attack on placebo to enter the open-label phase and receive the active drug,” the researchers wrote. “The trial design used unequal randomization to minimize exposure to placebo; because patients were not permitted to receive concomitant immunosuppressant treatment in this trial, the design limited the number of patients not receiving any treatment for the disorder. Placebo was selected with the consideration that no drugs were approved for the treatment of NMOSD when the trial was designed.” Recent trials of eculizumab, inebilizumab, and satralizumab have found that the agents are effective treatments for NMOSD. In 2019, the Food and Drug Administration approved eculizumab, a complement inhibitor, for the treatment of AQP4-IgG–seropositive NMOSD.
For the primary endpoint of SakuraStar, the researchers defined relapses as new or worsening objective neurologic symptoms with at least one of the following:
- Increase of 1 or more EDSS points from a baseline EDSS score of more than 0, or increase of 2 or more EDSS points from a baseline EDSS score of 0
- Increase of 2 or more points on at least one appropriate symptom-specific functional system score for pyramidal, cerebellar, brain stem, sensory, bowel or bladder, or a single eye
- Increase of 1 or more points on more than one symptom-specific functional system score with a baseline of at least 1
- Increase of 1 or more points on a single-eye symptom-specific functional system score with a baseline score of at least 1
In addition, symptoms had to be attributable to NMOSD; persist for more than 24 hours; and not be attributable to confounding clinical factors such as fever, infection, injury, change in mood, or adverse reactions to medications. Researchers assessed EDSS and functional system scores within 7 days of a patient reporting symptoms.
The double-blind treatment period ended 1.5 years after the last enrolled patient was assigned to satralizumab or placebo. More than 80% of the participants were women, including 73% of the satralizumab group and 97% of the placebo group. In all, 95 participants were assigned to a treatment between 2014 and 2017 – 63 to satralizumab and 32 to placebo. Relapses occurred in 19 patients receiving satralizumab (30%) and 16 receiving placebo (50%). The hazard ratio was 0.45.
“Patients treated with placebo showed a shorter time to relapse and a higher withdrawal rate than did patients treated with satralizumab,” wrote Dr. Traboulsee and colleagues. The Kaplan-Meier method suggested that 76% of patients on satralizumab had not relapsed at 48 weeks, compared with 62% of patients on placebo. And at 96 weeks, 72% of patients on satralizumab had not relapsed, compared with 51% of patients on placebo.
Among patients who were AQP4-IgG seropositive, the proportion with protocol-defined relapse was 22% in the satralizumab group versus 57% in the placebo group. Among patients who were AQP4-IgG seronegative, the proportion with a protocol-defined relapse was 46% in the satralizumab group versus 33% in the placebo group.
The most common adverse events were urinary tract infection and upper respiratory tract infection, and most adverse events were mild to moderate. A higher rate of severe adverse events was reported in the satralizumab group than in the placebo group (32.1 vs. 9.9 events per 100 patient-years). The investigators considered most of the severe adverse events unrelated to the study treatment. “None of the severe adverse events led to discontinuation of the study drug except one severe event of pneumonia in the satralizumab group,” the researchers wrote.
Data confirm efficacy of IL-6 blockade
“Satralizumab was well tolerated and no meaningful adverse effects from the drug were reported and no deaths occurred,” said Michael Levy, MD, PhD, director of the NMO clinic and research laboratory at Massachusetts General Hospital, Boston, in an accompanying editorial. “This trial of satralizumab was done shortly after the completion of a parallel trial of satralizumab in patients with NMOSD in which the same dose of satralizumab reduced the risk of relapse by 62%, compared with placebo. The main difference between these two trials is that, in the first published study, participants were permitted to use background immunotherapy; otherwise, the trial designs were nearly identical, and the enrolled participants are comparable. Together, the findings from these studies suggest that background therapy seems to provide only a small additional benefit to satralizumab alone.”
Dr. Levy also discussed findings from a phase 2 study of tocilizumab for the prevention of relapse in patients with NMOSD published in the same issue of the Lancet Neurology. The satralizumab and tocilizumab data have “confirmed that IL-6 blockade reduces the risk of relapse in patients with NMOSD,” Dr. Levy said. “IL-6 is a crucial component of the immune system, but when IL-6 production is altered during autoimmune attacks and sepsis, there can be severe consequences.”
The phase 2 trial of tocilizumab, which was described at the 2019 annual congress of the European Committee for Treatment and Research in Multiple Sclerosis, included 118 patients, 87% of whom were AQP4-IgG seropositive. Patients received intravenous tocilizumab or oral azathioprine for up to 60 weeks. Overall, 14% of patients in the tocilizumab group relapsed, compared with 47% of patients in the azathioprine group.
“The main differences between this trial of tocilizumab and the two satralizumab trials are that the tocilizumab was administered intravenously, rather than subcutaneously, the study duration was approximately 1 year, and the investigators were not masked to the treatment allocation,” Dr. Levy said. “Similar to satralizumab, adverse effects with tocilizumab were mild, including asymptomatic elevations in liver enzymes and an increased incidence of respiratory and urinary infections, with no significant differences identified between the tocilizumab and azathioprine groups.”
Various immunopathologic mechanisms may influence outcomes in NMOSD. While satralizumab and tocilizumab target IL-6, eculizumab is a C5 complement inhibitor and inebilizumab is a CD19 B-cell depleting monoclonal antibody, Dr. Levy said. “The safety concerns regarding these approaches are all substantially outweighed by the benefit of preventing NMOSD relapses.”
A need to understand AQP4-IgG–seronegative disease
SakuraStar “provides convincing data for the efficacy of satralizumab monotherapy in NMOSD with subgroup analysis showing that the benefit was seen in AQP4-IgG seropositive patients,” commented Dean M. Wingerchuk, MD, director of the division of multiple sclerosis and autoimmune neurology at the Mayo Clinic in Phoenix. “The results help confirm the key role of IL-6 in the pathobiology of AQP4-IgG–seropositive disease.”
Questions about AQP4-IgG seronegative disease remain. “The results are quite similar to the SakuraSky trial, in which satralizumab was used in conjunction with other background immunosuppressive therapies, suggesting that the primary benefit may be derived primarily from satralizumab. Both trials also showed that satralizumab did not benefit the NMOSD without AQP4-IgG subgroup though the subject numbers are rather small. We need to know more about the clinical and laboratory characteristics of the seronegative patients as they likely comprise a heterogeneous group. For example, did any of them have other autoantibodies such as MOG-IgG? Depending on the results, those details may help us understand the relative role of IL-6 in AQP4-IgG–seronegative subgroups, an important area of further study.”
SakuraStar was funded by Chugai Pharmaceutical, a member of the Roche group. Dr. Traboulsee reported grants, personal fees, and nonfinancial support from Chugai Pharmaceutical during the study, and several coauthors were employees of Chugai Pharmaceutical. Additional coauthors reported personal fees from Chugai, Roche, and other companies. Dr. Levy has received consulting fees from Alexion, Viela Bio, Chugai Pharmaceutical, Quest Diagnostics, and UCB Pharmaceuticals.
SOURCE: Traboulsee A et al. Lancet Neurol. 2020;19(5):402-12.
FROM THE LANCET NEUROLOGY
Letters: Disappointment in the Wrapping
To the Editor: I am very disappointed to continue receiving my copies of the Federal Practitioner in nonrecyclable plastic. As a health care professional, I am on the mailing list for numerous other medical publications, all of which seem to be able to utilize recyclable plastic wrappers. I hope you can rectify this problem, which is an embarrassment to me, a serviceconnected veteran.
C. William Kaiser, MD
To the Editor: I am very disappointed to continue receiving my copies of the Federal Practitioner in nonrecyclable plastic. As a health care professional, I am on the mailing list for numerous other medical publications, all of which seem to be able to utilize recyclable plastic wrappers. I hope you can rectify this problem, which is an embarrassment to me, a serviceconnected veteran.
C. William Kaiser, MD
To the Editor: I am very disappointed to continue receiving my copies of the Federal Practitioner in nonrecyclable plastic. As a health care professional, I am on the mailing list for numerous other medical publications, all of which seem to be able to utilize recyclable plastic wrappers. I hope you can rectify this problem, which is an embarrassment to me, a serviceconnected veteran.
C. William Kaiser, MD
Doctors advise asthmatics to continue therapy during pandemic
“In fact, there’s no data to support this at this time. Maintaining adequate asthma control is the current CDC recommendation,” said pediatric pulmonologist John Carl, MD, of Cleveland Clinic Children’s Hospital. Patients, he said, should be advised to “follow your asthma action plan as outlined by your primary care or specialty clinician and communicate about evolving symptoms, such as fever rather than just congestion, wheezing, and coughing, etc.”
Dr. Carl spoke in a May 7 webinar about asthma and COVID-19 with Lakiea Wright, M.D., a physician specializing in internal medicine and allergy and immunology at Brigham and Women’s Hospital in Boston and medical director of clinical affairs for Thermo Fisher Scientific’s ImmunoDiagnostics division. The webinar, sponsored by Thermo Fisher Scientific, included discussion of COVID-19 risks, disease management, and distinguishing between the virus and asthma.
In a follow-up interview, Dr. Wright said she’s hearing from patients and parents who are concerned about whether people with asthma face a higher risk of COVID-19 infection. There’s no evidence that they do, she said, but “the CDC states that individuals with moderate to severe asthma may be higher risk for moderate to severe disease from COVID-19 if they were to become infected.”
Indeed, she said, “it is well established that viruses can trigger asthma.” But, as she also noted, early research about the risk in patients with asthma is conflicting.
“Some studies suggest asthma may be a risk factor for hospitalization while other data suggests asthma is not a common risk factor for those hospitalized,” Dr. Wright said.
She highlighted a recent study that suggests people with allergic asthma have “a reduced ACE2 gene expression in airway cells and thus decreased susceptibility to infection” by the novel coronavirus (J Allergy Clin Immunol. 2020 Apr 22. doi: 10.1016/j.jaci.2020.04.009).
Dr. Wright cautioned, however, that “this is a hypothesis and will need to be studied more.”
For now, she said, patients “should follow their asthma action plan and take their inhalers, including inhaled corticosteroids, as prescribed by their health care providers.”
Most patients are reasonable and do comply when their physicians explain why they should take a medication,” she noted.
Dr. Carl agreed, and added that a short course of oral corticosteroids are also recommended to manage minor exacerbations and “prevent patients from having to arrive as inpatients in more acute settings and risk health system–related exposures to the current pandemic.”
He cautioned, however, that metered-dose inhalers are preferable to nebulizers, and side vent ports should be avoided since they can aerosolize infectious agents and put health care providers and family members at risk.
Unfortunately, he said, there’s been a shortage of short-acting beta agonist albuterol inhalers. This has been linked to hospitals trying to avoid the use of nebulizers.
Dr. Wright advised colleagues to focus on unique symptoms first, then address overlapping symptoms and other symptoms to differentiate between COVID-19 and asthma/allergy.
She noted that environmental allergy symptoms alone do not cause fever, a hallmark of COVID-19. Shortness of breath can be a distinguishing symptom for the virus, because this is not a common symptom of environmental allergies unless the patient has asthma, Dr. Wright said.
Cough can be an overlapping symptom because in environmental allergies, postnasal drip from allergic rhinitis can trigger cough, she explained. Nasal congestion and/or runny nose can develop with viral illnesses in general, but these are symptoms not included in the CDC’s list of the most common COVID-19 symptoms. Severe fatigue and body aches aren’t symptoms consistent with environmental allergies, Dr. Wright said.
Both Dr. Carl and Dr. Wright emphasized the importance of continuing routine asthma therapy during the pandemic.
“When discussing the importance of taking their inhaled steroids with patients, I also remind patients that asthma management is comprehensive,” Dr. Wright said. “I want them to take their medications, but I also want them avoid or minimize exposure to triggers. Allergic and nonallergic triggers such as environmental tobacco smoke can exacerbate asthma.”
In addition, she said, “it’s important to take a detailed medical history to identify triggers. And it’s important to conduct allergy testing to common environmental allergens to help identify allergic triggers and tailor environmental allergen control strategies based on the results. All of these strategies help patients keep their asthma well-controlled.”
Dr. Carl and Dr. Wright report having no relevant disclosures.
“In fact, there’s no data to support this at this time. Maintaining adequate asthma control is the current CDC recommendation,” said pediatric pulmonologist John Carl, MD, of Cleveland Clinic Children’s Hospital. Patients, he said, should be advised to “follow your asthma action plan as outlined by your primary care or specialty clinician and communicate about evolving symptoms, such as fever rather than just congestion, wheezing, and coughing, etc.”
Dr. Carl spoke in a May 7 webinar about asthma and COVID-19 with Lakiea Wright, M.D., a physician specializing in internal medicine and allergy and immunology at Brigham and Women’s Hospital in Boston and medical director of clinical affairs for Thermo Fisher Scientific’s ImmunoDiagnostics division. The webinar, sponsored by Thermo Fisher Scientific, included discussion of COVID-19 risks, disease management, and distinguishing between the virus and asthma.
In a follow-up interview, Dr. Wright said she’s hearing from patients and parents who are concerned about whether people with asthma face a higher risk of COVID-19 infection. There’s no evidence that they do, she said, but “the CDC states that individuals with moderate to severe asthma may be higher risk for moderate to severe disease from COVID-19 if they were to become infected.”
Indeed, she said, “it is well established that viruses can trigger asthma.” But, as she also noted, early research about the risk in patients with asthma is conflicting.
“Some studies suggest asthma may be a risk factor for hospitalization while other data suggests asthma is not a common risk factor for those hospitalized,” Dr. Wright said.
She highlighted a recent study that suggests people with allergic asthma have “a reduced ACE2 gene expression in airway cells and thus decreased susceptibility to infection” by the novel coronavirus (J Allergy Clin Immunol. 2020 Apr 22. doi: 10.1016/j.jaci.2020.04.009).
Dr. Wright cautioned, however, that “this is a hypothesis and will need to be studied more.”
For now, she said, patients “should follow their asthma action plan and take their inhalers, including inhaled corticosteroids, as prescribed by their health care providers.”
Most patients are reasonable and do comply when their physicians explain why they should take a medication,” she noted.
Dr. Carl agreed, and added that a short course of oral corticosteroids are also recommended to manage minor exacerbations and “prevent patients from having to arrive as inpatients in more acute settings and risk health system–related exposures to the current pandemic.”
He cautioned, however, that metered-dose inhalers are preferable to nebulizers, and side vent ports should be avoided since they can aerosolize infectious agents and put health care providers and family members at risk.
Unfortunately, he said, there’s been a shortage of short-acting beta agonist albuterol inhalers. This has been linked to hospitals trying to avoid the use of nebulizers.
Dr. Wright advised colleagues to focus on unique symptoms first, then address overlapping symptoms and other symptoms to differentiate between COVID-19 and asthma/allergy.
She noted that environmental allergy symptoms alone do not cause fever, a hallmark of COVID-19. Shortness of breath can be a distinguishing symptom for the virus, because this is not a common symptom of environmental allergies unless the patient has asthma, Dr. Wright said.
Cough can be an overlapping symptom because in environmental allergies, postnasal drip from allergic rhinitis can trigger cough, she explained. Nasal congestion and/or runny nose can develop with viral illnesses in general, but these are symptoms not included in the CDC’s list of the most common COVID-19 symptoms. Severe fatigue and body aches aren’t symptoms consistent with environmental allergies, Dr. Wright said.
Both Dr. Carl and Dr. Wright emphasized the importance of continuing routine asthma therapy during the pandemic.
“When discussing the importance of taking their inhaled steroids with patients, I also remind patients that asthma management is comprehensive,” Dr. Wright said. “I want them to take their medications, but I also want them avoid or minimize exposure to triggers. Allergic and nonallergic triggers such as environmental tobacco smoke can exacerbate asthma.”
In addition, she said, “it’s important to take a detailed medical history to identify triggers. And it’s important to conduct allergy testing to common environmental allergens to help identify allergic triggers and tailor environmental allergen control strategies based on the results. All of these strategies help patients keep their asthma well-controlled.”
Dr. Carl and Dr. Wright report having no relevant disclosures.
“In fact, there’s no data to support this at this time. Maintaining adequate asthma control is the current CDC recommendation,” said pediatric pulmonologist John Carl, MD, of Cleveland Clinic Children’s Hospital. Patients, he said, should be advised to “follow your asthma action plan as outlined by your primary care or specialty clinician and communicate about evolving symptoms, such as fever rather than just congestion, wheezing, and coughing, etc.”
Dr. Carl spoke in a May 7 webinar about asthma and COVID-19 with Lakiea Wright, M.D., a physician specializing in internal medicine and allergy and immunology at Brigham and Women’s Hospital in Boston and medical director of clinical affairs for Thermo Fisher Scientific’s ImmunoDiagnostics division. The webinar, sponsored by Thermo Fisher Scientific, included discussion of COVID-19 risks, disease management, and distinguishing between the virus and asthma.
In a follow-up interview, Dr. Wright said she’s hearing from patients and parents who are concerned about whether people with asthma face a higher risk of COVID-19 infection. There’s no evidence that they do, she said, but “the CDC states that individuals with moderate to severe asthma may be higher risk for moderate to severe disease from COVID-19 if they were to become infected.”
Indeed, she said, “it is well established that viruses can trigger asthma.” But, as she also noted, early research about the risk in patients with asthma is conflicting.
“Some studies suggest asthma may be a risk factor for hospitalization while other data suggests asthma is not a common risk factor for those hospitalized,” Dr. Wright said.
She highlighted a recent study that suggests people with allergic asthma have “a reduced ACE2 gene expression in airway cells and thus decreased susceptibility to infection” by the novel coronavirus (J Allergy Clin Immunol. 2020 Apr 22. doi: 10.1016/j.jaci.2020.04.009).
Dr. Wright cautioned, however, that “this is a hypothesis and will need to be studied more.”
For now, she said, patients “should follow their asthma action plan and take their inhalers, including inhaled corticosteroids, as prescribed by their health care providers.”
Most patients are reasonable and do comply when their physicians explain why they should take a medication,” she noted.
Dr. Carl agreed, and added that a short course of oral corticosteroids are also recommended to manage minor exacerbations and “prevent patients from having to arrive as inpatients in more acute settings and risk health system–related exposures to the current pandemic.”
He cautioned, however, that metered-dose inhalers are preferable to nebulizers, and side vent ports should be avoided since they can aerosolize infectious agents and put health care providers and family members at risk.
Unfortunately, he said, there’s been a shortage of short-acting beta agonist albuterol inhalers. This has been linked to hospitals trying to avoid the use of nebulizers.
Dr. Wright advised colleagues to focus on unique symptoms first, then address overlapping symptoms and other symptoms to differentiate between COVID-19 and asthma/allergy.
She noted that environmental allergy symptoms alone do not cause fever, a hallmark of COVID-19. Shortness of breath can be a distinguishing symptom for the virus, because this is not a common symptom of environmental allergies unless the patient has asthma, Dr. Wright said.
Cough can be an overlapping symptom because in environmental allergies, postnasal drip from allergic rhinitis can trigger cough, she explained. Nasal congestion and/or runny nose can develop with viral illnesses in general, but these are symptoms not included in the CDC’s list of the most common COVID-19 symptoms. Severe fatigue and body aches aren’t symptoms consistent with environmental allergies, Dr. Wright said.
Both Dr. Carl and Dr. Wright emphasized the importance of continuing routine asthma therapy during the pandemic.
“When discussing the importance of taking their inhaled steroids with patients, I also remind patients that asthma management is comprehensive,” Dr. Wright said. “I want them to take their medications, but I also want them avoid or minimize exposure to triggers. Allergic and nonallergic triggers such as environmental tobacco smoke can exacerbate asthma.”
In addition, she said, “it’s important to take a detailed medical history to identify triggers. And it’s important to conduct allergy testing to common environmental allergens to help identify allergic triggers and tailor environmental allergen control strategies based on the results. All of these strategies help patients keep their asthma well-controlled.”
Dr. Carl and Dr. Wright report having no relevant disclosures.
Novel agent for obstructive HCM nets functional gains; top-line results
Patients with obstructive hypertrophic cardiomyopathy (HCM) who took an investigational agent that targets cardiac myosin over about 7 months showed across-the-board improvements in functional capacity, symptoms, and left ventricular outflow obstruction in a randomized, controlled trial.
Treatment with the oral drug mavacamten (or MYK-461) was well tolerated and showed no untoward safety issues, compared with placebo in the phase 3 EXPLORER-HCM trial, its developer, MyoKardia, announced in a press release. The top-line trial results were made public in advance of a more expansive presentation at a later date.
The company describes mavacamten as an allosteric modulator of cardiac myosin that “reduces cardiac muscle contractility by inhibiting excessive myosin-actin cross-bridge formation that results in hypercontractility, left ventricular hypertrophy and reduced compliance.”
In the EXPLORER-HCM trial, with its 251 patients with symptomatic obstructive HCM, 37% of those randomly assigned to receive once-daily mavacamten and 17% of those given placebo (P =.0005) reached the functional primary endpoint by 30 weeks, the company reported.
The primary endpoint was a composite of either a ≥1.5 mL/kg per min improvement in peak VO2 along with symptomatic improvement or ≥3.0 mL/kg per min improvement without deterioration of symptom status.
Patients taking mavacamten also showed significant improvement in the secondary endpoints of left ventricular outflow tract peak gradient after exercise, NYHA functional class, Kansas City Cardiomyopathy Questionnaire Clinical Summary scores, and HCM Symptom Questionnaire Shortness of Breath Domain score, all at P = .0001, and peak VO2 at P = .0006, MyoKardia reported.
The company said beyond its bid to have the drug approved for obstructive HCM, based on its mechanism of action it foresees the drug as a potential treatment for nonobstructive HCM and for some patients with heart failure with preserved ejection fraction.
This article first appeared on Medscape.com.
Patients with obstructive hypertrophic cardiomyopathy (HCM) who took an investigational agent that targets cardiac myosin over about 7 months showed across-the-board improvements in functional capacity, symptoms, and left ventricular outflow obstruction in a randomized, controlled trial.
Treatment with the oral drug mavacamten (or MYK-461) was well tolerated and showed no untoward safety issues, compared with placebo in the phase 3 EXPLORER-HCM trial, its developer, MyoKardia, announced in a press release. The top-line trial results were made public in advance of a more expansive presentation at a later date.
The company describes mavacamten as an allosteric modulator of cardiac myosin that “reduces cardiac muscle contractility by inhibiting excessive myosin-actin cross-bridge formation that results in hypercontractility, left ventricular hypertrophy and reduced compliance.”
In the EXPLORER-HCM trial, with its 251 patients with symptomatic obstructive HCM, 37% of those randomly assigned to receive once-daily mavacamten and 17% of those given placebo (P =.0005) reached the functional primary endpoint by 30 weeks, the company reported.
The primary endpoint was a composite of either a ≥1.5 mL/kg per min improvement in peak VO2 along with symptomatic improvement or ≥3.0 mL/kg per min improvement without deterioration of symptom status.
Patients taking mavacamten also showed significant improvement in the secondary endpoints of left ventricular outflow tract peak gradient after exercise, NYHA functional class, Kansas City Cardiomyopathy Questionnaire Clinical Summary scores, and HCM Symptom Questionnaire Shortness of Breath Domain score, all at P = .0001, and peak VO2 at P = .0006, MyoKardia reported.
The company said beyond its bid to have the drug approved for obstructive HCM, based on its mechanism of action it foresees the drug as a potential treatment for nonobstructive HCM and for some patients with heart failure with preserved ejection fraction.
This article first appeared on Medscape.com.
Patients with obstructive hypertrophic cardiomyopathy (HCM) who took an investigational agent that targets cardiac myosin over about 7 months showed across-the-board improvements in functional capacity, symptoms, and left ventricular outflow obstruction in a randomized, controlled trial.
Treatment with the oral drug mavacamten (or MYK-461) was well tolerated and showed no untoward safety issues, compared with placebo in the phase 3 EXPLORER-HCM trial, its developer, MyoKardia, announced in a press release. The top-line trial results were made public in advance of a more expansive presentation at a later date.
The company describes mavacamten as an allosteric modulator of cardiac myosin that “reduces cardiac muscle contractility by inhibiting excessive myosin-actin cross-bridge formation that results in hypercontractility, left ventricular hypertrophy and reduced compliance.”
In the EXPLORER-HCM trial, with its 251 patients with symptomatic obstructive HCM, 37% of those randomly assigned to receive once-daily mavacamten and 17% of those given placebo (P =.0005) reached the functional primary endpoint by 30 weeks, the company reported.
The primary endpoint was a composite of either a ≥1.5 mL/kg per min improvement in peak VO2 along with symptomatic improvement or ≥3.0 mL/kg per min improvement without deterioration of symptom status.
Patients taking mavacamten also showed significant improvement in the secondary endpoints of left ventricular outflow tract peak gradient after exercise, NYHA functional class, Kansas City Cardiomyopathy Questionnaire Clinical Summary scores, and HCM Symptom Questionnaire Shortness of Breath Domain score, all at P = .0001, and peak VO2 at P = .0006, MyoKardia reported.
The company said beyond its bid to have the drug approved for obstructive HCM, based on its mechanism of action it foresees the drug as a potential treatment for nonobstructive HCM and for some patients with heart failure with preserved ejection fraction.
This article first appeared on Medscape.com.
COVID-19 quarantine: Managing pediatric behavioral issues
We are living through unprecedented challenges, faced with profound uncertainties about the public health, the economy, the safety of our workplaces, the risks of gathering with friends and family, and even about the rhythm of the school year. Parents always have sought guidance from their pediatric providers when they are uncertain about their children’s health, behavior, and development. We want to share some guidance with you about several of the most common questions we have been hearing in the past few months, in the hope that it may prove useful in your conversations with patients and families.
What happens when we are so busy at home that our 2-year-old is ignored for much of the day?
If they are fortunate enough to be able to work from home, but have lost their child care, many parents are suddenly facing the sustained challenge of parenting while working. Even older children will have a tough time remembering that home is now a workplace, and they can’t interrupt their parents during a Zoom meeting. But older children will understand. Younger children (preschoolers) simply will not be able to understand that their parents are in sight but not fully available to them. They are exquisitely sensitive to their parents’ attention. If they are consistently ignored, behavioral problems can emerge. If both parents are at home, they should try to arrange a schedule taking turns so that one of them could turn their full attention to their kids if need be. If a working parent can be out of sight (i.e., in another room), it makes the situation easier for everyone.
If there is only one parent at home, that mom or dad should consider arranging a babysitter or sharing child care with a friend, with some reasonable safety provisions in place. The small risk of exposure to the virus is balanced by the risk of sustained invalidation in a developing child. Help parents set reasonable expectations for how productive they can be at home. If possible, they can manage their employer’s expectations, so that they do not find themselves in the impossible bind of choosing between a crying child and a crucial deadline. If they can work near the child (and be prepared for interruptions) when reading emails or writing, that may be enough availability for the child. And parents should not be discouraged when they have to repeatedly remind their children that they adore them, but also have to work while they are at home right now. Using age-appropriate screen time as a babysitter for a few hours each day is a perfectly acceptable part of a plan. Simply planning regular breaks when their children can have their attention will make the day easier for everyone at home.
What can I do about my 13-year-old who is lying around the house all day?
This is a time to pick your battles. If children can keep their regular sleep schedule, get their schoolwork done, and do some physical exercise every day, they are doing great. And if parents are continuously complaining that they are being lazy, it will probably cease to mean much to them. Instead, focus on clear, simple expectations, and parents should live by them, too. If parents can exercise with them, or try a new activity, that is a wonderful way to model self-care and trying new things. It is important to remember that the developmental task for a 13-year-old is to establish new avenues of independence that they will drive down further with each passing year. Give them some leeway to experiment and figure out their own way of handling this challenge, although it is bound to create some tension. Parents should always acknowledge how hard it is to stick with schoolwork without school, exercise without a team, practice music without a band, or do your work without an office!
What do we do about our 16-year-old who is staying up all night and sleeping until the late afternoon?
Adolescents naturally have their sleep cycle shift, so they are sleepy later and sleep longer. But staying up all night is usually about texting with friends or playing video games. The problem is that their sleep schedule can flip. They will not be able to participate in online class or enjoy exercise in the sun, and they rarely get enough sleep during the daytime, making them more irritable, anxious, inattentive, and tired. This will only make managing their schoolwork harder and increase the chances of conflict at home. So it is important to preserve rules around sleep. You might extend bedtime by an hour or so, but preserve rules and bedtime routines. Sleep is essential to health, well-being, and resilience, and all are critical during times of uncertainty and change.
We think our 17-year-old is using marijuana, and it might be a problem.
When parents think their children may have a problem with drugs, the children almost certainly do, as parents are typically the last to know about the extent of their use. Sheltering in place together may make their drug use much more apparent, and offer an opportunity for parents to respond. Talk with them about it. Let them know what you have noticed. See if they can tell you honestly about their drug use. Kids who are only experimenting socially are unlikely to be using drugs at home under quarantine. If you are truly calm and curious, they are more likely to be honest, and it could be a relief for them to discuss it with you. Find out what they think it helps, and what – if anything – they are worried about. Then share your concerns about marijuana use and the developing brain, and the risk of addiction. If they think it is “medical” use, remind them that anxiety or mood symptoms get better with therapy, whereas drugs (including marijuana) and alcohol actually worsen those problems. It is also a time to establish home rules, explain them, and enforce them. They will have your support while stopping and may learn that they are actually sleeping and feeling better after a few weeks without marijuana.
Parents should not hesitate to reach out to pediatric providers for guidance on local resources for assessment and treatment for substance abuse and addiction. These are medical problems, and they can become serious if untreated.
My 12-year-old perfectionist is very stressed about getting her work done well now that she is home schooling. How do I help her relax?
Some children, especially our anxious perfectionists, may respond to the switch to home school with great effort and organization. These kids usually are not the ones parents worry about. But they are very prone to expanding anxiety without the regular support and feedback of teachers. The school environment naturally encourages their taking chances and normalizes the setbacks and failures that are an essential part of learning something new. At home, parents are inclined to let these kids work independently. But they benefit from regular check-ins that are not focused on work completion or scores. Instead, ask about what they are doing that is hardest, and let them teach you about it. Model how you approach a new challenge, and how you regroup and try again when you don’t get it right. Finally, this is a good age to start discussing “reasonable expectations.” No one can “do their best” all the time; not parents, not professional athletes, not even machines can sustain long bursts of maximum speed without problems. Help them to start experimenting with different speeds and levels of effort, and see how it feels.
My 10-year-old is very anxious about catching coronavirus or one of us catching it. How do I help ease her anxiety when there is no certainty about how to prevent it?
Anxiety is a normal response to a situation with as much uncertainty as this one. But some are prone to more profound anxiety, and parents may find they are doing a lot of reassuring throughout the day. For especially anxious children (and adults), accommodating the anxiety by avoiding the stressful situation is a common response that provides temporary relief. But accommodation and avoidance actually fuel anxiety, and make it harder and harder to manage. It is important to talk about the “accommodations” we all are doing, how masks are recommended to protect others (not ourselves) and to slow down the spread of a new illness so our hospitals aren’t overwhelmed. It can seem counterintuitive, but rather than jumping to reassurance or dismissing their sense of risk, ask your children to play the full movie of what they are most worried about. What happens if they get sick? If you get sick? If they are worried about dying, go ahead and ask what they think happens then. You are demonstrating that you have confidence they can handle these feelings, and you are modeling curiosity – not avoidance – yourself. Correct any misunderstandings, check on facts together, acknowledge uncertainty. It also is very important for parents to assess whether their own anxiety level makes this task especially hard or may even be contributing to their children’s level of worry. Each of us is managing anxiety right now, and this moment presents an opportunity for all of us to learn about how we can face and bear it, learn to manage, and even master it.
We are all getting cabin fever at home and snapping at each other constantly. How do we keep the peace without just hiding in our rooms all day?
Cabin fever seems inevitable when a family is suddenly at home together all day every day with no end in sight. But if we establish some simple and realistic routines and preserve some structure without being rigid, it can go a long way to helping each member of a family to find their equilibrium in this new normal. Structure can be about preserving normal sleep and meal times. Ensuring everyone is getting adequate, restful sleep and is not hungry is probably the most powerful way to keep irritability and conflict low. It is also helpful to establish some new routines. These should be simple enough to be memorable and should be realistic. You might identify predictable blocks of time that are dedicated to school (or work), exercise, creative time, and family time. While much of the day may find each family member doing some independent activity, it helps when these “blocks” are the same for everybody. Try to consistently do one or two things together, like a walk after the family dinner or family game time. And also remember that everyone needs some alone time. Respect their need for this, and it will help you to explain when you need it. If someone wants to sit out the family Yahtzee tournament, don’t shame or punish them. Just invite them again the next night!
What are going to be the consequences of all this screen time?
The great majority of kids (and parents) will not suffer any adverse consequences from the increased amount of time spent in front of screens when these activities are varied and serve a useful purpose – including distraction, senseless fun, and social time. Beyond letter or email writing, screen and phone time are the only ways to stay socially connected while physically distant. But parents are the experts on their kids. Youth who are depressed and have in the past wanted to escape into long hours of video games or YouTube videos should not be allowed to do that now. Youth with attentional issues who have a hard time stopping video games will still have that difficulty. If they are getting adequate sleep and regular exercise, and are doing most of their school work and staying socially connected, screens are not dangerous. They are proving to be a wonderful tool to help us visit libraries and museums, take dance classes, learn new languages, follow the news, order groceries, or enjoy a movie together. If we stay connected to those we care about and to the world, then this time – although marked by profound suffering and loss – may prove to be a time when we were able to slow down and remember what truly matters in our lives.
Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. They have no relevant financial disclosures. Email them at pdnews@mdedge.com.
We are living through unprecedented challenges, faced with profound uncertainties about the public health, the economy, the safety of our workplaces, the risks of gathering with friends and family, and even about the rhythm of the school year. Parents always have sought guidance from their pediatric providers when they are uncertain about their children’s health, behavior, and development. We want to share some guidance with you about several of the most common questions we have been hearing in the past few months, in the hope that it may prove useful in your conversations with patients and families.
What happens when we are so busy at home that our 2-year-old is ignored for much of the day?
If they are fortunate enough to be able to work from home, but have lost their child care, many parents are suddenly facing the sustained challenge of parenting while working. Even older children will have a tough time remembering that home is now a workplace, and they can’t interrupt their parents during a Zoom meeting. But older children will understand. Younger children (preschoolers) simply will not be able to understand that their parents are in sight but not fully available to them. They are exquisitely sensitive to their parents’ attention. If they are consistently ignored, behavioral problems can emerge. If both parents are at home, they should try to arrange a schedule taking turns so that one of them could turn their full attention to their kids if need be. If a working parent can be out of sight (i.e., in another room), it makes the situation easier for everyone.
If there is only one parent at home, that mom or dad should consider arranging a babysitter or sharing child care with a friend, with some reasonable safety provisions in place. The small risk of exposure to the virus is balanced by the risk of sustained invalidation in a developing child. Help parents set reasonable expectations for how productive they can be at home. If possible, they can manage their employer’s expectations, so that they do not find themselves in the impossible bind of choosing between a crying child and a crucial deadline. If they can work near the child (and be prepared for interruptions) when reading emails or writing, that may be enough availability for the child. And parents should not be discouraged when they have to repeatedly remind their children that they adore them, but also have to work while they are at home right now. Using age-appropriate screen time as a babysitter for a few hours each day is a perfectly acceptable part of a plan. Simply planning regular breaks when their children can have their attention will make the day easier for everyone at home.
What can I do about my 13-year-old who is lying around the house all day?
This is a time to pick your battles. If children can keep their regular sleep schedule, get their schoolwork done, and do some physical exercise every day, they are doing great. And if parents are continuously complaining that they are being lazy, it will probably cease to mean much to them. Instead, focus on clear, simple expectations, and parents should live by them, too. If parents can exercise with them, or try a new activity, that is a wonderful way to model self-care and trying new things. It is important to remember that the developmental task for a 13-year-old is to establish new avenues of independence that they will drive down further with each passing year. Give them some leeway to experiment and figure out their own way of handling this challenge, although it is bound to create some tension. Parents should always acknowledge how hard it is to stick with schoolwork without school, exercise without a team, practice music without a band, or do your work without an office!
What do we do about our 16-year-old who is staying up all night and sleeping until the late afternoon?
Adolescents naturally have their sleep cycle shift, so they are sleepy later and sleep longer. But staying up all night is usually about texting with friends or playing video games. The problem is that their sleep schedule can flip. They will not be able to participate in online class or enjoy exercise in the sun, and they rarely get enough sleep during the daytime, making them more irritable, anxious, inattentive, and tired. This will only make managing their schoolwork harder and increase the chances of conflict at home. So it is important to preserve rules around sleep. You might extend bedtime by an hour or so, but preserve rules and bedtime routines. Sleep is essential to health, well-being, and resilience, and all are critical during times of uncertainty and change.
We think our 17-year-old is using marijuana, and it might be a problem.
When parents think their children may have a problem with drugs, the children almost certainly do, as parents are typically the last to know about the extent of their use. Sheltering in place together may make their drug use much more apparent, and offer an opportunity for parents to respond. Talk with them about it. Let them know what you have noticed. See if they can tell you honestly about their drug use. Kids who are only experimenting socially are unlikely to be using drugs at home under quarantine. If you are truly calm and curious, they are more likely to be honest, and it could be a relief for them to discuss it with you. Find out what they think it helps, and what – if anything – they are worried about. Then share your concerns about marijuana use and the developing brain, and the risk of addiction. If they think it is “medical” use, remind them that anxiety or mood symptoms get better with therapy, whereas drugs (including marijuana) and alcohol actually worsen those problems. It is also a time to establish home rules, explain them, and enforce them. They will have your support while stopping and may learn that they are actually sleeping and feeling better after a few weeks without marijuana.
Parents should not hesitate to reach out to pediatric providers for guidance on local resources for assessment and treatment for substance abuse and addiction. These are medical problems, and they can become serious if untreated.
My 12-year-old perfectionist is very stressed about getting her work done well now that she is home schooling. How do I help her relax?
Some children, especially our anxious perfectionists, may respond to the switch to home school with great effort and organization. These kids usually are not the ones parents worry about. But they are very prone to expanding anxiety without the regular support and feedback of teachers. The school environment naturally encourages their taking chances and normalizes the setbacks and failures that are an essential part of learning something new. At home, parents are inclined to let these kids work independently. But they benefit from regular check-ins that are not focused on work completion or scores. Instead, ask about what they are doing that is hardest, and let them teach you about it. Model how you approach a new challenge, and how you regroup and try again when you don’t get it right. Finally, this is a good age to start discussing “reasonable expectations.” No one can “do their best” all the time; not parents, not professional athletes, not even machines can sustain long bursts of maximum speed without problems. Help them to start experimenting with different speeds and levels of effort, and see how it feels.
My 10-year-old is very anxious about catching coronavirus or one of us catching it. How do I help ease her anxiety when there is no certainty about how to prevent it?
Anxiety is a normal response to a situation with as much uncertainty as this one. But some are prone to more profound anxiety, and parents may find they are doing a lot of reassuring throughout the day. For especially anxious children (and adults), accommodating the anxiety by avoiding the stressful situation is a common response that provides temporary relief. But accommodation and avoidance actually fuel anxiety, and make it harder and harder to manage. It is important to talk about the “accommodations” we all are doing, how masks are recommended to protect others (not ourselves) and to slow down the spread of a new illness so our hospitals aren’t overwhelmed. It can seem counterintuitive, but rather than jumping to reassurance or dismissing their sense of risk, ask your children to play the full movie of what they are most worried about. What happens if they get sick? If you get sick? If they are worried about dying, go ahead and ask what they think happens then. You are demonstrating that you have confidence they can handle these feelings, and you are modeling curiosity – not avoidance – yourself. Correct any misunderstandings, check on facts together, acknowledge uncertainty. It also is very important for parents to assess whether their own anxiety level makes this task especially hard or may even be contributing to their children’s level of worry. Each of us is managing anxiety right now, and this moment presents an opportunity for all of us to learn about how we can face and bear it, learn to manage, and even master it.
We are all getting cabin fever at home and snapping at each other constantly. How do we keep the peace without just hiding in our rooms all day?
Cabin fever seems inevitable when a family is suddenly at home together all day every day with no end in sight. But if we establish some simple and realistic routines and preserve some structure without being rigid, it can go a long way to helping each member of a family to find their equilibrium in this new normal. Structure can be about preserving normal sleep and meal times. Ensuring everyone is getting adequate, restful sleep and is not hungry is probably the most powerful way to keep irritability and conflict low. It is also helpful to establish some new routines. These should be simple enough to be memorable and should be realistic. You might identify predictable blocks of time that are dedicated to school (or work), exercise, creative time, and family time. While much of the day may find each family member doing some independent activity, it helps when these “blocks” are the same for everybody. Try to consistently do one or two things together, like a walk after the family dinner or family game time. And also remember that everyone needs some alone time. Respect their need for this, and it will help you to explain when you need it. If someone wants to sit out the family Yahtzee tournament, don’t shame or punish them. Just invite them again the next night!
What are going to be the consequences of all this screen time?
The great majority of kids (and parents) will not suffer any adverse consequences from the increased amount of time spent in front of screens when these activities are varied and serve a useful purpose – including distraction, senseless fun, and social time. Beyond letter or email writing, screen and phone time are the only ways to stay socially connected while physically distant. But parents are the experts on their kids. Youth who are depressed and have in the past wanted to escape into long hours of video games or YouTube videos should not be allowed to do that now. Youth with attentional issues who have a hard time stopping video games will still have that difficulty. If they are getting adequate sleep and regular exercise, and are doing most of their school work and staying socially connected, screens are not dangerous. They are proving to be a wonderful tool to help us visit libraries and museums, take dance classes, learn new languages, follow the news, order groceries, or enjoy a movie together. If we stay connected to those we care about and to the world, then this time – although marked by profound suffering and loss – may prove to be a time when we were able to slow down and remember what truly matters in our lives.
Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. They have no relevant financial disclosures. Email them at pdnews@mdedge.com.
We are living through unprecedented challenges, faced with profound uncertainties about the public health, the economy, the safety of our workplaces, the risks of gathering with friends and family, and even about the rhythm of the school year. Parents always have sought guidance from their pediatric providers when they are uncertain about their children’s health, behavior, and development. We want to share some guidance with you about several of the most common questions we have been hearing in the past few months, in the hope that it may prove useful in your conversations with patients and families.
What happens when we are so busy at home that our 2-year-old is ignored for much of the day?
If they are fortunate enough to be able to work from home, but have lost their child care, many parents are suddenly facing the sustained challenge of parenting while working. Even older children will have a tough time remembering that home is now a workplace, and they can’t interrupt their parents during a Zoom meeting. But older children will understand. Younger children (preschoolers) simply will not be able to understand that their parents are in sight but not fully available to them. They are exquisitely sensitive to their parents’ attention. If they are consistently ignored, behavioral problems can emerge. If both parents are at home, they should try to arrange a schedule taking turns so that one of them could turn their full attention to their kids if need be. If a working parent can be out of sight (i.e., in another room), it makes the situation easier for everyone.
If there is only one parent at home, that mom or dad should consider arranging a babysitter or sharing child care with a friend, with some reasonable safety provisions in place. The small risk of exposure to the virus is balanced by the risk of sustained invalidation in a developing child. Help parents set reasonable expectations for how productive they can be at home. If possible, they can manage their employer’s expectations, so that they do not find themselves in the impossible bind of choosing between a crying child and a crucial deadline. If they can work near the child (and be prepared for interruptions) when reading emails or writing, that may be enough availability for the child. And parents should not be discouraged when they have to repeatedly remind their children that they adore them, but also have to work while they are at home right now. Using age-appropriate screen time as a babysitter for a few hours each day is a perfectly acceptable part of a plan. Simply planning regular breaks when their children can have their attention will make the day easier for everyone at home.
What can I do about my 13-year-old who is lying around the house all day?
This is a time to pick your battles. If children can keep their regular sleep schedule, get their schoolwork done, and do some physical exercise every day, they are doing great. And if parents are continuously complaining that they are being lazy, it will probably cease to mean much to them. Instead, focus on clear, simple expectations, and parents should live by them, too. If parents can exercise with them, or try a new activity, that is a wonderful way to model self-care and trying new things. It is important to remember that the developmental task for a 13-year-old is to establish new avenues of independence that they will drive down further with each passing year. Give them some leeway to experiment and figure out their own way of handling this challenge, although it is bound to create some tension. Parents should always acknowledge how hard it is to stick with schoolwork without school, exercise without a team, practice music without a band, or do your work without an office!
What do we do about our 16-year-old who is staying up all night and sleeping until the late afternoon?
Adolescents naturally have their sleep cycle shift, so they are sleepy later and sleep longer. But staying up all night is usually about texting with friends or playing video games. The problem is that their sleep schedule can flip. They will not be able to participate in online class or enjoy exercise in the sun, and they rarely get enough sleep during the daytime, making them more irritable, anxious, inattentive, and tired. This will only make managing their schoolwork harder and increase the chances of conflict at home. So it is important to preserve rules around sleep. You might extend bedtime by an hour or so, but preserve rules and bedtime routines. Sleep is essential to health, well-being, and resilience, and all are critical during times of uncertainty and change.
We think our 17-year-old is using marijuana, and it might be a problem.
When parents think their children may have a problem with drugs, the children almost certainly do, as parents are typically the last to know about the extent of their use. Sheltering in place together may make their drug use much more apparent, and offer an opportunity for parents to respond. Talk with them about it. Let them know what you have noticed. See if they can tell you honestly about their drug use. Kids who are only experimenting socially are unlikely to be using drugs at home under quarantine. If you are truly calm and curious, they are more likely to be honest, and it could be a relief for them to discuss it with you. Find out what they think it helps, and what – if anything – they are worried about. Then share your concerns about marijuana use and the developing brain, and the risk of addiction. If they think it is “medical” use, remind them that anxiety or mood symptoms get better with therapy, whereas drugs (including marijuana) and alcohol actually worsen those problems. It is also a time to establish home rules, explain them, and enforce them. They will have your support while stopping and may learn that they are actually sleeping and feeling better after a few weeks without marijuana.
Parents should not hesitate to reach out to pediatric providers for guidance on local resources for assessment and treatment for substance abuse and addiction. These are medical problems, and they can become serious if untreated.
My 12-year-old perfectionist is very stressed about getting her work done well now that she is home schooling. How do I help her relax?
Some children, especially our anxious perfectionists, may respond to the switch to home school with great effort and organization. These kids usually are not the ones parents worry about. But they are very prone to expanding anxiety without the regular support and feedback of teachers. The school environment naturally encourages their taking chances and normalizes the setbacks and failures that are an essential part of learning something new. At home, parents are inclined to let these kids work independently. But they benefit from regular check-ins that are not focused on work completion or scores. Instead, ask about what they are doing that is hardest, and let them teach you about it. Model how you approach a new challenge, and how you regroup and try again when you don’t get it right. Finally, this is a good age to start discussing “reasonable expectations.” No one can “do their best” all the time; not parents, not professional athletes, not even machines can sustain long bursts of maximum speed without problems. Help them to start experimenting with different speeds and levels of effort, and see how it feels.
My 10-year-old is very anxious about catching coronavirus or one of us catching it. How do I help ease her anxiety when there is no certainty about how to prevent it?
Anxiety is a normal response to a situation with as much uncertainty as this one. But some are prone to more profound anxiety, and parents may find they are doing a lot of reassuring throughout the day. For especially anxious children (and adults), accommodating the anxiety by avoiding the stressful situation is a common response that provides temporary relief. But accommodation and avoidance actually fuel anxiety, and make it harder and harder to manage. It is important to talk about the “accommodations” we all are doing, how masks are recommended to protect others (not ourselves) and to slow down the spread of a new illness so our hospitals aren’t overwhelmed. It can seem counterintuitive, but rather than jumping to reassurance or dismissing their sense of risk, ask your children to play the full movie of what they are most worried about. What happens if they get sick? If you get sick? If they are worried about dying, go ahead and ask what they think happens then. You are demonstrating that you have confidence they can handle these feelings, and you are modeling curiosity – not avoidance – yourself. Correct any misunderstandings, check on facts together, acknowledge uncertainty. It also is very important for parents to assess whether their own anxiety level makes this task especially hard or may even be contributing to their children’s level of worry. Each of us is managing anxiety right now, and this moment presents an opportunity for all of us to learn about how we can face and bear it, learn to manage, and even master it.
We are all getting cabin fever at home and snapping at each other constantly. How do we keep the peace without just hiding in our rooms all day?
Cabin fever seems inevitable when a family is suddenly at home together all day every day with no end in sight. But if we establish some simple and realistic routines and preserve some structure without being rigid, it can go a long way to helping each member of a family to find their equilibrium in this new normal. Structure can be about preserving normal sleep and meal times. Ensuring everyone is getting adequate, restful sleep and is not hungry is probably the most powerful way to keep irritability and conflict low. It is also helpful to establish some new routines. These should be simple enough to be memorable and should be realistic. You might identify predictable blocks of time that are dedicated to school (or work), exercise, creative time, and family time. While much of the day may find each family member doing some independent activity, it helps when these “blocks” are the same for everybody. Try to consistently do one or two things together, like a walk after the family dinner or family game time. And also remember that everyone needs some alone time. Respect their need for this, and it will help you to explain when you need it. If someone wants to sit out the family Yahtzee tournament, don’t shame or punish them. Just invite them again the next night!
What are going to be the consequences of all this screen time?
The great majority of kids (and parents) will not suffer any adverse consequences from the increased amount of time spent in front of screens when these activities are varied and serve a useful purpose – including distraction, senseless fun, and social time. Beyond letter or email writing, screen and phone time are the only ways to stay socially connected while physically distant. But parents are the experts on their kids. Youth who are depressed and have in the past wanted to escape into long hours of video games or YouTube videos should not be allowed to do that now. Youth with attentional issues who have a hard time stopping video games will still have that difficulty. If they are getting adequate sleep and regular exercise, and are doing most of their school work and staying socially connected, screens are not dangerous. They are proving to be a wonderful tool to help us visit libraries and museums, take dance classes, learn new languages, follow the news, order groceries, or enjoy a movie together. If we stay connected to those we care about and to the world, then this time – although marked by profound suffering and loss – may prove to be a time when we were able to slow down and remember what truly matters in our lives.
Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. They have no relevant financial disclosures. Email them at pdnews@mdedge.com.
COVID-19 will likely change docs’ incentive targets, bonuses: Survey
“Employed physicians are often getting a guaranteed salary for a month or two, but no bonuses or extra distributions,” Joel Greenwald, MD, a financial adviser for physicians in St. Louis Park, Minn., told Medscape Medical News.
“This amounts to salary reductions of 10% to 30%,” he said.
The COVID-19 crisis dramatically reversed the consistent upward trajectory of physician compensation, according to a Medical Group Management Association (MGMA) survey, as reported by Medscape Medical News.
The survey, conducted April 7-8, found that practices have reported an average 55% drop in income. The report also found an average decrease in patient volume of 60%.
Before pandemic, salaries were rising
The pandemic interrupted a steady gain in compensation for this year compared to last, according to the Medscape Physician Compensation Report 2020.
The report reflects data gathered from October 4, 2019, to February 10, 2020, and includes online survey responses from 17,000 physicians in more than 30 specialties.
Before the pandemic, primary care physician (PCP) pay was up 2.5%, to $243,000, from the previous year’s average of $237,000. Specialists saw a 1.5% increase, from $341,000 in 2019 to $346,000 this year.
Reported compensation for employed physicians included salary, bonus, and profit-sharing contributions. For those self-employed, compensation includes earnings after taxes and deductible business expenses before income tax.
This report reflects only full-time salaries. But most physicians work more than full time. The report notes that physicians overall spent 37.8 hours a week seeing patients. Add to that the 15.6 average hours spent on paperwork, and doctors are averaging 53.4 hours a week.
Administrative demands varied widely by specialty. Physicians in critical care, for example, spent the most hours on paperwork (19.1 per week), and ophthalmologists spent the least on those tasks, at 9.8.
Orthopedists top earners again
The top four specialties were the same this year as they were last year and were ranked in the same order: orthopedists made the most, at $511,000, followed by plastic surgeons, at $479,000, otolaryngologists, at $455,000, and cardiologists, at $438,000.
Pediatricians and public health/preventive medicine physicians made the least, at $232,000, followed by family physicians ($234,000) and diabetes/endocrinology specialists ($236,000).
Despite the low ranking, public health/preventive medicine providers had the biggest compensation increase of all physicians, up 11% from last year. Two specialties saw a decrease: otolaryngology salaries dropped 1%, and dermatology pay dropped 2%. Pay in gastroenterology and diabetes/endocrinology was virtually unchanged from last year.
Kentucky has highest pay
Ranked by state, physicians in Kentucky made the most on average ($346,000). Utah, Ohio, and North Carolina were new to the top 10 in physician pay this year, pushing out Connecticut, Arkansas, and Nevada.
More than half of all physicians receive incentive bonuses (58% of PCPs and 55% of specialists).
The average incentive bonus is 13% of salary, but that varies by specialty. Orthopedists got an average $96,000 bonus, whereas family physicians got $24,000.
According to the report, “Among physicians who have an incentive bonus, about a third of both PCPs and specialists say the prospect of an incentive bonus has encouraged them to work longer hours.”
Gender gap similar to previous year
Consistent with Medscape compensation reports over the past decade, this year’s report shows a large gender gap in pay. Among PCPs, men made 25% more than women ($264,000 vs. $212,000); among specialists, they made 31% more than their female colleagues ($375,000 vs. $286,000).
Some specialties report positive changes from growing awareness of the gap.
“Many organizations have been carefully analyzing their culture, transparency, and pay practices to make sure they aren’t unintentionally discriminating against any group of employees,” Halee Fischer-Wright, MD, pediatrician and CEO of MGMA, told Medscape Medical News.
She added that the growing physician shortage has given all physicians more leverage in salary demands and that increased recognition of the gender gap is giving women more confidence and more evidence to use in negotiations.
Three specialties have seen large increases in the past 5 years in the percentage of women physicians. Obstetrics/gynecology and pediatrics both saw increases from 50% in 2015 to 58% in 2020. Additionally, women now account for 54% of rheumatologists, up from 29% in 2015.
Would you choose your specialty again?
Of responding physicians who were asked if they would choose their specialty again, internists were least likely to say yes (66%), followed by nephrologists (69%) and family physicians (70%).
Orthopedists were most likely to say they would choose the same specialty (97%), followed by oncologists (96%) and ophthalmologists and dermatologists (both at 95%).
Most physicians overall (77%) said they would choose medicine again.
Despite aggravations and pressures, in this survey and in previous years, physicians have indicated that the top rewards are “gratitude/relationships with patients,” “being very good at what I do/finding answers, diagnoses,” and “knowing that I make the world a better place.” From 24% to 27% ranked those rewards most important.
“Making good money at a job I like” came in fourth, at 12%.
This article first appeared on Medscape.com.
“Employed physicians are often getting a guaranteed salary for a month or two, but no bonuses or extra distributions,” Joel Greenwald, MD, a financial adviser for physicians in St. Louis Park, Minn., told Medscape Medical News.
“This amounts to salary reductions of 10% to 30%,” he said.
The COVID-19 crisis dramatically reversed the consistent upward trajectory of physician compensation, according to a Medical Group Management Association (MGMA) survey, as reported by Medscape Medical News.
The survey, conducted April 7-8, found that practices have reported an average 55% drop in income. The report also found an average decrease in patient volume of 60%.
Before pandemic, salaries were rising
The pandemic interrupted a steady gain in compensation for this year compared to last, according to the Medscape Physician Compensation Report 2020.
The report reflects data gathered from October 4, 2019, to February 10, 2020, and includes online survey responses from 17,000 physicians in more than 30 specialties.
Before the pandemic, primary care physician (PCP) pay was up 2.5%, to $243,000, from the previous year’s average of $237,000. Specialists saw a 1.5% increase, from $341,000 in 2019 to $346,000 this year.
Reported compensation for employed physicians included salary, bonus, and profit-sharing contributions. For those self-employed, compensation includes earnings after taxes and deductible business expenses before income tax.
This report reflects only full-time salaries. But most physicians work more than full time. The report notes that physicians overall spent 37.8 hours a week seeing patients. Add to that the 15.6 average hours spent on paperwork, and doctors are averaging 53.4 hours a week.
Administrative demands varied widely by specialty. Physicians in critical care, for example, spent the most hours on paperwork (19.1 per week), and ophthalmologists spent the least on those tasks, at 9.8.
Orthopedists top earners again
The top four specialties were the same this year as they were last year and were ranked in the same order: orthopedists made the most, at $511,000, followed by plastic surgeons, at $479,000, otolaryngologists, at $455,000, and cardiologists, at $438,000.
Pediatricians and public health/preventive medicine physicians made the least, at $232,000, followed by family physicians ($234,000) and diabetes/endocrinology specialists ($236,000).
Despite the low ranking, public health/preventive medicine providers had the biggest compensation increase of all physicians, up 11% from last year. Two specialties saw a decrease: otolaryngology salaries dropped 1%, and dermatology pay dropped 2%. Pay in gastroenterology and diabetes/endocrinology was virtually unchanged from last year.
Kentucky has highest pay
Ranked by state, physicians in Kentucky made the most on average ($346,000). Utah, Ohio, and North Carolina were new to the top 10 in physician pay this year, pushing out Connecticut, Arkansas, and Nevada.
More than half of all physicians receive incentive bonuses (58% of PCPs and 55% of specialists).
The average incentive bonus is 13% of salary, but that varies by specialty. Orthopedists got an average $96,000 bonus, whereas family physicians got $24,000.
According to the report, “Among physicians who have an incentive bonus, about a third of both PCPs and specialists say the prospect of an incentive bonus has encouraged them to work longer hours.”
Gender gap similar to previous year
Consistent with Medscape compensation reports over the past decade, this year’s report shows a large gender gap in pay. Among PCPs, men made 25% more than women ($264,000 vs. $212,000); among specialists, they made 31% more than their female colleagues ($375,000 vs. $286,000).
Some specialties report positive changes from growing awareness of the gap.
“Many organizations have been carefully analyzing their culture, transparency, and pay practices to make sure they aren’t unintentionally discriminating against any group of employees,” Halee Fischer-Wright, MD, pediatrician and CEO of MGMA, told Medscape Medical News.
She added that the growing physician shortage has given all physicians more leverage in salary demands and that increased recognition of the gender gap is giving women more confidence and more evidence to use in negotiations.
Three specialties have seen large increases in the past 5 years in the percentage of women physicians. Obstetrics/gynecology and pediatrics both saw increases from 50% in 2015 to 58% in 2020. Additionally, women now account for 54% of rheumatologists, up from 29% in 2015.
Would you choose your specialty again?
Of responding physicians who were asked if they would choose their specialty again, internists were least likely to say yes (66%), followed by nephrologists (69%) and family physicians (70%).
Orthopedists were most likely to say they would choose the same specialty (97%), followed by oncologists (96%) and ophthalmologists and dermatologists (both at 95%).
Most physicians overall (77%) said they would choose medicine again.
Despite aggravations and pressures, in this survey and in previous years, physicians have indicated that the top rewards are “gratitude/relationships with patients,” “being very good at what I do/finding answers, diagnoses,” and “knowing that I make the world a better place.” From 24% to 27% ranked those rewards most important.
“Making good money at a job I like” came in fourth, at 12%.
This article first appeared on Medscape.com.
“Employed physicians are often getting a guaranteed salary for a month or two, but no bonuses or extra distributions,” Joel Greenwald, MD, a financial adviser for physicians in St. Louis Park, Minn., told Medscape Medical News.
“This amounts to salary reductions of 10% to 30%,” he said.
The COVID-19 crisis dramatically reversed the consistent upward trajectory of physician compensation, according to a Medical Group Management Association (MGMA) survey, as reported by Medscape Medical News.
The survey, conducted April 7-8, found that practices have reported an average 55% drop in income. The report also found an average decrease in patient volume of 60%.
Before pandemic, salaries were rising
The pandemic interrupted a steady gain in compensation for this year compared to last, according to the Medscape Physician Compensation Report 2020.
The report reflects data gathered from October 4, 2019, to February 10, 2020, and includes online survey responses from 17,000 physicians in more than 30 specialties.
Before the pandemic, primary care physician (PCP) pay was up 2.5%, to $243,000, from the previous year’s average of $237,000. Specialists saw a 1.5% increase, from $341,000 in 2019 to $346,000 this year.
Reported compensation for employed physicians included salary, bonus, and profit-sharing contributions. For those self-employed, compensation includes earnings after taxes and deductible business expenses before income tax.
This report reflects only full-time salaries. But most physicians work more than full time. The report notes that physicians overall spent 37.8 hours a week seeing patients. Add to that the 15.6 average hours spent on paperwork, and doctors are averaging 53.4 hours a week.
Administrative demands varied widely by specialty. Physicians in critical care, for example, spent the most hours on paperwork (19.1 per week), and ophthalmologists spent the least on those tasks, at 9.8.
Orthopedists top earners again
The top four specialties were the same this year as they were last year and were ranked in the same order: orthopedists made the most, at $511,000, followed by plastic surgeons, at $479,000, otolaryngologists, at $455,000, and cardiologists, at $438,000.
Pediatricians and public health/preventive medicine physicians made the least, at $232,000, followed by family physicians ($234,000) and diabetes/endocrinology specialists ($236,000).
Despite the low ranking, public health/preventive medicine providers had the biggest compensation increase of all physicians, up 11% from last year. Two specialties saw a decrease: otolaryngology salaries dropped 1%, and dermatology pay dropped 2%. Pay in gastroenterology and diabetes/endocrinology was virtually unchanged from last year.
Kentucky has highest pay
Ranked by state, physicians in Kentucky made the most on average ($346,000). Utah, Ohio, and North Carolina were new to the top 10 in physician pay this year, pushing out Connecticut, Arkansas, and Nevada.
More than half of all physicians receive incentive bonuses (58% of PCPs and 55% of specialists).
The average incentive bonus is 13% of salary, but that varies by specialty. Orthopedists got an average $96,000 bonus, whereas family physicians got $24,000.
According to the report, “Among physicians who have an incentive bonus, about a third of both PCPs and specialists say the prospect of an incentive bonus has encouraged them to work longer hours.”
Gender gap similar to previous year
Consistent with Medscape compensation reports over the past decade, this year’s report shows a large gender gap in pay. Among PCPs, men made 25% more than women ($264,000 vs. $212,000); among specialists, they made 31% more than their female colleagues ($375,000 vs. $286,000).
Some specialties report positive changes from growing awareness of the gap.
“Many organizations have been carefully analyzing their culture, transparency, and pay practices to make sure they aren’t unintentionally discriminating against any group of employees,” Halee Fischer-Wright, MD, pediatrician and CEO of MGMA, told Medscape Medical News.
She added that the growing physician shortage has given all physicians more leverage in salary demands and that increased recognition of the gender gap is giving women more confidence and more evidence to use in negotiations.
Three specialties have seen large increases in the past 5 years in the percentage of women physicians. Obstetrics/gynecology and pediatrics both saw increases from 50% in 2015 to 58% in 2020. Additionally, women now account for 54% of rheumatologists, up from 29% in 2015.
Would you choose your specialty again?
Of responding physicians who were asked if they would choose their specialty again, internists were least likely to say yes (66%), followed by nephrologists (69%) and family physicians (70%).
Orthopedists were most likely to say they would choose the same specialty (97%), followed by oncologists (96%) and ophthalmologists and dermatologists (both at 95%).
Most physicians overall (77%) said they would choose medicine again.
Despite aggravations and pressures, in this survey and in previous years, physicians have indicated that the top rewards are “gratitude/relationships with patients,” “being very good at what I do/finding answers, diagnoses,” and “knowing that I make the world a better place.” From 24% to 27% ranked those rewards most important.
“Making good money at a job I like” came in fourth, at 12%.
This article first appeared on Medscape.com.