AVAHO

The Food and Drug Administration has approved ivosidenib (Tibsovo) for newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation in patients who are at least 75 years old or have comorbidities preventing the use of intensive induction chemotherapy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

In July 2018, the FDA approved ivosidenib for adults with relapsed or refractory AML with a susceptible IDH1 mutation.

The latest approval was based on results from an open-label, single-arm, multicenter trial of patients with newly diagnosed AML with an IDH1 mutation. Patients were treated with 500 mg ivosidenib daily until disease progression, development of unacceptable toxicity, or hematopoietic stem cell transplantation; the median age of the 28 patients treated with ivosidenib was 77 years.

Of the 28 patients treated, 12 achieved complete remission or complete remission with partial hematologic recovery; 7 of the 17 transfusion-dependent patients achieved transfusion independence for at least 8 weeks.

The most common adverse events were diarrhea, fatigue, edema, decreased appetite, leukocytosis, nausea, arthralgia, abdominal pain, dyspnea, differentiation syndrome, and myalgia. The drug’s prescribing information includes a boxed warning on the risk of differentiation syndrome.

“The recommended ivosidenib dose is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treatment is recommended for a minimum of 6 months to allow time for clinical response,” the FDA noted.

Find the full press release on the FDA website.

lfranki@mdedge.com

The Food and Drug Administration has approved ivosidenib (Tibsovo) for newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation in patients who are at least 75 years old or have comorbidities preventing the use of intensive induction chemotherapy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

In July 2018, the FDA approved ivosidenib for adults with relapsed or refractory AML with a susceptible IDH1 mutation.

The latest approval was based on results from an open-label, single-arm, multicenter trial of patients with newly diagnosed AML with an IDH1 mutation. Patients were treated with 500 mg ivosidenib daily until disease progression, development of unacceptable toxicity, or hematopoietic stem cell transplantation; the median age of the 28 patients treated with ivosidenib was 77 years.

Of the 28 patients treated, 12 achieved complete remission or complete remission with partial hematologic recovery; 7 of the 17 transfusion-dependent patients achieved transfusion independence for at least 8 weeks.

The most common adverse events were diarrhea, fatigue, edema, decreased appetite, leukocytosis, nausea, arthralgia, abdominal pain, dyspnea, differentiation syndrome, and myalgia. The drug’s prescribing information includes a boxed warning on the risk of differentiation syndrome.

“The recommended ivosidenib dose is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treatment is recommended for a minimum of 6 months to allow time for clinical response,” the FDA noted.

Find the full press release on the FDA website.

lfranki@mdedge.com

The Food and Drug Administration has approved ivosidenib (Tibsovo) for newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation in patients who are at least 75 years old or have comorbidities preventing the use of intensive induction chemotherapy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

In July 2018, the FDA approved ivosidenib for adults with relapsed or refractory AML with a susceptible IDH1 mutation.

The latest approval was based on results from an open-label, single-arm, multicenter trial of patients with newly diagnosed AML with an IDH1 mutation. Patients were treated with 500 mg ivosidenib daily until disease progression, development of unacceptable toxicity, or hematopoietic stem cell transplantation; the median age of the 28 patients treated with ivosidenib was 77 years.

Of the 28 patients treated, 12 achieved complete remission or complete remission with partial hematologic recovery; 7 of the 17 transfusion-dependent patients achieved transfusion independence for at least 8 weeks.

The most common adverse events were diarrhea, fatigue, edema, decreased appetite, leukocytosis, nausea, arthralgia, abdominal pain, dyspnea, differentiation syndrome, and myalgia. The drug’s prescribing information includes a boxed warning on the risk of differentiation syndrome.

“The recommended ivosidenib dose is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treatment is recommended for a minimum of 6 months to allow time for clinical response,” the FDA noted.

Find the full press release on the FDA website.

lfranki@mdedge.com

As systemic therapies for advanced melanoma increase, some historical prognostic factors continue to hold true while refined and novel risk factors are emerging, according to the results of three studies published in JAMA Dermatology.

Among the most prominent findings of those studies are that ulceration, mitotic index, and head and neck location in localized disease were predictive of early recurrence; time to recurrence was not associated with survival in unresectable stage IV melanoma; and certain gene markers may be linked with particular types of metastasis.

The first study, conducted by Lena A. von Schuckmann, MBBS, of the University of Queensland School of Public Health in Australia, and colleagues, evaluated the risk of early melanoma recurrence in patients with localized disease.

“With the introduction of targeted and immune therapies for treatment of metastatic melanoma, including possible adjuvant therapy, a detailed understanding of the risk of melanoma recurrence may assist clinicians to advise patients with a primary tumor at high risk of disease metastasis,” the researchers wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0440).

They conducted a prospective cohort study of 700 patients with high-risk, category T1b to T4b cutaneous melanoma, refined from an initial recruitment population of 1,254 individuals. Using self-administered patient questionnaires in conjunction with histologic, imaging, and clinical data over the course of 2 years, the investigators looked for factors that predicted recurrence.

Of 700 patients, 94 (13.4%) had disease recurrence, most often (70.2%) locoregional recurrence. Independent predictors of recurrence included mitotic rate greater than 3/mm², thickness, ulceration, and primary tumor location on the head or neck.

Patients with negative single lymph node biopsy (SLNB) were less likely to have recurrence than were those who did not undergo SLNB. Among 64 patients whose locoregional disease was excised, 37 (57.8%) were disease free at 2 years, whereas 7 patients (10.9%) had new locoregional disease and 20 patients (31.3%) developed a new distant recurrence.

“[O]ur data appear to support the recommendation for careful scar and regional skin and lymph node examination during patient follow-up,” the investigators concluded, alluding to the relatively high rate of locoregional recurrence. “Subsequent recurrences occurring at distant sites were more likely to involve multiple organs, which is consistent with other studies.”

The second melanoma article, investigating associations between time to relapse and survival, was authored by Anaïs Vallet, MD, of Hôpital Saint-Louis, Paris, and colleagues.

“Although the kinetics of metastatic disease seem to be correlated with patient survival, the first relapse is not predictable, and data from the literature on the topic are controversial,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0425). “We hypothesized that the progression of the metastatic disease would be associated with the time from primary excision to the first distant recurrence of melanoma.”

To test this hypothesis, the investigators analyzed data from 638 patients with unresectable stage III or IV melanoma. Inclusion required first-line treatment with chemotherapy, targeted therapies, or immunotherapies. The interval between primary excision and distant disease recurrence, measured as a categorical and continuous variable, was compared with overall survival and progression-free survival. The analysis revealed no associations between time to recurrence and either survival measure, even when stratified by treatment.

“Now that immunotherapies and targeted therapies have been approved in the adjuvant setting for patients with stage III disease, it would be interesting to analyze recurrence-free survival and [progression-free survival] in relapsing patients who previously received adjuvant therapies,” the investigators wrote.

The third study was conducted by Laura Calomarde-Rees, MD, of Instituto Valenciano de Oncología, València, Spain, and colleagues.

“Our aim was to identify risk factors associated with lymphatic (locoregional metastasis) or hematogenous (distant metastasis) progression because these have not been studied separately to date in patients with localized melanoma,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0069).

The retrospective study involved 1,177 patients with stage I to II melanoma. Multiple disease variables were evaluated in the context of each type of metastasis, including age, sex, tumor location, and others.

The investigators found locoregional spread was most often associated with vascular invasion (hazard ratio [HR], 3.2), greater Breslow thickness (HR, 5.4; thickness greater than 4 mm), acral location (HR, 2.4), head/neck location (HR, 1.7), and age greater than 55 years (HR, 1.9).

Distant metastasis was most often associated with greater Breslow thickness (HR, 10.4; thickness greater than 4 mm), TERT promoter mutations (HR, 2.9), BRAF mutations (HR, 1.9), and absence of regression (HR, 0.1).

“Risk factors for lymphatic and hematogenous metastasis differ,” the investigators concluded. “A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies.”

Dr. von Schuckmann and colleagues disclosed study funding from the National Health and Medical Research Council and other relationships with the Norwegian Cancer Society project. Dr. Vallet and colleagues reported study support from French National Cancer Institute, MSD, BMS, Roche, and Novartis; and additional relationships with Incyte, Amgen, Pfizer, and others. Dr. Calomarde-Rees and colleagues disclosed no conflicts of interest.

As systemic therapies for advanced melanoma increase, some historical prognostic factors continue to hold true while refined and novel risk factors are emerging, according to the results of three studies published in JAMA Dermatology.

Among the most prominent findings of those studies are that ulceration, mitotic index, and head and neck location in localized disease were predictive of early recurrence; time to recurrence was not associated with survival in unresectable stage IV melanoma; and certain gene markers may be linked with particular types of metastasis.

The first study, conducted by Lena A. von Schuckmann, MBBS, of the University of Queensland School of Public Health in Australia, and colleagues, evaluated the risk of early melanoma recurrence in patients with localized disease.

“With the introduction of targeted and immune therapies for treatment of metastatic melanoma, including possible adjuvant therapy, a detailed understanding of the risk of melanoma recurrence may assist clinicians to advise patients with a primary tumor at high risk of disease metastasis,” the researchers wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0440).

They conducted a prospective cohort study of 700 patients with high-risk, category T1b to T4b cutaneous melanoma, refined from an initial recruitment population of 1,254 individuals. Using self-administered patient questionnaires in conjunction with histologic, imaging, and clinical data over the course of 2 years, the investigators looked for factors that predicted recurrence.

Of 700 patients, 94 (13.4%) had disease recurrence, most often (70.2%) locoregional recurrence. Independent predictors of recurrence included mitotic rate greater than 3/mm², thickness, ulceration, and primary tumor location on the head or neck.

Patients with negative single lymph node biopsy (SLNB) were less likely to have recurrence than were those who did not undergo SLNB. Among 64 patients whose locoregional disease was excised, 37 (57.8%) were disease free at 2 years, whereas 7 patients (10.9%) had new locoregional disease and 20 patients (31.3%) developed a new distant recurrence.

“[O]ur data appear to support the recommendation for careful scar and regional skin and lymph node examination during patient follow-up,” the investigators concluded, alluding to the relatively high rate of locoregional recurrence. “Subsequent recurrences occurring at distant sites were more likely to involve multiple organs, which is consistent with other studies.”

The second melanoma article, investigating associations between time to relapse and survival, was authored by Anaïs Vallet, MD, of Hôpital Saint-Louis, Paris, and colleagues.

“Although the kinetics of metastatic disease seem to be correlated with patient survival, the first relapse is not predictable, and data from the literature on the topic are controversial,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0425). “We hypothesized that the progression of the metastatic disease would be associated with the time from primary excision to the first distant recurrence of melanoma.”

To test this hypothesis, the investigators analyzed data from 638 patients with unresectable stage III or IV melanoma. Inclusion required first-line treatment with chemotherapy, targeted therapies, or immunotherapies. The interval between primary excision and distant disease recurrence, measured as a categorical and continuous variable, was compared with overall survival and progression-free survival. The analysis revealed no associations between time to recurrence and either survival measure, even when stratified by treatment.

“Now that immunotherapies and targeted therapies have been approved in the adjuvant setting for patients with stage III disease, it would be interesting to analyze recurrence-free survival and [progression-free survival] in relapsing patients who previously received adjuvant therapies,” the investigators wrote.

The third study was conducted by Laura Calomarde-Rees, MD, of Instituto Valenciano de Oncología, València, Spain, and colleagues.

“Our aim was to identify risk factors associated with lymphatic (locoregional metastasis) or hematogenous (distant metastasis) progression because these have not been studied separately to date in patients with localized melanoma,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0069).

The retrospective study involved 1,177 patients with stage I to II melanoma. Multiple disease variables were evaluated in the context of each type of metastasis, including age, sex, tumor location, and others.

The investigators found locoregional spread was most often associated with vascular invasion (hazard ratio [HR], 3.2), greater Breslow thickness (HR, 5.4; thickness greater than 4 mm), acral location (HR, 2.4), head/neck location (HR, 1.7), and age greater than 55 years (HR, 1.9).

Distant metastasis was most often associated with greater Breslow thickness (HR, 10.4; thickness greater than 4 mm), TERT promoter mutations (HR, 2.9), BRAF mutations (HR, 1.9), and absence of regression (HR, 0.1).

“Risk factors for lymphatic and hematogenous metastasis differ,” the investigators concluded. “A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies.”

Dr. von Schuckmann and colleagues disclosed study funding from the National Health and Medical Research Council and other relationships with the Norwegian Cancer Society project. Dr. Vallet and colleagues reported study support from French National Cancer Institute, MSD, BMS, Roche, and Novartis; and additional relationships with Incyte, Amgen, Pfizer, and others. Dr. Calomarde-Rees and colleagues disclosed no conflicts of interest.

As systemic therapies for advanced melanoma increase, some historical prognostic factors continue to hold true while refined and novel risk factors are emerging, according to the results of three studies published in JAMA Dermatology.

Among the most prominent findings of those studies are that ulceration, mitotic index, and head and neck location in localized disease were predictive of early recurrence; time to recurrence was not associated with survival in unresectable stage IV melanoma; and certain gene markers may be linked with particular types of metastasis.

The first study, conducted by Lena A. von Schuckmann, MBBS, of the University of Queensland School of Public Health in Australia, and colleagues, evaluated the risk of early melanoma recurrence in patients with localized disease.

“With the introduction of targeted and immune therapies for treatment of metastatic melanoma, including possible adjuvant therapy, a detailed understanding of the risk of melanoma recurrence may assist clinicians to advise patients with a primary tumor at high risk of disease metastasis,” the researchers wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0440).

They conducted a prospective cohort study of 700 patients with high-risk, category T1b to T4b cutaneous melanoma, refined from an initial recruitment population of 1,254 individuals. Using self-administered patient questionnaires in conjunction with histologic, imaging, and clinical data over the course of 2 years, the investigators looked for factors that predicted recurrence.

Of 700 patients, 94 (13.4%) had disease recurrence, most often (70.2%) locoregional recurrence. Independent predictors of recurrence included mitotic rate greater than 3/mm², thickness, ulceration, and primary tumor location on the head or neck.

Patients with negative single lymph node biopsy (SLNB) were less likely to have recurrence than were those who did not undergo SLNB. Among 64 patients whose locoregional disease was excised, 37 (57.8%) were disease free at 2 years, whereas 7 patients (10.9%) had new locoregional disease and 20 patients (31.3%) developed a new distant recurrence.

“[O]ur data appear to support the recommendation for careful scar and regional skin and lymph node examination during patient follow-up,” the investigators concluded, alluding to the relatively high rate of locoregional recurrence. “Subsequent recurrences occurring at distant sites were more likely to involve multiple organs, which is consistent with other studies.”

The second melanoma article, investigating associations between time to relapse and survival, was authored by Anaïs Vallet, MD, of Hôpital Saint-Louis, Paris, and colleagues.

“Although the kinetics of metastatic disease seem to be correlated with patient survival, the first relapse is not predictable, and data from the literature on the topic are controversial,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0425). “We hypothesized that the progression of the metastatic disease would be associated with the time from primary excision to the first distant recurrence of melanoma.”

To test this hypothesis, the investigators analyzed data from 638 patients with unresectable stage III or IV melanoma. Inclusion required first-line treatment with chemotherapy, targeted therapies, or immunotherapies. The interval between primary excision and distant disease recurrence, measured as a categorical and continuous variable, was compared with overall survival and progression-free survival. The analysis revealed no associations between time to recurrence and either survival measure, even when stratified by treatment.

“Now that immunotherapies and targeted therapies have been approved in the adjuvant setting for patients with stage III disease, it would be interesting to analyze recurrence-free survival and [progression-free survival] in relapsing patients who previously received adjuvant therapies,” the investigators wrote.

The third study was conducted by Laura Calomarde-Rees, MD, of Instituto Valenciano de Oncología, València, Spain, and colleagues.

“Our aim was to identify risk factors associated with lymphatic (locoregional metastasis) or hematogenous (distant metastasis) progression because these have not been studied separately to date in patients with localized melanoma,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0069).

The retrospective study involved 1,177 patients with stage I to II melanoma. Multiple disease variables were evaluated in the context of each type of metastasis, including age, sex, tumor location, and others.

The investigators found locoregional spread was most often associated with vascular invasion (hazard ratio [HR], 3.2), greater Breslow thickness (HR, 5.4; thickness greater than 4 mm), acral location (HR, 2.4), head/neck location (HR, 1.7), and age greater than 55 years (HR, 1.9).

Distant metastasis was most often associated with greater Breslow thickness (HR, 10.4; thickness greater than 4 mm), TERT promoter mutations (HR, 2.9), BRAF mutations (HR, 1.9), and absence of regression (HR, 0.1).

“Risk factors for lymphatic and hematogenous metastasis differ,” the investigators concluded. “A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies.”

Dr. von Schuckmann and colleagues disclosed study funding from the National Health and Medical Research Council and other relationships with the Norwegian Cancer Society project. Dr. Vallet and colleagues reported study support from French National Cancer Institute, MSD, BMS, Roche, and Novartis; and additional relationships with Incyte, Amgen, Pfizer, and others. Dr. Calomarde-Rees and colleagues disclosed no conflicts of interest.

Treatment deintensification for patients with p16+ oropharyngeal cancer (OPC) should occur only in the context of a clinical trial, according to a provisional clinical opinion released by the American Society of Clinical Oncology (ASCO).

“The hypothesis that deescalation of treatment intensity for patients with p16+ OPC can reduce long-term toxicity without compromising survival is compelling and necessitates careful study and the analysis of well-designed clinical trials before changing current treatment standards, wrote David J. Adelstein, MD, of Case Western Reserve University, Cleveland, along with his associates on the expert panel. Their report is in the Journal of Clinical Oncology.

The panel undertook a review of the literature for evidence pertaining to the treatment of patients with HPV-mediated p16+ OPC with radiation, transoral surgery, concomitant chemoradiotherapy, and chemotherapy, in addition to immunotherapy and targeted therapy. Both randomized and nonrandomized studies were included in the review, and expert consensus opinion was taken into consideration.

After the review, the panelists concluded that the presumption that deintensified treatment in patients with p16+ OPC can lower long-term adverse effects without impacting survival is still a hypothesis that warrants further testing. While early findings of deintensified treatment techniques show promise, current treatment recommendations have not changed, they said.

“The standard of care for the definitive nonoperative management of cisplatin-eligible patients with advanced disease is concurrent chemoradiation with high-dose cisplatin given every 3 weeks,” the panel wrote. “For patients undergoing initial surgical resection, adjuvant chemoradiation with concurrent high-dose cisplatin given every 3 weeks is recommended for patients with positive margins and/or extranodal tumor extension,” they added.

At present, they recommend that deintensified treatment for patients with p16+ OPC should occur only in the context of a clinical trial.

The panel acknowledged that establishing definitive recommendations for all possible clinical scenarios is challenging because of restrictive exclusion criteria in key clinical trials. As a result, the accuracy of outcome data may be limited to specific patient populations.

More information on the provisional clinical opinion is available on the ASCO website.

ASCO funded the study. The authors reported financial affiliations with AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech, PDS Biotechnology, and several others.

SOURCE: Adelstein DJ et al. J Clin Oncol. 2019 Apr 25. doi: 10.1200/JCO.19.00441.

Treatment deintensification for patients with p16+ oropharyngeal cancer (OPC) should occur only in the context of a clinical trial, according to a provisional clinical opinion released by the American Society of Clinical Oncology (ASCO).

“The hypothesis that deescalation of treatment intensity for patients with p16+ OPC can reduce long-term toxicity without compromising survival is compelling and necessitates careful study and the analysis of well-designed clinical trials before changing current treatment standards, wrote David J. Adelstein, MD, of Case Western Reserve University, Cleveland, along with his associates on the expert panel. Their report is in the Journal of Clinical Oncology.

The panel undertook a review of the literature for evidence pertaining to the treatment of patients with HPV-mediated p16+ OPC with radiation, transoral surgery, concomitant chemoradiotherapy, and chemotherapy, in addition to immunotherapy and targeted therapy. Both randomized and nonrandomized studies were included in the review, and expert consensus opinion was taken into consideration.

After the review, the panelists concluded that the presumption that deintensified treatment in patients with p16+ OPC can lower long-term adverse effects without impacting survival is still a hypothesis that warrants further testing. While early findings of deintensified treatment techniques show promise, current treatment recommendations have not changed, they said.

“The standard of care for the definitive nonoperative management of cisplatin-eligible patients with advanced disease is concurrent chemoradiation with high-dose cisplatin given every 3 weeks,” the panel wrote. “For patients undergoing initial surgical resection, adjuvant chemoradiation with concurrent high-dose cisplatin given every 3 weeks is recommended for patients with positive margins and/or extranodal tumor extension,” they added.

At present, they recommend that deintensified treatment for patients with p16+ OPC should occur only in the context of a clinical trial.

The panel acknowledged that establishing definitive recommendations for all possible clinical scenarios is challenging because of restrictive exclusion criteria in key clinical trials. As a result, the accuracy of outcome data may be limited to specific patient populations.

More information on the provisional clinical opinion is available on the ASCO website.

ASCO funded the study. The authors reported financial affiliations with AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech, PDS Biotechnology, and several others.

SOURCE: Adelstein DJ et al. J Clin Oncol. 2019 Apr 25. doi: 10.1200/JCO.19.00441.

Treatment deintensification for patients with p16+ oropharyngeal cancer (OPC) should occur only in the context of a clinical trial, according to a provisional clinical opinion released by the American Society of Clinical Oncology (ASCO).

“The hypothesis that deescalation of treatment intensity for patients with p16+ OPC can reduce long-term toxicity without compromising survival is compelling and necessitates careful study and the analysis of well-designed clinical trials before changing current treatment standards, wrote David J. Adelstein, MD, of Case Western Reserve University, Cleveland, along with his associates on the expert panel. Their report is in the Journal of Clinical Oncology.

The panel undertook a review of the literature for evidence pertaining to the treatment of patients with HPV-mediated p16+ OPC with radiation, transoral surgery, concomitant chemoradiotherapy, and chemotherapy, in addition to immunotherapy and targeted therapy. Both randomized and nonrandomized studies were included in the review, and expert consensus opinion was taken into consideration.

After the review, the panelists concluded that the presumption that deintensified treatment in patients with p16+ OPC can lower long-term adverse effects without impacting survival is still a hypothesis that warrants further testing. While early findings of deintensified treatment techniques show promise, current treatment recommendations have not changed, they said.

“The standard of care for the definitive nonoperative management of cisplatin-eligible patients with advanced disease is concurrent chemoradiation with high-dose cisplatin given every 3 weeks,” the panel wrote. “For patients undergoing initial surgical resection, adjuvant chemoradiation with concurrent high-dose cisplatin given every 3 weeks is recommended for patients with positive margins and/or extranodal tumor extension,” they added.

At present, they recommend that deintensified treatment for patients with p16+ OPC should occur only in the context of a clinical trial.

The panel acknowledged that establishing definitive recommendations for all possible clinical scenarios is challenging because of restrictive exclusion criteria in key clinical trials. As a result, the accuracy of outcome data may be limited to specific patient populations.

More information on the provisional clinical opinion is available on the ASCO website.

ASCO funded the study. The authors reported financial affiliations with AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech, PDS Biotechnology, and several others.

SOURCE: Adelstein DJ et al. J Clin Oncol. 2019 Apr 25. doi: 10.1200/JCO.19.00441.

Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.

The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.

“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.

The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.

The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 10⁶, 150 × 10⁶, 450 × 10⁶, or 800 × 10⁶ CAR T cells. In the expansion phase, the treatment was given at either 150 x 10⁶ or 450 x 10⁶ CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.

After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.

All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.

The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.

SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.

Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.

The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.

“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.

The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.

The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 10⁶, 150 × 10⁶, 450 × 10⁶, or 800 × 10⁶ CAR T cells. In the expansion phase, the treatment was given at either 150 x 10⁶ or 450 x 10⁶ CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.

After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.

All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.

The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.

SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.

Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.

The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.

“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.

The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.

The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 10⁶, 150 × 10⁶, 450 × 10⁶, or 800 × 10⁶ CAR T cells. In the expansion phase, the treatment was given at either 150 x 10⁶ or 450 x 10⁶ CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.

After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.

All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.

The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.

SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.

ATLANTA – Combined treatment with a programmed death-ligand 1 (PD-L1) inhibitor, the oral CHK1 inhibitor SRA737, and low-dose gemcitabine for small cell lung cancer (SCLC) resulted in dramatic antitumor activity and established a strong antitumor microenvironment in a preclinical model.

The findings provide a “strong rationale” for combining these agents in patients with SCLC, Triparna Sen, PhD, reported in a late-breaking abstract presentation at the annual meeting of the American Association for Cancer Research.

Dr. Sen and her colleagues assessed this triple regimen based on encouraging prior findings, including their own recent finding that DNA damage response (DDR) inhibition “actually increases antitumor immunity in this cancer type” by activating the STING/TBK1/RF3 innate immune pathway and increasing levels of chemokines-CXCL10 and CCL5 that induced activation of cytotoxic T lymphocytes.

“Based on this background and studies published in other cancer types, we hypothesized that ... SRA737... a very highly selective potent checkpoint inhibitor ... will upregulate the innate immune signaling, resulting in improved antitumor immune response in combination with anti–PD-L1,” she said, noting that bladder and colorectal cancer models were also studied.

The results varied by cancer type, but encouraging results in SCLC led to in vivo study, said Dr. Sen, who was a postdoctoral fellow, instructor, and member of the Byers Laboratory at MD Anderson Cancer Center, Houston, at the time the research was conducted.

She and her colleagues injected immunocompetent mice with Trp53, Rb1, and p130 triple-knockout SCLC cell lines that are “very highly representative of what we see in patients,” and resulting tumors were treated with SRA737 alone or in combination with an anti–PD-L1 agent.

PD-L1 alone did not work, and SRA737 with 5- out of 7-day dosing was associated with a significant delay in tumor growth.

“However, the combination does much better than either of the single agents alone. ... we never had tumor growth beyond baseline and there was regression as early as 12 days,” she said, noting that the combination activates the STING pathway.

Similar findings were seen for bladder and colorectal cancer models, she noted.

The next question is how chemotherapy plus immune checkpoint blockade – the currently approved first-line therapy in SCLC – can be improved, and how chemotherapy modulates the immune microenvironment in SCLC, she said.

To explore this, she and her colleagues treated the mice with subtherapeutic doses of SRA737 on 2 out of 7 days with low-dose gemcitabine, followed by anti–PD-L1 therapy, or with single-agent therapy and various double-agent combinations.

Again, none of the agents worked on their own.

“Even with the double combinations you see very, very modest benefit,” she said. “With the triple combination we wipe out the tumors; as early as 14 days we have 8 out of 10 complete responses, and we have followed the tumors up to 2 months and they stay gone.”

“In a nutshell, this works,” she added.

Additional analyses showed that the CD3+ T cells increase with the gemcitabine/SRA737 combination, and even more so with the triple-combination therapy.

“So we not only increase the CD3+ total T cells, we do increase CD8+ cytotoxic T cells,” she said. “Interestingly, we also decrease exhausted T-cell populations, and also [regulatory T] cells.”

Additionally, the M1 macrophage population was significantly higher with the triple regimen, there was a trend toward a decrease in the antimacrophage population, and there was a higher population of dendritic cells and myeloid-derived suppressor cells.

“What I believe is we are still scratching the surface, and we need to go deeper into the tumor microenvironment and see how these combinations really work,” she said, concluding that SRA737 is cytotoxic and induces micro-nuclei formation in a subset of SCLC and other cancer models in vitro, that in combination with anti–PD-L1 it activates innate immune signaling and causes tumor regression in SCLC, and that with low-dose gemcitabine it results in durable tumor regression in combination with SRA737 and anti–PD-L1.

“What is the most interesting is that this triple combination enhances antitumor immunity by increasing cytotoxic T-cell infiltration, decreasing T-cell exhaustion, and a favorable modulation of antigen presenting cells,” she said. “Why do we care? The anti–PD-L1 drug ... atezolizumab ... is right now FDA approved as a first-line treatment in combination with chemotherapy, and we already have DDR inhibitors in the clinic, we have PARP inhibitors in the clinic, we have checkpoint inhibitors in the clinic, SRA737 is in the clinic.

“So our preclinical data provides a strong rationale for combining low-dose gemcitabine with checkpoint inhibition and with anti–PD-L1 to enhance the clinical efficacy of these drugs,” she concluded.

Dr. Sen reported having no disclosures.

sworcester@mdedge.com

SOURCE: Sen T et al. AACR 2019, Abstract LB-148.

ATLANTA – Combined treatment with a programmed death-ligand 1 (PD-L1) inhibitor, the oral CHK1 inhibitor SRA737, and low-dose gemcitabine for small cell lung cancer (SCLC) resulted in dramatic antitumor activity and established a strong antitumor microenvironment in a preclinical model.

The findings provide a “strong rationale” for combining these agents in patients with SCLC, Triparna Sen, PhD, reported in a late-breaking abstract presentation at the annual meeting of the American Association for Cancer Research.

Dr. Sen and her colleagues assessed this triple regimen based on encouraging prior findings, including their own recent finding that DNA damage response (DDR) inhibition “actually increases antitumor immunity in this cancer type” by activating the STING/TBK1/RF3 innate immune pathway and increasing levels of chemokines-CXCL10 and CCL5 that induced activation of cytotoxic T lymphocytes.

“Based on this background and studies published in other cancer types, we hypothesized that ... SRA737... a very highly selective potent checkpoint inhibitor ... will upregulate the innate immune signaling, resulting in improved antitumor immune response in combination with anti–PD-L1,” she said, noting that bladder and colorectal cancer models were also studied.

The results varied by cancer type, but encouraging results in SCLC led to in vivo study, said Dr. Sen, who was a postdoctoral fellow, instructor, and member of the Byers Laboratory at MD Anderson Cancer Center, Houston, at the time the research was conducted.

She and her colleagues injected immunocompetent mice with Trp53, Rb1, and p130 triple-knockout SCLC cell lines that are “very highly representative of what we see in patients,” and resulting tumors were treated with SRA737 alone or in combination with an anti–PD-L1 agent.

PD-L1 alone did not work, and SRA737 with 5- out of 7-day dosing was associated with a significant delay in tumor growth.

“However, the combination does much better than either of the single agents alone. ... we never had tumor growth beyond baseline and there was regression as early as 12 days,” she said, noting that the combination activates the STING pathway.

Similar findings were seen for bladder and colorectal cancer models, she noted.

The next question is how chemotherapy plus immune checkpoint blockade – the currently approved first-line therapy in SCLC – can be improved, and how chemotherapy modulates the immune microenvironment in SCLC, she said.

To explore this, she and her colleagues treated the mice with subtherapeutic doses of SRA737 on 2 out of 7 days with low-dose gemcitabine, followed by anti–PD-L1 therapy, or with single-agent therapy and various double-agent combinations.

Again, none of the agents worked on their own.

“Even with the double combinations you see very, very modest benefit,” she said. “With the triple combination we wipe out the tumors; as early as 14 days we have 8 out of 10 complete responses, and we have followed the tumors up to 2 months and they stay gone.”

“In a nutshell, this works,” she added.

Additional analyses showed that the CD3+ T cells increase with the gemcitabine/SRA737 combination, and even more so with the triple-combination therapy.

“So we not only increase the CD3+ total T cells, we do increase CD8+ cytotoxic T cells,” she said. “Interestingly, we also decrease exhausted T-cell populations, and also [regulatory T] cells.”

Additionally, the M1 macrophage population was significantly higher with the triple regimen, there was a trend toward a decrease in the antimacrophage population, and there was a higher population of dendritic cells and myeloid-derived suppressor cells.

“What I believe is we are still scratching the surface, and we need to go deeper into the tumor microenvironment and see how these combinations really work,” she said, concluding that SRA737 is cytotoxic and induces micro-nuclei formation in a subset of SCLC and other cancer models in vitro, that in combination with anti–PD-L1 it activates innate immune signaling and causes tumor regression in SCLC, and that with low-dose gemcitabine it results in durable tumor regression in combination with SRA737 and anti–PD-L1.

“What is the most interesting is that this triple combination enhances antitumor immunity by increasing cytotoxic T-cell infiltration, decreasing T-cell exhaustion, and a favorable modulation of antigen presenting cells,” she said. “Why do we care? The anti–PD-L1 drug ... atezolizumab ... is right now FDA approved as a first-line treatment in combination with chemotherapy, and we already have DDR inhibitors in the clinic, we have PARP inhibitors in the clinic, we have checkpoint inhibitors in the clinic, SRA737 is in the clinic.

“So our preclinical data provides a strong rationale for combining low-dose gemcitabine with checkpoint inhibition and with anti–PD-L1 to enhance the clinical efficacy of these drugs,” she concluded.

Dr. Sen reported having no disclosures.

sworcester@mdedge.com

SOURCE: Sen T et al. AACR 2019, Abstract LB-148.

ATLANTA – Combined treatment with a programmed death-ligand 1 (PD-L1) inhibitor, the oral CHK1 inhibitor SRA737, and low-dose gemcitabine for small cell lung cancer (SCLC) resulted in dramatic antitumor activity and established a strong antitumor microenvironment in a preclinical model.

The findings provide a “strong rationale” for combining these agents in patients with SCLC, Triparna Sen, PhD, reported in a late-breaking abstract presentation at the annual meeting of the American Association for Cancer Research.

Dr. Sen and her colleagues assessed this triple regimen based on encouraging prior findings, including their own recent finding that DNA damage response (DDR) inhibition “actually increases antitumor immunity in this cancer type” by activating the STING/TBK1/RF3 innate immune pathway and increasing levels of chemokines-CXCL10 and CCL5 that induced activation of cytotoxic T lymphocytes.

“Based on this background and studies published in other cancer types, we hypothesized that ... SRA737... a very highly selective potent checkpoint inhibitor ... will upregulate the innate immune signaling, resulting in improved antitumor immune response in combination with anti–PD-L1,” she said, noting that bladder and colorectal cancer models were also studied.

The results varied by cancer type, but encouraging results in SCLC led to in vivo study, said Dr. Sen, who was a postdoctoral fellow, instructor, and member of the Byers Laboratory at MD Anderson Cancer Center, Houston, at the time the research was conducted.

She and her colleagues injected immunocompetent mice with Trp53, Rb1, and p130 triple-knockout SCLC cell lines that are “very highly representative of what we see in patients,” and resulting tumors were treated with SRA737 alone or in combination with an anti–PD-L1 agent.

PD-L1 alone did not work, and SRA737 with 5- out of 7-day dosing was associated with a significant delay in tumor growth.

“However, the combination does much better than either of the single agents alone. ... we never had tumor growth beyond baseline and there was regression as early as 12 days,” she said, noting that the combination activates the STING pathway.

Similar findings were seen for bladder and colorectal cancer models, she noted.

The next question is how chemotherapy plus immune checkpoint blockade – the currently approved first-line therapy in SCLC – can be improved, and how chemotherapy modulates the immune microenvironment in SCLC, she said.

To explore this, she and her colleagues treated the mice with subtherapeutic doses of SRA737 on 2 out of 7 days with low-dose gemcitabine, followed by anti–PD-L1 therapy, or with single-agent therapy and various double-agent combinations.

Again, none of the agents worked on their own.

“Even with the double combinations you see very, very modest benefit,” she said. “With the triple combination we wipe out the tumors; as early as 14 days we have 8 out of 10 complete responses, and we have followed the tumors up to 2 months and they stay gone.”

“In a nutshell, this works,” she added.

Additional analyses showed that the CD3+ T cells increase with the gemcitabine/SRA737 combination, and even more so with the triple-combination therapy.

“So we not only increase the CD3+ total T cells, we do increase CD8+ cytotoxic T cells,” she said. “Interestingly, we also decrease exhausted T-cell populations, and also [regulatory T] cells.”

Additionally, the M1 macrophage population was significantly higher with the triple regimen, there was a trend toward a decrease in the antimacrophage population, and there was a higher population of dendritic cells and myeloid-derived suppressor cells.

“What I believe is we are still scratching the surface, and we need to go deeper into the tumor microenvironment and see how these combinations really work,” she said, concluding that SRA737 is cytotoxic and induces micro-nuclei formation in a subset of SCLC and other cancer models in vitro, that in combination with anti–PD-L1 it activates innate immune signaling and causes tumor regression in SCLC, and that with low-dose gemcitabine it results in durable tumor regression in combination with SRA737 and anti–PD-L1.

“What is the most interesting is that this triple combination enhances antitumor immunity by increasing cytotoxic T-cell infiltration, decreasing T-cell exhaustion, and a favorable modulation of antigen presenting cells,” she said. “Why do we care? The anti–PD-L1 drug ... atezolizumab ... is right now FDA approved as a first-line treatment in combination with chemotherapy, and we already have DDR inhibitors in the clinic, we have PARP inhibitors in the clinic, we have checkpoint inhibitors in the clinic, SRA737 is in the clinic.

“So our preclinical data provides a strong rationale for combining low-dose gemcitabine with checkpoint inhibition and with anti–PD-L1 to enhance the clinical efficacy of these drugs,” she concluded.

Dr. Sen reported having no disclosures.

sworcester@mdedge.com

SOURCE: Sen T et al. AACR 2019, Abstract LB-148.

The clinical scenario is as follows: A 62-year-old woman comes to see me for a new diagnosis of grade 1 endometrial cancer. She has a normal body mass index of 24 kg/m², a history of four prior full-term pregnancies, no family history of malignancy, and no medical comorbidities. She is otherwise a specimen of good health, and has no clear identifiable risk factors for this malignancy. She then reports that she transitioned through menopause at age 52 years and developed severe hot flashes with sleep and mood disturbance. She did not wish to take conventional hormone replacement therapy (HT) because she had heard it causes cancer. She subsequently researched the Internet and found a provider who has been prescribing compounded bioidentical hormone therapy (CBHT) for her for the past 10 years. She submits saliva for testing of her estrogen levels, and the provider uses this data to compound the appropriate doses of “natural” estrogens and testosterone for her which she applies via vaginal or transdermal creams. She has been prescribed a progesterone suppository, but she doesn’t always take that because she doesn’t notice that it has any effect on how she feels. “Doctor, did my bioidentical hormones give me this uterine cancer?”

Alexander Raths/Fotolia

My answer is, of course, I don’t know. Cancer is a complex disease with a complex array of causative and promoting factors. However, we do know that taking estrogen unopposed with adequate progesterone can cause the development of uterine cancer and its precursor state.¹ If those bioidentical estrogens were effective at controlling her menopausal symptoms, they likely were effective at stimulating her endometrium at the same time.

What are compounded bioidentical hormones?

The term “bioidentical” refers to having the same molecular structure as that which is found in the human body. Examples of bioidentical estrogens include 17-beta-estradiol, estrone, and estriol – which are produced from yams and soy. Micronized progesterone is an example of a bioidentical progesterone. Many of these drugs are approved by the Food and Drug Administration, and prescribed and dispensed by conventional pharmacies.

An alternative, and increasingly popular, version of bioidentical hormones are CBHs. It should be recognized that this is a marketing, and not a scientific, term. These products utilize hormones, in some cases FDA-approved bioidentical hormones, that are broken down and blended by specialized pharmacies and reconstituted (compounded) into different, and sometimes “customized,” dosing and delivery methods (such as capsules, patches, gels, creams, lozenges, suppositories). Frequently used compounded products utilize multiple formulations of estrogens in doublets and triplets as well as progesterone, testosterone, and dehydroepiandrosterone.

How do they differ from synthetic hormones?

Distributors of CBHs state that they differ from conventional HT (synthetic and bioidentical) because of the customization process from which they promise greater efficacy and a sense of personalized medicine. The distributors frequently utilize assays from saliva, blood, vaginal secretions, and urine to measure a woman’s hormone levels, and titrate her compounded formulation based on those results. It should be noted that there is no data to support that titration of hormones to blood, salivary, or urine levels is efficacious or ensures greater safety than titration based on symptom management.

Critics of CBHT, which includes the North American Menopause Society² and the American College of Obstetricians and Gynecologists,³ highlight that the main difference between CBHT and HT is lack of FDA regulation over the CBHT industry. Many of these agents are delivered transdermally and therefore are classified as “dietary supplements.” As such, they do not require FDA regulation or proof of safety or efficacy.

What drives patients’ decision to use compounded bioidentical hormones?

After the Womens’ Health Initiative study was published in 2002⁵, all FDA-regulated estrogen preparations were required to carry specific warnings, particularly in relation to the increased risk for MI, venous thromboembolic events, and breast cancer. There was a clear uptake in use of CBHT after this study was reported. By avoiding FDA regulations, distributors of CBHTs may have avoided providing Womens’ Health Initiative information to patients. The absence of an insert with a written warning, in and of itself, makes these preparations seem safer to the patient.

But is it entirely a lack of information that drives demand for CBHTs? Surveys of current or former users suggest the motivations are more complex than that. A survey of 21 past or present CBHT users inquired about reasons for use of CBHT over conventional HT.⁶ Their responses were categorized as either push motivations away from conventional therapy versus pull motivations toward CBHT. About 95% of current and former users cited distrust of the biomedicine and pharmaceutical industry as reasons for use of CBHT. Fear about the safety of conventional HT, particularly with respect to cancer risk, also was strongly cited at 81%. Motivations pulling toward CBHT included its efficacy (76%) and perception that CBHT is “safer” than conventional HT (76%).

Women in this study also appreciated the tailored, individualized approach that often is associated with CBHT, in which providers spend long consultations discussing individual patient needs and concerns. They enjoy the idea of a customized blend that is created, as opposed to a standard dosing regimen, and intuitively trust the reliability of blood and saliva testing as a prescriptive tool.

Are bioidentical hormones safe with respect to cancer risk?

Hormones themselves are not inert substances, including those derived in vivo and those from plants. They have powerful effects in the human body and can promote malignant transformation or proliferation, alter metabolic pathways, stimulate vascular tone, influence coagulation pathways, along with many other effects. A hormone’s potential for deleterious effect can be present regardless of how that hormone is synthesized, procured, or prepared. While there are no data to suggest that CBHT is associated with increased cancer risk, compared with conventional HT, there are by no means any data to suggest it is safer. Unopposed compounded estrogens place women at increased risk for endometrial cancers, and the prolonged use of hormonal therapy, compounded or otherwise, after menopause increases the risk for breast cancer.

How should we counsel patients?

Patients who desire compounded bioidentical hormone preparations should be counseled that little is known about the safety of these preparations, compared with conventional hormone preparations. The fact that the components are often plant based rather than synthetic does not inherently alter their potential negative impact on biologic pathways. Patients should be educated regarding the difference between FDA-regulated products and nonregulated products so that they can understand that lack of a boxed warning on a non-FDA regulated product does not mean an absence of risk. Women should be informed of the potential inaccuracies in dosing and strength of the CBH preparations they receive.

We should recognize that our patients strongly desire a relationship with their provider in which they are listened to, understood, and treated as individuals. If conversations regarding hormone use are approached with these principles, we will optimize the likelihood our patients are receptive to the highest quality information and not pulled in the direction of unregulated products.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported that she had no conflicts of interest. Email Dr. Rossi at obnews@mdedge.com.

References:

1. Maturitas. 2014 Jan;77(1):4-6.

2. Menopause. 2014 Dec;21(12):1298-300.

3. Fertil Steril. 2012 Aug;98(2):308-12.

4. Report: Limited FDA survey of compounded drug products (Silver Spring, Md.: U.S. Food and Drug Administration, 2009).

5. JAMA. 2002;288(3):321-33.

6. BMC Womens Health. 2017 Oct 2;17(1):97.

The clinical scenario is as follows: A 62-year-old woman comes to see me for a new diagnosis of grade 1 endometrial cancer. She has a normal body mass index of 24 kg/m², a history of four prior full-term pregnancies, no family history of malignancy, and no medical comorbidities. She is otherwise a specimen of good health, and has no clear identifiable risk factors for this malignancy. She then reports that she transitioned through menopause at age 52 years and developed severe hot flashes with sleep and mood disturbance. She did not wish to take conventional hormone replacement therapy (HT) because she had heard it causes cancer. She subsequently researched the Internet and found a provider who has been prescribing compounded bioidentical hormone therapy (CBHT) for her for the past 10 years. She submits saliva for testing of her estrogen levels, and the provider uses this data to compound the appropriate doses of “natural” estrogens and testosterone for her which she applies via vaginal or transdermal creams. She has been prescribed a progesterone suppository, but she doesn’t always take that because she doesn’t notice that it has any effect on how she feels. “Doctor, did my bioidentical hormones give me this uterine cancer?”

Alexander Raths/Fotolia

My answer is, of course, I don’t know. Cancer is a complex disease with a complex array of causative and promoting factors. However, we do know that taking estrogen unopposed with adequate progesterone can cause the development of uterine cancer and its precursor state.¹ If those bioidentical estrogens were effective at controlling her menopausal symptoms, they likely were effective at stimulating her endometrium at the same time.

What are compounded bioidentical hormones?

The term “bioidentical” refers to having the same molecular structure as that which is found in the human body. Examples of bioidentical estrogens include 17-beta-estradiol, estrone, and estriol – which are produced from yams and soy. Micronized progesterone is an example of a bioidentical progesterone. Many of these drugs are approved by the Food and Drug Administration, and prescribed and dispensed by conventional pharmacies.

An alternative, and increasingly popular, version of bioidentical hormones are CBHs. It should be recognized that this is a marketing, and not a scientific, term. These products utilize hormones, in some cases FDA-approved bioidentical hormones, that are broken down and blended by specialized pharmacies and reconstituted (compounded) into different, and sometimes “customized,” dosing and delivery methods (such as capsules, patches, gels, creams, lozenges, suppositories). Frequently used compounded products utilize multiple formulations of estrogens in doublets and triplets as well as progesterone, testosterone, and dehydroepiandrosterone.

How do they differ from synthetic hormones?

Distributors of CBHs state that they differ from conventional HT (synthetic and bioidentical) because of the customization process from which they promise greater efficacy and a sense of personalized medicine. The distributors frequently utilize assays from saliva, blood, vaginal secretions, and urine to measure a woman’s hormone levels, and titrate her compounded formulation based on those results. It should be noted that there is no data to support that titration of hormones to blood, salivary, or urine levels is efficacious or ensures greater safety than titration based on symptom management.

Critics of CBHT, which includes the North American Menopause Society² and the American College of Obstetricians and Gynecologists,³ highlight that the main difference between CBHT and HT is lack of FDA regulation over the CBHT industry. Many of these agents are delivered transdermally and therefore are classified as “dietary supplements.” As such, they do not require FDA regulation or proof of safety or efficacy.

What drives patients’ decision to use compounded bioidentical hormones?

After the Womens’ Health Initiative study was published in 2002⁵, all FDA-regulated estrogen preparations were required to carry specific warnings, particularly in relation to the increased risk for MI, venous thromboembolic events, and breast cancer. There was a clear uptake in use of CBHT after this study was reported. By avoiding FDA regulations, distributors of CBHTs may have avoided providing Womens’ Health Initiative information to patients. The absence of an insert with a written warning, in and of itself, makes these preparations seem safer to the patient.

But is it entirely a lack of information that drives demand for CBHTs? Surveys of current or former users suggest the motivations are more complex than that. A survey of 21 past or present CBHT users inquired about reasons for use of CBHT over conventional HT.⁶ Their responses were categorized as either push motivations away from conventional therapy versus pull motivations toward CBHT. About 95% of current and former users cited distrust of the biomedicine and pharmaceutical industry as reasons for use of CBHT. Fear about the safety of conventional HT, particularly with respect to cancer risk, also was strongly cited at 81%. Motivations pulling toward CBHT included its efficacy (76%) and perception that CBHT is “safer” than conventional HT (76%).

Women in this study also appreciated the tailored, individualized approach that often is associated with CBHT, in which providers spend long consultations discussing individual patient needs and concerns. They enjoy the idea of a customized blend that is created, as opposed to a standard dosing regimen, and intuitively trust the reliability of blood and saliva testing as a prescriptive tool.

Are bioidentical hormones safe with respect to cancer risk?

Hormones themselves are not inert substances, including those derived in vivo and those from plants. They have powerful effects in the human body and can promote malignant transformation or proliferation, alter metabolic pathways, stimulate vascular tone, influence coagulation pathways, along with many other effects. A hormone’s potential for deleterious effect can be present regardless of how that hormone is synthesized, procured, or prepared. While there are no data to suggest that CBHT is associated with increased cancer risk, compared with conventional HT, there are by no means any data to suggest it is safer. Unopposed compounded estrogens place women at increased risk for endometrial cancers, and the prolonged use of hormonal therapy, compounded or otherwise, after menopause increases the risk for breast cancer.

How should we counsel patients?

Patients who desire compounded bioidentical hormone preparations should be counseled that little is known about the safety of these preparations, compared with conventional hormone preparations. The fact that the components are often plant based rather than synthetic does not inherently alter their potential negative impact on biologic pathways. Patients should be educated regarding the difference between FDA-regulated products and nonregulated products so that they can understand that lack of a boxed warning on a non-FDA regulated product does not mean an absence of risk. Women should be informed of the potential inaccuracies in dosing and strength of the CBH preparations they receive.

We should recognize that our patients strongly desire a relationship with their provider in which they are listened to, understood, and treated as individuals. If conversations regarding hormone use are approached with these principles, we will optimize the likelihood our patients are receptive to the highest quality information and not pulled in the direction of unregulated products.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported that she had no conflicts of interest. Email Dr. Rossi at obnews@mdedge.com.

References:

1. Maturitas. 2014 Jan;77(1):4-6.

2. Menopause. 2014 Dec;21(12):1298-300.

3. Fertil Steril. 2012 Aug;98(2):308-12.

4. Report: Limited FDA survey of compounded drug products (Silver Spring, Md.: U.S. Food and Drug Administration, 2009).

5. JAMA. 2002;288(3):321-33.

6. BMC Womens Health. 2017 Oct 2;17(1):97.

The clinical scenario is as follows: A 62-year-old woman comes to see me for a new diagnosis of grade 1 endometrial cancer. She has a normal body mass index of 24 kg/m², a history of four prior full-term pregnancies, no family history of malignancy, and no medical comorbidities. She is otherwise a specimen of good health, and has no clear identifiable risk factors for this malignancy. She then reports that she transitioned through menopause at age 52 years and developed severe hot flashes with sleep and mood disturbance. She did not wish to take conventional hormone replacement therapy (HT) because she had heard it causes cancer. She subsequently researched the Internet and found a provider who has been prescribing compounded bioidentical hormone therapy (CBHT) for her for the past 10 years. She submits saliva for testing of her estrogen levels, and the provider uses this data to compound the appropriate doses of “natural” estrogens and testosterone for her which she applies via vaginal or transdermal creams. She has been prescribed a progesterone suppository, but she doesn’t always take that because she doesn’t notice that it has any effect on how she feels. “Doctor, did my bioidentical hormones give me this uterine cancer?”

Alexander Raths/Fotolia

My answer is, of course, I don’t know. Cancer is a complex disease with a complex array of causative and promoting factors. However, we do know that taking estrogen unopposed with adequate progesterone can cause the development of uterine cancer and its precursor state.¹ If those bioidentical estrogens were effective at controlling her menopausal symptoms, they likely were effective at stimulating her endometrium at the same time.

What are compounded bioidentical hormones?

The term “bioidentical” refers to having the same molecular structure as that which is found in the human body. Examples of bioidentical estrogens include 17-beta-estradiol, estrone, and estriol – which are produced from yams and soy. Micronized progesterone is an example of a bioidentical progesterone. Many of these drugs are approved by the Food and Drug Administration, and prescribed and dispensed by conventional pharmacies.

An alternative, and increasingly popular, version of bioidentical hormones are CBHs. It should be recognized that this is a marketing, and not a scientific, term. These products utilize hormones, in some cases FDA-approved bioidentical hormones, that are broken down and blended by specialized pharmacies and reconstituted (compounded) into different, and sometimes “customized,” dosing and delivery methods (such as capsules, patches, gels, creams, lozenges, suppositories). Frequently used compounded products utilize multiple formulations of estrogens in doublets and triplets as well as progesterone, testosterone, and dehydroepiandrosterone.

How do they differ from synthetic hormones?

Distributors of CBHs state that they differ from conventional HT (synthetic and bioidentical) because of the customization process from which they promise greater efficacy and a sense of personalized medicine. The distributors frequently utilize assays from saliva, blood, vaginal secretions, and urine to measure a woman’s hormone levels, and titrate her compounded formulation based on those results. It should be noted that there is no data to support that titration of hormones to blood, salivary, or urine levels is efficacious or ensures greater safety than titration based on symptom management.

Critics of CBHT, which includes the North American Menopause Society² and the American College of Obstetricians and Gynecologists,³ highlight that the main difference between CBHT and HT is lack of FDA regulation over the CBHT industry. Many of these agents are delivered transdermally and therefore are classified as “dietary supplements.” As such, they do not require FDA regulation or proof of safety or efficacy.

What drives patients’ decision to use compounded bioidentical hormones?

After the Womens’ Health Initiative study was published in 2002⁵, all FDA-regulated estrogen preparations were required to carry specific warnings, particularly in relation to the increased risk for MI, venous thromboembolic events, and breast cancer. There was a clear uptake in use of CBHT after this study was reported. By avoiding FDA regulations, distributors of CBHTs may have avoided providing Womens’ Health Initiative information to patients. The absence of an insert with a written warning, in and of itself, makes these preparations seem safer to the patient.

But is it entirely a lack of information that drives demand for CBHTs? Surveys of current or former users suggest the motivations are more complex than that. A survey of 21 past or present CBHT users inquired about reasons for use of CBHT over conventional HT.⁶ Their responses were categorized as either push motivations away from conventional therapy versus pull motivations toward CBHT. About 95% of current and former users cited distrust of the biomedicine and pharmaceutical industry as reasons for use of CBHT. Fear about the safety of conventional HT, particularly with respect to cancer risk, also was strongly cited at 81%. Motivations pulling toward CBHT included its efficacy (76%) and perception that CBHT is “safer” than conventional HT (76%).

Women in this study also appreciated the tailored, individualized approach that often is associated with CBHT, in which providers spend long consultations discussing individual patient needs and concerns. They enjoy the idea of a customized blend that is created, as opposed to a standard dosing regimen, and intuitively trust the reliability of blood and saliva testing as a prescriptive tool.

Are bioidentical hormones safe with respect to cancer risk?

Hormones themselves are not inert substances, including those derived in vivo and those from plants. They have powerful effects in the human body and can promote malignant transformation or proliferation, alter metabolic pathways, stimulate vascular tone, influence coagulation pathways, along with many other effects. A hormone’s potential for deleterious effect can be present regardless of how that hormone is synthesized, procured, or prepared. While there are no data to suggest that CBHT is associated with increased cancer risk, compared with conventional HT, there are by no means any data to suggest it is safer. Unopposed compounded estrogens place women at increased risk for endometrial cancers, and the prolonged use of hormonal therapy, compounded or otherwise, after menopause increases the risk for breast cancer.

How should we counsel patients?

Patients who desire compounded bioidentical hormone preparations should be counseled that little is known about the safety of these preparations, compared with conventional hormone preparations. The fact that the components are often plant based rather than synthetic does not inherently alter their potential negative impact on biologic pathways. Patients should be educated regarding the difference between FDA-regulated products and nonregulated products so that they can understand that lack of a boxed warning on a non-FDA regulated product does not mean an absence of risk. Women should be informed of the potential inaccuracies in dosing and strength of the CBH preparations they receive.

We should recognize that our patients strongly desire a relationship with their provider in which they are listened to, understood, and treated as individuals. If conversations regarding hormone use are approached with these principles, we will optimize the likelihood our patients are receptive to the highest quality information and not pulled in the direction of unregulated products.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported that she had no conflicts of interest. Email Dr. Rossi at obnews@mdedge.com.

References:

1. Maturitas. 2014 Jan;77(1):4-6.

2. Menopause. 2014 Dec;21(12):1298-300.

3. Fertil Steril. 2012 Aug;98(2):308-12.

4. Report: Limited FDA survey of compounded drug products (Silver Spring, Md.: U.S. Food and Drug Administration, 2009).

5. JAMA. 2002;288(3):321-33.

6. BMC Womens Health. 2017 Oct 2;17(1):97.

MAUI, HAWAII – The incidence of lymphoma in patients with RA appears to have been dropping during the past 2 decades – and for rheumatologists, that’s news you can use.

Bruce Jancin/MDedge News

“I think this is encouraging data about where we’re headed with therapy. And it’s encouraging data for your patients, that maybe more effective therapies can lead to a lower risk of cancer,” John J. Cush, MD, commented at the 2019 Rheumatology Winter Clinical Symposium.

“Patients are always worried about cancer,” observed symposium director Arthur Kavanaugh, MD. “I think this is very useful data to bring to a discussion with patients.”

The study they highlighted was presented at the 2018 annual meeting of the American College of Rheumatology by Namrata Singh, MD, of the University of Iowa, Iowa City and coinvestigators from Veterans Affairs medical centers around the country. They analyzed the incidence of lymphomas as well as all-site cancers in 50,870 men with RA in the national VA health care system during 2001-2015 and compared the rates with the background rates in the general U.S. population as captured in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

The key finding: While the standardized incidence ratio for the development of lymphoma in the RA patients during 2001-2005 was 190% greater than in the SEER population, the SIR dropped to 1.6 in 2006-2010 and stayed low in 2011-2015.

“These are the only data I’m aware of that say maybe lymphomas are becoming less frequent among RA patients,” said Dr. Kavanaugh, professor of medicine at the University of California, San Diego.

Historically, RA has been associated with roughly a 100% increased risk of lymphoma. The source of the increased risk has been a matter of controversy: Is it the result of immunostimulation triggered by high RA disease activity, or a side effect of the drugs employed in treatment of the disease? The clear implication of the VA study is that it’s all about disease activity.

“The lymphoma rate is higher early in the use of our new therapies, in 2001-2005, because the patients who went on TNF [tumor necrosis factor] inhibitors then had the most disease activity. But with time, patients are getting those treatments earlier. Does this [lower lymphoma rate] reflect a change in the practice of rheumatology? I think it does,” according to Dr. Cush, professor of medicine and rheumatology at Baylor University Medical Center, Dallas.

Dr. Kavanaugh agreed. “Now, if we’re treating early and treating to target, we should see less lymphomas than we did back in the day.”

The rate of cancers at all sites in the VA RA patients has been going down as well, with the SIR dropping from 1.8 in 2001-2005 to close to 1, the background rate in the general population.

“What’s great about this study is this is a large data set. You really can’t compare an RA population on and off treatment. The right comparison is to a normal population – and SEER accounts for something like 14% of the U.S. population,” Dr. Cush said.

Previous support for the notion that the increased lymphoma risk associated with RA was a function of disease activity came from a Swedish study of 378 RA patients in the prebiologic era who developed lymphoma and a matched cohort of 378 others without lymphoma. The investigators found that patients with moderate overall RA disease activity were at a 700% increased risk of lymphoma, compared with those with low overall disease activity, and that patients with high RA disease activity were at a 6,900% increased risk (Arthritis Rheum. 2006 Mar;54[3]:692-701). But that was a cross-sectional study, whereas the VA study examined trends over time.

The VA RA cohort had a mean age of 64 years. About 60% were current or ex-smokers, 65% were positive for rheumatoid factor, and 62% were positive for anticyclic citrullinated peptide.

Dr. Kavanaugh said that, because of the potential for referral bias in the VA study, he’s eager to see the findings reproduced in another data set.

Both Dr. Cush and Dr. Kavanaugh reported serving as a consultant to and/or receiving research funding from numerous pharmaceutical companies.

bjancin@mdedge.com

MAUI, HAWAII – The incidence of lymphoma in patients with RA appears to have been dropping during the past 2 decades – and for rheumatologists, that’s news you can use.

Bruce Jancin/MDedge News

“I think this is encouraging data about where we’re headed with therapy. And it’s encouraging data for your patients, that maybe more effective therapies can lead to a lower risk of cancer,” John J. Cush, MD, commented at the 2019 Rheumatology Winter Clinical Symposium.

“Patients are always worried about cancer,” observed symposium director Arthur Kavanaugh, MD. “I think this is very useful data to bring to a discussion with patients.”

The study they highlighted was presented at the 2018 annual meeting of the American College of Rheumatology by Namrata Singh, MD, of the University of Iowa, Iowa City and coinvestigators from Veterans Affairs medical centers around the country. They analyzed the incidence of lymphomas as well as all-site cancers in 50,870 men with RA in the national VA health care system during 2001-2015 and compared the rates with the background rates in the general U.S. population as captured in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

The key finding: While the standardized incidence ratio for the development of lymphoma in the RA patients during 2001-2005 was 190% greater than in the SEER population, the SIR dropped to 1.6 in 2006-2010 and stayed low in 2011-2015.

“These are the only data I’m aware of that say maybe lymphomas are becoming less frequent among RA patients,” said Dr. Kavanaugh, professor of medicine at the University of California, San Diego.

Historically, RA has been associated with roughly a 100% increased risk of lymphoma. The source of the increased risk has been a matter of controversy: Is it the result of immunostimulation triggered by high RA disease activity, or a side effect of the drugs employed in treatment of the disease? The clear implication of the VA study is that it’s all about disease activity.

“The lymphoma rate is higher early in the use of our new therapies, in 2001-2005, because the patients who went on TNF [tumor necrosis factor] inhibitors then had the most disease activity. But with time, patients are getting those treatments earlier. Does this [lower lymphoma rate] reflect a change in the practice of rheumatology? I think it does,” according to Dr. Cush, professor of medicine and rheumatology at Baylor University Medical Center, Dallas.

Dr. Kavanaugh agreed. “Now, if we’re treating early and treating to target, we should see less lymphomas than we did back in the day.”

The rate of cancers at all sites in the VA RA patients has been going down as well, with the SIR dropping from 1.8 in 2001-2005 to close to 1, the background rate in the general population.

“What’s great about this study is this is a large data set. You really can’t compare an RA population on and off treatment. The right comparison is to a normal population – and SEER accounts for something like 14% of the U.S. population,” Dr. Cush said.

Previous support for the notion that the increased lymphoma risk associated with RA was a function of disease activity came from a Swedish study of 378 RA patients in the prebiologic era who developed lymphoma and a matched cohort of 378 others without lymphoma. The investigators found that patients with moderate overall RA disease activity were at a 700% increased risk of lymphoma, compared with those with low overall disease activity, and that patients with high RA disease activity were at a 6,900% increased risk (Arthritis Rheum. 2006 Mar;54[3]:692-701). But that was a cross-sectional study, whereas the VA study examined trends over time.

The VA RA cohort had a mean age of 64 years. About 60% were current or ex-smokers, 65% were positive for rheumatoid factor, and 62% were positive for anticyclic citrullinated peptide.

Dr. Kavanaugh said that, because of the potential for referral bias in the VA study, he’s eager to see the findings reproduced in another data set.

Both Dr. Cush and Dr. Kavanaugh reported serving as a consultant to and/or receiving research funding from numerous pharmaceutical companies.

bjancin@mdedge.com

MAUI, HAWAII – The incidence of lymphoma in patients with RA appears to have been dropping during the past 2 decades – and for rheumatologists, that’s news you can use.

Bruce Jancin/MDedge News

“I think this is encouraging data about where we’re headed with therapy. And it’s encouraging data for your patients, that maybe more effective therapies can lead to a lower risk of cancer,” John J. Cush, MD, commented at the 2019 Rheumatology Winter Clinical Symposium.

“Patients are always worried about cancer,” observed symposium director Arthur Kavanaugh, MD. “I think this is very useful data to bring to a discussion with patients.”

The study they highlighted was presented at the 2018 annual meeting of the American College of Rheumatology by Namrata Singh, MD, of the University of Iowa, Iowa City and coinvestigators from Veterans Affairs medical centers around the country. They analyzed the incidence of lymphomas as well as all-site cancers in 50,870 men with RA in the national VA health care system during 2001-2015 and compared the rates with the background rates in the general U.S. population as captured in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

The key finding: While the standardized incidence ratio for the development of lymphoma in the RA patients during 2001-2005 was 190% greater than in the SEER population, the SIR dropped to 1.6 in 2006-2010 and stayed low in 2011-2015.

“These are the only data I’m aware of that say maybe lymphomas are becoming less frequent among RA patients,” said Dr. Kavanaugh, professor of medicine at the University of California, San Diego.

Historically, RA has been associated with roughly a 100% increased risk of lymphoma. The source of the increased risk has been a matter of controversy: Is it the result of immunostimulation triggered by high RA disease activity, or a side effect of the drugs employed in treatment of the disease? The clear implication of the VA study is that it’s all about disease activity.

“The lymphoma rate is higher early in the use of our new therapies, in 2001-2005, because the patients who went on TNF [tumor necrosis factor] inhibitors then had the most disease activity. But with time, patients are getting those treatments earlier. Does this [lower lymphoma rate] reflect a change in the practice of rheumatology? I think it does,” according to Dr. Cush, professor of medicine and rheumatology at Baylor University Medical Center, Dallas.

Dr. Kavanaugh agreed. “Now, if we’re treating early and treating to target, we should see less lymphomas than we did back in the day.”

The rate of cancers at all sites in the VA RA patients has been going down as well, with the SIR dropping from 1.8 in 2001-2005 to close to 1, the background rate in the general population.

“What’s great about this study is this is a large data set. You really can’t compare an RA population on and off treatment. The right comparison is to a normal population – and SEER accounts for something like 14% of the U.S. population,” Dr. Cush said.

Previous support for the notion that the increased lymphoma risk associated with RA was a function of disease activity came from a Swedish study of 378 RA patients in the prebiologic era who developed lymphoma and a matched cohort of 378 others without lymphoma. The investigators found that patients with moderate overall RA disease activity were at a 700% increased risk of lymphoma, compared with those with low overall disease activity, and that patients with high RA disease activity were at a 6,900% increased risk (Arthritis Rheum. 2006 Mar;54[3]:692-701). But that was a cross-sectional study, whereas the VA study examined trends over time.

The VA RA cohort had a mean age of 64 years. About 60% were current or ex-smokers, 65% were positive for rheumatoid factor, and 62% were positive for anticyclic citrullinated peptide.

Dr. Kavanaugh said that, because of the potential for referral bias in the VA study, he’s eager to see the findings reproduced in another data set.

Both Dr. Cush and Dr. Kavanaugh reported serving as a consultant to and/or receiving research funding from numerous pharmaceutical companies.

bjancin@mdedge.com

VIENNA – Treatment of individuals chronically infected with hepatitis B virus (HBV) with the nucleotide analog tenofovir disoproxil fumarate significantly linked with a substantial cut in the incidence of hepatocellular carcinoma (HCC) compared with those who received the nucleoside analog entecavir, according to a review of more than 29,000 Hong Kong patients.

Mitchel L. Zoler/MDedge News

This is the second reported study to find that association. In January 2019, a study of more than 24,000 Korean residents chronically infected with HBV showed a similar, statistically significant link between treatment with tenofovir disoproxil fumarate (Viread) and a lower incidence of HCC compared with patients treated with entecavir (Baraclude) (JAMA Oncol. 2019 Jan;5[1]:30-6), Grace L.H. Wong, MD, said at the meeting, sponsored by the European Association for the Study of the Liver (EASL).

However, another report published just a few days before Dr. Wong spoke failed to find an association between tenofovir disoproxil treatment of HBV and the subsequent rate of HCC compared with patients treated with entecavir. That study comprised nearly 2,900 HBV patients treated at any of four Korean medical centers (J Hepatol. 2019 Apr. doi: 10.1016/j.jhep.2019.03.028).

Dr. Wong noted that although current guidelines from EASL cite both tenofovir disoproxil and entecavir (as well as tenofovir alafenamide [Vemlidy]) as first-line treatments for chronic HBV infection (J Hepatol. 2017 Aug;67[2]:370-98), some evidence suggests that tenofovir disoproxil might produce effects subtly different from those of entecavir.

At the meeting in Vienna, for example, a report on 176 Japanese patients with chronic HBV showed that those who were treated with a nucleotide analog such as tenofovir disoproxil produced higher serum levels of interferon-lamda3 compared with patients treated with entecavir, and increased levels of this interferon could improve clearance of HBV surface antigen (J Hepatol. 2019 April;70[1]:e477). The most recent EASL guidelines for treatment of chronic hepatitis B infection also list tenofovir disoproxil, entecavir, and tenofovir alafenamide as preferred agents (Hepatology. 2018 April;67[4]:1560-99).

The data Dr. Wong and her associates analyzed came from health records kept for about 80% of Hong Kong’s population in the Clinical Data Analysis and Recording System of the Hospital Authority of Hong Kong. From January 2010 to June 2018, this database included 28,041 consecutive patients chronically infected with HBV and treated with entecavir, and 1,309 consecutive patients treated with tenofovir disoproxil. These numbers excluded patients treated for less than 6 months, patients coinfected with hepatitis C or D virus, patients with cancer diagnosed or a liver transplanted before or during their first 6 months on treatment, and patients previously treated with an interferon or nucleos(t)ide.

During an average follow-up of 2.8 years of tenofovir disoproxil treatment, 8 patients developed HCC, and during an average follow-up of 3.7 years of entecavir treatment, 1,386 patients developed HCC, reported Dr. Wong, a hepatologist and professor of medicine at the Chinese University of Hong Kong.

In a multivariate analysis that adjusted for demographic and clinical differences, treatment with tenofovir disoproxil linked with a statistically significant 68% reduced rate of HCC development compared with the entecavir-treated patients, she said. In a propensity score–weighted analysis, tenofovir disoproxil linked with a statistically significant 64% reduced rate of incident HCC, and in a propensity score–matched analysis tenofovir disoproxil linked with a 58% reduced rate of HCC, although in this analysis, which excluded many of the entecavir-treated patients and hence had less statistical power, the difference just missed statistical significance.

As an additional step to try to rule out the possible effect of unadjusted confounders, Dr. Wong and associates analyzed the links between tenofovir disoproxil and entecavir treatment and two negative-control outcomes, the incidence of lung cancer and the incidence of acute myocardial infarction. Neither of these outcomes showed a statistically significant link with one of the HBV treatments, suggesting that the link between treatment and HCC incidence did not appear because of an unadjusted confounding bias, Dr. Wong said. The Hong Kong database did not include enough patients treated with tenofovir alafenamide to allow assessment of this drug, she added.

Dr. Wong has been an adviser to Gilead and a speaker for Abbott, AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Roche. Tenofovir disoproxil fumarate is marketed by Gilead, and entecavir is marketed by Bristol-Myers Squibb. 

mzoler@mdedge.com

SOURCE: Wong GL et al. J Hepatol. 2019 April;70[1]:e128.

VIENNA – Treatment of individuals chronically infected with hepatitis B virus (HBV) with the nucleotide analog tenofovir disoproxil fumarate significantly linked with a substantial cut in the incidence of hepatocellular carcinoma (HCC) compared with those who received the nucleoside analog entecavir, according to a review of more than 29,000 Hong Kong patients.

Mitchel L. Zoler/MDedge News

This is the second reported study to find that association. In January 2019, a study of more than 24,000 Korean residents chronically infected with HBV showed a similar, statistically significant link between treatment with tenofovir disoproxil fumarate (Viread) and a lower incidence of HCC compared with patients treated with entecavir (Baraclude) (JAMA Oncol. 2019 Jan;5[1]:30-6), Grace L.H. Wong, MD, said at the meeting, sponsored by the European Association for the Study of the Liver (EASL).

However, another report published just a few days before Dr. Wong spoke failed to find an association between tenofovir disoproxil treatment of HBV and the subsequent rate of HCC compared with patients treated with entecavir. That study comprised nearly 2,900 HBV patients treated at any of four Korean medical centers (J Hepatol. 2019 Apr. doi: 10.1016/j.jhep.2019.03.028).

Dr. Wong noted that although current guidelines from EASL cite both tenofovir disoproxil and entecavir (as well as tenofovir alafenamide [Vemlidy]) as first-line treatments for chronic HBV infection (J Hepatol. 2017 Aug;67[2]:370-98), some evidence suggests that tenofovir disoproxil might produce effects subtly different from those of entecavir.

At the meeting in Vienna, for example, a report on 176 Japanese patients with chronic HBV showed that those who were treated with a nucleotide analog such as tenofovir disoproxil produced higher serum levels of interferon-lamda3 compared with patients treated with entecavir, and increased levels of this interferon could improve clearance of HBV surface antigen (J Hepatol. 2019 April;70[1]:e477). The most recent EASL guidelines for treatment of chronic hepatitis B infection also list tenofovir disoproxil, entecavir, and tenofovir alafenamide as preferred agents (Hepatology. 2018 April;67[4]:1560-99).

The data Dr. Wong and her associates analyzed came from health records kept for about 80% of Hong Kong’s population in the Clinical Data Analysis and Recording System of the Hospital Authority of Hong Kong. From January 2010 to June 2018, this database included 28,041 consecutive patients chronically infected with HBV and treated with entecavir, and 1,309 consecutive patients treated with tenofovir disoproxil. These numbers excluded patients treated for less than 6 months, patients coinfected with hepatitis C or D virus, patients with cancer diagnosed or a liver transplanted before or during their first 6 months on treatment, and patients previously treated with an interferon or nucleos(t)ide.

During an average follow-up of 2.8 years of tenofovir disoproxil treatment, 8 patients developed HCC, and during an average follow-up of 3.7 years of entecavir treatment, 1,386 patients developed HCC, reported Dr. Wong, a hepatologist and professor of medicine at the Chinese University of Hong Kong.

In a multivariate analysis that adjusted for demographic and clinical differences, treatment with tenofovir disoproxil linked with a statistically significant 68% reduced rate of HCC development compared with the entecavir-treated patients, she said. In a propensity score–weighted analysis, tenofovir disoproxil linked with a statistically significant 64% reduced rate of incident HCC, and in a propensity score–matched analysis tenofovir disoproxil linked with a 58% reduced rate of HCC, although in this analysis, which excluded many of the entecavir-treated patients and hence had less statistical power, the difference just missed statistical significance.

As an additional step to try to rule out the possible effect of unadjusted confounders, Dr. Wong and associates analyzed the links between tenofovir disoproxil and entecavir treatment and two negative-control outcomes, the incidence of lung cancer and the incidence of acute myocardial infarction. Neither of these outcomes showed a statistically significant link with one of the HBV treatments, suggesting that the link between treatment and HCC incidence did not appear because of an unadjusted confounding bias, Dr. Wong said. The Hong Kong database did not include enough patients treated with tenofovir alafenamide to allow assessment of this drug, she added.

Dr. Wong has been an adviser to Gilead and a speaker for Abbott, AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Roche. Tenofovir disoproxil fumarate is marketed by Gilead, and entecavir is marketed by Bristol-Myers Squibb. 

mzoler@mdedge.com

SOURCE: Wong GL et al. J Hepatol. 2019 April;70[1]:e128.

VIENNA – Treatment of individuals chronically infected with hepatitis B virus (HBV) with the nucleotide analog tenofovir disoproxil fumarate significantly linked with a substantial cut in the incidence of hepatocellular carcinoma (HCC) compared with those who received the nucleoside analog entecavir, according to a review of more than 29,000 Hong Kong patients.

Mitchel L. Zoler/MDedge News

This is the second reported study to find that association. In January 2019, a study of more than 24,000 Korean residents chronically infected with HBV showed a similar, statistically significant link between treatment with tenofovir disoproxil fumarate (Viread) and a lower incidence of HCC compared with patients treated with entecavir (Baraclude) (JAMA Oncol. 2019 Jan;5[1]:30-6), Grace L.H. Wong, MD, said at the meeting, sponsored by the European Association for the Study of the Liver (EASL).

However, another report published just a few days before Dr. Wong spoke failed to find an association between tenofovir disoproxil treatment of HBV and the subsequent rate of HCC compared with patients treated with entecavir. That study comprised nearly 2,900 HBV patients treated at any of four Korean medical centers (J Hepatol. 2019 Apr. doi: 10.1016/j.jhep.2019.03.028).

Dr. Wong noted that although current guidelines from EASL cite both tenofovir disoproxil and entecavir (as well as tenofovir alafenamide [Vemlidy]) as first-line treatments for chronic HBV infection (J Hepatol. 2017 Aug;67[2]:370-98), some evidence suggests that tenofovir disoproxil might produce effects subtly different from those of entecavir.

At the meeting in Vienna, for example, a report on 176 Japanese patients with chronic HBV showed that those who were treated with a nucleotide analog such as tenofovir disoproxil produced higher serum levels of interferon-lamda3 compared with patients treated with entecavir, and increased levels of this interferon could improve clearance of HBV surface antigen (J Hepatol. 2019 April;70[1]:e477). The most recent EASL guidelines for treatment of chronic hepatitis B infection also list tenofovir disoproxil, entecavir, and tenofovir alafenamide as preferred agents (Hepatology. 2018 April;67[4]:1560-99).

The data Dr. Wong and her associates analyzed came from health records kept for about 80% of Hong Kong’s population in the Clinical Data Analysis and Recording System of the Hospital Authority of Hong Kong. From January 2010 to June 2018, this database included 28,041 consecutive patients chronically infected with HBV and treated with entecavir, and 1,309 consecutive patients treated with tenofovir disoproxil. These numbers excluded patients treated for less than 6 months, patients coinfected with hepatitis C or D virus, patients with cancer diagnosed or a liver transplanted before or during their first 6 months on treatment, and patients previously treated with an interferon or nucleos(t)ide.

During an average follow-up of 2.8 years of tenofovir disoproxil treatment, 8 patients developed HCC, and during an average follow-up of 3.7 years of entecavir treatment, 1,386 patients developed HCC, reported Dr. Wong, a hepatologist and professor of medicine at the Chinese University of Hong Kong.

In a multivariate analysis that adjusted for demographic and clinical differences, treatment with tenofovir disoproxil linked with a statistically significant 68% reduced rate of HCC development compared with the entecavir-treated patients, she said. In a propensity score–weighted analysis, tenofovir disoproxil linked with a statistically significant 64% reduced rate of incident HCC, and in a propensity score–matched analysis tenofovir disoproxil linked with a 58% reduced rate of HCC, although in this analysis, which excluded many of the entecavir-treated patients and hence had less statistical power, the difference just missed statistical significance.

As an additional step to try to rule out the possible effect of unadjusted confounders, Dr. Wong and associates analyzed the links between tenofovir disoproxil and entecavir treatment and two negative-control outcomes, the incidence of lung cancer and the incidence of acute myocardial infarction. Neither of these outcomes showed a statistically significant link with one of the HBV treatments, suggesting that the link between treatment and HCC incidence did not appear because of an unadjusted confounding bias, Dr. Wong said. The Hong Kong database did not include enough patients treated with tenofovir alafenamide to allow assessment of this drug, she added.

Dr. Wong has been an adviser to Gilead and a speaker for Abbott, AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Roche. Tenofovir disoproxil fumarate is marketed by Gilead, and entecavir is marketed by Bristol-Myers Squibb. 

mzoler@mdedge.com

SOURCE: Wong GL et al. J Hepatol. 2019 April;70[1]:e128.

Higher reliance on electronic health records (EHRs) in ambulatory oncology practice was significantly associated with reduced safety actions among oncology nurses and prescribers, according to results of a statewide survey.

“The purpose of this study was to investigate the degree to which EHRs, satisfaction with technology, and clinician communication enable a safety culture in ambulatory oncology treatment settings,” wrote Minal R. Patel, PhD, MPH, of the University of Michigan, Ann Arbor, and colleagues. The report is published in the Journal of Oncology Practice.

The researchers conducted a statewide survey of 297 oncology nurses and prescribers in 29 ambulatory oncology practices in Michigan. They obtained quantitative data for May to October 2017 from clinician surveys and practice logs at these clinical sites.

The study methodology was built by use of the sociotechnical framework, which examined how EHR technologies influenced the safe administration of chemotherapy.

Eligible survey participants included physicians, nurses, physician assistants, and nurse practitioners who cared for adult patients receiving infusion treatments for cancer.

A total of 438 clinicians were recruited and confirmed to be eligible, and 297 (68%) completed a survey.

After analysis, the researchers found that higher reliance on electronic health records in practice was associated with reduced safety scores (P less than .001). The mean safety score was reported to be 5.3 (standard deviation, 1.1; practice-level range, 4.9-5.4).

In an opposite manner, increased satisfaction with technology and better-quality communication were associated with higher safety actions.

The researchers acknowledged a key limitation of the study was cross-sectional design. As a result, confounding factors could influence the findings.

“Careful attention to technology adoption and updates coupled with high-quality communication skills across clinicians are promising strategies to administer high-risk treatments safely in ambulatory oncology settings,” they concluded.

The study was supported by grant funding from the Agency for Healthcare Research and Quality and the National Cancer Institute. No conflicts of interest were reported.

SOURCE: Patel MR et al. J Oncol Pract. 2019 Apr 22. doi: 10.1200/JOP.18.00507.

Higher reliance on electronic health records (EHRs) in ambulatory oncology practice was significantly associated with reduced safety actions among oncology nurses and prescribers, according to results of a statewide survey.

“The purpose of this study was to investigate the degree to which EHRs, satisfaction with technology, and clinician communication enable a safety culture in ambulatory oncology treatment settings,” wrote Minal R. Patel, PhD, MPH, of the University of Michigan, Ann Arbor, and colleagues. The report is published in the Journal of Oncology Practice.

The researchers conducted a statewide survey of 297 oncology nurses and prescribers in 29 ambulatory oncology practices in Michigan. They obtained quantitative data for May to October 2017 from clinician surveys and practice logs at these clinical sites.

The study methodology was built by use of the sociotechnical framework, which examined how EHR technologies influenced the safe administration of chemotherapy.

Eligible survey participants included physicians, nurses, physician assistants, and nurse practitioners who cared for adult patients receiving infusion treatments for cancer.

A total of 438 clinicians were recruited and confirmed to be eligible, and 297 (68%) completed a survey.

After analysis, the researchers found that higher reliance on electronic health records in practice was associated with reduced safety scores (P less than .001). The mean safety score was reported to be 5.3 (standard deviation, 1.1; practice-level range, 4.9-5.4).

In an opposite manner, increased satisfaction with technology and better-quality communication were associated with higher safety actions.

The researchers acknowledged a key limitation of the study was cross-sectional design. As a result, confounding factors could influence the findings.

“Careful attention to technology adoption and updates coupled with high-quality communication skills across clinicians are promising strategies to administer high-risk treatments safely in ambulatory oncology settings,” they concluded.

The study was supported by grant funding from the Agency for Healthcare Research and Quality and the National Cancer Institute. No conflicts of interest were reported.

SOURCE: Patel MR et al. J Oncol Pract. 2019 Apr 22. doi: 10.1200/JOP.18.00507.

Higher reliance on electronic health records (EHRs) in ambulatory oncology practice was significantly associated with reduced safety actions among oncology nurses and prescribers, according to results of a statewide survey.

“The purpose of this study was to investigate the degree to which EHRs, satisfaction with technology, and clinician communication enable a safety culture in ambulatory oncology treatment settings,” wrote Minal R. Patel, PhD, MPH, of the University of Michigan, Ann Arbor, and colleagues. The report is published in the Journal of Oncology Practice.

The researchers conducted a statewide survey of 297 oncology nurses and prescribers in 29 ambulatory oncology practices in Michigan. They obtained quantitative data for May to October 2017 from clinician surveys and practice logs at these clinical sites.

The study methodology was built by use of the sociotechnical framework, which examined how EHR technologies influenced the safe administration of chemotherapy.

Eligible survey participants included physicians, nurses, physician assistants, and nurse practitioners who cared for adult patients receiving infusion treatments for cancer.

A total of 438 clinicians were recruited and confirmed to be eligible, and 297 (68%) completed a survey.

After analysis, the researchers found that higher reliance on electronic health records in practice was associated with reduced safety scores (P less than .001). The mean safety score was reported to be 5.3 (standard deviation, 1.1; practice-level range, 4.9-5.4).

In an opposite manner, increased satisfaction with technology and better-quality communication were associated with higher safety actions.

The researchers acknowledged a key limitation of the study was cross-sectional design. As a result, confounding factors could influence the findings.

“Careful attention to technology adoption and updates coupled with high-quality communication skills across clinicians are promising strategies to administer high-risk treatments safely in ambulatory oncology settings,” they concluded.

The study was supported by grant funding from the Agency for Healthcare Research and Quality and the National Cancer Institute. No conflicts of interest were reported.

SOURCE: Patel MR et al. J Oncol Pract. 2019 Apr 22. doi: 10.1200/JOP.18.00507.

For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.

Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.

During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.

This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.

Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.

During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.

After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.

With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.

However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.

“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.

Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.

SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.

For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.

Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.

During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.

This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.

Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.

During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.

After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.

With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.

However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.

“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.

Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.

SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.

For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.

Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.

During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.

This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.

Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.

During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.

After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.

With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.

However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.

“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.

Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.

SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.