Conference Coverage

The benefit of giving pembolizumab (Keytruda, Merck) in the neoadjuvant and adjuvant setting to patients with early triple-negative breast cancer (TNBC) extends across subgroups and clinical situations, suggests the latest analysis from KEYNOTE-522.

The original trial data in more than 1,100 patients with early-stage TNBC indicated that adding pembrolizumab to chemotherapy prior to surgery and giving the drug for a year afterward improves event-free survival (EFS) over placebo by 37%.

Now, the researchers conducted a series of prespecified sensitivity and subgroup analyses, finding remarkably consistent EFS outcomes whether considering the addition of adjuvant chemotherapy, positive surgical margins, or disease characteristics such as nodal status and disease stage.

The analyses showed that the benefit with pembrolizumab over placebo was “robust,” said study presenter Peter Schmid, MD, PhD, Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London.

“These results further support pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery as a new standard of care treatment regimen for patients with high-risk, early-stage TNBC,” he said.

The research was presented at the San Antonio Breast Cancer Symposium on Dec. 7.

Hope S. Rugo, MD, who was invited to comment on the findings, noted that, while the sensitivity analyses showed the benefit with pembrolizumab was seen across the board, the numbers in each group of interest were “very small, making any impact unlikely.”

She continued that there also remain a number of unanswered questions, chief among them being: “Does everybody need a checkpoint inhibitor? Perhaps studies ... could help us understand which patients might do well with chemotherapy alone.”

Dr. Rugo, who is professor of medicine in the division of hematology and oncology at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, , added that “we need to understand the balance of risk and toxicity” asking whether there are patients whose risk of an immunotoxicity is “so high that we should not give them a checkpoint inhibitor.”

It is not clear what constitutes the optimal chemotherapy backbone. “Does everybody need carboplatin? Does everyone need a year of pembrolizumab, even with a pathologic complete response given the intriguing data from GeparNUEVO and previously the I-SPY trial?” she asked.

“Of course, we don’t know the answers to those questions,” she said, but it is nevertheless possible to draw a roadmap for the treatment of early TNBC, although the choice of adjuvant therapy following surgery is less clear.

Dr. Rugo conducted a Twitter poll to canvas opinion on what to give to patients following surgery, depending on whether or not they have a pathological complete response.

At 73%, most of almost 200 respondents said patients with a pathological complete response should continue pembrolizumab for 1 year, while 72% said that patients without a pathological complete response should receive combination therapy of pembrolizumab and either capecitabine or olaparib, depending on mutational status.

Dr. Schmid began his presentation by noting that KEYNOTE-522 was the first prospective, randomized, phase 3 trial of pembrolizumab in early TNBC in the neoadjuvant and adjuvant setting.

Previously presented results showed that adding neoadjuvant pembrolizumab to chemotherapy was associated with a clinically meaningful increase in pathological complete response, while continuing with adjuvant chemotherapy after surgery led to a clinically meaningful improvement in EFS.

Consequently, the Food and Drug Administration approved pembrolizumab in this setting for patients with high-risk early-stage TNBC.

He reminded the audience that the trial included 1,174 patients randomized 2:1 to pembrolizumab or placebo every 3 weeks alongside eight cycles of chemotherapy, followed by pembrolizumab over placebo alone for up to nine cycles after undergoing definitive surgery.

After a median follow-up of 39.1 months, 15.7% of patients treated with pembrolizumab experienced an event versus 23.9% of those in the placebo group, at a hazard ratio of 0.63 (P = .00031). At 36 months, the EFS rate was 84.5% with pembrolizumab and 76.8% in patients treated with placebo.

Dr. Schmid said that they then performed five prespecified sensitivity analyses, which revealed that the results were “consistent with the primary EFS in all five sensitivity analyses, showing the robustnesses of the event-free survival benefit in the pembrolizumab arm.”

The first analysis, he continued, is of “particular interest as it considered the impact of postsurgery new anticancer therapy. For example, the use of adjuvant capecitabine.”

Censoring 31 patients from the pembrolizumab arm who received the drug and 13 of those given placebo, the team found that the hazard ratio for EFS for pembrolizumab versus placebo was 0.64.

Removing “positive margin at last surgery” as part of the definition of EFS also did not change the results substantially, with the HR for EFS for pembrolizumab versus placebo at 0.65.

Subgroup analysis revealed “consistent EFS results,” Dr. Schmid said, irrespective of whether stratifying the patients by nodal status, overall disease stage, menopausal status, HER2 status, or lactate dehydrogenase levels.

While patients in both treatment arms who had nodal involvement had worse outcomes than those without, those in the pembrolizumab arm “still had improved outcomes, compared with placebo, suggesting that it provides benefit regardless of nodal status.”

“Similarly, the EFS benefit with pembrolizumab was irrespective of disease stage,” Dr. Schmid said. Although the EFS improvement was greater in patients with stage II rather than III disease, at a HR of 0.60 versus 0.68, it highlights “the importance of early intervention.”

He said that the “rate of adverse events with pembrolizumab was low, especially in the adjuvant setting.”

Following his presentation, Dr. Schmid was asked whether he would consider retrying immunotherapy in patients after progression on pembrolizumab.

He replied that this is currently a “data-free zone.”

However, he said: “If a patient responded immunotherapy initially, had a disease-free interval and then has recurrence, then I would consider, if the patient is PD-L1 [programmed death–ligand 1] positive, at that time to add immunotherapy. We can’t say whether those patients will derive the same benefit” as that seen in randomized controlled trials in later stage TNBC, he added, “but there is, in my opinion, little to lose, especially if we have already established the patient tolerates immunotherapy well in that setting.”

Dr. Schmid continued that he “personally found it reassuring” that, in the current study, even patients without a complete pathological response “still showed a substantially better event-free survival compared to patients without immunotherapy, so I personally would consider immunotherapy for those patients when they relapse but we can discuss what the optimal disease-free interval is.”

The study was funded by Merck Sharp and Dohme. Both Dr. Rugo and Dr. Schmid reported relationships numerous pharmaceutical companies.

.

The benefit of giving pembolizumab (Keytruda, Merck) in the neoadjuvant and adjuvant setting to patients with early triple-negative breast cancer (TNBC) extends across subgroups and clinical situations, suggests the latest analysis from KEYNOTE-522.

The original trial data in more than 1,100 patients with early-stage TNBC indicated that adding pembrolizumab to chemotherapy prior to surgery and giving the drug for a year afterward improves event-free survival (EFS) over placebo by 37%.

Now, the researchers conducted a series of prespecified sensitivity and subgroup analyses, finding remarkably consistent EFS outcomes whether considering the addition of adjuvant chemotherapy, positive surgical margins, or disease characteristics such as nodal status and disease stage.

The analyses showed that the benefit with pembrolizumab over placebo was “robust,” said study presenter Peter Schmid, MD, PhD, Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London.

“These results further support pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery as a new standard of care treatment regimen for patients with high-risk, early-stage TNBC,” he said.

The research was presented at the San Antonio Breast Cancer Symposium on Dec. 7.

Hope S. Rugo, MD, who was invited to comment on the findings, noted that, while the sensitivity analyses showed the benefit with pembrolizumab was seen across the board, the numbers in each group of interest were “very small, making any impact unlikely.”

She continued that there also remain a number of unanswered questions, chief among them being: “Does everybody need a checkpoint inhibitor? Perhaps studies ... could help us understand which patients might do well with chemotherapy alone.”

Dr. Rugo, who is professor of medicine in the division of hematology and oncology at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, , added that “we need to understand the balance of risk and toxicity” asking whether there are patients whose risk of an immunotoxicity is “so high that we should not give them a checkpoint inhibitor.”

It is not clear what constitutes the optimal chemotherapy backbone. “Does everybody need carboplatin? Does everyone need a year of pembrolizumab, even with a pathologic complete response given the intriguing data from GeparNUEVO and previously the I-SPY trial?” she asked.

“Of course, we don’t know the answers to those questions,” she said, but it is nevertheless possible to draw a roadmap for the treatment of early TNBC, although the choice of adjuvant therapy following surgery is less clear.

Dr. Rugo conducted a Twitter poll to canvas opinion on what to give to patients following surgery, depending on whether or not they have a pathological complete response.

At 73%, most of almost 200 respondents said patients with a pathological complete response should continue pembrolizumab for 1 year, while 72% said that patients without a pathological complete response should receive combination therapy of pembrolizumab and either capecitabine or olaparib, depending on mutational status.

Dr. Schmid began his presentation by noting that KEYNOTE-522 was the first prospective, randomized, phase 3 trial of pembrolizumab in early TNBC in the neoadjuvant and adjuvant setting.

Previously presented results showed that adding neoadjuvant pembrolizumab to chemotherapy was associated with a clinically meaningful increase in pathological complete response, while continuing with adjuvant chemotherapy after surgery led to a clinically meaningful improvement in EFS.

Consequently, the Food and Drug Administration approved pembrolizumab in this setting for patients with high-risk early-stage TNBC.

He reminded the audience that the trial included 1,174 patients randomized 2:1 to pembrolizumab or placebo every 3 weeks alongside eight cycles of chemotherapy, followed by pembrolizumab over placebo alone for up to nine cycles after undergoing definitive surgery.

After a median follow-up of 39.1 months, 15.7% of patients treated with pembrolizumab experienced an event versus 23.9% of those in the placebo group, at a hazard ratio of 0.63 (P = .00031). At 36 months, the EFS rate was 84.5% with pembrolizumab and 76.8% in patients treated with placebo.

Dr. Schmid said that they then performed five prespecified sensitivity analyses, which revealed that the results were “consistent with the primary EFS in all five sensitivity analyses, showing the robustnesses of the event-free survival benefit in the pembrolizumab arm.”

The first analysis, he continued, is of “particular interest as it considered the impact of postsurgery new anticancer therapy. For example, the use of adjuvant capecitabine.”

Censoring 31 patients from the pembrolizumab arm who received the drug and 13 of those given placebo, the team found that the hazard ratio for EFS for pembrolizumab versus placebo was 0.64.

Removing “positive margin at last surgery” as part of the definition of EFS also did not change the results substantially, with the HR for EFS for pembrolizumab versus placebo at 0.65.

Subgroup analysis revealed “consistent EFS results,” Dr. Schmid said, irrespective of whether stratifying the patients by nodal status, overall disease stage, menopausal status, HER2 status, or lactate dehydrogenase levels.

While patients in both treatment arms who had nodal involvement had worse outcomes than those without, those in the pembrolizumab arm “still had improved outcomes, compared with placebo, suggesting that it provides benefit regardless of nodal status.”

“Similarly, the EFS benefit with pembrolizumab was irrespective of disease stage,” Dr. Schmid said. Although the EFS improvement was greater in patients with stage II rather than III disease, at a HR of 0.60 versus 0.68, it highlights “the importance of early intervention.”

He said that the “rate of adverse events with pembrolizumab was low, especially in the adjuvant setting.”

Following his presentation, Dr. Schmid was asked whether he would consider retrying immunotherapy in patients after progression on pembrolizumab.

He replied that this is currently a “data-free zone.”

However, he said: “If a patient responded immunotherapy initially, had a disease-free interval and then has recurrence, then I would consider, if the patient is PD-L1 [programmed death–ligand 1] positive, at that time to add immunotherapy. We can’t say whether those patients will derive the same benefit” as that seen in randomized controlled trials in later stage TNBC, he added, “but there is, in my opinion, little to lose, especially if we have already established the patient tolerates immunotherapy well in that setting.”

Dr. Schmid continued that he “personally found it reassuring” that, in the current study, even patients without a complete pathological response “still showed a substantially better event-free survival compared to patients without immunotherapy, so I personally would consider immunotherapy for those patients when they relapse but we can discuss what the optimal disease-free interval is.”

The study was funded by Merck Sharp and Dohme. Both Dr. Rugo and Dr. Schmid reported relationships numerous pharmaceutical companies.

.

The benefit of giving pembolizumab (Keytruda, Merck) in the neoadjuvant and adjuvant setting to patients with early triple-negative breast cancer (TNBC) extends across subgroups and clinical situations, suggests the latest analysis from KEYNOTE-522.

The original trial data in more than 1,100 patients with early-stage TNBC indicated that adding pembrolizumab to chemotherapy prior to surgery and giving the drug for a year afterward improves event-free survival (EFS) over placebo by 37%.

Now, the researchers conducted a series of prespecified sensitivity and subgroup analyses, finding remarkably consistent EFS outcomes whether considering the addition of adjuvant chemotherapy, positive surgical margins, or disease characteristics such as nodal status and disease stage.

The analyses showed that the benefit with pembrolizumab over placebo was “robust,” said study presenter Peter Schmid, MD, PhD, Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London.

“These results further support pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery as a new standard of care treatment regimen for patients with high-risk, early-stage TNBC,” he said.

The research was presented at the San Antonio Breast Cancer Symposium on Dec. 7.

Hope S. Rugo, MD, who was invited to comment on the findings, noted that, while the sensitivity analyses showed the benefit with pembrolizumab was seen across the board, the numbers in each group of interest were “very small, making any impact unlikely.”

She continued that there also remain a number of unanswered questions, chief among them being: “Does everybody need a checkpoint inhibitor? Perhaps studies ... could help us understand which patients might do well with chemotherapy alone.”

Dr. Rugo, who is professor of medicine in the division of hematology and oncology at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, , added that “we need to understand the balance of risk and toxicity” asking whether there are patients whose risk of an immunotoxicity is “so high that we should not give them a checkpoint inhibitor.”

It is not clear what constitutes the optimal chemotherapy backbone. “Does everybody need carboplatin? Does everyone need a year of pembrolizumab, even with a pathologic complete response given the intriguing data from GeparNUEVO and previously the I-SPY trial?” she asked.

“Of course, we don’t know the answers to those questions,” she said, but it is nevertheless possible to draw a roadmap for the treatment of early TNBC, although the choice of adjuvant therapy following surgery is less clear.

Dr. Rugo conducted a Twitter poll to canvas opinion on what to give to patients following surgery, depending on whether or not they have a pathological complete response.

At 73%, most of almost 200 respondents said patients with a pathological complete response should continue pembrolizumab for 1 year, while 72% said that patients without a pathological complete response should receive combination therapy of pembrolizumab and either capecitabine or olaparib, depending on mutational status.

Dr. Schmid began his presentation by noting that KEYNOTE-522 was the first prospective, randomized, phase 3 trial of pembrolizumab in early TNBC in the neoadjuvant and adjuvant setting.

Previously presented results showed that adding neoadjuvant pembrolizumab to chemotherapy was associated with a clinically meaningful increase in pathological complete response, while continuing with adjuvant chemotherapy after surgery led to a clinically meaningful improvement in EFS.

Consequently, the Food and Drug Administration approved pembrolizumab in this setting for patients with high-risk early-stage TNBC.

He reminded the audience that the trial included 1,174 patients randomized 2:1 to pembrolizumab or placebo every 3 weeks alongside eight cycles of chemotherapy, followed by pembrolizumab over placebo alone for up to nine cycles after undergoing definitive surgery.

After a median follow-up of 39.1 months, 15.7% of patients treated with pembrolizumab experienced an event versus 23.9% of those in the placebo group, at a hazard ratio of 0.63 (P = .00031). At 36 months, the EFS rate was 84.5% with pembrolizumab and 76.8% in patients treated with placebo.

Dr. Schmid said that they then performed five prespecified sensitivity analyses, which revealed that the results were “consistent with the primary EFS in all five sensitivity analyses, showing the robustnesses of the event-free survival benefit in the pembrolizumab arm.”

The first analysis, he continued, is of “particular interest as it considered the impact of postsurgery new anticancer therapy. For example, the use of adjuvant capecitabine.”

Censoring 31 patients from the pembrolizumab arm who received the drug and 13 of those given placebo, the team found that the hazard ratio for EFS for pembrolizumab versus placebo was 0.64.

Removing “positive margin at last surgery” as part of the definition of EFS also did not change the results substantially, with the HR for EFS for pembrolizumab versus placebo at 0.65.

Subgroup analysis revealed “consistent EFS results,” Dr. Schmid said, irrespective of whether stratifying the patients by nodal status, overall disease stage, menopausal status, HER2 status, or lactate dehydrogenase levels.

While patients in both treatment arms who had nodal involvement had worse outcomes than those without, those in the pembrolizumab arm “still had improved outcomes, compared with placebo, suggesting that it provides benefit regardless of nodal status.”

“Similarly, the EFS benefit with pembrolizumab was irrespective of disease stage,” Dr. Schmid said. Although the EFS improvement was greater in patients with stage II rather than III disease, at a HR of 0.60 versus 0.68, it highlights “the importance of early intervention.”

He said that the “rate of adverse events with pembrolizumab was low, especially in the adjuvant setting.”

Following his presentation, Dr. Schmid was asked whether he would consider retrying immunotherapy in patients after progression on pembrolizumab.

He replied that this is currently a “data-free zone.”

However, he said: “If a patient responded immunotherapy initially, had a disease-free interval and then has recurrence, then I would consider, if the patient is PD-L1 [programmed death–ligand 1] positive, at that time to add immunotherapy. We can’t say whether those patients will derive the same benefit” as that seen in randomized controlled trials in later stage TNBC, he added, “but there is, in my opinion, little to lose, especially if we have already established the patient tolerates immunotherapy well in that setting.”

Dr. Schmid continued that he “personally found it reassuring” that, in the current study, even patients without a complete pathological response “still showed a substantially better event-free survival compared to patients without immunotherapy, so I personally would consider immunotherapy for those patients when they relapse but we can discuss what the optimal disease-free interval is.”

The study was funded by Merck Sharp and Dohme. Both Dr. Rugo and Dr. Schmid reported relationships numerous pharmaceutical companies.

.

Tumor biology and socioeconomics only partly explain why acute lymphoblastic leukemia survival outcomes are worse for young Hispanic and Black patients than White patients, but they don’t explain it entirely, according to a report at the American Society of Hematology annual meeting.

Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.

When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.

However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.

Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.

Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.

However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.

“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.

Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.

Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.

Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.

Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.

aotto@mdedge.com

Tumor biology and socioeconomics only partly explain why acute lymphoblastic leukemia survival outcomes are worse for young Hispanic and Black patients than White patients, but they don’t explain it entirely, according to a report at the American Society of Hematology annual meeting.

Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.

When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.

However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.

Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.

Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.

However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.

“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.

Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.

Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.

Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.

Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.

aotto@mdedge.com

Tumor biology and socioeconomics only partly explain why acute lymphoblastic leukemia survival outcomes are worse for young Hispanic and Black patients than White patients, but they don’t explain it entirely, according to a report at the American Society of Hematology annual meeting.

Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.

When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.

However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.

Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.

Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.

However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.

“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.

Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.

Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.

Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.

Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.

aotto@mdedge.com

Tisagenlecleucel failed to outperform standard of care treatment when given as a second-line treatment for certain patients with relapsed/refractory aggressive non-Hodgkin lymphomas, according to results of a randomized, phase 3 trial.

The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.

Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.

Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.

“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.

Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.

The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.

About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.

The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.

“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”

Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.

The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.

While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.

In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.

Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.

“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.

There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.

“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.

In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.

Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m² and 90 mg/m², respectively.

Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.

Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.

Tisagenlecleucel failed to outperform standard of care treatment when given as a second-line treatment for certain patients with relapsed/refractory aggressive non-Hodgkin lymphomas, according to results of a randomized, phase 3 trial.

The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.

Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.

Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.

“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.

Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.

The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.

About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.

The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.

“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”

Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.

The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.

While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.

In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.

Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.

“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.

There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.

“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.

In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.

Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m² and 90 mg/m², respectively.

Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.

Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.

Tisagenlecleucel failed to outperform standard of care treatment when given as a second-line treatment for certain patients with relapsed/refractory aggressive non-Hodgkin lymphomas, according to results of a randomized, phase 3 trial.

The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.

Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.

Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.

“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.

Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.

The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.

About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.

The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.

“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”

Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.

The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.

While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.

In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.

Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.

“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.

There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.

“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.

In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.

Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m² and 90 mg/m², respectively.

Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.

Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.

ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.

Now, results from an ongoing study suggest that the combination of the tyrosine kinase inhibitor (TKI) dastatinib (Sprycel) with the bispecific T-cell engager (BiTE) blinatumomab (Blincyto), together with prednisone, may significantly improve remission rates and prolong both progression-free and overall survival among older and/or less fit patients with Ph+ALL.

The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).

Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.

At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.

“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.

“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
 

Early promise

A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.

“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.

“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.

“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.

Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.

“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
 

Study results

The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.

Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.

Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.

Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.

Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.

Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.

Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.

In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.

These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.

The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.

Now, results from an ongoing study suggest that the combination of the tyrosine kinase inhibitor (TKI) dastatinib (Sprycel) with the bispecific T-cell engager (BiTE) blinatumomab (Blincyto), together with prednisone, may significantly improve remission rates and prolong both progression-free and overall survival among older and/or less fit patients with Ph+ALL.

The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).

Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.

At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.

“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.

“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
 

Early promise

A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.

“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.

“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.

“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.

Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.

“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
 

Study results

The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.

Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.

Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.

Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.

Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.

Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.

Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.

In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.

These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.

The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.

Now, results from an ongoing study suggest that the combination of the tyrosine kinase inhibitor (TKI) dastatinib (Sprycel) with the bispecific T-cell engager (BiTE) blinatumomab (Blincyto), together with prednisone, may significantly improve remission rates and prolong both progression-free and overall survival among older and/or less fit patients with Ph+ALL.

The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).

Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.

At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.

“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.

“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
 

Early promise

A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.

“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.

“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.

“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.

Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.

“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
 

Study results

The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.

Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.

Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.

Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.

Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.

Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.

Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.

In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.

These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.

The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Although their ages were similar, patients with epilepsy were nearly 1.5 times more likely to die of COVID-19 than other infected patients at a hospital system during the first 14 months of the pandemic, according to a new study presented at the annual meeting of the American Epilepsy Society. While the findings are preliminary and not yet adjusted for various confounders, the authors say they are a warning sign that patients with epilepsy may face higher risks.

“These findings suggest that epilepsy may be a pre-existing condition that places patients at increased risk for death if hospitalized with a COVID-19 infection. It may offer neurologists guidance when counseling patients on critical preventative measures such as masking, social distancing, and most importantly, vaccination,” lead author Claire Ufongene, a student at Icahn School of Medicine at Mount Sinai, New York, said in an interview.

According to Ms. Ufongene, there’s sparse data about COVID-19 outcomes in patients with epilepsy, although she highlighted a 2021 meta-analysis of 13 studies that found a higher risk of severity (odds ratio, 1.69; 95% confidence interval, 1.11-2.59, P = .010) and mortality (OR, 1.71; 95% CI, 1.14-2.56, P = .010).

For the new study, researchers retrospectively tracked identified 334 patients with epilepsy and COVID-19 and 9,499 other patients with COVID-19 from March 15, 2020, to May 17, 2021. All were treated at hospitals within the New York–based Icahn School of Medicine at Mount Sinai.

The groups of patients with and without epilepsy were similar in some ways: 45% and 46%, respectively, were female (P = .674), and their ages were similar (average, 62 years and 65 years, respectively; P = .02). Racial makeup was also similar (non-Hispanic groups made up 27.8% of those with epilepsy and 24.5% of those without; the difference was not statistically significant).

“In addition, more of those with epilepsy were English speaking [83.2% vs. 77.9%] and had Medicaid insurance [50.9% vs. 38.9%], while fewer of those with epilepsy had private insurance [16.2% vs. 25.5%] or were Spanish speaking [14.0% vs. 9.3%],” study coauthor Nathalie Jette, MD, MSc, a neurologist at Icahn School of Medicine at Mount Sinai, said in an interview.

In terms of outcomes, patients with epilepsy were much more likely to need ventilator support (37.7% vs. 14.3%; P < .001), to be admitted to the ICU (39.2% vs. 17.7%; P < .001), and to die in the hospital (29.6% vs. 19.9%; P < .001).

“Most patients we follow in our practices with epilepsy who experienced COVID-19 in general have had symptoms similar to the general population,” Dr. Jette said. “There are rare instances where COVID-19 can result in an exacerbation of seizures in some with pre-existing epilepsy. This is not surprising as infections in particular can decrease the seizure threshold and result in breakthrough seizures in people living with epilepsy.”
 

Loss of seizure control

How might epilepsy be related to worse outcomes in COVID-19? Andrew Wilner, MD, a neurologist and internist at University of Tennessee Health Science Center, Memphis, who’s familiar with the study findings, said COVID-19 itself may not worsen epilepsy. “Evidence to suggest that COVID-19 directly affects the central nervous system is extremely limited. As such, one would not expect that a COVID-19 infection would cause epilepsy or exacerbate epilepsy,” he said. “However, patients with epilepsy who suffer from infections may be predisposed to decreased seizure control. Consequently, it would not be surprising if patients with epilepsy who also had COVID-19 had loss of seizure control and even status epilepticus, which could adversely affect their hospital course. However, there are no data on this potential phenomenon.”

Dr. Wilner suspected that comorbidities explain the higher mortality in patients with epilepsy. “The findings are probably most useful in that they call attention to the fact that epilepsy patients are more vulnerable to a host of comorbidities and resultant poorer outcomes due to any acute illness.”

As for treatment, Dr. Wilner urged colleagues to make sure that hospitalized patients with epilepsy “continue to receive their antiepileptic medications, which they may no longer be able to take orally. They may need to be switched temporarily to an intravenous formulation.”

In an interview, Selim Benbadis, MD, a neurologist from the University of South Florida, Tampa, suggested that antiseizure medications may play a role in the COVID-19 disease course because they can reduce the efficacy of other medications, although he noted that drug treatments for COVID-19 were limited early on. He recommended that neurologists “avoid old enzyme-inducing seizure medications, as is generally recommended.”

No study funding is reported. The study authors and Dr. Benbadis reported no relevant disclosures. Dr. Wilner is a medical adviser for the epilepsy disease management program for CVS/Health.

Although their ages were similar, patients with epilepsy were nearly 1.5 times more likely to die of COVID-19 than other infected patients at a hospital system during the first 14 months of the pandemic, according to a new study presented at the annual meeting of the American Epilepsy Society. While the findings are preliminary and not yet adjusted for various confounders, the authors say they are a warning sign that patients with epilepsy may face higher risks.

“These findings suggest that epilepsy may be a pre-existing condition that places patients at increased risk for death if hospitalized with a COVID-19 infection. It may offer neurologists guidance when counseling patients on critical preventative measures such as masking, social distancing, and most importantly, vaccination,” lead author Claire Ufongene, a student at Icahn School of Medicine at Mount Sinai, New York, said in an interview.

According to Ms. Ufongene, there’s sparse data about COVID-19 outcomes in patients with epilepsy, although she highlighted a 2021 meta-analysis of 13 studies that found a higher risk of severity (odds ratio, 1.69; 95% confidence interval, 1.11-2.59, P = .010) and mortality (OR, 1.71; 95% CI, 1.14-2.56, P = .010).

For the new study, researchers retrospectively tracked identified 334 patients with epilepsy and COVID-19 and 9,499 other patients with COVID-19 from March 15, 2020, to May 17, 2021. All were treated at hospitals within the New York–based Icahn School of Medicine at Mount Sinai.

The groups of patients with and without epilepsy were similar in some ways: 45% and 46%, respectively, were female (P = .674), and their ages were similar (average, 62 years and 65 years, respectively; P = .02). Racial makeup was also similar (non-Hispanic groups made up 27.8% of those with epilepsy and 24.5% of those without; the difference was not statistically significant).

“In addition, more of those with epilepsy were English speaking [83.2% vs. 77.9%] and had Medicaid insurance [50.9% vs. 38.9%], while fewer of those with epilepsy had private insurance [16.2% vs. 25.5%] or were Spanish speaking [14.0% vs. 9.3%],” study coauthor Nathalie Jette, MD, MSc, a neurologist at Icahn School of Medicine at Mount Sinai, said in an interview.

In terms of outcomes, patients with epilepsy were much more likely to need ventilator support (37.7% vs. 14.3%; P < .001), to be admitted to the ICU (39.2% vs. 17.7%; P < .001), and to die in the hospital (29.6% vs. 19.9%; P < .001).

“Most patients we follow in our practices with epilepsy who experienced COVID-19 in general have had symptoms similar to the general population,” Dr. Jette said. “There are rare instances where COVID-19 can result in an exacerbation of seizures in some with pre-existing epilepsy. This is not surprising as infections in particular can decrease the seizure threshold and result in breakthrough seizures in people living with epilepsy.”
 

Loss of seizure control

How might epilepsy be related to worse outcomes in COVID-19? Andrew Wilner, MD, a neurologist and internist at University of Tennessee Health Science Center, Memphis, who’s familiar with the study findings, said COVID-19 itself may not worsen epilepsy. “Evidence to suggest that COVID-19 directly affects the central nervous system is extremely limited. As such, one would not expect that a COVID-19 infection would cause epilepsy or exacerbate epilepsy,” he said. “However, patients with epilepsy who suffer from infections may be predisposed to decreased seizure control. Consequently, it would not be surprising if patients with epilepsy who also had COVID-19 had loss of seizure control and even status epilepticus, which could adversely affect their hospital course. However, there are no data on this potential phenomenon.”

Dr. Wilner suspected that comorbidities explain the higher mortality in patients with epilepsy. “The findings are probably most useful in that they call attention to the fact that epilepsy patients are more vulnerable to a host of comorbidities and resultant poorer outcomes due to any acute illness.”

As for treatment, Dr. Wilner urged colleagues to make sure that hospitalized patients with epilepsy “continue to receive their antiepileptic medications, which they may no longer be able to take orally. They may need to be switched temporarily to an intravenous formulation.”

In an interview, Selim Benbadis, MD, a neurologist from the University of South Florida, Tampa, suggested that antiseizure medications may play a role in the COVID-19 disease course because they can reduce the efficacy of other medications, although he noted that drug treatments for COVID-19 were limited early on. He recommended that neurologists “avoid old enzyme-inducing seizure medications, as is generally recommended.”

No study funding is reported. The study authors and Dr. Benbadis reported no relevant disclosures. Dr. Wilner is a medical adviser for the epilepsy disease management program for CVS/Health.

Although their ages were similar, patients with epilepsy were nearly 1.5 times more likely to die of COVID-19 than other infected patients at a hospital system during the first 14 months of the pandemic, according to a new study presented at the annual meeting of the American Epilepsy Society. While the findings are preliminary and not yet adjusted for various confounders, the authors say they are a warning sign that patients with epilepsy may face higher risks.

“These findings suggest that epilepsy may be a pre-existing condition that places patients at increased risk for death if hospitalized with a COVID-19 infection. It may offer neurologists guidance when counseling patients on critical preventative measures such as masking, social distancing, and most importantly, vaccination,” lead author Claire Ufongene, a student at Icahn School of Medicine at Mount Sinai, New York, said in an interview.

According to Ms. Ufongene, there’s sparse data about COVID-19 outcomes in patients with epilepsy, although she highlighted a 2021 meta-analysis of 13 studies that found a higher risk of severity (odds ratio, 1.69; 95% confidence interval, 1.11-2.59, P = .010) and mortality (OR, 1.71; 95% CI, 1.14-2.56, P = .010).

For the new study, researchers retrospectively tracked identified 334 patients with epilepsy and COVID-19 and 9,499 other patients with COVID-19 from March 15, 2020, to May 17, 2021. All were treated at hospitals within the New York–based Icahn School of Medicine at Mount Sinai.

The groups of patients with and without epilepsy were similar in some ways: 45% and 46%, respectively, were female (P = .674), and their ages were similar (average, 62 years and 65 years, respectively; P = .02). Racial makeup was also similar (non-Hispanic groups made up 27.8% of those with epilepsy and 24.5% of those without; the difference was not statistically significant).

“In addition, more of those with epilepsy were English speaking [83.2% vs. 77.9%] and had Medicaid insurance [50.9% vs. 38.9%], while fewer of those with epilepsy had private insurance [16.2% vs. 25.5%] or were Spanish speaking [14.0% vs. 9.3%],” study coauthor Nathalie Jette, MD, MSc, a neurologist at Icahn School of Medicine at Mount Sinai, said in an interview.

In terms of outcomes, patients with epilepsy were much more likely to need ventilator support (37.7% vs. 14.3%; P < .001), to be admitted to the ICU (39.2% vs. 17.7%; P < .001), and to die in the hospital (29.6% vs. 19.9%; P < .001).

“Most patients we follow in our practices with epilepsy who experienced COVID-19 in general have had symptoms similar to the general population,” Dr. Jette said. “There are rare instances where COVID-19 can result in an exacerbation of seizures in some with pre-existing epilepsy. This is not surprising as infections in particular can decrease the seizure threshold and result in breakthrough seizures in people living with epilepsy.”
 

Loss of seizure control

How might epilepsy be related to worse outcomes in COVID-19? Andrew Wilner, MD, a neurologist and internist at University of Tennessee Health Science Center, Memphis, who’s familiar with the study findings, said COVID-19 itself may not worsen epilepsy. “Evidence to suggest that COVID-19 directly affects the central nervous system is extremely limited. As such, one would not expect that a COVID-19 infection would cause epilepsy or exacerbate epilepsy,” he said. “However, patients with epilepsy who suffer from infections may be predisposed to decreased seizure control. Consequently, it would not be surprising if patients with epilepsy who also had COVID-19 had loss of seizure control and even status epilepticus, which could adversely affect their hospital course. However, there are no data on this potential phenomenon.”

Dr. Wilner suspected that comorbidities explain the higher mortality in patients with epilepsy. “The findings are probably most useful in that they call attention to the fact that epilepsy patients are more vulnerable to a host of comorbidities and resultant poorer outcomes due to any acute illness.”

As for treatment, Dr. Wilner urged colleagues to make sure that hospitalized patients with epilepsy “continue to receive their antiepileptic medications, which they may no longer be able to take orally. They may need to be switched temporarily to an intravenous formulation.”

In an interview, Selim Benbadis, MD, a neurologist from the University of South Florida, Tampa, suggested that antiseizure medications may play a role in the COVID-19 disease course because they can reduce the efficacy of other medications, although he noted that drug treatments for COVID-19 were limited early on. He recommended that neurologists “avoid old enzyme-inducing seizure medications, as is generally recommended.”

No study funding is reported. The study authors and Dr. Benbadis reported no relevant disclosures. Dr. Wilner is a medical adviser for the epilepsy disease management program for CVS/Health.

ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.

The results come from the phase 3 AGILE trial. The ivosidenib-azacitidine (IVO-AZA) combination was associated with a 67% reduction in the risk of treatment failure, relapse, or death, and 56% improvement in overall survival, reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.

Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).

“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.

Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.

“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.

The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.

“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.

The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
 

AGILE results

For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m², delivered subcutaneously or intravenously, or azacitidine plus placebo.

In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.

The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.

The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.

At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).

The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.

Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).

Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.

Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.

Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.

He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.

The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.

A version of this article first appeared on Medscape.com.

ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.

The results come from the phase 3 AGILE trial. The ivosidenib-azacitidine (IVO-AZA) combination was associated with a 67% reduction in the risk of treatment failure, relapse, or death, and 56% improvement in overall survival, reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.

Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).

“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.

Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.

“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.

The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.

“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.

The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
 

AGILE results

For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m², delivered subcutaneously or intravenously, or azacitidine plus placebo.

In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.

The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.

The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.

At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).

The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.

Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).

Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.

Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.

Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.

He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.

The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.

A version of this article first appeared on Medscape.com.

ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.

The results come from the phase 3 AGILE trial. The ivosidenib-azacitidine (IVO-AZA) combination was associated with a 67% reduction in the risk of treatment failure, relapse, or death, and 56% improvement in overall survival, reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.

Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).

“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.

Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.

“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.

The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.

“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.

The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
 

AGILE results

For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m², delivered subcutaneously or intravenously, or azacitidine plus placebo.

In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.

The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.

The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.

At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).

The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.

Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).

Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.

Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.

Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.

He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.

The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.

A version of this article first appeared on Medscape.com.

ATLANTA - A new drug recently introduced for use in the treatment of refractory/relapsed multiple myeloma looks like it will also find a role in the treatment of patients with newly diagnosed transplant-eligible multiple myeloma.

The drug is isatuximab (Sarclisa, Sanofi), an anti-CD38 antibody that was approved last year for use in patients with advanced disease.

Now it has shown benefit in patients who have been newly diagnosed with the disease. When isatuximab was added onto a usual triplet therapy for myeloma, it increased the likelihood that patients would be negative for minimal residual disease (MRD) at the end of the induction phase of treatment, thereby increasing their chances for a successful autologous stem cell transplant (ASCT).

The new results come from the GMMG-HD7 trial, in which all patients were treated with the triplet combination of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd).

Some patients, after randomization, also received isatuximab, and in this group, the MRD-negativity rate was 50.1% at the end of induction therapy compared with 35.6% for patients treated with RVd alone.  

Patients who are MRD-negative at the time of ASCT have significantly better outcomes than patients who remain MRD-positive.

“Isa-RVd is the first regimen to demonstrate significant MRD-negativity benefit at the end of induction versus RVd in a phase 3 trial,” reported Hartmut Goldschmidt, MD, from University Hospital Heidelberg, Germany.

“The benefits of the addition of Isa to RVd versus RVd regarding MRD negativity after induction therapy was consistent in all subgroups,” he added.

Dr. Goldschmidt spoke at a press briefing prior to his presentation of the data here at the annual meeting of the American Society of Hematology (ASH).

“I think that these data are encouraging, but they are preliminary, and we need mature data to be absolutely certain about whether this presents a major advance in treatment,” commented Ravi Vij, MD, from the Siteman Cancer Center and Washington University School of Medicine in St. Louis. Dr. Vij was not involved in the study.

“We know that for transplant-eligible patients, for whom this trial was conducted, the field is moving toward giving four drugs for induction,” he said in an interview with this news organization.

He noted that the combination of RVd with the other currently available anti-CD38 antibody, daratumumab (Darzalex), was approved for this indication in the United States in Jan. 2021.

Dr. Vij said that isatuximab has been slow to catch on in the United States both because it was approved after clinicians had already become familiar with daratumumab and because it is given intravenously, compared with subcutaneous administration of the latest formulation of daratumumab.

“Whereas isatuximab can take an hour-and-a-half with each infusion, daratumumab takes 5 minutes for an injection and the patient is out of there, so it is convenient both for the patient and the treating institution,” he said.
 

MRD vs. CR?

Dr. Goldschmidt was asked during the briefing about whether MRD-negativity or complete response rates are better predictors of progression-free survival (PFS). He replied that with current standardized sequencing techniques and sensitivity down to 10-6, “it’s a big benefit to analyze MRD negativity, and there is ongoing discussion between colleagues from the myeloma group with the Food and Drug Administration about how we can merge the data and predict PFS and overall survival.”

Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer, Vancouver, who moderated the briefing, commented that “we’re desperately looking for surrogate markers to speed up answers to clinical trials, and I think MRD in myeloma is quickly becoming a very important surrogate marker.”
 

GMMG-7 results

For their trial, Dr. Goldschmidt and colleagues enrolled 662 patients with newly diagnosed multiple myeloma who were candidates for high-dose therapy and ASCT and after stratification by revised International Staging System (r-ISS) criteria, randomly assigned them six three-week cycles of induction therapy with Isa-RVd or RVd alone.

Following ASCT, patients were again randomized to maintenance with either isatuximab plus lenalidomide or lenalidomide alone.

As noted before, MRD rates at the end of induction were 50.1% with Isa-RVd versus 35.6% with RVd alone, translating to a hazard ratio favoring the four-drug combination of 1.83 (P < .001).

Treatment with Isa-RVd was the only significant predictor for the likelihood of MRD negativity in a multivariate analysis controlling for treatment group, r-ISS status, performance status, renal impairment, age, and sex.

Although the rate of complete responses at the end of induction was similar between the treatment groups, the rate of very good partial response or better was higher with the isatuximab-containing combination (77.3% vs. 60.5%; P < .001).

The respective rates of disease progression at the end of induction in the Isa-RVd and RVd groups were 1.5% versus 4.0%.

The rates of adverse events were generally similar between the groups, except a higher proportion of patients had leukocytopenia or neutropenia in the Isa-RVd than the RVdgroup (26.4% vs. 9.1%). There were four deaths in the Isa-RVd group and eight in the RVd group. Most of the deaths were attributable to disease progression or COVID-19, said Dr. Goldschmidt.

The study was funded by Sanofi. Dr. Goldschmidt has disclosed honoraria and research grants from Sanofi and others. Dr. Vij has disclosed honoraria or advisory board activities from various companies, including Sanofi. Dr. Sehn is a consultant for and has received honoraria from various companies, not including Sanofi.

A version of this article first appeared on Medscape.com.

ATLANTA - A new drug recently introduced for use in the treatment of refractory/relapsed multiple myeloma looks like it will also find a role in the treatment of patients with newly diagnosed transplant-eligible multiple myeloma.

The drug is isatuximab (Sarclisa, Sanofi), an anti-CD38 antibody that was approved last year for use in patients with advanced disease.

Now it has shown benefit in patients who have been newly diagnosed with the disease. When isatuximab was added onto a usual triplet therapy for myeloma, it increased the likelihood that patients would be negative for minimal residual disease (MRD) at the end of the induction phase of treatment, thereby increasing their chances for a successful autologous stem cell transplant (ASCT).

The new results come from the GMMG-HD7 trial, in which all patients were treated with the triplet combination of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd).

Some patients, after randomization, also received isatuximab, and in this group, the MRD-negativity rate was 50.1% at the end of induction therapy compared with 35.6% for patients treated with RVd alone.  

Patients who are MRD-negative at the time of ASCT have significantly better outcomes than patients who remain MRD-positive.

“Isa-RVd is the first regimen to demonstrate significant MRD-negativity benefit at the end of induction versus RVd in a phase 3 trial,” reported Hartmut Goldschmidt, MD, from University Hospital Heidelberg, Germany.

“The benefits of the addition of Isa to RVd versus RVd regarding MRD negativity after induction therapy was consistent in all subgroups,” he added.

Dr. Goldschmidt spoke at a press briefing prior to his presentation of the data here at the annual meeting of the American Society of Hematology (ASH).

“I think that these data are encouraging, but they are preliminary, and we need mature data to be absolutely certain about whether this presents a major advance in treatment,” commented Ravi Vij, MD, from the Siteman Cancer Center and Washington University School of Medicine in St. Louis. Dr. Vij was not involved in the study.

“We know that for transplant-eligible patients, for whom this trial was conducted, the field is moving toward giving four drugs for induction,” he said in an interview with this news organization.

He noted that the combination of RVd with the other currently available anti-CD38 antibody, daratumumab (Darzalex), was approved for this indication in the United States in Jan. 2021.

Dr. Vij said that isatuximab has been slow to catch on in the United States both because it was approved after clinicians had already become familiar with daratumumab and because it is given intravenously, compared with subcutaneous administration of the latest formulation of daratumumab.

“Whereas isatuximab can take an hour-and-a-half with each infusion, daratumumab takes 5 minutes for an injection and the patient is out of there, so it is convenient both for the patient and the treating institution,” he said.
 

MRD vs. CR?

Dr. Goldschmidt was asked during the briefing about whether MRD-negativity or complete response rates are better predictors of progression-free survival (PFS). He replied that with current standardized sequencing techniques and sensitivity down to 10-6, “it’s a big benefit to analyze MRD negativity, and there is ongoing discussion between colleagues from the myeloma group with the Food and Drug Administration about how we can merge the data and predict PFS and overall survival.”

Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer, Vancouver, who moderated the briefing, commented that “we’re desperately looking for surrogate markers to speed up answers to clinical trials, and I think MRD in myeloma is quickly becoming a very important surrogate marker.”
 

GMMG-7 results

For their trial, Dr. Goldschmidt and colleagues enrolled 662 patients with newly diagnosed multiple myeloma who were candidates for high-dose therapy and ASCT and after stratification by revised International Staging System (r-ISS) criteria, randomly assigned them six three-week cycles of induction therapy with Isa-RVd or RVd alone.

Following ASCT, patients were again randomized to maintenance with either isatuximab plus lenalidomide or lenalidomide alone.

As noted before, MRD rates at the end of induction were 50.1% with Isa-RVd versus 35.6% with RVd alone, translating to a hazard ratio favoring the four-drug combination of 1.83 (P < .001).

Treatment with Isa-RVd was the only significant predictor for the likelihood of MRD negativity in a multivariate analysis controlling for treatment group, r-ISS status, performance status, renal impairment, age, and sex.

Although the rate of complete responses at the end of induction was similar between the treatment groups, the rate of very good partial response or better was higher with the isatuximab-containing combination (77.3% vs. 60.5%; P < .001).

The respective rates of disease progression at the end of induction in the Isa-RVd and RVd groups were 1.5% versus 4.0%.

The rates of adverse events were generally similar between the groups, except a higher proportion of patients had leukocytopenia or neutropenia in the Isa-RVd than the RVdgroup (26.4% vs. 9.1%). There were four deaths in the Isa-RVd group and eight in the RVd group. Most of the deaths were attributable to disease progression or COVID-19, said Dr. Goldschmidt.

The study was funded by Sanofi. Dr. Goldschmidt has disclosed honoraria and research grants from Sanofi and others. Dr. Vij has disclosed honoraria or advisory board activities from various companies, including Sanofi. Dr. Sehn is a consultant for and has received honoraria from various companies, not including Sanofi.

A version of this article first appeared on Medscape.com.

ATLANTA - A new drug recently introduced for use in the treatment of refractory/relapsed multiple myeloma looks like it will also find a role in the treatment of patients with newly diagnosed transplant-eligible multiple myeloma.

The drug is isatuximab (Sarclisa, Sanofi), an anti-CD38 antibody that was approved last year for use in patients with advanced disease.

Now it has shown benefit in patients who have been newly diagnosed with the disease. When isatuximab was added onto a usual triplet therapy for myeloma, it increased the likelihood that patients would be negative for minimal residual disease (MRD) at the end of the induction phase of treatment, thereby increasing their chances for a successful autologous stem cell transplant (ASCT).

The new results come from the GMMG-HD7 trial, in which all patients were treated with the triplet combination of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd).

Some patients, after randomization, also received isatuximab, and in this group, the MRD-negativity rate was 50.1% at the end of induction therapy compared with 35.6% for patients treated with RVd alone.  

Patients who are MRD-negative at the time of ASCT have significantly better outcomes than patients who remain MRD-positive.

“Isa-RVd is the first regimen to demonstrate significant MRD-negativity benefit at the end of induction versus RVd in a phase 3 trial,” reported Hartmut Goldschmidt, MD, from University Hospital Heidelberg, Germany.

“The benefits of the addition of Isa to RVd versus RVd regarding MRD negativity after induction therapy was consistent in all subgroups,” he added.

Dr. Goldschmidt spoke at a press briefing prior to his presentation of the data here at the annual meeting of the American Society of Hematology (ASH).

“I think that these data are encouraging, but they are preliminary, and we need mature data to be absolutely certain about whether this presents a major advance in treatment,” commented Ravi Vij, MD, from the Siteman Cancer Center and Washington University School of Medicine in St. Louis. Dr. Vij was not involved in the study.

“We know that for transplant-eligible patients, for whom this trial was conducted, the field is moving toward giving four drugs for induction,” he said in an interview with this news organization.

He noted that the combination of RVd with the other currently available anti-CD38 antibody, daratumumab (Darzalex), was approved for this indication in the United States in Jan. 2021.

Dr. Vij said that isatuximab has been slow to catch on in the United States both because it was approved after clinicians had already become familiar with daratumumab and because it is given intravenously, compared with subcutaneous administration of the latest formulation of daratumumab.

“Whereas isatuximab can take an hour-and-a-half with each infusion, daratumumab takes 5 minutes for an injection and the patient is out of there, so it is convenient both for the patient and the treating institution,” he said.
 

MRD vs. CR?

Dr. Goldschmidt was asked during the briefing about whether MRD-negativity or complete response rates are better predictors of progression-free survival (PFS). He replied that with current standardized sequencing techniques and sensitivity down to 10-6, “it’s a big benefit to analyze MRD negativity, and there is ongoing discussion between colleagues from the myeloma group with the Food and Drug Administration about how we can merge the data and predict PFS and overall survival.”

Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer, Vancouver, who moderated the briefing, commented that “we’re desperately looking for surrogate markers to speed up answers to clinical trials, and I think MRD in myeloma is quickly becoming a very important surrogate marker.”
 

GMMG-7 results

For their trial, Dr. Goldschmidt and colleagues enrolled 662 patients with newly diagnosed multiple myeloma who were candidates for high-dose therapy and ASCT and after stratification by revised International Staging System (r-ISS) criteria, randomly assigned them six three-week cycles of induction therapy with Isa-RVd or RVd alone.

Following ASCT, patients were again randomized to maintenance with either isatuximab plus lenalidomide or lenalidomide alone.

As noted before, MRD rates at the end of induction were 50.1% with Isa-RVd versus 35.6% with RVd alone, translating to a hazard ratio favoring the four-drug combination of 1.83 (P < .001).

Treatment with Isa-RVd was the only significant predictor for the likelihood of MRD negativity in a multivariate analysis controlling for treatment group, r-ISS status, performance status, renal impairment, age, and sex.

Although the rate of complete responses at the end of induction was similar between the treatment groups, the rate of very good partial response or better was higher with the isatuximab-containing combination (77.3% vs. 60.5%; P < .001).

The respective rates of disease progression at the end of induction in the Isa-RVd and RVd groups were 1.5% versus 4.0%.

The rates of adverse events were generally similar between the groups, except a higher proportion of patients had leukocytopenia or neutropenia in the Isa-RVd than the RVdgroup (26.4% vs. 9.1%). There were four deaths in the Isa-RVd group and eight in the RVd group. Most of the deaths were attributable to disease progression or COVID-19, said Dr. Goldschmidt.

The study was funded by Sanofi. Dr. Goldschmidt has disclosed honoraria and research grants from Sanofi and others. Dr. Vij has disclosed honoraria or advisory board activities from various companies, including Sanofi. Dr. Sehn is a consultant for and has received honoraria from various companies, not including Sanofi.

A version of this article first appeared on Medscape.com.

SAN ANTONIO – A small study suggests the frequent use of antibiotics among women with triple-negative breast cancer, may have an impact on overall and breast cancer–specific mortality.

The study was recently presented at the San Antonio Breast Cancer Symposium by Julia D. Ransohoff, MD, of Stanford (Calif.) University.

Gut-associated lymphoid tissues are the largest component of the immune system. They influence both local and systemic immune responses, but the use of antimicrobials can decrease circulating and tumor-infiltrating lymphocytes that effect the immune repertoire and in turn, the survival of women with triple-negative breast cancer.

Dr. Ransohoff and colleagues hypothesized that increasing antimicrobial exposure in the presence of time-varying absolute lymphocyte counts may lead to higher overall and breast cancer–specific mortality. Their analysis is based on data from the population-based Surveillance, Epidemiology, and End Results registry and electronic medical records from Stanford University and Sutter Health. It included 772 women who were treated for triple-negative breast cancer between 2000 and 2014. The women were followed for an average of 104 months.

In an earlier analysis of this same group, Dr. Ransohoff found that higher minimum absolute lymphocyte counts were associated with lower overall mortality (hazard ratio, 0.23; 95% confidence interval, 0.16-0.35) and breast cancer mortality (HR, 0.19; 95% CI, 0.11-0.34) The association between higher peripheral lymphocyte counts and tumor-infiltrating lymphocytes was significant.

In the analysis of relationships between antibiotic use and mortality, 85% of women (n = 654) were prescribed antibiotics after having been diagnosed with triple-negative breast cancer. The death rate among patients who were prescribed antibiotics was 23% (153/654), compared with 20% (24/118) among the patients who were not treated with antibiotics (which accounts for 15% of the entire group).

For total antibiotic exposure, the HR for overall mortality was 1.06 (95% CI, 1.03-1.09; P < .001) and 1.07 for breast cancer–specific mortality (95% CI, 1.04-1.10; P < .001). For unique antibiotic exposure (not counting repeat prescriptions of the same antibiotic), the HR for overall mortality was 1.17 (95% CI, 1.12-1.22; P < .001) and 1.18 for breast cancer–specific mortality (95% CI, 1.12-1.24; P < .001). 

“These were all statistically significant associations derived from a statistical model that takes into account baseline patient characteristics, so the reported hazard ratios, to the best of our ability, represent the risk of death associated with antibiotic use adjusted for other baseline covariates. We’ve attempted to account for differences at baseline that may indicate patients are sicker, and so the reported risk represents mortality related with antibiotic exposure,” Dr. Ransohoff said.

Elucidating the role of the microbiome in mediating absolute lymphocyte counts and immune response may inform interventions to reduce triple-negative mortality, she said.

SAN ANTONIO – A small study suggests the frequent use of antibiotics among women with triple-negative breast cancer, may have an impact on overall and breast cancer–specific mortality.

The study was recently presented at the San Antonio Breast Cancer Symposium by Julia D. Ransohoff, MD, of Stanford (Calif.) University.

Gut-associated lymphoid tissues are the largest component of the immune system. They influence both local and systemic immune responses, but the use of antimicrobials can decrease circulating and tumor-infiltrating lymphocytes that effect the immune repertoire and in turn, the survival of women with triple-negative breast cancer.

Dr. Ransohoff and colleagues hypothesized that increasing antimicrobial exposure in the presence of time-varying absolute lymphocyte counts may lead to higher overall and breast cancer–specific mortality. Their analysis is based on data from the population-based Surveillance, Epidemiology, and End Results registry and electronic medical records from Stanford University and Sutter Health. It included 772 women who were treated for triple-negative breast cancer between 2000 and 2014. The women were followed for an average of 104 months.

In an earlier analysis of this same group, Dr. Ransohoff found that higher minimum absolute lymphocyte counts were associated with lower overall mortality (hazard ratio, 0.23; 95% confidence interval, 0.16-0.35) and breast cancer mortality (HR, 0.19; 95% CI, 0.11-0.34) The association between higher peripheral lymphocyte counts and tumor-infiltrating lymphocytes was significant.

In the analysis of relationships between antibiotic use and mortality, 85% of women (n = 654) were prescribed antibiotics after having been diagnosed with triple-negative breast cancer. The death rate among patients who were prescribed antibiotics was 23% (153/654), compared with 20% (24/118) among the patients who were not treated with antibiotics (which accounts for 15% of the entire group).

For total antibiotic exposure, the HR for overall mortality was 1.06 (95% CI, 1.03-1.09; P < .001) and 1.07 for breast cancer–specific mortality (95% CI, 1.04-1.10; P < .001). For unique antibiotic exposure (not counting repeat prescriptions of the same antibiotic), the HR for overall mortality was 1.17 (95% CI, 1.12-1.22; P < .001) and 1.18 for breast cancer–specific mortality (95% CI, 1.12-1.24; P < .001). 

“These were all statistically significant associations derived from a statistical model that takes into account baseline patient characteristics, so the reported hazard ratios, to the best of our ability, represent the risk of death associated with antibiotic use adjusted for other baseline covariates. We’ve attempted to account for differences at baseline that may indicate patients are sicker, and so the reported risk represents mortality related with antibiotic exposure,” Dr. Ransohoff said.

Elucidating the role of the microbiome in mediating absolute lymphocyte counts and immune response may inform interventions to reduce triple-negative mortality, she said.

SAN ANTONIO – A small study suggests the frequent use of antibiotics among women with triple-negative breast cancer, may have an impact on overall and breast cancer–specific mortality.

The study was recently presented at the San Antonio Breast Cancer Symposium by Julia D. Ransohoff, MD, of Stanford (Calif.) University.

Gut-associated lymphoid tissues are the largest component of the immune system. They influence both local and systemic immune responses, but the use of antimicrobials can decrease circulating and tumor-infiltrating lymphocytes that effect the immune repertoire and in turn, the survival of women with triple-negative breast cancer.

Dr. Ransohoff and colleagues hypothesized that increasing antimicrobial exposure in the presence of time-varying absolute lymphocyte counts may lead to higher overall and breast cancer–specific mortality. Their analysis is based on data from the population-based Surveillance, Epidemiology, and End Results registry and electronic medical records from Stanford University and Sutter Health. It included 772 women who were treated for triple-negative breast cancer between 2000 and 2014. The women were followed for an average of 104 months.

In an earlier analysis of this same group, Dr. Ransohoff found that higher minimum absolute lymphocyte counts were associated with lower overall mortality (hazard ratio, 0.23; 95% confidence interval, 0.16-0.35) and breast cancer mortality (HR, 0.19; 95% CI, 0.11-0.34) The association between higher peripheral lymphocyte counts and tumor-infiltrating lymphocytes was significant.

In the analysis of relationships between antibiotic use and mortality, 85% of women (n = 654) were prescribed antibiotics after having been diagnosed with triple-negative breast cancer. The death rate among patients who were prescribed antibiotics was 23% (153/654), compared with 20% (24/118) among the patients who were not treated with antibiotics (which accounts for 15% of the entire group).

For total antibiotic exposure, the HR for overall mortality was 1.06 (95% CI, 1.03-1.09; P < .001) and 1.07 for breast cancer–specific mortality (95% CI, 1.04-1.10; P < .001). For unique antibiotic exposure (not counting repeat prescriptions of the same antibiotic), the HR for overall mortality was 1.17 (95% CI, 1.12-1.22; P < .001) and 1.18 for breast cancer–specific mortality (95% CI, 1.12-1.24; P < .001). 

“These were all statistically significant associations derived from a statistical model that takes into account baseline patient characteristics, so the reported hazard ratios, to the best of our ability, represent the risk of death associated with antibiotic use adjusted for other baseline covariates. We’ve attempted to account for differences at baseline that may indicate patients are sicker, and so the reported risk represents mortality related with antibiotic exposure,” Dr. Ransohoff said.

Elucidating the role of the microbiome in mediating absolute lymphocyte counts and immune response may inform interventions to reduce triple-negative mortality, she said.

Supplementation with omega-3 polyunsaturated fatty acids (PUFA) leads to gut microbial changes that may protect against inflammation, according to a new analysis of obese and overweight, postmenopausal women who participated in a weight loss trial.

The study was presented by Katherine Cook, PhD, during a poster session at the San Antonio Breast Cancer Symposium. Dr. Cook is a researcher at Wake Forest University, Winston-Salem, N.C.

Obesity increases risk of breast cancer, but it also alters the composition of the gut microbiome. Obesity is associated with a greater frequency of Firmicute bacteria phyla, compared with Bacteroidetes phyla, while abnormally low ratios are associated with inflammatory bowel disease.

In mice, the researchers previously showed that diet can lead to changes in the microbiome of both the gut and the breast. They conducted fecal transplants between mice who were fed normal or high-fat diets (HFD), and then used a chemical carcinogenesis model to investigate the impact on tumor outcomes. They observed changes in the microbiota populations in both the gut and the mammary glands when mice fed a normal diet received fecal transplants from HFD mice. On the other hand, when HFD mice received fecal transplants from mice with normal diets, the transplants countered the increase in serum lipopolysaccharide levels associated with HFD. In vitro models showed that microbiota from HFD mice also altered the epithelial permeability of breast tissue, and infection of breast cancer cells with HFD microbiota led to greater proliferation.

The researchers also examined breast cancer tissue from women who received omega-3 PUFA supplements or placebo before undergoing primary tumor resection, and found that there were differences in the proportional abundance of specific microbes between tumor and adjacent normal tissue, with the former having excess of Lachnospiraceae and Ruminococcus. The finding suggests that these bacteria may grow better in a tumor microenvironment, and could play a role in breast cancer cell signaling. The supplements altered the microbiota of both normal and breast cancer tissue.

In the study presented at SABCS, the researchers analyzed fecal samples from 34 obese and overweight postmenopausal women involved in a weight-loss trial, who received 3.25 g/day of omega-3 PUFA supplements or placebo combined with calorie restriction and exercise. They performed metagenomic sequencing from the fecal samples at baseline and 6 months to determine microbiome populations.

Women who experienced weight loss, with or without omega-3 PUFA supplementation, had a decline in the abundance of Firmicutes phyla – a group linked to inflammation risk – as a percentage of overall bacterial phyla. The researchers found a similar trend among women who received omega-3 PUFA, regardless of how much weight they lost. At the species level, those who received supplements had higher proportional abundance of Phocaeicola massiliensis and reduced proportions of Faecalibacterium prausnitzii, R. lactaris, Blautia obeum, and Dorea formicigenerans (P < .05).

Weight loss combined with supplementation also seemed to affect gut microbiota, with subjects who lost more than 10% of their body weight and received omega-3 PUFA supplements having elevated Bacteriodetes and reduced Firmicutes, compared with all other groups (P < .05).

At 6 months, the researchers grouped women by mean body fat composition, and found both positive and negative correlations among different bacterial species. Finally, the researchers looked at serum levels of the inflammatory cytokines interleukin-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor–alpha at 6 months. Women with elevated levels of at least two cytokines had higher levels of two species of mucin-degrading bacteria. Levels of MCP-1 alone also correlated with greater proportions of mucin-degrading bacteria (P < .05).

The authors concluded that increasing omega-3 PUFA uptake to about 2% of total daily calorie intake could push the gut microbiome in a direction that improves intestinal permeability parameters and reduces chronic inflammation. These changes could lead to a reduction in the risk for postmenopausal breast cancer.

The study was funded by the Breast Cancer Research Foundation.

Supplementation with omega-3 polyunsaturated fatty acids (PUFA) leads to gut microbial changes that may protect against inflammation, according to a new analysis of obese and overweight, postmenopausal women who participated in a weight loss trial.

The study was presented by Katherine Cook, PhD, during a poster session at the San Antonio Breast Cancer Symposium. Dr. Cook is a researcher at Wake Forest University, Winston-Salem, N.C.

Obesity increases risk of breast cancer, but it also alters the composition of the gut microbiome. Obesity is associated with a greater frequency of Firmicute bacteria phyla, compared with Bacteroidetes phyla, while abnormally low ratios are associated with inflammatory bowel disease.

In mice, the researchers previously showed that diet can lead to changes in the microbiome of both the gut and the breast. They conducted fecal transplants between mice who were fed normal or high-fat diets (HFD), and then used a chemical carcinogenesis model to investigate the impact on tumor outcomes. They observed changes in the microbiota populations in both the gut and the mammary glands when mice fed a normal diet received fecal transplants from HFD mice. On the other hand, when HFD mice received fecal transplants from mice with normal diets, the transplants countered the increase in serum lipopolysaccharide levels associated with HFD. In vitro models showed that microbiota from HFD mice also altered the epithelial permeability of breast tissue, and infection of breast cancer cells with HFD microbiota led to greater proliferation.

The researchers also examined breast cancer tissue from women who received omega-3 PUFA supplements or placebo before undergoing primary tumor resection, and found that there were differences in the proportional abundance of specific microbes between tumor and adjacent normal tissue, with the former having excess of Lachnospiraceae and Ruminococcus. The finding suggests that these bacteria may grow better in a tumor microenvironment, and could play a role in breast cancer cell signaling. The supplements altered the microbiota of both normal and breast cancer tissue.

In the study presented at SABCS, the researchers analyzed fecal samples from 34 obese and overweight postmenopausal women involved in a weight-loss trial, who received 3.25 g/day of omega-3 PUFA supplements or placebo combined with calorie restriction and exercise. They performed metagenomic sequencing from the fecal samples at baseline and 6 months to determine microbiome populations.

Women who experienced weight loss, with or without omega-3 PUFA supplementation, had a decline in the abundance of Firmicutes phyla – a group linked to inflammation risk – as a percentage of overall bacterial phyla. The researchers found a similar trend among women who received omega-3 PUFA, regardless of how much weight they lost. At the species level, those who received supplements had higher proportional abundance of Phocaeicola massiliensis and reduced proportions of Faecalibacterium prausnitzii, R. lactaris, Blautia obeum, and Dorea formicigenerans (P < .05).

Weight loss combined with supplementation also seemed to affect gut microbiota, with subjects who lost more than 10% of their body weight and received omega-3 PUFA supplements having elevated Bacteriodetes and reduced Firmicutes, compared with all other groups (P < .05).

At 6 months, the researchers grouped women by mean body fat composition, and found both positive and negative correlations among different bacterial species. Finally, the researchers looked at serum levels of the inflammatory cytokines interleukin-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor–alpha at 6 months. Women with elevated levels of at least two cytokines had higher levels of two species of mucin-degrading bacteria. Levels of MCP-1 alone also correlated with greater proportions of mucin-degrading bacteria (P < .05).

The authors concluded that increasing omega-3 PUFA uptake to about 2% of total daily calorie intake could push the gut microbiome in a direction that improves intestinal permeability parameters and reduces chronic inflammation. These changes could lead to a reduction in the risk for postmenopausal breast cancer.

The study was funded by the Breast Cancer Research Foundation.

Supplementation with omega-3 polyunsaturated fatty acids (PUFA) leads to gut microbial changes that may protect against inflammation, according to a new analysis of obese and overweight, postmenopausal women who participated in a weight loss trial.

The study was presented by Katherine Cook, PhD, during a poster session at the San Antonio Breast Cancer Symposium. Dr. Cook is a researcher at Wake Forest University, Winston-Salem, N.C.

Obesity increases risk of breast cancer, but it also alters the composition of the gut microbiome. Obesity is associated with a greater frequency of Firmicute bacteria phyla, compared with Bacteroidetes phyla, while abnormally low ratios are associated with inflammatory bowel disease.

In mice, the researchers previously showed that diet can lead to changes in the microbiome of both the gut and the breast. They conducted fecal transplants between mice who were fed normal or high-fat diets (HFD), and then used a chemical carcinogenesis model to investigate the impact on tumor outcomes. They observed changes in the microbiota populations in both the gut and the mammary glands when mice fed a normal diet received fecal transplants from HFD mice. On the other hand, when HFD mice received fecal transplants from mice with normal diets, the transplants countered the increase in serum lipopolysaccharide levels associated with HFD. In vitro models showed that microbiota from HFD mice also altered the epithelial permeability of breast tissue, and infection of breast cancer cells with HFD microbiota led to greater proliferation.

The researchers also examined breast cancer tissue from women who received omega-3 PUFA supplements or placebo before undergoing primary tumor resection, and found that there were differences in the proportional abundance of specific microbes between tumor and adjacent normal tissue, with the former having excess of Lachnospiraceae and Ruminococcus. The finding suggests that these bacteria may grow better in a tumor microenvironment, and could play a role in breast cancer cell signaling. The supplements altered the microbiota of both normal and breast cancer tissue.

In the study presented at SABCS, the researchers analyzed fecal samples from 34 obese and overweight postmenopausal women involved in a weight-loss trial, who received 3.25 g/day of omega-3 PUFA supplements or placebo combined with calorie restriction and exercise. They performed metagenomic sequencing from the fecal samples at baseline and 6 months to determine microbiome populations.

Women who experienced weight loss, with or without omega-3 PUFA supplementation, had a decline in the abundance of Firmicutes phyla – a group linked to inflammation risk – as a percentage of overall bacterial phyla. The researchers found a similar trend among women who received omega-3 PUFA, regardless of how much weight they lost. At the species level, those who received supplements had higher proportional abundance of Phocaeicola massiliensis and reduced proportions of Faecalibacterium prausnitzii, R. lactaris, Blautia obeum, and Dorea formicigenerans (P < .05).

Weight loss combined with supplementation also seemed to affect gut microbiota, with subjects who lost more than 10% of their body weight and received omega-3 PUFA supplements having elevated Bacteriodetes and reduced Firmicutes, compared with all other groups (P < .05).

At 6 months, the researchers grouped women by mean body fat composition, and found both positive and negative correlations among different bacterial species. Finally, the researchers looked at serum levels of the inflammatory cytokines interleukin-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor–alpha at 6 months. Women with elevated levels of at least two cytokines had higher levels of two species of mucin-degrading bacteria. Levels of MCP-1 alone also correlated with greater proportions of mucin-degrading bacteria (P < .05).

The authors concluded that increasing omega-3 PUFA uptake to about 2% of total daily calorie intake could push the gut microbiome in a direction that improves intestinal permeability parameters and reduces chronic inflammation. These changes could lead to a reduction in the risk for postmenopausal breast cancer.

The study was funded by the Breast Cancer Research Foundation.

SAN ANTONIO – Sedative-hypnotic medications, such as benzodiazepines and nonbenzodiazepine sedative-hypnotics commonly used to treat chemotherapy-related nausea, anxiety, and insomnia in women being treated for breast cancer, put women at high risk of dependency after chemotherapy treatment, shows a new study.

While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.

The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.

Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.

New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).

It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”

Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.

There were no funding or other conflicts of interest associated with this study.

SAN ANTONIO – Sedative-hypnotic medications, such as benzodiazepines and nonbenzodiazepine sedative-hypnotics commonly used to treat chemotherapy-related nausea, anxiety, and insomnia in women being treated for breast cancer, put women at high risk of dependency after chemotherapy treatment, shows a new study.

While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.

The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.

Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.

New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).

It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”

Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.

There were no funding or other conflicts of interest associated with this study.

SAN ANTONIO – Sedative-hypnotic medications, such as benzodiazepines and nonbenzodiazepine sedative-hypnotics commonly used to treat chemotherapy-related nausea, anxiety, and insomnia in women being treated for breast cancer, put women at high risk of dependency after chemotherapy treatment, shows a new study.

While benzodiazepines and nonbenzodiazepine sedative-hypnotics are effective for these indications, misuse and increased health care utilization can ensue from their prolonged use, said Jacob C. Cogan, MD, a fellow in oncology/hematology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York. Dr. Cogan recently presented the results of the study at the San Antonio Breast Cancer Symposium.

The study included patients with breast cancer who received adjuvant chemotherapy between 2008 and 2017. Prescriptions for sedatives were divided into three periods: 365 days prior to chemotherapy to the start of chemotherapy (period one); start of chemotherapy to 90 days after the end of chemotherapy (period two); and 90-365 days after chemotherapy (period three). Patients who filled at least one benzodiazepine prescription in period two and patients who filled at least two benzodiazepine in period three were classified as new persistent benzodiazepine users. The same definitions were then used for nonbenzodiazepine sedative-hypnotics.

Among 17,532 benzodiazepine-naive patients (mean age, 57 years) and 21,863 nonbenzodiazepine sedative-hypnotic drug–naive patients (mean age, 56 years) who received adjuvant chemotherapy for breast cancer, lumpectomies were performed for a small majority (56.6% benzodiazepine naive, 55.1% nonbenzodiazepine sedative-hypnotics naive) versus mastectomy, and about half of patients received less than 4 months of chemotherapy (48.0% benzodiazepine naive, 48.6% nonbenzodiazepine sedative-hypnotics naive). Among benzodiazepine-naive patients, 4,447 (25.4%) filled at least one benzodiazepine prescription during chemotherapy, and 2,160 (9.9%) filled at least one nonbenzodiazepine sedative-hypnotic prescription during chemotherapy. The rate of new persistent benzodiazepine use after initial exposure during chemotherapy was 26.8% (n = 1,192). Similarly, 33.8% (n = 730) of nonbenzodiazepine sedative-hypnotics users became new persistent users. In addition, 115 patients became new persistent users of both types of sedative-hypnotics.

New persistent benzodiazepine use was associated with several characteristics: age 50-65 (odds ratio, 1.23; P = .01) and age greater than 65 (OR, 1.38, P = .005) relative to age less than 49; as well as Medicaid insurance, relative to commercial and Medicare insurance (OR, 1.68; P < .0001). Both new persistent benzodiazepine and nonbenzodiazepine sedative-hypnotics use was associated with chemotherapy duration of less than 4 months relative to 4 or more months of chemotherapy (OR, 1.17; P = .03 for benzodiazepines; OR, 1.58; P < .0001 for nonbenzodiazepine sedative-hypnotics).

It is not clear why shorter chemotherapy duration is associated with more new persistent use, Dr. Cogan said. “It may be that, paradoxically, a shorter duration of treatment could lead to more anxiety about recurrence. These patients may need closer monitoring of mental health symptoms and earlier referral for psychological services.”

Dr. Cogan said that providers should take steps to ensure that benzodiazepines and nonbenzodiazepine sedatives are used appropriately, which includes tapering dosages and, when appropriate, encouraging nonpharmacologic strategies.

There were no funding or other conflicts of interest associated with this study.