Nancy A. Melville

AURORA, COLO. – Frexalimab, a novel, second-generation anti-CD40L antibody, shows “strikingly positive” effects in the treatment of relapsing multiple sclerosis (MS), significantly reducing disease activity.

“We should be very excited about these results, which are better than expected and fundamentally tackle autoimmunity,” said study investigator Gavin Giovannoni, MD, PhD, chair of neurology at the Blizard Institute of Barts, London, and the London School of Medicine and Dentistry. “It will be interesting to see if this treatment reestablishes immune tolerance and induces long-term remission,” he said.

The late-breaking study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

Significant lesion reduction

With a variety of disease-modifying therapies available for MS, frexalimab would be unique as a novel second-generation monoclonal antibody designed to block the costimulatory CD40/CD40L cellular pathway. Importantly, the mechanism is believed to potentially modify T- and B-cell activation and innate immune cell function, for an effect of reducing inflammation without depleting B cells.

To investigate the drug’s efficacy and safety, Dr. Giovannoni and his colleagues conducted the phase 2, multicenter trial, in which 129 participants with relapsing MS were randomized to one of four groups – high-dose frexalimab (n = 52); low-dose frexalimab (n = 51); or placebo (n = 12 high-dose, n = 14 low-dose), for the 12-week placebo-controlled period, followed by an open-label extension period that is currently ongoing.

Among 125 participants who completed the study’s 12-week double-blind period, those receiving high-dose frexalimab had an 89% greater reduction in the number of new gadolinium-enhancing T1-lesions, compared with the pooled placebo group (P = .0004), meeting the study’s primary endpoint. After 24 weeks, as many as 96% of those in the high-dose frexalimab arm were free of gadolinium-enhanced T1 lesions.

The frexalimab low-dose group also had a lower, but significant, reduction in the number of new gadolinium-enhanced T1-lesions of 79% versus the pooled placebo group (P = .0021).

Both of the frexalimab groups also had reductions in enlarging T2-lesions and total gadolinium-enhanced T1-lesions.

In the high-dose group, data on 38 participants with open-label data from week 37 showed no new gadolinium-enhanced lesions.

In terms of safety, frexalimab was well tolerated over the 12-week study, with headache and COVID-19 reported among 4% or fewer participants. No serious adverse events were reported.

Looking ahead at safety, Dr. Giovannoni noted that “a known unknown is infections, but this is a problem with all therapies that work via immunosuppressive mechanisms, not only therapies targeting CD40L.” That said, “we didn’t see a big infection signal in the trial, which is reassuring. It also shows the immune system has built-in redundancy and many mechanisms to fight infections,” he added.

In his newsletter, Dr. Giovannoni characterized the study’s results as “strikingly positive,” adding that they “are the most exciting to emerge in MS in the last 12-24 months.”

Overall, “these are the first randomized controlled phase 2 data for a CD40L inhibitor in MS and indicate potential for further development of frexalimab as a high-efficacy therapy,” the investigators noted. “Frexalimab led to a pronounced reduction of new gadolinium-enhancing lesions by 3 months and was well-tolerated,” they added.
 

An intriguing mechanism

Commenting on the study, Salim Chahin, MD, an assistant professor of neurology in the John L. Trotter MS Center in the department of neurology at Washington University, St. Louis, said that frexalimab represents an intriguing mechanistic approach to MS.

“In the world of MS and neuroimmunology, this is indeed a unique mechanism that has not been explored before,” Dr. Chahin said.

“Therapies targeting CD40 and CD40L are not new but were previously associated with unfavorable side effects, mainly thromboembolic events that halted their development,” he said, noting that the drug appears to avoid these side effects, providing good phase 2 efficacy data.

Dr. Chahin agreed that the phase 3 data will be watched closely for further safety and efficacy issues. “Indeed, it is difficult to interpret the occurrence of COVID-19 infections, given the timing of the phase 2 study, or their severity, but based on the mechanism of action, it is possible that this drug will be associated with a more favorable safety profile than some of the currently approved MS treatments,” Dr. Chahin said.

“But phase 3 trial data are much needed to clarify the immunosuppressive risk.”

The study received funding from Sanofi. Dr. Giovannoni’s disclosures include current or recent relationships with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD, Moderna, Serono, Moderna, Novartis, Sandoz, Sanofi, and Roche/Genentech. Dr. Chahin reports no relevant financial relationships.

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

AURORA, COLO. – Frexalimab, a novel, second-generation anti-CD40L antibody, shows “strikingly positive” effects in the treatment of relapsing multiple sclerosis (MS), significantly reducing disease activity.

“We should be very excited about these results, which are better than expected and fundamentally tackle autoimmunity,” said study investigator Gavin Giovannoni, MD, PhD, chair of neurology at the Blizard Institute of Barts, London, and the London School of Medicine and Dentistry. “It will be interesting to see if this treatment reestablishes immune tolerance and induces long-term remission,” he said.

The late-breaking study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

Significant lesion reduction

With a variety of disease-modifying therapies available for MS, frexalimab would be unique as a novel second-generation monoclonal antibody designed to block the costimulatory CD40/CD40L cellular pathway. Importantly, the mechanism is believed to potentially modify T- and B-cell activation and innate immune cell function, for an effect of reducing inflammation without depleting B cells.

To investigate the drug’s efficacy and safety, Dr. Giovannoni and his colleagues conducted the phase 2, multicenter trial, in which 129 participants with relapsing MS were randomized to one of four groups – high-dose frexalimab (n = 52); low-dose frexalimab (n = 51); or placebo (n = 12 high-dose, n = 14 low-dose), for the 12-week placebo-controlled period, followed by an open-label extension period that is currently ongoing.

Among 125 participants who completed the study’s 12-week double-blind period, those receiving high-dose frexalimab had an 89% greater reduction in the number of new gadolinium-enhancing T1-lesions, compared with the pooled placebo group (P = .0004), meeting the study’s primary endpoint. After 24 weeks, as many as 96% of those in the high-dose frexalimab arm were free of gadolinium-enhanced T1 lesions.

The frexalimab low-dose group also had a lower, but significant, reduction in the number of new gadolinium-enhanced T1-lesions of 79% versus the pooled placebo group (P = .0021).

Both of the frexalimab groups also had reductions in enlarging T2-lesions and total gadolinium-enhanced T1-lesions.

In the high-dose group, data on 38 participants with open-label data from week 37 showed no new gadolinium-enhanced lesions.

In terms of safety, frexalimab was well tolerated over the 12-week study, with headache and COVID-19 reported among 4% or fewer participants. No serious adverse events were reported.

Looking ahead at safety, Dr. Giovannoni noted that “a known unknown is infections, but this is a problem with all therapies that work via immunosuppressive mechanisms, not only therapies targeting CD40L.” That said, “we didn’t see a big infection signal in the trial, which is reassuring. It also shows the immune system has built-in redundancy and many mechanisms to fight infections,” he added.

In his newsletter, Dr. Giovannoni characterized the study’s results as “strikingly positive,” adding that they “are the most exciting to emerge in MS in the last 12-24 months.”

Overall, “these are the first randomized controlled phase 2 data for a CD40L inhibitor in MS and indicate potential for further development of frexalimab as a high-efficacy therapy,” the investigators noted. “Frexalimab led to a pronounced reduction of new gadolinium-enhancing lesions by 3 months and was well-tolerated,” they added.
 

An intriguing mechanism

Commenting on the study, Salim Chahin, MD, an assistant professor of neurology in the John L. Trotter MS Center in the department of neurology at Washington University, St. Louis, said that frexalimab represents an intriguing mechanistic approach to MS.

“In the world of MS and neuroimmunology, this is indeed a unique mechanism that has not been explored before,” Dr. Chahin said.

“Therapies targeting CD40 and CD40L are not new but were previously associated with unfavorable side effects, mainly thromboembolic events that halted their development,” he said, noting that the drug appears to avoid these side effects, providing good phase 2 efficacy data.

Dr. Chahin agreed that the phase 3 data will be watched closely for further safety and efficacy issues. “Indeed, it is difficult to interpret the occurrence of COVID-19 infections, given the timing of the phase 2 study, or their severity, but based on the mechanism of action, it is possible that this drug will be associated with a more favorable safety profile than some of the currently approved MS treatments,” Dr. Chahin said.

“But phase 3 trial data are much needed to clarify the immunosuppressive risk.”

The study received funding from Sanofi. Dr. Giovannoni’s disclosures include current or recent relationships with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD, Moderna, Serono, Moderna, Novartis, Sandoz, Sanofi, and Roche/Genentech. Dr. Chahin reports no relevant financial relationships.

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

AURORA, COLO. – Frexalimab, a novel, second-generation anti-CD40L antibody, shows “strikingly positive” effects in the treatment of relapsing multiple sclerosis (MS), significantly reducing disease activity.

“We should be very excited about these results, which are better than expected and fundamentally tackle autoimmunity,” said study investigator Gavin Giovannoni, MD, PhD, chair of neurology at the Blizard Institute of Barts, London, and the London School of Medicine and Dentistry. “It will be interesting to see if this treatment reestablishes immune tolerance and induces long-term remission,” he said.

The late-breaking study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

Significant lesion reduction

With a variety of disease-modifying therapies available for MS, frexalimab would be unique as a novel second-generation monoclonal antibody designed to block the costimulatory CD40/CD40L cellular pathway. Importantly, the mechanism is believed to potentially modify T- and B-cell activation and innate immune cell function, for an effect of reducing inflammation without depleting B cells.

To investigate the drug’s efficacy and safety, Dr. Giovannoni and his colleagues conducted the phase 2, multicenter trial, in which 129 participants with relapsing MS were randomized to one of four groups – high-dose frexalimab (n = 52); low-dose frexalimab (n = 51); or placebo (n = 12 high-dose, n = 14 low-dose), for the 12-week placebo-controlled period, followed by an open-label extension period that is currently ongoing.

Among 125 participants who completed the study’s 12-week double-blind period, those receiving high-dose frexalimab had an 89% greater reduction in the number of new gadolinium-enhancing T1-lesions, compared with the pooled placebo group (P = .0004), meeting the study’s primary endpoint. After 24 weeks, as many as 96% of those in the high-dose frexalimab arm were free of gadolinium-enhanced T1 lesions.

The frexalimab low-dose group also had a lower, but significant, reduction in the number of new gadolinium-enhanced T1-lesions of 79% versus the pooled placebo group (P = .0021).

Both of the frexalimab groups also had reductions in enlarging T2-lesions and total gadolinium-enhanced T1-lesions.

In the high-dose group, data on 38 participants with open-label data from week 37 showed no new gadolinium-enhanced lesions.

In terms of safety, frexalimab was well tolerated over the 12-week study, with headache and COVID-19 reported among 4% or fewer participants. No serious adverse events were reported.

Looking ahead at safety, Dr. Giovannoni noted that “a known unknown is infections, but this is a problem with all therapies that work via immunosuppressive mechanisms, not only therapies targeting CD40L.” That said, “we didn’t see a big infection signal in the trial, which is reassuring. It also shows the immune system has built-in redundancy and many mechanisms to fight infections,” he added.

In his newsletter, Dr. Giovannoni characterized the study’s results as “strikingly positive,” adding that they “are the most exciting to emerge in MS in the last 12-24 months.”

Overall, “these are the first randomized controlled phase 2 data for a CD40L inhibitor in MS and indicate potential for further development of frexalimab as a high-efficacy therapy,” the investigators noted. “Frexalimab led to a pronounced reduction of new gadolinium-enhancing lesions by 3 months and was well-tolerated,” they added.
 

An intriguing mechanism

Commenting on the study, Salim Chahin, MD, an assistant professor of neurology in the John L. Trotter MS Center in the department of neurology at Washington University, St. Louis, said that frexalimab represents an intriguing mechanistic approach to MS.

“In the world of MS and neuroimmunology, this is indeed a unique mechanism that has not been explored before,” Dr. Chahin said.

“Therapies targeting CD40 and CD40L are not new but were previously associated with unfavorable side effects, mainly thromboembolic events that halted their development,” he said, noting that the drug appears to avoid these side effects, providing good phase 2 efficacy data.

Dr. Chahin agreed that the phase 3 data will be watched closely for further safety and efficacy issues. “Indeed, it is difficult to interpret the occurrence of COVID-19 infections, given the timing of the phase 2 study, or their severity, but based on the mechanism of action, it is possible that this drug will be associated with a more favorable safety profile than some of the currently approved MS treatments,” Dr. Chahin said.

“But phase 3 trial data are much needed to clarify the immunosuppressive risk.”

The study received funding from Sanofi. Dr. Giovannoni’s disclosures include current or recent relationships with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD, Moderna, Serono, Moderna, Novartis, Sandoz, Sanofi, and Roche/Genentech. Dr. Chahin reports no relevant financial relationships.

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

The CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel, Bristol-Myers Squibb), showed efficacy in achieving complete responses among patients with relapsed or refractory chronic lymphocytic leukemia (r/r CLL) or small lymphocytic lymphoma (SLL), after treatment with a Bruton kinase inhibitor (BTKi) and BCL2 inhibitor.

The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.

“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.

Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.

“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.

With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.

In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.

The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 10⁶ CAR-positive viable T cells of liso-cel.

With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).

Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.

The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.

The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).

The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.

The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.

In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.

Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.

Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.

For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.

Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.

One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.

“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.

She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.

“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.

For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”

Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.

“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
 

Largest data set to date

Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.

“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.

“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”

Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.

Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.

In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”

Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.

“The results of this study are very exciting,” she said during her discussion in the session.

“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”

Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”

The results were also published in The Lancet.

The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.

The CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel, Bristol-Myers Squibb), showed efficacy in achieving complete responses among patients with relapsed or refractory chronic lymphocytic leukemia (r/r CLL) or small lymphocytic lymphoma (SLL), after treatment with a Bruton kinase inhibitor (BTKi) and BCL2 inhibitor.

The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.

“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.

Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.

“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.

With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.

In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.

The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 10⁶ CAR-positive viable T cells of liso-cel.

With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).

Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.

The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.

The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).

The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.

The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.

In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.

Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.

Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.

For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.

Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.

One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.

“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.

She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.

“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.

For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”

Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.

“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
 

Largest data set to date

Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.

“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.

“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”

Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.

Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.

In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”

Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.

“The results of this study are very exciting,” she said during her discussion in the session.

“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”

Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”

The results were also published in The Lancet.

The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.

The CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel, Bristol-Myers Squibb), showed efficacy in achieving complete responses among patients with relapsed or refractory chronic lymphocytic leukemia (r/r CLL) or small lymphocytic lymphoma (SLL), after treatment with a Bruton kinase inhibitor (BTKi) and BCL2 inhibitor.

The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.

“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.

Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.

“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.

With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.

In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.

The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 10⁶ CAR-positive viable T cells of liso-cel.

With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).

Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.

The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.

The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).

The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.

The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.

In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.

Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.

Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.

For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.

Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.

One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.

“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.

She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.

“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.

For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”

Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.

“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
 

Largest data set to date

Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.

“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.

“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”

Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.

Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.

In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”

Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.

“The results of this study are very exciting,” she said during her discussion in the session.

“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”

Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”

The results were also published in The Lancet.

The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.

For patients with primary mediastinal B-cell lymphoma (PMBCL) who achieved a complete metabolic response after immunochemotherapy, radiation therapy may be safely omitted without heightening their risks of relapse or disease progression – thereby sparing them the toxicity and costs of this additional treatment.

“This study is the largest prospective study of PMBCL ever conducted,” said first author Emanuele Zucca, MD, consultant and head of the lymphoma unit at the Oncology Institute of Southern Switzerland in Bellinzona. Dr. Zucca presented the findings at the annual meeting of the American Society of Clinical Oncology (ASCO).

The results of the research underscore that “mediastinal radiation therapy in patients with complete remission after frontline immunochemotherapy can be safely omitted,” he said.

While PMBCL has a relatively low incidence, representing fewer than 5% of cases of non-Hodgkin lymphoma, the cancer is over-represented in young White women between approximately 30 and 40 years of age, and is a notably aggressive form of diffuse large B-cell lymphoma.

However, in patients who rapidly achieve remission with dose-intensive immunochemotherapy, the prognosis is good.

In such cases, the use of mediastinal radiation therapy has been seen as a measure to further consolidate the immunochemotherapy response, but the additional treatment comes at the cost of an increased risk of second malignancies, as well as coronary or valvular heart disease.

Meanwhile, in recent decades promising data has shown that aggressive chemoimmunotherapy regimens alone, such as DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) can be enough for patients achieving a complete remission, while novel approaches such as checkpoint inhibitors and CAR T-cell therapy further show benefits in patients with lymphoma that relapses after treatment.

With ongoing controversy over whether to include the added radiation therapy among patients with a complete metabolic response, Dr. Zucca and his colleagues conducted the IELSG37 international study, enrolling 545 patients from 74 centers in 13 countries, including 336 women, with newly diagnosed PMBCL.

The patients were treated with induction chemoimmunotherapy with rituximab and anthracycline-based therapy based on local practice, and response assessed among of 530 of the 545 patients showed that 268 (50.6%) achieved a complete metabolic response.

Those patients were then randomized to either observation (n = 132) or consolidation radiation therapy (30 Gy; n = 136). The characteristics between the two groups were similar, with a mean age of 35.5, and about 65% female.

With a median follow-up of 63 months (range, 48-60 months), the primary endpoint of progression-free survival at 30 months was not significantly different between the observation arm (98.5%) and radiation therapy arm (96.2%; P = .278).

After adjustment for factors including sex, chemotherapy, country, and positron emission tomography (PET) response score, the estimated relative effect of radiotherapy versus observation was a hazard ratio of 0.68, and the absolute risk reduction associated with radiotherapy at 30 months was 1.2% after adjustment.

The number needed to treat is high, at 126.3 after stratification, and the 5-year overall survival was excellent in both arms, at 99%.

“What this tells us is that treatment with radiation therapy in well over 100 patients is needed just to avoid a single recurrence,” Dr. Zucca explained.

Overall survival after 3 years was excellent and identical in both arms, at about 99%.

To date, three severe cardiac events and three second cancers have been recorded in the study, all occurring among patients randomized to receive radiation therapy.

Dr. Zucca noted that longer follow-up is needed to better examine late toxicities.

“The long-term toxicities of mediastinal radiotherapy are well documented, particularly second breast, thyroid, and lung cancers and increased risk of coronary or valvular heart disease, in a patient group dominated by young adults,” Dr. Zucca said in a press statement.

“This study shows chemoimmunotherapy alone is an effective treatment for primary mediastinal B-cell lymphoma and strongly supports omitting radiotherapy without impacting chances of cure.”

Commenting on the study, Corey W. Speers, MD, PhD, assistant professor, radiation oncology, department of surgery, University of Michigan Hospital, Ann Arbor, said the findings have important clinical implications.

“We all should be encouraged by the low rates in this trial, which are lower than expected,” Dr. Speers said in a press briefing.

In further comments, he added that “these results will inform and likely change clinical practice.”

Dr. Speers said the study is notable for being the first of its kind.

“This clinical question has not previously been directly addressed, and this is the first study to do so,” he said.

“With more effective systemic therapies, many patients have their lymphoma disappear with early aggressive treatment, and although radiation is very effective at treating lymphoma, it has not been clear if it is needed in these patients that have an early rapid response to systemic therapy before starting radiation,” Dr. Speers explained.

“We have struggled as oncologists to know whether omitting this effective radiotherapy would compromise outcomes, and thus many were inclined to continue offering it to patients, even with the great early response. This study helps answer this critical question,” he said.

The results add reassuring evidence, buttressing efforts to avoid unnecessary interventions that may provide little or no benefit, Dr. Speers added.

“We are now in an era of ‘less being more’ as we seek ways to provide optimal quality and quantity of life to patients with cancer and their families, and this is just another example of the tremendous progress being made.”

Further commenting on the study at the press briefing, Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, said the research supports ASCO’s ongoing efforts to reduce the toxicities of cancer treatment.

“Our ASCO vision is a world where cancer is either prevented or cured, and every patient is cured – and every survivor is healthy, and that part about every survivor being healthy is what we’re working on here [in this study],” Dr. Gralow said.

The study was funded by the Swiss Cancer League and Cancer Research UK, with partial support from the Swiss National Science Foundation. Dr. Zucca reported relationships with AstraZeneca, Beigene, Celgene, Incyte, Janssen, Merck, Roche, Celltrion Healthcare, Kite, and Abbvie. Dr. Speers disclosed his coinvention of technology that assesses radiosensitivity and predicts benefits from adjutant radiotherapy.

For patients with primary mediastinal B-cell lymphoma (PMBCL) who achieved a complete metabolic response after immunochemotherapy, radiation therapy may be safely omitted without heightening their risks of relapse or disease progression – thereby sparing them the toxicity and costs of this additional treatment.

“This study is the largest prospective study of PMBCL ever conducted,” said first author Emanuele Zucca, MD, consultant and head of the lymphoma unit at the Oncology Institute of Southern Switzerland in Bellinzona. Dr. Zucca presented the findings at the annual meeting of the American Society of Clinical Oncology (ASCO).

The results of the research underscore that “mediastinal radiation therapy in patients with complete remission after frontline immunochemotherapy can be safely omitted,” he said.

While PMBCL has a relatively low incidence, representing fewer than 5% of cases of non-Hodgkin lymphoma, the cancer is over-represented in young White women between approximately 30 and 40 years of age, and is a notably aggressive form of diffuse large B-cell lymphoma.

However, in patients who rapidly achieve remission with dose-intensive immunochemotherapy, the prognosis is good.

In such cases, the use of mediastinal radiation therapy has been seen as a measure to further consolidate the immunochemotherapy response, but the additional treatment comes at the cost of an increased risk of second malignancies, as well as coronary or valvular heart disease.

Meanwhile, in recent decades promising data has shown that aggressive chemoimmunotherapy regimens alone, such as DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) can be enough for patients achieving a complete remission, while novel approaches such as checkpoint inhibitors and CAR T-cell therapy further show benefits in patients with lymphoma that relapses after treatment.

With ongoing controversy over whether to include the added radiation therapy among patients with a complete metabolic response, Dr. Zucca and his colleagues conducted the IELSG37 international study, enrolling 545 patients from 74 centers in 13 countries, including 336 women, with newly diagnosed PMBCL.

The patients were treated with induction chemoimmunotherapy with rituximab and anthracycline-based therapy based on local practice, and response assessed among of 530 of the 545 patients showed that 268 (50.6%) achieved a complete metabolic response.

Those patients were then randomized to either observation (n = 132) or consolidation radiation therapy (30 Gy; n = 136). The characteristics between the two groups were similar, with a mean age of 35.5, and about 65% female.

With a median follow-up of 63 months (range, 48-60 months), the primary endpoint of progression-free survival at 30 months was not significantly different between the observation arm (98.5%) and radiation therapy arm (96.2%; P = .278).

After adjustment for factors including sex, chemotherapy, country, and positron emission tomography (PET) response score, the estimated relative effect of radiotherapy versus observation was a hazard ratio of 0.68, and the absolute risk reduction associated with radiotherapy at 30 months was 1.2% after adjustment.

The number needed to treat is high, at 126.3 after stratification, and the 5-year overall survival was excellent in both arms, at 99%.

“What this tells us is that treatment with radiation therapy in well over 100 patients is needed just to avoid a single recurrence,” Dr. Zucca explained.

Overall survival after 3 years was excellent and identical in both arms, at about 99%.

To date, three severe cardiac events and three second cancers have been recorded in the study, all occurring among patients randomized to receive radiation therapy.

Dr. Zucca noted that longer follow-up is needed to better examine late toxicities.

“The long-term toxicities of mediastinal radiotherapy are well documented, particularly second breast, thyroid, and lung cancers and increased risk of coronary or valvular heart disease, in a patient group dominated by young adults,” Dr. Zucca said in a press statement.

“This study shows chemoimmunotherapy alone is an effective treatment for primary mediastinal B-cell lymphoma and strongly supports omitting radiotherapy without impacting chances of cure.”

Commenting on the study, Corey W. Speers, MD, PhD, assistant professor, radiation oncology, department of surgery, University of Michigan Hospital, Ann Arbor, said the findings have important clinical implications.

“We all should be encouraged by the low rates in this trial, which are lower than expected,” Dr. Speers said in a press briefing.

In further comments, he added that “these results will inform and likely change clinical practice.”

Dr. Speers said the study is notable for being the first of its kind.

“This clinical question has not previously been directly addressed, and this is the first study to do so,” he said.

“With more effective systemic therapies, many patients have their lymphoma disappear with early aggressive treatment, and although radiation is very effective at treating lymphoma, it has not been clear if it is needed in these patients that have an early rapid response to systemic therapy before starting radiation,” Dr. Speers explained.

“We have struggled as oncologists to know whether omitting this effective radiotherapy would compromise outcomes, and thus many were inclined to continue offering it to patients, even with the great early response. This study helps answer this critical question,” he said.

The results add reassuring evidence, buttressing efforts to avoid unnecessary interventions that may provide little or no benefit, Dr. Speers added.

“We are now in an era of ‘less being more’ as we seek ways to provide optimal quality and quantity of life to patients with cancer and their families, and this is just another example of the tremendous progress being made.”

Further commenting on the study at the press briefing, Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, said the research supports ASCO’s ongoing efforts to reduce the toxicities of cancer treatment.

“Our ASCO vision is a world where cancer is either prevented or cured, and every patient is cured – and every survivor is healthy, and that part about every survivor being healthy is what we’re working on here [in this study],” Dr. Gralow said.

The study was funded by the Swiss Cancer League and Cancer Research UK, with partial support from the Swiss National Science Foundation. Dr. Zucca reported relationships with AstraZeneca, Beigene, Celgene, Incyte, Janssen, Merck, Roche, Celltrion Healthcare, Kite, and Abbvie. Dr. Speers disclosed his coinvention of technology that assesses radiosensitivity and predicts benefits from adjutant radiotherapy.

For patients with primary mediastinal B-cell lymphoma (PMBCL) who achieved a complete metabolic response after immunochemotherapy, radiation therapy may be safely omitted without heightening their risks of relapse or disease progression – thereby sparing them the toxicity and costs of this additional treatment.

“This study is the largest prospective study of PMBCL ever conducted,” said first author Emanuele Zucca, MD, consultant and head of the lymphoma unit at the Oncology Institute of Southern Switzerland in Bellinzona. Dr. Zucca presented the findings at the annual meeting of the American Society of Clinical Oncology (ASCO).

The results of the research underscore that “mediastinal radiation therapy in patients with complete remission after frontline immunochemotherapy can be safely omitted,” he said.

While PMBCL has a relatively low incidence, representing fewer than 5% of cases of non-Hodgkin lymphoma, the cancer is over-represented in young White women between approximately 30 and 40 years of age, and is a notably aggressive form of diffuse large B-cell lymphoma.

However, in patients who rapidly achieve remission with dose-intensive immunochemotherapy, the prognosis is good.

In such cases, the use of mediastinal radiation therapy has been seen as a measure to further consolidate the immunochemotherapy response, but the additional treatment comes at the cost of an increased risk of second malignancies, as well as coronary or valvular heart disease.

Meanwhile, in recent decades promising data has shown that aggressive chemoimmunotherapy regimens alone, such as DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) can be enough for patients achieving a complete remission, while novel approaches such as checkpoint inhibitors and CAR T-cell therapy further show benefits in patients with lymphoma that relapses after treatment.

With ongoing controversy over whether to include the added radiation therapy among patients with a complete metabolic response, Dr. Zucca and his colleagues conducted the IELSG37 international study, enrolling 545 patients from 74 centers in 13 countries, including 336 women, with newly diagnosed PMBCL.

The patients were treated with induction chemoimmunotherapy with rituximab and anthracycline-based therapy based on local practice, and response assessed among of 530 of the 545 patients showed that 268 (50.6%) achieved a complete metabolic response.

Those patients were then randomized to either observation (n = 132) or consolidation radiation therapy (30 Gy; n = 136). The characteristics between the two groups were similar, with a mean age of 35.5, and about 65% female.

With a median follow-up of 63 months (range, 48-60 months), the primary endpoint of progression-free survival at 30 months was not significantly different between the observation arm (98.5%) and radiation therapy arm (96.2%; P = .278).

After adjustment for factors including sex, chemotherapy, country, and positron emission tomography (PET) response score, the estimated relative effect of radiotherapy versus observation was a hazard ratio of 0.68, and the absolute risk reduction associated with radiotherapy at 30 months was 1.2% after adjustment.

The number needed to treat is high, at 126.3 after stratification, and the 5-year overall survival was excellent in both arms, at 99%.

“What this tells us is that treatment with radiation therapy in well over 100 patients is needed just to avoid a single recurrence,” Dr. Zucca explained.

Overall survival after 3 years was excellent and identical in both arms, at about 99%.

To date, three severe cardiac events and three second cancers have been recorded in the study, all occurring among patients randomized to receive radiation therapy.

Dr. Zucca noted that longer follow-up is needed to better examine late toxicities.

“The long-term toxicities of mediastinal radiotherapy are well documented, particularly second breast, thyroid, and lung cancers and increased risk of coronary or valvular heart disease, in a patient group dominated by young adults,” Dr. Zucca said in a press statement.

“This study shows chemoimmunotherapy alone is an effective treatment for primary mediastinal B-cell lymphoma and strongly supports omitting radiotherapy without impacting chances of cure.”

Commenting on the study, Corey W. Speers, MD, PhD, assistant professor, radiation oncology, department of surgery, University of Michigan Hospital, Ann Arbor, said the findings have important clinical implications.

“We all should be encouraged by the low rates in this trial, which are lower than expected,” Dr. Speers said in a press briefing.

In further comments, he added that “these results will inform and likely change clinical practice.”

Dr. Speers said the study is notable for being the first of its kind.

“This clinical question has not previously been directly addressed, and this is the first study to do so,” he said.

“With more effective systemic therapies, many patients have their lymphoma disappear with early aggressive treatment, and although radiation is very effective at treating lymphoma, it has not been clear if it is needed in these patients that have an early rapid response to systemic therapy before starting radiation,” Dr. Speers explained.

“We have struggled as oncologists to know whether omitting this effective radiotherapy would compromise outcomes, and thus many were inclined to continue offering it to patients, even with the great early response. This study helps answer this critical question,” he said.

The results add reassuring evidence, buttressing efforts to avoid unnecessary interventions that may provide little or no benefit, Dr. Speers added.

“We are now in an era of ‘less being more’ as we seek ways to provide optimal quality and quantity of life to patients with cancer and their families, and this is just another example of the tremendous progress being made.”

Further commenting on the study at the press briefing, Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, said the research supports ASCO’s ongoing efforts to reduce the toxicities of cancer treatment.

“Our ASCO vision is a world where cancer is either prevented or cured, and every patient is cured – and every survivor is healthy, and that part about every survivor being healthy is what we’re working on here [in this study],” Dr. Gralow said.

The study was funded by the Swiss Cancer League and Cancer Research UK, with partial support from the Swiss National Science Foundation. Dr. Zucca reported relationships with AstraZeneca, Beigene, Celgene, Incyte, Janssen, Merck, Roche, Celltrion Healthcare, Kite, and Abbvie. Dr. Speers disclosed his coinvention of technology that assesses radiosensitivity and predicts benefits from adjutant radiotherapy.

DENVER – Multiple treatment transitions in patients with neuromyelitis optica spectrum disorder (NMOSD) for nonmedical reasons are associated with increased neurological harm, including relapse risk and disease progression, new research shows.

“For the first time, we were able to quantify clinical outcomes associated with treatment transitions in people with NMOSD. Our data highlight that aspects outside of therapeutic efficacy may be remarkably meaningful in the effective suppression of disease advancement,” said senior investigator Darin T. Okuda, MD, professor of neurology and director of the neuroinnovation program at University of Texas Southwestern Medical Center in Dallas.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Treatment delayed?

NMOSD, an inflammatory syndrome of the central nervous system, can cause irreversible disability. As treatments have improved over time, transitioning from one medication to newer options has become increasingly common.

To better understand the effects of multiple treatment transitions, the researchers conducted a retrospective analysis of electronic medical records of 164 patients with aquaporin-4 IgG–positive NMOSD. Of these individuals, 89 met the study’s inclusion criteria.

Of the participants, 89% were female, and the median disease duration was 10.1 years. Forty-two patients had switched therapies at least once; 26 switched at least twice; 12 switched at least three times; six switched four times; and three switched therapies five times or more for a total of 174 treatment transitions.

Patients were stratified into two groups – those who transitioned for medical reasons (53.4%), and those who switched because of nonmedical/tolerability reasons (46.6%).

Top reasons for transitioning in the medical category included clinical relapse and/or new MRI activity (29.9%), physician-directed transition (11.5%), and increased physical or clinical disability (4.0%). Leading reasons for nonmedical transitions were side effects (16.7%), adherence/persistence (8.1%), and cost/access (5.75%).

A recurrent event survival analysis showed that, after just one transition for nonmedical or tolerability reasons, outcomes significantly improved, with the risk of hospitalization decreasing 40.3% (P = .005), the risk of relapse decreasing by 53.1% (P = .002), and the risk of advancement on MRI decreasing by 65.9% (P = .005).

Conversely, each additional drug discontinuation in the nonmedical group was associated with worse outcomes. These included a 25.2% increased risk of hospitalization (P = .0003), a 24.4% increase in relapse risk (P = .06), and a 41.9% increased risk of MRI advancement (P = .03).

In terms of transitions for medical reasons, there was a significantly increased risk of MRI advancement with the first switch (32.2%; P = .005). However, no significant increases in risk were associated with each additional transition (P = .33).

The median time spent on the first treatment was 306 days in the transition for medical reasons group and 378 days for the nonmedical/tolerability group.

The median duration of time spent between treatments during the initial transition was just 7 days among those transitioning for medical reasons versus 91 days for nonmedical reasons, with the median duration of additional transitions also substantially longer in the nonmedical reasons group, at 22 and 80 days, respectively.

“The median time spent on a first-line therapy regardless of [whether] that first transition was due to a medical or nonmedical tolerability reason was similar; however, the duration of that initial transition was 13 times longer if the transition had to do with a nonmedical or tolerability reason,” first author Alexander D. Smith, a clinical data specialist at UT Southwestern Medical Center, told conference delegates. “Similarly, each additional transition was almost four times longer if it had to do with a nonmedical or tolerability reason,” he said.

Dr. Okuda noted the longer window between treatment transitions may be a key factor in the different outcomes between the groups. “A central theory involves the increased amount of time between treatments,” he said.

“The reasons for the delay in starting a new treatment may be related to a variety of factors, including laboratory testing required to start a new treatment, third-party administrator coverage, time for the resolution of adverse reactions, and/or personal factors from the individual undergoing treatment, etc.”

Another factor, Mr. Smith said in his talk, is that, “when people are left miserable by a prior treatment exposure, they may simply be hesitant to get on the next therapy.”

The finding that only MRI advancement was associated with transitions for medical reasons suggests that worsening disease activity is not necessarily behind increased transitions, with nonmedical reasons often the cause, and more likely to be associated with the worse outcomes.

With the time between treatments a possible culprit, Dr. Okuda said the clinical implications are that “treatment transitions, regardless of the reason, should occur as quickly as possible to reduce the risk for disease progression associated with NMOSD.”

Mr. Smith echoed the suggestion, adding that “it’s important that even if disease activity is not present, complacency should be avoided.”

“Clinicians and third-party administrators should work to ensure that people with NMOSD have accelerated switches onto their next therapy, even if that disease activity is not present. In a sense, rapid treatment transitions may have equitable benefits to the treatments themselves,” Mr. Smith added.

Important research

Commenting on the study, Shailee Shah, MD, an assistant professor in the Neuroimmunology division at Vanderbilt University Medical Center, in Nashville, Tenn., noted the findings are consistent with generally higher concerns around switching treatments for nonmedical reasons.

“In general, if a high-efficacy medication is started, it appears that patients are less likely to require a transition to a different medication. It is a little harder to predict who may have issues with tolerability or nonmedical reasons to transition medications, and many providers would likely agree that these transitions do raise some concerns about the risk of relapse or hospitalization in the interim,” she said.

Dr. Shah added that in her experience patients who require multiple transitions are either started on lower-efficacy medications at treatment initiation or have highly refractory disease.

The study’s findings underscore that “identifying additional risk factors and underlying reasons for these findings will be imperative in the future,” Dr. Shah said.

The study was supported by Revert Health, a corporation founded by Dr. Okuda. Dr. Okuda reports receiving personal compensation for consulting and advisory services from Alexion, Biogen, Celgene/Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Janssen Pharmaceuticals, Novartis, Osmotica Pharmaceuticals, RVL Pharmaceuticals, TG Therapeutics, Viela Bio, and research support from Biogen, EMD Serono/Merck, and Novartis. Dr. Shah reports that she has served on advisory boards for Horizon, Alexion, and Genentech.

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

DENVER – Multiple treatment transitions in patients with neuromyelitis optica spectrum disorder (NMOSD) for nonmedical reasons are associated with increased neurological harm, including relapse risk and disease progression, new research shows.

“For the first time, we were able to quantify clinical outcomes associated with treatment transitions in people with NMOSD. Our data highlight that aspects outside of therapeutic efficacy may be remarkably meaningful in the effective suppression of disease advancement,” said senior investigator Darin T. Okuda, MD, professor of neurology and director of the neuroinnovation program at University of Texas Southwestern Medical Center in Dallas.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Treatment delayed?

NMOSD, an inflammatory syndrome of the central nervous system, can cause irreversible disability. As treatments have improved over time, transitioning from one medication to newer options has become increasingly common.

To better understand the effects of multiple treatment transitions, the researchers conducted a retrospective analysis of electronic medical records of 164 patients with aquaporin-4 IgG–positive NMOSD. Of these individuals, 89 met the study’s inclusion criteria.

Of the participants, 89% were female, and the median disease duration was 10.1 years. Forty-two patients had switched therapies at least once; 26 switched at least twice; 12 switched at least three times; six switched four times; and three switched therapies five times or more for a total of 174 treatment transitions.

Patients were stratified into two groups – those who transitioned for medical reasons (53.4%), and those who switched because of nonmedical/tolerability reasons (46.6%).

Top reasons for transitioning in the medical category included clinical relapse and/or new MRI activity (29.9%), physician-directed transition (11.5%), and increased physical or clinical disability (4.0%). Leading reasons for nonmedical transitions were side effects (16.7%), adherence/persistence (8.1%), and cost/access (5.75%).

A recurrent event survival analysis showed that, after just one transition for nonmedical or tolerability reasons, outcomes significantly improved, with the risk of hospitalization decreasing 40.3% (P = .005), the risk of relapse decreasing by 53.1% (P = .002), and the risk of advancement on MRI decreasing by 65.9% (P = .005).

Conversely, each additional drug discontinuation in the nonmedical group was associated with worse outcomes. These included a 25.2% increased risk of hospitalization (P = .0003), a 24.4% increase in relapse risk (P = .06), and a 41.9% increased risk of MRI advancement (P = .03).

In terms of transitions for medical reasons, there was a significantly increased risk of MRI advancement with the first switch (32.2%; P = .005). However, no significant increases in risk were associated with each additional transition (P = .33).

The median time spent on the first treatment was 306 days in the transition for medical reasons group and 378 days for the nonmedical/tolerability group.

The median duration of time spent between treatments during the initial transition was just 7 days among those transitioning for medical reasons versus 91 days for nonmedical reasons, with the median duration of additional transitions also substantially longer in the nonmedical reasons group, at 22 and 80 days, respectively.

“The median time spent on a first-line therapy regardless of [whether] that first transition was due to a medical or nonmedical tolerability reason was similar; however, the duration of that initial transition was 13 times longer if the transition had to do with a nonmedical or tolerability reason,” first author Alexander D. Smith, a clinical data specialist at UT Southwestern Medical Center, told conference delegates. “Similarly, each additional transition was almost four times longer if it had to do with a nonmedical or tolerability reason,” he said.

Dr. Okuda noted the longer window between treatment transitions may be a key factor in the different outcomes between the groups. “A central theory involves the increased amount of time between treatments,” he said.

“The reasons for the delay in starting a new treatment may be related to a variety of factors, including laboratory testing required to start a new treatment, third-party administrator coverage, time for the resolution of adverse reactions, and/or personal factors from the individual undergoing treatment, etc.”

Another factor, Mr. Smith said in his talk, is that, “when people are left miserable by a prior treatment exposure, they may simply be hesitant to get on the next therapy.”

The finding that only MRI advancement was associated with transitions for medical reasons suggests that worsening disease activity is not necessarily behind increased transitions, with nonmedical reasons often the cause, and more likely to be associated with the worse outcomes.

With the time between treatments a possible culprit, Dr. Okuda said the clinical implications are that “treatment transitions, regardless of the reason, should occur as quickly as possible to reduce the risk for disease progression associated with NMOSD.”

Mr. Smith echoed the suggestion, adding that “it’s important that even if disease activity is not present, complacency should be avoided.”

“Clinicians and third-party administrators should work to ensure that people with NMOSD have accelerated switches onto their next therapy, even if that disease activity is not present. In a sense, rapid treatment transitions may have equitable benefits to the treatments themselves,” Mr. Smith added.

Important research

Commenting on the study, Shailee Shah, MD, an assistant professor in the Neuroimmunology division at Vanderbilt University Medical Center, in Nashville, Tenn., noted the findings are consistent with generally higher concerns around switching treatments for nonmedical reasons.

“In general, if a high-efficacy medication is started, it appears that patients are less likely to require a transition to a different medication. It is a little harder to predict who may have issues with tolerability or nonmedical reasons to transition medications, and many providers would likely agree that these transitions do raise some concerns about the risk of relapse or hospitalization in the interim,” she said.

Dr. Shah added that in her experience patients who require multiple transitions are either started on lower-efficacy medications at treatment initiation or have highly refractory disease.

The study’s findings underscore that “identifying additional risk factors and underlying reasons for these findings will be imperative in the future,” Dr. Shah said.

The study was supported by Revert Health, a corporation founded by Dr. Okuda. Dr. Okuda reports receiving personal compensation for consulting and advisory services from Alexion, Biogen, Celgene/Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Janssen Pharmaceuticals, Novartis, Osmotica Pharmaceuticals, RVL Pharmaceuticals, TG Therapeutics, Viela Bio, and research support from Biogen, EMD Serono/Merck, and Novartis. Dr. Shah reports that she has served on advisory boards for Horizon, Alexion, and Genentech.

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

DENVER – Multiple treatment transitions in patients with neuromyelitis optica spectrum disorder (NMOSD) for nonmedical reasons are associated with increased neurological harm, including relapse risk and disease progression, new research shows.

“For the first time, we were able to quantify clinical outcomes associated with treatment transitions in people with NMOSD. Our data highlight that aspects outside of therapeutic efficacy may be remarkably meaningful in the effective suppression of disease advancement,” said senior investigator Darin T. Okuda, MD, professor of neurology and director of the neuroinnovation program at University of Texas Southwestern Medical Center in Dallas.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Treatment delayed?

NMOSD, an inflammatory syndrome of the central nervous system, can cause irreversible disability. As treatments have improved over time, transitioning from one medication to newer options has become increasingly common.

To better understand the effects of multiple treatment transitions, the researchers conducted a retrospective analysis of electronic medical records of 164 patients with aquaporin-4 IgG–positive NMOSD. Of these individuals, 89 met the study’s inclusion criteria.

Of the participants, 89% were female, and the median disease duration was 10.1 years. Forty-two patients had switched therapies at least once; 26 switched at least twice; 12 switched at least three times; six switched four times; and three switched therapies five times or more for a total of 174 treatment transitions.

Patients were stratified into two groups – those who transitioned for medical reasons (53.4%), and those who switched because of nonmedical/tolerability reasons (46.6%).

Top reasons for transitioning in the medical category included clinical relapse and/or new MRI activity (29.9%), physician-directed transition (11.5%), and increased physical or clinical disability (4.0%). Leading reasons for nonmedical transitions were side effects (16.7%), adherence/persistence (8.1%), and cost/access (5.75%).

A recurrent event survival analysis showed that, after just one transition for nonmedical or tolerability reasons, outcomes significantly improved, with the risk of hospitalization decreasing 40.3% (P = .005), the risk of relapse decreasing by 53.1% (P = .002), and the risk of advancement on MRI decreasing by 65.9% (P = .005).

Conversely, each additional drug discontinuation in the nonmedical group was associated with worse outcomes. These included a 25.2% increased risk of hospitalization (P = .0003), a 24.4% increase in relapse risk (P = .06), and a 41.9% increased risk of MRI advancement (P = .03).

In terms of transitions for medical reasons, there was a significantly increased risk of MRI advancement with the first switch (32.2%; P = .005). However, no significant increases in risk were associated with each additional transition (P = .33).

The median time spent on the first treatment was 306 days in the transition for medical reasons group and 378 days for the nonmedical/tolerability group.

The median duration of time spent between treatments during the initial transition was just 7 days among those transitioning for medical reasons versus 91 days for nonmedical reasons, with the median duration of additional transitions also substantially longer in the nonmedical reasons group, at 22 and 80 days, respectively.

“The median time spent on a first-line therapy regardless of [whether] that first transition was due to a medical or nonmedical tolerability reason was similar; however, the duration of that initial transition was 13 times longer if the transition had to do with a nonmedical or tolerability reason,” first author Alexander D. Smith, a clinical data specialist at UT Southwestern Medical Center, told conference delegates. “Similarly, each additional transition was almost four times longer if it had to do with a nonmedical or tolerability reason,” he said.

Dr. Okuda noted the longer window between treatment transitions may be a key factor in the different outcomes between the groups. “A central theory involves the increased amount of time between treatments,” he said.

“The reasons for the delay in starting a new treatment may be related to a variety of factors, including laboratory testing required to start a new treatment, third-party administrator coverage, time for the resolution of adverse reactions, and/or personal factors from the individual undergoing treatment, etc.”

Another factor, Mr. Smith said in his talk, is that, “when people are left miserable by a prior treatment exposure, they may simply be hesitant to get on the next therapy.”

The finding that only MRI advancement was associated with transitions for medical reasons suggests that worsening disease activity is not necessarily behind increased transitions, with nonmedical reasons often the cause, and more likely to be associated with the worse outcomes.

With the time between treatments a possible culprit, Dr. Okuda said the clinical implications are that “treatment transitions, regardless of the reason, should occur as quickly as possible to reduce the risk for disease progression associated with NMOSD.”

Mr. Smith echoed the suggestion, adding that “it’s important that even if disease activity is not present, complacency should be avoided.”

“Clinicians and third-party administrators should work to ensure that people with NMOSD have accelerated switches onto their next therapy, even if that disease activity is not present. In a sense, rapid treatment transitions may have equitable benefits to the treatments themselves,” Mr. Smith added.

Important research

Commenting on the study, Shailee Shah, MD, an assistant professor in the Neuroimmunology division at Vanderbilt University Medical Center, in Nashville, Tenn., noted the findings are consistent with generally higher concerns around switching treatments for nonmedical reasons.

“In general, if a high-efficacy medication is started, it appears that patients are less likely to require a transition to a different medication. It is a little harder to predict who may have issues with tolerability or nonmedical reasons to transition medications, and many providers would likely agree that these transitions do raise some concerns about the risk of relapse or hospitalization in the interim,” she said.

Dr. Shah added that in her experience patients who require multiple transitions are either started on lower-efficacy medications at treatment initiation or have highly refractory disease.

The study’s findings underscore that “identifying additional risk factors and underlying reasons for these findings will be imperative in the future,” Dr. Shah said.

The study was supported by Revert Health, a corporation founded by Dr. Okuda. Dr. Okuda reports receiving personal compensation for consulting and advisory services from Alexion, Biogen, Celgene/Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Janssen Pharmaceuticals, Novartis, Osmotica Pharmaceuticals, RVL Pharmaceuticals, TG Therapeutics, Viela Bio, and research support from Biogen, EMD Serono/Merck, and Novartis. Dr. Shah reports that she has served on advisory boards for Horizon, Alexion, and Genentech.

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

DENVER – The use of the monoclonal antibody satralizumab (Enspryng) for the long-term treatment of anti–aquaporin-4 (AQP4) antibody–positive neuromyelitis optica spectrum disorder (NMOSD) provides sustained freedom from relapse with no new safety concerns over 5 years, new research shows.  

“In long-term observations, we are seeing a nice, sustained suppression of relapses early, as well as late, in treatment,” said study investigator Anthony Traboulsee, MD, University of British Columbia, Vancouver, in presenting the findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“It remains very tolerable with no participants discontinuing because of side effects,” he said. “And importantly, [there are] no signs of a delayed risk of infections for both monotherapy and combination therapy.”

Satralizumab, a monoclonal recycling antibody, targets the interleukin (IL)–6 receptor, which is elevated in the serum and cerebrospinal fluid of patients in NMOSD.

The drug was approved by the Food and Drug Administration in 2020 for the treatment of AQP4 antibody–positive NMOSD after favorable results from two key trials: SAkuraSky and SAkuraStar.

The FDA approval marked satralizumab as the third therapy for NMOSD, following eculizumab (Soliris) and inebilizumab (Uplizna).

Satralizumab is administered in subcutaneous injections every 4 weeks after a run-in period of injections at weeks 0, 2, and 4.

Longest trial to date

To evaluate the drug’s long-term efficacy in the treatment of AQP4 IgG–positive NMOSD, patients from the two previous phase 3 trials were entered into the single arm, open-label SAkuraMoon study and continued treatment with the satralizumab 120 mg injections once monthly, with or without immunosuppressive therapy.

The study included 106 patients (mean age 44 years, 89.6% women), all of whom had received one or more doses of satralizumab by the data cutoff of January 2022.

With a median duration of satralizumab exposure of 5 years, the overall adjusted annualized rate of investigator protocol-defined relapse (ARR) was 0.09.

Longitudinal assessment further showed no significant increase in the relapse rate over the course of the study, with an ARR rate of 0.16 at year 1; 0.10 at year 2; 0.05 at year 3; and 0.07 at year 4.

At week 240 (4.6 years), 72% of satralizumab-treated patients were relapse-free, with 91% free from severe relapse.

In addition, 85% of patients had no sustained disability, as measured by Expanded Disability Status Scale (EDSS) worsening, over the study period.  

Asked if there are potential subgroups of patients who may be more susceptible to the worsening of disability, Dr. Traboulsee responded “not that we can tell as of yet.”

“I would like to explore this further as this is a relatively new observation, and, as far as I know, this is the longest follow-up for an NMO treatment trial cohort,” he said.

Favorable safety profile

The safety profile was also favorable, consistent with results in the earlier trials. The longer exposure to satralizumab was not associated with a higher risk of severe (grade 3 or higher) laboratory changes versus the double-blind studies. “Rates of adverse events and serious adverse events with overall satralizumab treatment were comparable with the double-blind periods,” said Dr. Traboulsee.

“With satralizumab combined with immunosuppressant therapy, we’re not seeing an increased rate of infections, because it’s not an immune suppressant – it doesn’t suppress lymphocytes or lower immunoglobulin,” he added.

While the use of combination therapy has been an important clinical concern, Dr. Traboulsee noted that “this does not appear to be the case with satralizumab when combined with daily prednisone or daily azathioprine.”

“There is no increased risk of infections, compared with placebo, and it interestingly appears lower than patients on prednisone or azathioprine alone,” he said.

While the median follow-up was 5 years, some in the clinical trial population have been on treatment for up to 7.9 years.

“Based on the current safety and efficacy data, they could stay on this therapy indefinitely, in my opinion,” Dr. Traboulsee said.

In addition to its long-term safety and efficacy, satralizumab “is easy for patients to take and does not require access to an infusion center. It’s easy for physicians to monitor safety, especially since no additional vaccinations or precautions are required beyond what is done in routine care.”

“What I conclude from that clinically is that this is a highly effective and safe therapy by itself or in combination with another agent,” Dr. Traboulsee said.

He noted that the lack of a bump in infections is “really encouraging and very important with a chronic disease that affects elderly patients. So far, so good,” he added.

‘A good first-line therapy’

Commenting on the study, Shailee Shah, MD, an assistant professor in the neuroimmunology division at Vanderbilt University Medical Center, Nashville, Tenn., agreed that the findings bode well for satralizumab’s long-term benefits.

“These are promising results and suggest that satralizumab is very effective in the long term, and even when patients relapse, those relapses are less severe than they would likely be if the patient were off therapy,” she said.

She noted that, while the ability to self-administer injections with satralizumab is convenient, preferences vary.

“This is patient dependent,” Dr. Shah said. “For some patients an injectable medication is ideal but for others an infusion medication [such as eculizumab] is preferred.”

Overall, however, Dr. Shah described satralizumab as “a good first-line therapy for patients with NMOSD in addition to eculizumab/ravulizumab and inebilizumab.”

“It is reasonable to consider this medication in isolation or with concomitant immunosuppressive therapy,” she said.

Dr. Traboulsee’s disclosures include relationships with Novartis, Roche, Sanofi (Genzyme), Ingo Kleiter, Alexion, Almirall, Bayer, Biogen, Celgene, Genentech, Hexal, Horizon, Merck, and Sanofi. Dr. Shah reports that she has served on advisory boards for Horizon, Alexion, and Genentech.

DENVER – The use of the monoclonal antibody satralizumab (Enspryng) for the long-term treatment of anti–aquaporin-4 (AQP4) antibody–positive neuromyelitis optica spectrum disorder (NMOSD) provides sustained freedom from relapse with no new safety concerns over 5 years, new research shows.  

“In long-term observations, we are seeing a nice, sustained suppression of relapses early, as well as late, in treatment,” said study investigator Anthony Traboulsee, MD, University of British Columbia, Vancouver, in presenting the findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“It remains very tolerable with no participants discontinuing because of side effects,” he said. “And importantly, [there are] no signs of a delayed risk of infections for both monotherapy and combination therapy.”

Satralizumab, a monoclonal recycling antibody, targets the interleukin (IL)–6 receptor, which is elevated in the serum and cerebrospinal fluid of patients in NMOSD.

The drug was approved by the Food and Drug Administration in 2020 for the treatment of AQP4 antibody–positive NMOSD after favorable results from two key trials: SAkuraSky and SAkuraStar.

The FDA approval marked satralizumab as the third therapy for NMOSD, following eculizumab (Soliris) and inebilizumab (Uplizna).

Satralizumab is administered in subcutaneous injections every 4 weeks after a run-in period of injections at weeks 0, 2, and 4.

Longest trial to date

To evaluate the drug’s long-term efficacy in the treatment of AQP4 IgG–positive NMOSD, patients from the two previous phase 3 trials were entered into the single arm, open-label SAkuraMoon study and continued treatment with the satralizumab 120 mg injections once monthly, with or without immunosuppressive therapy.

The study included 106 patients (mean age 44 years, 89.6% women), all of whom had received one or more doses of satralizumab by the data cutoff of January 2022.

With a median duration of satralizumab exposure of 5 years, the overall adjusted annualized rate of investigator protocol-defined relapse (ARR) was 0.09.

Longitudinal assessment further showed no significant increase in the relapse rate over the course of the study, with an ARR rate of 0.16 at year 1; 0.10 at year 2; 0.05 at year 3; and 0.07 at year 4.

At week 240 (4.6 years), 72% of satralizumab-treated patients were relapse-free, with 91% free from severe relapse.

In addition, 85% of patients had no sustained disability, as measured by Expanded Disability Status Scale (EDSS) worsening, over the study period.  

Asked if there are potential subgroups of patients who may be more susceptible to the worsening of disability, Dr. Traboulsee responded “not that we can tell as of yet.”

“I would like to explore this further as this is a relatively new observation, and, as far as I know, this is the longest follow-up for an NMO treatment trial cohort,” he said.

Favorable safety profile

The safety profile was also favorable, consistent with results in the earlier trials. The longer exposure to satralizumab was not associated with a higher risk of severe (grade 3 or higher) laboratory changes versus the double-blind studies. “Rates of adverse events and serious adverse events with overall satralizumab treatment were comparable with the double-blind periods,” said Dr. Traboulsee.

“With satralizumab combined with immunosuppressant therapy, we’re not seeing an increased rate of infections, because it’s not an immune suppressant – it doesn’t suppress lymphocytes or lower immunoglobulin,” he added.

While the use of combination therapy has been an important clinical concern, Dr. Traboulsee noted that “this does not appear to be the case with satralizumab when combined with daily prednisone or daily azathioprine.”

“There is no increased risk of infections, compared with placebo, and it interestingly appears lower than patients on prednisone or azathioprine alone,” he said.

While the median follow-up was 5 years, some in the clinical trial population have been on treatment for up to 7.9 years.

“Based on the current safety and efficacy data, they could stay on this therapy indefinitely, in my opinion,” Dr. Traboulsee said.

In addition to its long-term safety and efficacy, satralizumab “is easy for patients to take and does not require access to an infusion center. It’s easy for physicians to monitor safety, especially since no additional vaccinations or precautions are required beyond what is done in routine care.”

“What I conclude from that clinically is that this is a highly effective and safe therapy by itself or in combination with another agent,” Dr. Traboulsee said.

He noted that the lack of a bump in infections is “really encouraging and very important with a chronic disease that affects elderly patients. So far, so good,” he added.

‘A good first-line therapy’

Commenting on the study, Shailee Shah, MD, an assistant professor in the neuroimmunology division at Vanderbilt University Medical Center, Nashville, Tenn., agreed that the findings bode well for satralizumab’s long-term benefits.

“These are promising results and suggest that satralizumab is very effective in the long term, and even when patients relapse, those relapses are less severe than they would likely be if the patient were off therapy,” she said.

She noted that, while the ability to self-administer injections with satralizumab is convenient, preferences vary.

“This is patient dependent,” Dr. Shah said. “For some patients an injectable medication is ideal but for others an infusion medication [such as eculizumab] is preferred.”

Overall, however, Dr. Shah described satralizumab as “a good first-line therapy for patients with NMOSD in addition to eculizumab/ravulizumab and inebilizumab.”

“It is reasonable to consider this medication in isolation or with concomitant immunosuppressive therapy,” she said.

Dr. Traboulsee’s disclosures include relationships with Novartis, Roche, Sanofi (Genzyme), Ingo Kleiter, Alexion, Almirall, Bayer, Biogen, Celgene, Genentech, Hexal, Horizon, Merck, and Sanofi. Dr. Shah reports that she has served on advisory boards for Horizon, Alexion, and Genentech.

DENVER – The use of the monoclonal antibody satralizumab (Enspryng) for the long-term treatment of anti–aquaporin-4 (AQP4) antibody–positive neuromyelitis optica spectrum disorder (NMOSD) provides sustained freedom from relapse with no new safety concerns over 5 years, new research shows.  

“In long-term observations, we are seeing a nice, sustained suppression of relapses early, as well as late, in treatment,” said study investigator Anthony Traboulsee, MD, University of British Columbia, Vancouver, in presenting the findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“It remains very tolerable with no participants discontinuing because of side effects,” he said. “And importantly, [there are] no signs of a delayed risk of infections for both monotherapy and combination therapy.”

Satralizumab, a monoclonal recycling antibody, targets the interleukin (IL)–6 receptor, which is elevated in the serum and cerebrospinal fluid of patients in NMOSD.

The drug was approved by the Food and Drug Administration in 2020 for the treatment of AQP4 antibody–positive NMOSD after favorable results from two key trials: SAkuraSky and SAkuraStar.

The FDA approval marked satralizumab as the third therapy for NMOSD, following eculizumab (Soliris) and inebilizumab (Uplizna).

Satralizumab is administered in subcutaneous injections every 4 weeks after a run-in period of injections at weeks 0, 2, and 4.

Longest trial to date

To evaluate the drug’s long-term efficacy in the treatment of AQP4 IgG–positive NMOSD, patients from the two previous phase 3 trials were entered into the single arm, open-label SAkuraMoon study and continued treatment with the satralizumab 120 mg injections once monthly, with or without immunosuppressive therapy.

The study included 106 patients (mean age 44 years, 89.6% women), all of whom had received one or more doses of satralizumab by the data cutoff of January 2022.

With a median duration of satralizumab exposure of 5 years, the overall adjusted annualized rate of investigator protocol-defined relapse (ARR) was 0.09.

Longitudinal assessment further showed no significant increase in the relapse rate over the course of the study, with an ARR rate of 0.16 at year 1; 0.10 at year 2; 0.05 at year 3; and 0.07 at year 4.

At week 240 (4.6 years), 72% of satralizumab-treated patients were relapse-free, with 91% free from severe relapse.

In addition, 85% of patients had no sustained disability, as measured by Expanded Disability Status Scale (EDSS) worsening, over the study period.  

Asked if there are potential subgroups of patients who may be more susceptible to the worsening of disability, Dr. Traboulsee responded “not that we can tell as of yet.”

“I would like to explore this further as this is a relatively new observation, and, as far as I know, this is the longest follow-up for an NMO treatment trial cohort,” he said.

Favorable safety profile

The safety profile was also favorable, consistent with results in the earlier trials. The longer exposure to satralizumab was not associated with a higher risk of severe (grade 3 or higher) laboratory changes versus the double-blind studies. “Rates of adverse events and serious adverse events with overall satralizumab treatment were comparable with the double-blind periods,” said Dr. Traboulsee.

“With satralizumab combined with immunosuppressant therapy, we’re not seeing an increased rate of infections, because it’s not an immune suppressant – it doesn’t suppress lymphocytes or lower immunoglobulin,” he added.

While the use of combination therapy has been an important clinical concern, Dr. Traboulsee noted that “this does not appear to be the case with satralizumab when combined with daily prednisone or daily azathioprine.”

“There is no increased risk of infections, compared with placebo, and it interestingly appears lower than patients on prednisone or azathioprine alone,” he said.

While the median follow-up was 5 years, some in the clinical trial population have been on treatment for up to 7.9 years.

“Based on the current safety and efficacy data, they could stay on this therapy indefinitely, in my opinion,” Dr. Traboulsee said.

In addition to its long-term safety and efficacy, satralizumab “is easy for patients to take and does not require access to an infusion center. It’s easy for physicians to monitor safety, especially since no additional vaccinations or precautions are required beyond what is done in routine care.”

“What I conclude from that clinically is that this is a highly effective and safe therapy by itself or in combination with another agent,” Dr. Traboulsee said.

He noted that the lack of a bump in infections is “really encouraging and very important with a chronic disease that affects elderly patients. So far, so good,” he added.

‘A good first-line therapy’

Commenting on the study, Shailee Shah, MD, an assistant professor in the neuroimmunology division at Vanderbilt University Medical Center, Nashville, Tenn., agreed that the findings bode well for satralizumab’s long-term benefits.

“These are promising results and suggest that satralizumab is very effective in the long term, and even when patients relapse, those relapses are less severe than they would likely be if the patient were off therapy,” she said.

She noted that, while the ability to self-administer injections with satralizumab is convenient, preferences vary.

“This is patient dependent,” Dr. Shah said. “For some patients an injectable medication is ideal but for others an infusion medication [such as eculizumab] is preferred.”

Overall, however, Dr. Shah described satralizumab as “a good first-line therapy for patients with NMOSD in addition to eculizumab/ravulizumab and inebilizumab.”

“It is reasonable to consider this medication in isolation or with concomitant immunosuppressive therapy,” she said.

Dr. Traboulsee’s disclosures include relationships with Novartis, Roche, Sanofi (Genzyme), Ingo Kleiter, Alexion, Almirall, Bayer, Biogen, Celgene, Genentech, Hexal, Horizon, Merck, and Sanofi. Dr. Shah reports that she has served on advisory boards for Horizon, Alexion, and Genentech.

Across patients’ age groups, adding the immune checkpoint inhibitor nivolumab to chemotherapy significantly improves progression-free survival in advanced stage Hodgkin lymphoma while also reducing toxicities, making it a new standard of care, compared with the CD30-targeting drug brentuximab vedotin.

“[SWOG] S1826, the largest Hodgkin lymphoma study in National Clinical Trials Network history, is a key step toward harmonizing the pediatric and adult treatment of advanced-stage Hodgkin lymphoma,” the authors reported in late-breaking research presented at the annual meeting of the American Society of Clinical Oncology.

“Based on the magnitude of the benefit and with nivolumab being better tolerated than brentuximab, we anticipate that these results will be practice changing and nivolumab [and chemotherapy] will become a new standard of care,” lead author Alex Francisco Herrera, MD, an associate professor and chief of the division of lymphoma in the department of hematology and hematopoietic cell transplantation, City of Hope Medical Center, Duarte, Calif., said in an interview.

The randomized SWOG S1826 trial of 976 patients with newly diagnosed stage 3 or 4 Hodgkin lymphoma included patients ranging in age from as young as 12 to 83 years, and at a median follow-up of 12.1 months, the addition of nivolumab to the chemotherapy regimen of doxorubicin, vinblastine, and dacarbazine (AVD) was associated with as much as a 52% reduction in the risk of disease-related death, compared with the addition of brentuximab.

The results are especially important considering that Hodgkin lymphoma disproportionately affects younger patients, including those in their teens, 20s, and 30s, Dr. Herrera noted in an interview.

“We found that treatment with nivolumab reduced the risk of progression by half, and, importantly, the benefit was observed across subgroups,” he said.
 

Relapse/refractory disease common in advanced HL

In general, outcomes are relatively good even for stage III or IV Hodgkin lymphoma; however, about a quarter of patients still have relapses or refractory disease.

While the introduction of novel frontline treatment with brentuximab-AVD was important in improving overall survival, the regimen adds toxicity, particularly among older patients, and many pediatric patients receiving the therapy still require radiation therapy, with its undesirable side effects.

Meanwhile, the progressive death 1 inhibitor nivolumab, approved by the Food and Drug Administration, gained interest as a potentially ideal alternative in light of Hodgkin lymphoma’s status basically as “the poster child for PD-1 blockade,” Dr. Herrera said.

“There are genetic changes in the Hodgkin lymphoma tumor cell that lead to expression of PD-1 ligands on the surface of Hodgkin lymphoma cells, and when we use a drug like nivolumab, we see that even patients with the most treatment-resistant rates of lymphoma have as much as a 70% response rate,” he explained in a press briefing.

To further investigate, the first-of-its-kind collaboration of adult and pediatric cancer teams conducted the S1826 trial to evaluate the treatment across age groups with stage 3 and 4 Hodgkin lymphoma.

For the study, conducted between July 2019 and October 2022, 976 patients were randomized to treatment either with nivolumab (n = 489) or brentuximab (n = 487), each in combination with the AVD regimen.

Of the patients, the median age was 27, with 24% under the age of 18, 10% over 60 and 32% with IPS 4-7. Among them, 56% were male and 76% were White.

For the primary endpoint, at a median follow-up of 12.1 months, the rate of progression-free survival was significantly higher in the nivolumab arm (hazard ratio, 0.48; one-sided P = .0005), with the rate of 1-year survival at 94% in the nivolumab group versus 86% in the brentuximab group, for a 52% reduction in the risk of disease-related death with nivolumab versus brentuximab.

A total of 11 deaths occurred in the brentuximab group, 7 of which were related to adverse events, compared with 4 deaths in the nivolumab group, 3 of which were related to nivolumab.

Importantly, fewer than 1% of patients with nivolumab required radiation therapy.

“That’s a dramatic reduction of the proportion of the very youngest patients receiving radiotherapy,” Dr. Herrera noted.

Grade 3 or higher hematologic adverse events were higher in the nivolumab group, at 48.4%, including 45.1% that were grade 3 or higher neutropenia, compared with 30.5% with brentuximab, including 23.9% with grade 3 or higher neutropenia.

However, rates of any grade of febrile neutropenia were similar with nivolumab and brentuximab (5.6% vs. 6.4%, respectively), as were rates of pneumonitis (2.0% vs. 3.2%), ALT elevation (30.7% vs. 39.8%), and colitis (1% vs. 1.3%).

In addition, rates of hypo- and hyperthyroidism were more frequent after nivolumab (7% and 3% with nivolumab, respectively, vs. fewer than 1% with brentuximab).

But, of note, peripheral neuropathy of any grade was more common after brentuximab (sensory: 28.1% nivolumab vs. 54.2% brentuximab; motor: 4% nivolumab vs. 6.8% brentuximab).

“I can’t emphasize how important neuropathy is as a side effect in these young patients who have the rest of their life ahead of them,” Dr. Herrera explained. “It’s fantastic to be cured of cancer, but tough to not be able to feel your fingers and toes.”

With its broad inclusion of age groups and a diverse population, he added that the study was importantly a “representative” trial, reflecting a “real-world population.”

“Incredibly, a quarter of patients were under the age of 18; 10% were over the age of 60, a quarter of patients were Hispanic and Black, and in fact we had a quite good representation of higher-risk subgroups,” he said.

Looking forward, longer-term follow-up from this study will be important in determining if the improvement observed in disease-related deaths is maintained over time, Dr. Herrera noted.

“Additionally, it is crucial to obtain data on other key outcomes such as overall survival and quality of life from longer-term follow of this study,” he said.
 

‘A huge step forward’

Commenting on the study, Oreofe Odejide, MD, a medical oncologist at the Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, both in Boston, said that results were unprecedented.

“Although a majority of patients with advanced stage Hodgkin lymphoma will be cured with initial therapy, about 20% of patients still end up with relapsed or refractory disease,” she said in an interview. “Therefore, the findings from this study represent a huge step forward in the management of advanced Hodgkin lymphoma in children and adults, leading to an improved and well-tolerated standard of care.”

Dr. Odejide agreed that the findings are potentially practice changing.

“Brentuximab-AVD set a high bar for the treatment of advanced-stage Hodgkin lymphoma, as it was the first regimen to show a meaningful improvement in disease-related death compared to ABVD chemotherapy in several years,” she explained.

“The fact that the SWOG1826 trial now shows a significant benefit of nivolumab-AVD over brentuximab and included both pediatric and adult patients unlike prior studies, is highly compelling,” Dr. Odejide added. “This has strong potential to change the standard of care for patients with previously untreated, advanced-stage Hodgkin lymphoma.”

The study received funding from the National Cancer Institute and from Bristol-Myers Squibb. Dr. Herrera reported relationships with Abbvie, ADC Therapeutics, Adicet Bio, AstraZeneca/MedImmune, Bristol-Myers Squibb, Caribou Biosciences, Genentech/Roche, Genmab, Karyopharm Therapeutics, Merck, Pfizer, Regeneron, Seagen, Takeda, and Tubulis Gmbh. Dr. Odejide reported no disclosures.

Across patients’ age groups, adding the immune checkpoint inhibitor nivolumab to chemotherapy significantly improves progression-free survival in advanced stage Hodgkin lymphoma while also reducing toxicities, making it a new standard of care, compared with the CD30-targeting drug brentuximab vedotin.

“[SWOG] S1826, the largest Hodgkin lymphoma study in National Clinical Trials Network history, is a key step toward harmonizing the pediatric and adult treatment of advanced-stage Hodgkin lymphoma,” the authors reported in late-breaking research presented at the annual meeting of the American Society of Clinical Oncology.

“Based on the magnitude of the benefit and with nivolumab being better tolerated than brentuximab, we anticipate that these results will be practice changing and nivolumab [and chemotherapy] will become a new standard of care,” lead author Alex Francisco Herrera, MD, an associate professor and chief of the division of lymphoma in the department of hematology and hematopoietic cell transplantation, City of Hope Medical Center, Duarte, Calif., said in an interview.

The randomized SWOG S1826 trial of 976 patients with newly diagnosed stage 3 or 4 Hodgkin lymphoma included patients ranging in age from as young as 12 to 83 years, and at a median follow-up of 12.1 months, the addition of nivolumab to the chemotherapy regimen of doxorubicin, vinblastine, and dacarbazine (AVD) was associated with as much as a 52% reduction in the risk of disease-related death, compared with the addition of brentuximab.

The results are especially important considering that Hodgkin lymphoma disproportionately affects younger patients, including those in their teens, 20s, and 30s, Dr. Herrera noted in an interview.

“We found that treatment with nivolumab reduced the risk of progression by half, and, importantly, the benefit was observed across subgroups,” he said.
 

Relapse/refractory disease common in advanced HL

In general, outcomes are relatively good even for stage III or IV Hodgkin lymphoma; however, about a quarter of patients still have relapses or refractory disease.

While the introduction of novel frontline treatment with brentuximab-AVD was important in improving overall survival, the regimen adds toxicity, particularly among older patients, and many pediatric patients receiving the therapy still require radiation therapy, with its undesirable side effects.

Meanwhile, the progressive death 1 inhibitor nivolumab, approved by the Food and Drug Administration, gained interest as a potentially ideal alternative in light of Hodgkin lymphoma’s status basically as “the poster child for PD-1 blockade,” Dr. Herrera said.

“There are genetic changes in the Hodgkin lymphoma tumor cell that lead to expression of PD-1 ligands on the surface of Hodgkin lymphoma cells, and when we use a drug like nivolumab, we see that even patients with the most treatment-resistant rates of lymphoma have as much as a 70% response rate,” he explained in a press briefing.

To further investigate, the first-of-its-kind collaboration of adult and pediatric cancer teams conducted the S1826 trial to evaluate the treatment across age groups with stage 3 and 4 Hodgkin lymphoma.

For the study, conducted between July 2019 and October 2022, 976 patients were randomized to treatment either with nivolumab (n = 489) or brentuximab (n = 487), each in combination with the AVD regimen.

Of the patients, the median age was 27, with 24% under the age of 18, 10% over 60 and 32% with IPS 4-7. Among them, 56% were male and 76% were White.

For the primary endpoint, at a median follow-up of 12.1 months, the rate of progression-free survival was significantly higher in the nivolumab arm (hazard ratio, 0.48; one-sided P = .0005), with the rate of 1-year survival at 94% in the nivolumab group versus 86% in the brentuximab group, for a 52% reduction in the risk of disease-related death with nivolumab versus brentuximab.

A total of 11 deaths occurred in the brentuximab group, 7 of which were related to adverse events, compared with 4 deaths in the nivolumab group, 3 of which were related to nivolumab.

Importantly, fewer than 1% of patients with nivolumab required radiation therapy.

“That’s a dramatic reduction of the proportion of the very youngest patients receiving radiotherapy,” Dr. Herrera noted.

Grade 3 or higher hematologic adverse events were higher in the nivolumab group, at 48.4%, including 45.1% that were grade 3 or higher neutropenia, compared with 30.5% with brentuximab, including 23.9% with grade 3 or higher neutropenia.

However, rates of any grade of febrile neutropenia were similar with nivolumab and brentuximab (5.6% vs. 6.4%, respectively), as were rates of pneumonitis (2.0% vs. 3.2%), ALT elevation (30.7% vs. 39.8%), and colitis (1% vs. 1.3%).

In addition, rates of hypo- and hyperthyroidism were more frequent after nivolumab (7% and 3% with nivolumab, respectively, vs. fewer than 1% with brentuximab).

But, of note, peripheral neuropathy of any grade was more common after brentuximab (sensory: 28.1% nivolumab vs. 54.2% brentuximab; motor: 4% nivolumab vs. 6.8% brentuximab).

“I can’t emphasize how important neuropathy is as a side effect in these young patients who have the rest of their life ahead of them,” Dr. Herrera explained. “It’s fantastic to be cured of cancer, but tough to not be able to feel your fingers and toes.”

With its broad inclusion of age groups and a diverse population, he added that the study was importantly a “representative” trial, reflecting a “real-world population.”

“Incredibly, a quarter of patients were under the age of 18; 10% were over the age of 60, a quarter of patients were Hispanic and Black, and in fact we had a quite good representation of higher-risk subgroups,” he said.

Looking forward, longer-term follow-up from this study will be important in determining if the improvement observed in disease-related deaths is maintained over time, Dr. Herrera noted.

“Additionally, it is crucial to obtain data on other key outcomes such as overall survival and quality of life from longer-term follow of this study,” he said.
 

‘A huge step forward’

Commenting on the study, Oreofe Odejide, MD, a medical oncologist at the Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, both in Boston, said that results were unprecedented.

“Although a majority of patients with advanced stage Hodgkin lymphoma will be cured with initial therapy, about 20% of patients still end up with relapsed or refractory disease,” she said in an interview. “Therefore, the findings from this study represent a huge step forward in the management of advanced Hodgkin lymphoma in children and adults, leading to an improved and well-tolerated standard of care.”

Dr. Odejide agreed that the findings are potentially practice changing.

“Brentuximab-AVD set a high bar for the treatment of advanced-stage Hodgkin lymphoma, as it was the first regimen to show a meaningful improvement in disease-related death compared to ABVD chemotherapy in several years,” she explained.

“The fact that the SWOG1826 trial now shows a significant benefit of nivolumab-AVD over brentuximab and included both pediatric and adult patients unlike prior studies, is highly compelling,” Dr. Odejide added. “This has strong potential to change the standard of care for patients with previously untreated, advanced-stage Hodgkin lymphoma.”

The study received funding from the National Cancer Institute and from Bristol-Myers Squibb. Dr. Herrera reported relationships with Abbvie, ADC Therapeutics, Adicet Bio, AstraZeneca/MedImmune, Bristol-Myers Squibb, Caribou Biosciences, Genentech/Roche, Genmab, Karyopharm Therapeutics, Merck, Pfizer, Regeneron, Seagen, Takeda, and Tubulis Gmbh. Dr. Odejide reported no disclosures.

Across patients’ age groups, adding the immune checkpoint inhibitor nivolumab to chemotherapy significantly improves progression-free survival in advanced stage Hodgkin lymphoma while also reducing toxicities, making it a new standard of care, compared with the CD30-targeting drug brentuximab vedotin.

“[SWOG] S1826, the largest Hodgkin lymphoma study in National Clinical Trials Network history, is a key step toward harmonizing the pediatric and adult treatment of advanced-stage Hodgkin lymphoma,” the authors reported in late-breaking research presented at the annual meeting of the American Society of Clinical Oncology.

“Based on the magnitude of the benefit and with nivolumab being better tolerated than brentuximab, we anticipate that these results will be practice changing and nivolumab [and chemotherapy] will become a new standard of care,” lead author Alex Francisco Herrera, MD, an associate professor and chief of the division of lymphoma in the department of hematology and hematopoietic cell transplantation, City of Hope Medical Center, Duarte, Calif., said in an interview.

The randomized SWOG S1826 trial of 976 patients with newly diagnosed stage 3 or 4 Hodgkin lymphoma included patients ranging in age from as young as 12 to 83 years, and at a median follow-up of 12.1 months, the addition of nivolumab to the chemotherapy regimen of doxorubicin, vinblastine, and dacarbazine (AVD) was associated with as much as a 52% reduction in the risk of disease-related death, compared with the addition of brentuximab.

The results are especially important considering that Hodgkin lymphoma disproportionately affects younger patients, including those in their teens, 20s, and 30s, Dr. Herrera noted in an interview.

“We found that treatment with nivolumab reduced the risk of progression by half, and, importantly, the benefit was observed across subgroups,” he said.
 

Relapse/refractory disease common in advanced HL

In general, outcomes are relatively good even for stage III or IV Hodgkin lymphoma; however, about a quarter of patients still have relapses or refractory disease.

While the introduction of novel frontline treatment with brentuximab-AVD was important in improving overall survival, the regimen adds toxicity, particularly among older patients, and many pediatric patients receiving the therapy still require radiation therapy, with its undesirable side effects.

Meanwhile, the progressive death 1 inhibitor nivolumab, approved by the Food and Drug Administration, gained interest as a potentially ideal alternative in light of Hodgkin lymphoma’s status basically as “the poster child for PD-1 blockade,” Dr. Herrera said.

“There are genetic changes in the Hodgkin lymphoma tumor cell that lead to expression of PD-1 ligands on the surface of Hodgkin lymphoma cells, and when we use a drug like nivolumab, we see that even patients with the most treatment-resistant rates of lymphoma have as much as a 70% response rate,” he explained in a press briefing.

To further investigate, the first-of-its-kind collaboration of adult and pediatric cancer teams conducted the S1826 trial to evaluate the treatment across age groups with stage 3 and 4 Hodgkin lymphoma.

For the study, conducted between July 2019 and October 2022, 976 patients were randomized to treatment either with nivolumab (n = 489) or brentuximab (n = 487), each in combination with the AVD regimen.

Of the patients, the median age was 27, with 24% under the age of 18, 10% over 60 and 32% with IPS 4-7. Among them, 56% were male and 76% were White.

For the primary endpoint, at a median follow-up of 12.1 months, the rate of progression-free survival was significantly higher in the nivolumab arm (hazard ratio, 0.48; one-sided P = .0005), with the rate of 1-year survival at 94% in the nivolumab group versus 86% in the brentuximab group, for a 52% reduction in the risk of disease-related death with nivolumab versus brentuximab.

A total of 11 deaths occurred in the brentuximab group, 7 of which were related to adverse events, compared with 4 deaths in the nivolumab group, 3 of which were related to nivolumab.

Importantly, fewer than 1% of patients with nivolumab required radiation therapy.

“That’s a dramatic reduction of the proportion of the very youngest patients receiving radiotherapy,” Dr. Herrera noted.

Grade 3 or higher hematologic adverse events were higher in the nivolumab group, at 48.4%, including 45.1% that were grade 3 or higher neutropenia, compared with 30.5% with brentuximab, including 23.9% with grade 3 or higher neutropenia.

However, rates of any grade of febrile neutropenia were similar with nivolumab and brentuximab (5.6% vs. 6.4%, respectively), as were rates of pneumonitis (2.0% vs. 3.2%), ALT elevation (30.7% vs. 39.8%), and colitis (1% vs. 1.3%).

In addition, rates of hypo- and hyperthyroidism were more frequent after nivolumab (7% and 3% with nivolumab, respectively, vs. fewer than 1% with brentuximab).

But, of note, peripheral neuropathy of any grade was more common after brentuximab (sensory: 28.1% nivolumab vs. 54.2% brentuximab; motor: 4% nivolumab vs. 6.8% brentuximab).

“I can’t emphasize how important neuropathy is as a side effect in these young patients who have the rest of their life ahead of them,” Dr. Herrera explained. “It’s fantastic to be cured of cancer, but tough to not be able to feel your fingers and toes.”

With its broad inclusion of age groups and a diverse population, he added that the study was importantly a “representative” trial, reflecting a “real-world population.”

“Incredibly, a quarter of patients were under the age of 18; 10% were over the age of 60, a quarter of patients were Hispanic and Black, and in fact we had a quite good representation of higher-risk subgroups,” he said.

Looking forward, longer-term follow-up from this study will be important in determining if the improvement observed in disease-related deaths is maintained over time, Dr. Herrera noted.

“Additionally, it is crucial to obtain data on other key outcomes such as overall survival and quality of life from longer-term follow of this study,” he said.
 

‘A huge step forward’

Commenting on the study, Oreofe Odejide, MD, a medical oncologist at the Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, both in Boston, said that results were unprecedented.

“Although a majority of patients with advanced stage Hodgkin lymphoma will be cured with initial therapy, about 20% of patients still end up with relapsed or refractory disease,” she said in an interview. “Therefore, the findings from this study represent a huge step forward in the management of advanced Hodgkin lymphoma in children and adults, leading to an improved and well-tolerated standard of care.”

Dr. Odejide agreed that the findings are potentially practice changing.

“Brentuximab-AVD set a high bar for the treatment of advanced-stage Hodgkin lymphoma, as it was the first regimen to show a meaningful improvement in disease-related death compared to ABVD chemotherapy in several years,” she explained.

“The fact that the SWOG1826 trial now shows a significant benefit of nivolumab-AVD over brentuximab and included both pediatric and adult patients unlike prior studies, is highly compelling,” Dr. Odejide added. “This has strong potential to change the standard of care for patients with previously untreated, advanced-stage Hodgkin lymphoma.”

The study received funding from the National Cancer Institute and from Bristol-Myers Squibb. Dr. Herrera reported relationships with Abbvie, ADC Therapeutics, Adicet Bio, AstraZeneca/MedImmune, Bristol-Myers Squibb, Caribou Biosciences, Genentech/Roche, Genmab, Karyopharm Therapeutics, Merck, Pfizer, Regeneron, Seagen, Takeda, and Tubulis Gmbh. Dr. Odejide reported no disclosures.

Endocrinologists report steady increases in pay in the Medscape Endocrinologist Compensation Report 2023, but more doctors dropped insurers that pay the least, compared with last year, and only about two-thirds of respondents say they would choose medicine again as a career if given the chance.

In the survey of more than 10,000 physicians in over 29 specialties, endocrinologists’ annual salaries were up by about 4% from last year’s average of $257,000, to $267,000.

Those earnings still place them in the lowest five specialties in terms of pay, above infectious diseases, family medicine, pediatrics, and public health and preventive medicine. The latter is at the bottom of the list, with average annual earnings of $249,000.

Conversely, the top three specialties were plastic surgery, at an average of $619,000 per annum, followed by orthopedics, at $573,000, and cardiology, at $507,000.

Specialties in which the most significant changes in annual compensation occurred were led by oncology, with a 13% increase from 2022, followed by gastroenterology, with an 11% increase. On the opposite end, ophthalmologists experienced a 7% decline in earnings, while emergency medicine had a 6% decrease from 2022.

Since Medscape’s 2015 report, annual salaries for endocrinologists have increased by 36%. Similar patterns in compensation increases since 2015 occurred across all specialties. In contrast to some other specialties, endocrinologists did not experience a significant decline in earnings during the pandemic.

Across all specialties, men still earned more than women in the 2023 report – with a gap of 19% ($386,000 vs. $300,000). However, there appears to be progress, as the difference represents the lowest gender pay gap in 5 years.

This gradual improvement should likely continue as awareness of pay discrepancies grows and new generations emerge, said Theresa Rohr-Kirchgraber, MD, president of the American Medical Women’s Association and professor of medicine at AU/USA Medical Partnership, Athens, Ga., in the report.

“Due to efforts by many, some institutions and health care organizations have reviewed their salary lines and recognized the discrepancies not only between the sexes but also between new hires” and more established workers, she explained in the report.

“[The new hires] can be offered significantly more than those more senior physicians who have been working there for years and hired under a different pay structure,” she noted.

Nearly half of endocrinologists (45%) reported taking on extra work outside of their profession, up from 39% in the 2022 report. Among them, 31% reported other medical-related work, 8% reported “medical moonlighting,” 7% reported non–medical-related work, and 2% added more hours to their primary job as a physician.

Endocrinologists were in the lowest third of specialties in terms of their impressions of fair compensation, with only 45% reporting that they felt adequately paid. On the lowest end was infectious disease, with only 35% feeling their compensation is fair. By contrast, the highest response, 68%, was among psychiatrists.

Nevertheless, 85% of endocrinologists report that they would choose the same specialty again if given the chance. Responses ranged from 61% in internal medicine to 97% in plastic surgery.

Of note, fewer – 71% of endocrinologists – responded that they would choose medicine again, down from the 76% of endocrinologists who answered yes to the same question in 2022. At the bottom of the list was emergency medicine, with only 61% saying they would choose medicine again. The highest rates were in dermatology, at 86%, and allergy and immunology, at 84%.

In terms of time spent seeing patients, endocrinologists are more likely to see patients less than 30 hours per week, at 24%, compared with physicians overall, at 19%; 61% of endocrinologists report seeing patients 30-40 hours per week, versus 53% of all physicians.

Only 12% report seeing patients 41-50 hours per week, compared with 16% of all physicians. And 4% reported seeing patients 51 hours or more weekly, versus 11% of physicians overall.

The proportion of endocrinologists who reported that they would drop insurers that pay the least was notably up in the current report, at 25%, versus just 15% in the 2022 report; 22% indicated they would not drop insurers because “I need all payers”; 16% said no because “it’s inappropriate”; and the remainder responded no for other reasons.

Overall, the leading response by physicians for the most rewarding aspects of their job were “being good at what I am doing/finding answers, diagnoses,” reported by 32%, followed by “gratitude from/relationships with patients” (24%) and “making the world a better place (for example, helping others),” at 22%.

Conversely, the most challenging aspect, described by 20%, is “having so many rules and regulations,” followed by “difficulties getting fair reimbursement from or dealing with Medicare and/or other insurers (17%).”

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

Endocrinologists report steady increases in pay in the Medscape Endocrinologist Compensation Report 2023, but more doctors dropped insurers that pay the least, compared with last year, and only about two-thirds of respondents say they would choose medicine again as a career if given the chance.

In the survey of more than 10,000 physicians in over 29 specialties, endocrinologists’ annual salaries were up by about 4% from last year’s average of $257,000, to $267,000.

Those earnings still place them in the lowest five specialties in terms of pay, above infectious diseases, family medicine, pediatrics, and public health and preventive medicine. The latter is at the bottom of the list, with average annual earnings of $249,000.

Conversely, the top three specialties were plastic surgery, at an average of $619,000 per annum, followed by orthopedics, at $573,000, and cardiology, at $507,000.

Specialties in which the most significant changes in annual compensation occurred were led by oncology, with a 13% increase from 2022, followed by gastroenterology, with an 11% increase. On the opposite end, ophthalmologists experienced a 7% decline in earnings, while emergency medicine had a 6% decrease from 2022.

Since Medscape’s 2015 report, annual salaries for endocrinologists have increased by 36%. Similar patterns in compensation increases since 2015 occurred across all specialties. In contrast to some other specialties, endocrinologists did not experience a significant decline in earnings during the pandemic.

Across all specialties, men still earned more than women in the 2023 report – with a gap of 19% ($386,000 vs. $300,000). However, there appears to be progress, as the difference represents the lowest gender pay gap in 5 years.

This gradual improvement should likely continue as awareness of pay discrepancies grows and new generations emerge, said Theresa Rohr-Kirchgraber, MD, president of the American Medical Women’s Association and professor of medicine at AU/USA Medical Partnership, Athens, Ga., in the report.

“Due to efforts by many, some institutions and health care organizations have reviewed their salary lines and recognized the discrepancies not only between the sexes but also between new hires” and more established workers, she explained in the report.

“[The new hires] can be offered significantly more than those more senior physicians who have been working there for years and hired under a different pay structure,” she noted.

Nearly half of endocrinologists (45%) reported taking on extra work outside of their profession, up from 39% in the 2022 report. Among them, 31% reported other medical-related work, 8% reported “medical moonlighting,” 7% reported non–medical-related work, and 2% added more hours to their primary job as a physician.

Endocrinologists were in the lowest third of specialties in terms of their impressions of fair compensation, with only 45% reporting that they felt adequately paid. On the lowest end was infectious disease, with only 35% feeling their compensation is fair. By contrast, the highest response, 68%, was among psychiatrists.

Nevertheless, 85% of endocrinologists report that they would choose the same specialty again if given the chance. Responses ranged from 61% in internal medicine to 97% in plastic surgery.

Of note, fewer – 71% of endocrinologists – responded that they would choose medicine again, down from the 76% of endocrinologists who answered yes to the same question in 2022. At the bottom of the list was emergency medicine, with only 61% saying they would choose medicine again. The highest rates were in dermatology, at 86%, and allergy and immunology, at 84%.

In terms of time spent seeing patients, endocrinologists are more likely to see patients less than 30 hours per week, at 24%, compared with physicians overall, at 19%; 61% of endocrinologists report seeing patients 30-40 hours per week, versus 53% of all physicians.

Only 12% report seeing patients 41-50 hours per week, compared with 16% of all physicians. And 4% reported seeing patients 51 hours or more weekly, versus 11% of physicians overall.

The proportion of endocrinologists who reported that they would drop insurers that pay the least was notably up in the current report, at 25%, versus just 15% in the 2022 report; 22% indicated they would not drop insurers because “I need all payers”; 16% said no because “it’s inappropriate”; and the remainder responded no for other reasons.

Overall, the leading response by physicians for the most rewarding aspects of their job were “being good at what I am doing/finding answers, diagnoses,” reported by 32%, followed by “gratitude from/relationships with patients” (24%) and “making the world a better place (for example, helping others),” at 22%.

Conversely, the most challenging aspect, described by 20%, is “having so many rules and regulations,” followed by “difficulties getting fair reimbursement from or dealing with Medicare and/or other insurers (17%).”

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

Endocrinologists report steady increases in pay in the Medscape Endocrinologist Compensation Report 2023, but more doctors dropped insurers that pay the least, compared with last year, and only about two-thirds of respondents say they would choose medicine again as a career if given the chance.

In the survey of more than 10,000 physicians in over 29 specialties, endocrinologists’ annual salaries were up by about 4% from last year’s average of $257,000, to $267,000.

Those earnings still place them in the lowest five specialties in terms of pay, above infectious diseases, family medicine, pediatrics, and public health and preventive medicine. The latter is at the bottom of the list, with average annual earnings of $249,000.

Conversely, the top three specialties were plastic surgery, at an average of $619,000 per annum, followed by orthopedics, at $573,000, and cardiology, at $507,000.

Specialties in which the most significant changes in annual compensation occurred were led by oncology, with a 13% increase from 2022, followed by gastroenterology, with an 11% increase. On the opposite end, ophthalmologists experienced a 7% decline in earnings, while emergency medicine had a 6% decrease from 2022.

Since Medscape’s 2015 report, annual salaries for endocrinologists have increased by 36%. Similar patterns in compensation increases since 2015 occurred across all specialties. In contrast to some other specialties, endocrinologists did not experience a significant decline in earnings during the pandemic.

Across all specialties, men still earned more than women in the 2023 report – with a gap of 19% ($386,000 vs. $300,000). However, there appears to be progress, as the difference represents the lowest gender pay gap in 5 years.

This gradual improvement should likely continue as awareness of pay discrepancies grows and new generations emerge, said Theresa Rohr-Kirchgraber, MD, president of the American Medical Women’s Association and professor of medicine at AU/USA Medical Partnership, Athens, Ga., in the report.

“Due to efforts by many, some institutions and health care organizations have reviewed their salary lines and recognized the discrepancies not only between the sexes but also between new hires” and more established workers, she explained in the report.

“[The new hires] can be offered significantly more than those more senior physicians who have been working there for years and hired under a different pay structure,” she noted.

Nearly half of endocrinologists (45%) reported taking on extra work outside of their profession, up from 39% in the 2022 report. Among them, 31% reported other medical-related work, 8% reported “medical moonlighting,” 7% reported non–medical-related work, and 2% added more hours to their primary job as a physician.

Endocrinologists were in the lowest third of specialties in terms of their impressions of fair compensation, with only 45% reporting that they felt adequately paid. On the lowest end was infectious disease, with only 35% feeling their compensation is fair. By contrast, the highest response, 68%, was among psychiatrists.

Nevertheless, 85% of endocrinologists report that they would choose the same specialty again if given the chance. Responses ranged from 61% in internal medicine to 97% in plastic surgery.

Of note, fewer – 71% of endocrinologists – responded that they would choose medicine again, down from the 76% of endocrinologists who answered yes to the same question in 2022. At the bottom of the list was emergency medicine, with only 61% saying they would choose medicine again. The highest rates were in dermatology, at 86%, and allergy and immunology, at 84%.

In terms of time spent seeing patients, endocrinologists are more likely to see patients less than 30 hours per week, at 24%, compared with physicians overall, at 19%; 61% of endocrinologists report seeing patients 30-40 hours per week, versus 53% of all physicians.

Only 12% report seeing patients 41-50 hours per week, compared with 16% of all physicians. And 4% reported seeing patients 51 hours or more weekly, versus 11% of physicians overall.

The proportion of endocrinologists who reported that they would drop insurers that pay the least was notably up in the current report, at 25%, versus just 15% in the 2022 report; 22% indicated they would not drop insurers because “I need all payers”; 16% said no because “it’s inappropriate”; and the remainder responded no for other reasons.

Overall, the leading response by physicians for the most rewarding aspects of their job were “being good at what I am doing/finding answers, diagnoses,” reported by 32%, followed by “gratitude from/relationships with patients” (24%) and “making the world a better place (for example, helping others),” at 22%.

Conversely, the most challenging aspect, described by 20%, is “having so many rules and regulations,” followed by “difficulties getting fair reimbursement from or dealing with Medicare and/or other insurers (17%).”

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

The first-in-class erythroid maturation agent luspatercept showed significant improvement over the erythropoiesis-stimulating agent epoetin alfa in reducing dependency on red blood cell transfusions among patients with lower-risk myelodysplastic syndromes (LR-MDS) who are ESA naive.

“Luspatercept is the first and only therapy to demonstrate superiority in a head-to-head study against ESAs in [transfusion-dependent] LR-MDS,” first author Guillermo Garcia-Manero, MD, chief of the MDS section, department of leukemia, at the University of Texas MD Anderson Cancer Center, Houston, said in a premeeting press briefing in advance of the annual meeting of the American Society of Clinical Oncology.

“It should be considered a paradigm shift in the treatment of LR-MDS–associated anemia,” Dr. Garcia-Manero said.

Commenting on the study, Andrew Artz, MD, a professor at the Hematologic Malignancies Research Institute, City of Hope National Medical Center, Duarte, Calif., agreed that the results could be practice changing.

“We biologically expected luspatercept to best ESA [in ring sideroblast transfusion–dependent MDS], based on luspatercept often rescuing ESA failures in this setting,” Dr. Artz said in an interview.

“The results have the potential to change initial therapy for patients with low-risk red blood cell transfusion-dependent MDS,” he said.

In LR-MDS, which encompasses a variety of bone marrow disorders, chronic anemia is very common, and patients, who are typically elderly, can become burdened by developing dependencies on RBC transfusions.

Transfusion dependency, in addition to creating a host of challenges, can increase the risk of death by as much as 50%, compared with patients who are not transfusion dependent, Dr. Garcia-Manero noted.

While ESAs such as epoetin alfa are the first-line treatment for LR-MDS, patients who are dependent on transfusions are less likely to respond to the agents, hence “there is an unmet need for effective and durable options other than ESAs for treating anemia in patients with LR-MDS,” Dr. Garcia-Manero said.

Luspatercept, a first-in-class monoclonal antibody, has a mechanism of action that is distinct from ESAs, modulating the transforming growth factor–beta pathway and increasing erythrocytosis.

In the previous phase 3 MEDALIST trial, the drug was shown to have efficacy over placebo in reducing the severity of anemia in LR-MDS. In 2020, in what was deemed the first advance in MDS treatment in more than a decade, those results led to approval by the Food and Drug Administration for patients with LR-MDS with ring sideroblasts who are transfusion dependent and are refractory, intolerant, or ineligible to receive ESAs.

To further investigate luspatercept’s efficacy in a head-to-head comparison with an ESA in LR-MDS patients who are ESA naive, Dr. Garcia-Manero and colleagues conducted the phase 3 COMMANDS trial.

For the global, open-label study, patients with LR-MDS who were dependent on RBC transfusions and had no prior use of ESAs were randomized 1:1 to treatment either with subcutaneous luspatercept (starting dose, 1.0 mg/kg with titration up to 1.75 mg/kg; n = 178) once every 3 weeks or subcutaneous epoetin alfa (starting dose, 450 IU/kg with titration up to 1,050 IU/kg; n = 176) once every week, for a minimum of 24 weeks.

Patients in each arm were also able to receive best supportive care, including blood transfusions. Their baseline characteristics were similar in each arm.

For the primary endpoint, patients receiving luspatercept in the intent-to-treat population were nearly twice as likely as those treated with epoetin alfa to become independent of RBC transfusions, with a concurrent mean hemoglobin increase of 1.5 g/dL or more, for at least 12 weeks in the first 24 weeks on study, at a rate of 58.5% with luspatercept versus 31.2% with epoetin alfa (P < .0001).

In addition, patients treated with luspatercept had a longer median duration of transfusion independence, at 126.6 weeks versus 77 weeks in the epoetin alfa group (hazard ratio, 0.456).

Importantly, the statistically significant improvement with luspatercept was consistent among patients with ring sideroblasts (HR, 0.626) as well as without them (HR, 0.492). Dr. Garcia-Manero noted that about 70% of patients in the study had ring sideroblasts, consistent with their common occurrence in LR-MDS.

Luspatercept was also superior in secondary endpoints, including in achieving hematologic improvement, with an erythroid response of at least 8 weeks, per International Working Group 2006 criteria, which was achieved by 74.1% with luspatercept versus 51.3% with epoetin alfa (P < .0001).

The greater improvement with luspatercept was also observed in other subgroups, including based on baseline serum erythropoietin or levels of transfusion dependence, as well as SF381 mutation status.

In terms of safety, treatment emergent adverse events (TEAEs) of any grade were reported among 92.1% of luspatercept and 85.2% of epoetin alfa patients. Longer-term posttreatment safety analyses showed no significant differences between the groups in terms of progression to high-risk MDS, in five (2.8%) with luspatercept and seven(4.0%) epoetin alfa, and progression to acute myeloid leukemia, occurring in four (2.2%) luspatercept and five (2.8%) epoetin alfa patients.

Overall rates of death between the groups were also similar during the treatment and posttreatment periods (32 [18.0%] luspatercept; 32 [18.2%] epoetin alfa patients).

“The toxicity profile was consistent with previous clinical experience,” Dr. Garcia-Manero said.

Dr. Garcia-Manero underscored that “the results of the COMMANDS trial are very important.”

“ESAs are really not optimal agents [for LR-MDS], and these results indicate that luspatercept almost doubles response rates in this patient population, therefore becoming potentially the standard of care for patients with transfusion-dependent LR-MDS who have not received prior ESA treatment,” he said.

Further commenting, Dr. Artz added that the effects in patient subgroups will be of great interest as further data on luspatercept emerges.

“Of highest interest will be the differential responses among patients with and without ring sideroblasts, as well as by SF3B1 mutational status,” he said. Furthermore, “patient-centric data emerge as even more relevant when considering the quantitatively higher rates of treatment-emergent adverse effects in the luspatercept arm.”

“We need to understand how to best sequence anemia therapies in low-risk MDS when we have two active agents, or even if [there is] a role for combined ESA/luspatercept therapy,” he noted.

“The results are exciting, but we need the final data including relevant subsets before declaring luspatercept the winner,” Dr. Artz concluded.

The study was sponsored by Celgene/Bristol-Myers Squibb. Dr. Garcia-Manero reported relationships with Abbvie, Acceleron Pharma, Aprea Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Genentech, Gilead Sciences, and Novartis. Dr. Artz disclosed previous consulting relationships with Abbvie and Magenta Therapeutics.

The first-in-class erythroid maturation agent luspatercept showed significant improvement over the erythropoiesis-stimulating agent epoetin alfa in reducing dependency on red blood cell transfusions among patients with lower-risk myelodysplastic syndromes (LR-MDS) who are ESA naive.

“Luspatercept is the first and only therapy to demonstrate superiority in a head-to-head study against ESAs in [transfusion-dependent] LR-MDS,” first author Guillermo Garcia-Manero, MD, chief of the MDS section, department of leukemia, at the University of Texas MD Anderson Cancer Center, Houston, said in a premeeting press briefing in advance of the annual meeting of the American Society of Clinical Oncology.

“It should be considered a paradigm shift in the treatment of LR-MDS–associated anemia,” Dr. Garcia-Manero said.

Commenting on the study, Andrew Artz, MD, a professor at the Hematologic Malignancies Research Institute, City of Hope National Medical Center, Duarte, Calif., agreed that the results could be practice changing.

“We biologically expected luspatercept to best ESA [in ring sideroblast transfusion–dependent MDS], based on luspatercept often rescuing ESA failures in this setting,” Dr. Artz said in an interview.

“The results have the potential to change initial therapy for patients with low-risk red blood cell transfusion-dependent MDS,” he said.

In LR-MDS, which encompasses a variety of bone marrow disorders, chronic anemia is very common, and patients, who are typically elderly, can become burdened by developing dependencies on RBC transfusions.

Transfusion dependency, in addition to creating a host of challenges, can increase the risk of death by as much as 50%, compared with patients who are not transfusion dependent, Dr. Garcia-Manero noted.

While ESAs such as epoetin alfa are the first-line treatment for LR-MDS, patients who are dependent on transfusions are less likely to respond to the agents, hence “there is an unmet need for effective and durable options other than ESAs for treating anemia in patients with LR-MDS,” Dr. Garcia-Manero said.

Luspatercept, a first-in-class monoclonal antibody, has a mechanism of action that is distinct from ESAs, modulating the transforming growth factor–beta pathway and increasing erythrocytosis.

In the previous phase 3 MEDALIST trial, the drug was shown to have efficacy over placebo in reducing the severity of anemia in LR-MDS. In 2020, in what was deemed the first advance in MDS treatment in more than a decade, those results led to approval by the Food and Drug Administration for patients with LR-MDS with ring sideroblasts who are transfusion dependent and are refractory, intolerant, or ineligible to receive ESAs.

To further investigate luspatercept’s efficacy in a head-to-head comparison with an ESA in LR-MDS patients who are ESA naive, Dr. Garcia-Manero and colleagues conducted the phase 3 COMMANDS trial.

For the global, open-label study, patients with LR-MDS who were dependent on RBC transfusions and had no prior use of ESAs were randomized 1:1 to treatment either with subcutaneous luspatercept (starting dose, 1.0 mg/kg with titration up to 1.75 mg/kg; n = 178) once every 3 weeks or subcutaneous epoetin alfa (starting dose, 450 IU/kg with titration up to 1,050 IU/kg; n = 176) once every week, for a minimum of 24 weeks.

Patients in each arm were also able to receive best supportive care, including blood transfusions. Their baseline characteristics were similar in each arm.

For the primary endpoint, patients receiving luspatercept in the intent-to-treat population were nearly twice as likely as those treated with epoetin alfa to become independent of RBC transfusions, with a concurrent mean hemoglobin increase of 1.5 g/dL or more, for at least 12 weeks in the first 24 weeks on study, at a rate of 58.5% with luspatercept versus 31.2% with epoetin alfa (P < .0001).

In addition, patients treated with luspatercept had a longer median duration of transfusion independence, at 126.6 weeks versus 77 weeks in the epoetin alfa group (hazard ratio, 0.456).

Importantly, the statistically significant improvement with luspatercept was consistent among patients with ring sideroblasts (HR, 0.626) as well as without them (HR, 0.492). Dr. Garcia-Manero noted that about 70% of patients in the study had ring sideroblasts, consistent with their common occurrence in LR-MDS.

Luspatercept was also superior in secondary endpoints, including in achieving hematologic improvement, with an erythroid response of at least 8 weeks, per International Working Group 2006 criteria, which was achieved by 74.1% with luspatercept versus 51.3% with epoetin alfa (P < .0001).

The greater improvement with luspatercept was also observed in other subgroups, including based on baseline serum erythropoietin or levels of transfusion dependence, as well as SF381 mutation status.

In terms of safety, treatment emergent adverse events (TEAEs) of any grade were reported among 92.1% of luspatercept and 85.2% of epoetin alfa patients. Longer-term posttreatment safety analyses showed no significant differences between the groups in terms of progression to high-risk MDS, in five (2.8%) with luspatercept and seven(4.0%) epoetin alfa, and progression to acute myeloid leukemia, occurring in four (2.2%) luspatercept and five (2.8%) epoetin alfa patients.

Overall rates of death between the groups were also similar during the treatment and posttreatment periods (32 [18.0%] luspatercept; 32 [18.2%] epoetin alfa patients).

“The toxicity profile was consistent with previous clinical experience,” Dr. Garcia-Manero said.

Dr. Garcia-Manero underscored that “the results of the COMMANDS trial are very important.”

“ESAs are really not optimal agents [for LR-MDS], and these results indicate that luspatercept almost doubles response rates in this patient population, therefore becoming potentially the standard of care for patients with transfusion-dependent LR-MDS who have not received prior ESA treatment,” he said.

Further commenting, Dr. Artz added that the effects in patient subgroups will be of great interest as further data on luspatercept emerges.

“Of highest interest will be the differential responses among patients with and without ring sideroblasts, as well as by SF3B1 mutational status,” he said. Furthermore, “patient-centric data emerge as even more relevant when considering the quantitatively higher rates of treatment-emergent adverse effects in the luspatercept arm.”

“We need to understand how to best sequence anemia therapies in low-risk MDS when we have two active agents, or even if [there is] a role for combined ESA/luspatercept therapy,” he noted.

“The results are exciting, but we need the final data including relevant subsets before declaring luspatercept the winner,” Dr. Artz concluded.

The study was sponsored by Celgene/Bristol-Myers Squibb. Dr. Garcia-Manero reported relationships with Abbvie, Acceleron Pharma, Aprea Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Genentech, Gilead Sciences, and Novartis. Dr. Artz disclosed previous consulting relationships with Abbvie and Magenta Therapeutics.

The first-in-class erythroid maturation agent luspatercept showed significant improvement over the erythropoiesis-stimulating agent epoetin alfa in reducing dependency on red blood cell transfusions among patients with lower-risk myelodysplastic syndromes (LR-MDS) who are ESA naive.

“Luspatercept is the first and only therapy to demonstrate superiority in a head-to-head study against ESAs in [transfusion-dependent] LR-MDS,” first author Guillermo Garcia-Manero, MD, chief of the MDS section, department of leukemia, at the University of Texas MD Anderson Cancer Center, Houston, said in a premeeting press briefing in advance of the annual meeting of the American Society of Clinical Oncology.

“It should be considered a paradigm shift in the treatment of LR-MDS–associated anemia,” Dr. Garcia-Manero said.

Commenting on the study, Andrew Artz, MD, a professor at the Hematologic Malignancies Research Institute, City of Hope National Medical Center, Duarte, Calif., agreed that the results could be practice changing.

“We biologically expected luspatercept to best ESA [in ring sideroblast transfusion–dependent MDS], based on luspatercept often rescuing ESA failures in this setting,” Dr. Artz said in an interview.

“The results have the potential to change initial therapy for patients with low-risk red blood cell transfusion-dependent MDS,” he said.

In LR-MDS, which encompasses a variety of bone marrow disorders, chronic anemia is very common, and patients, who are typically elderly, can become burdened by developing dependencies on RBC transfusions.

Transfusion dependency, in addition to creating a host of challenges, can increase the risk of death by as much as 50%, compared with patients who are not transfusion dependent, Dr. Garcia-Manero noted.

While ESAs such as epoetin alfa are the first-line treatment for LR-MDS, patients who are dependent on transfusions are less likely to respond to the agents, hence “there is an unmet need for effective and durable options other than ESAs for treating anemia in patients with LR-MDS,” Dr. Garcia-Manero said.

Luspatercept, a first-in-class monoclonal antibody, has a mechanism of action that is distinct from ESAs, modulating the transforming growth factor–beta pathway and increasing erythrocytosis.

In the previous phase 3 MEDALIST trial, the drug was shown to have efficacy over placebo in reducing the severity of anemia in LR-MDS. In 2020, in what was deemed the first advance in MDS treatment in more than a decade, those results led to approval by the Food and Drug Administration for patients with LR-MDS with ring sideroblasts who are transfusion dependent and are refractory, intolerant, or ineligible to receive ESAs.

To further investigate luspatercept’s efficacy in a head-to-head comparison with an ESA in LR-MDS patients who are ESA naive, Dr. Garcia-Manero and colleagues conducted the phase 3 COMMANDS trial.

For the global, open-label study, patients with LR-MDS who were dependent on RBC transfusions and had no prior use of ESAs were randomized 1:1 to treatment either with subcutaneous luspatercept (starting dose, 1.0 mg/kg with titration up to 1.75 mg/kg; n = 178) once every 3 weeks or subcutaneous epoetin alfa (starting dose, 450 IU/kg with titration up to 1,050 IU/kg; n = 176) once every week, for a minimum of 24 weeks.

Patients in each arm were also able to receive best supportive care, including blood transfusions. Their baseline characteristics were similar in each arm.

For the primary endpoint, patients receiving luspatercept in the intent-to-treat population were nearly twice as likely as those treated with epoetin alfa to become independent of RBC transfusions, with a concurrent mean hemoglobin increase of 1.5 g/dL or more, for at least 12 weeks in the first 24 weeks on study, at a rate of 58.5% with luspatercept versus 31.2% with epoetin alfa (P < .0001).

In addition, patients treated with luspatercept had a longer median duration of transfusion independence, at 126.6 weeks versus 77 weeks in the epoetin alfa group (hazard ratio, 0.456).

Importantly, the statistically significant improvement with luspatercept was consistent among patients with ring sideroblasts (HR, 0.626) as well as without them (HR, 0.492). Dr. Garcia-Manero noted that about 70% of patients in the study had ring sideroblasts, consistent with their common occurrence in LR-MDS.

Luspatercept was also superior in secondary endpoints, including in achieving hematologic improvement, with an erythroid response of at least 8 weeks, per International Working Group 2006 criteria, which was achieved by 74.1% with luspatercept versus 51.3% with epoetin alfa (P < .0001).

The greater improvement with luspatercept was also observed in other subgroups, including based on baseline serum erythropoietin or levels of transfusion dependence, as well as SF381 mutation status.

In terms of safety, treatment emergent adverse events (TEAEs) of any grade were reported among 92.1% of luspatercept and 85.2% of epoetin alfa patients. Longer-term posttreatment safety analyses showed no significant differences between the groups in terms of progression to high-risk MDS, in five (2.8%) with luspatercept and seven(4.0%) epoetin alfa, and progression to acute myeloid leukemia, occurring in four (2.2%) luspatercept and five (2.8%) epoetin alfa patients.

Overall rates of death between the groups were also similar during the treatment and posttreatment periods (32 [18.0%] luspatercept; 32 [18.2%] epoetin alfa patients).

“The toxicity profile was consistent with previous clinical experience,” Dr. Garcia-Manero said.

Dr. Garcia-Manero underscored that “the results of the COMMANDS trial are very important.”

“ESAs are really not optimal agents [for LR-MDS], and these results indicate that luspatercept almost doubles response rates in this patient population, therefore becoming potentially the standard of care for patients with transfusion-dependent LR-MDS who have not received prior ESA treatment,” he said.

Further commenting, Dr. Artz added that the effects in patient subgroups will be of great interest as further data on luspatercept emerges.

“Of highest interest will be the differential responses among patients with and without ring sideroblasts, as well as by SF3B1 mutational status,” he said. Furthermore, “patient-centric data emerge as even more relevant when considering the quantitatively higher rates of treatment-emergent adverse effects in the luspatercept arm.”

“We need to understand how to best sequence anemia therapies in low-risk MDS when we have two active agents, or even if [there is] a role for combined ESA/luspatercept therapy,” he noted.

“The results are exciting, but we need the final data including relevant subsets before declaring luspatercept the winner,” Dr. Artz concluded.

The study was sponsored by Celgene/Bristol-Myers Squibb. Dr. Garcia-Manero reported relationships with Abbvie, Acceleron Pharma, Aprea Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Genentech, Gilead Sciences, and Novartis. Dr. Artz disclosed previous consulting relationships with Abbvie and Magenta Therapeutics.

Patients undergoing bariatric surgery for obesity showed significant declines in the use of lipid-lowering and antidiabetic medications up to 15 years after the procedure compared with patients with obesity who did not have such an operation. However, these declines didn’t extend to cardiovascular medication use.

“In this study, undergoing bariatric surgery was associated with a substantial and long-lasting reduction in the use of lipid-lowering and antidiabetic medications, compared with no surgery for obesity, while for cardiovascular medications this reduction was only transient,” the authors report in research published in JAMA Surgery.

“The results can aid in informed decision-making when considering bariatric surgery for patients with morbid obesity and inform patients and professionals about the expected long-term effects of medication use for obesity-related comorbidities,” they write.

The study “highlights the benefits of mandated databases that report metabolic bariatric surgery, obesity-related comorbidities, and medications,” writes Paulina Salminen, MD, in an accompanying editorial.

However, key limitations include a lack of weight data, which is important in light of previous studies showing that suboptimal weight loss after bariatric surgery is linked to a higher incidence of type 2 diabetes, dyslipidemia, and hypertension, note Dr. Salminen, of the department of digestive surgery, University Hospital, Turku, Finland, and colleagues.
 

Swedish, Finnish obesity data probed

When significant weight loss is achieved, bariatric surgery has been well documented to be associated with improvements in a variety of comorbidities, quality of life, and even life expectancy.

Key comorbidities shown to improve with the surgery include hyperlipidemia, cardiovascular disease, and type 2 diabetes.

However, data are lacking on the association between bariatric surgery and the use of medications for those conditions, particularly compared with people with obesity who don’t have bariatric surgery.

To investigate, first author Joonas H. Kauppila, MD, PhD, of Upper Gastrointestinal Surgery, Karolinska University Hospital, Stockholm, and colleagues conducted a population-based cohort study, evaluating data on 26,396 patients who underwent bariatric surgery with gastric bypass or sleeve gastrectomy in Sweden between 2005 and 2020 or Finland between 1995 and 2018.

Overall, 66.4% of patients were women and their median age was 50.

They were compared with five times as many matched controls with obesity who had not had bariatric surgery from the same population databases, representing a total of 131,980 patients who were matched based on age, country, sex, calendar year, and medication use.  

In terms of lipid-lowering medication, rates of use after bariatric surgery decreased from 20.3% at baseline to 12.9% after 2 years and bounced back somewhat to 17.6% after 15 years. Comparatively, in the no surgery group, baseline lipid-lowering medication use of 21.0% increased to 44.6% after 15 years, more than twice the rate of usage in the bariatric surgery group in the same period.

Antidiabetic medications were used by 27.7% of patients in the bariatric surgery group at baseline, with a drop to 10.0% after 2 years, followed by an increase to 23.5% after 15 years. In the no surgery group, the rate of antidiabetic medication use steadily increased from 27.7% at baseline to 54.2% after 15 years, which again was nearly double the rate of antidiabetic medication use in the bariatric surgery group at 15 years.

Meanwhile, cardiovascular medications were used by 60.2% of patients receiving bariatric surgery at baseline, with the rate decreasing to 43.2% after 2 years but increasing to 74.6% after 15 years. Among the nonbariatric surgery patients, use of cardiovascular medications increased from 54.4% at baseline to 83.3% after 15 years.
 

Causes?

As for the cause of the lack of any decline in use of cardiovascular medications versus other medications in the surgery patients, the authors speculate that the effect “may be related to aging and regain of weight over time after bariatric surgery, a phenomenon caused by hormonal, dietary, physical, and behavioral factors.”

“In contrast, as expected, a gradual increase in the use of all three medication groups was observed over time among the patients treated with no surgery for obesity,” they note.

The lower medication use with bariatric surgery can also translate to economic benefits, the authors add.

“Economically, the long-lasting reductions in medication use for hyperlipidemia, cardiovascular morbidity, and diabetes suggest that surgical treatment of morbid obesity may infer savings in medication expenses for patients, health care, and society,” they report.

“Future research may focus on subgroups that are most likely to benefit from bariatric surgery, including resolution and severity of comorbidities,” they continue.

In their editorial, Dr. Salminen and colleagues note that previous research has shown remission of dyslipidemia in up to 70% of patients after bariatric surgery that was independent of weight loss, which appears to support the sustained reduction in lipid-lowering medications following surgery observed in the current study, suggesting some benefits on lipids beyond weight loss.

Other limitations, however, include that the bariatric surgery group in the study was older and had more comorbidities than those in previous bariatric surgery studies.

“Future studies should assess this in a younger cohort with less disease at baseline and differentiation within cardiovascular disease regarding at least hypertension, ischemic heart disease, and heart failure,” the authors conclude.

The authors have reported no relevant financial relationships. Dr. Salminen has reported receiving grants from the Sigrid Jusélius Foundation, Academy of Finland, Government Research Grant Foundation, and the University of Turku (Finland).

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

Patients undergoing bariatric surgery for obesity showed significant declines in the use of lipid-lowering and antidiabetic medications up to 15 years after the procedure compared with patients with obesity who did not have such an operation. However, these declines didn’t extend to cardiovascular medication use.

“In this study, undergoing bariatric surgery was associated with a substantial and long-lasting reduction in the use of lipid-lowering and antidiabetic medications, compared with no surgery for obesity, while for cardiovascular medications this reduction was only transient,” the authors report in research published in JAMA Surgery.

“The results can aid in informed decision-making when considering bariatric surgery for patients with morbid obesity and inform patients and professionals about the expected long-term effects of medication use for obesity-related comorbidities,” they write.

The study “highlights the benefits of mandated databases that report metabolic bariatric surgery, obesity-related comorbidities, and medications,” writes Paulina Salminen, MD, in an accompanying editorial.

However, key limitations include a lack of weight data, which is important in light of previous studies showing that suboptimal weight loss after bariatric surgery is linked to a higher incidence of type 2 diabetes, dyslipidemia, and hypertension, note Dr. Salminen, of the department of digestive surgery, University Hospital, Turku, Finland, and colleagues.
 

Swedish, Finnish obesity data probed

When significant weight loss is achieved, bariatric surgery has been well documented to be associated with improvements in a variety of comorbidities, quality of life, and even life expectancy.

Key comorbidities shown to improve with the surgery include hyperlipidemia, cardiovascular disease, and type 2 diabetes.

However, data are lacking on the association between bariatric surgery and the use of medications for those conditions, particularly compared with people with obesity who don’t have bariatric surgery.

To investigate, first author Joonas H. Kauppila, MD, PhD, of Upper Gastrointestinal Surgery, Karolinska University Hospital, Stockholm, and colleagues conducted a population-based cohort study, evaluating data on 26,396 patients who underwent bariatric surgery with gastric bypass or sleeve gastrectomy in Sweden between 2005 and 2020 or Finland between 1995 and 2018.

Overall, 66.4% of patients were women and their median age was 50.

They were compared with five times as many matched controls with obesity who had not had bariatric surgery from the same population databases, representing a total of 131,980 patients who were matched based on age, country, sex, calendar year, and medication use.  

In terms of lipid-lowering medication, rates of use after bariatric surgery decreased from 20.3% at baseline to 12.9% after 2 years and bounced back somewhat to 17.6% after 15 years. Comparatively, in the no surgery group, baseline lipid-lowering medication use of 21.0% increased to 44.6% after 15 years, more than twice the rate of usage in the bariatric surgery group in the same period.

Antidiabetic medications were used by 27.7% of patients in the bariatric surgery group at baseline, with a drop to 10.0% after 2 years, followed by an increase to 23.5% after 15 years. In the no surgery group, the rate of antidiabetic medication use steadily increased from 27.7% at baseline to 54.2% after 15 years, which again was nearly double the rate of antidiabetic medication use in the bariatric surgery group at 15 years.

Meanwhile, cardiovascular medications were used by 60.2% of patients receiving bariatric surgery at baseline, with the rate decreasing to 43.2% after 2 years but increasing to 74.6% after 15 years. Among the nonbariatric surgery patients, use of cardiovascular medications increased from 54.4% at baseline to 83.3% after 15 years.
 

Causes?

As for the cause of the lack of any decline in use of cardiovascular medications versus other medications in the surgery patients, the authors speculate that the effect “may be related to aging and regain of weight over time after bariatric surgery, a phenomenon caused by hormonal, dietary, physical, and behavioral factors.”

“In contrast, as expected, a gradual increase in the use of all three medication groups was observed over time among the patients treated with no surgery for obesity,” they note.

The lower medication use with bariatric surgery can also translate to economic benefits, the authors add.

“Economically, the long-lasting reductions in medication use for hyperlipidemia, cardiovascular morbidity, and diabetes suggest that surgical treatment of morbid obesity may infer savings in medication expenses for patients, health care, and society,” they report.

“Future research may focus on subgroups that are most likely to benefit from bariatric surgery, including resolution and severity of comorbidities,” they continue.

In their editorial, Dr. Salminen and colleagues note that previous research has shown remission of dyslipidemia in up to 70% of patients after bariatric surgery that was independent of weight loss, which appears to support the sustained reduction in lipid-lowering medications following surgery observed in the current study, suggesting some benefits on lipids beyond weight loss.

Other limitations, however, include that the bariatric surgery group in the study was older and had more comorbidities than those in previous bariatric surgery studies.

“Future studies should assess this in a younger cohort with less disease at baseline and differentiation within cardiovascular disease regarding at least hypertension, ischemic heart disease, and heart failure,” the authors conclude.

The authors have reported no relevant financial relationships. Dr. Salminen has reported receiving grants from the Sigrid Jusélius Foundation, Academy of Finland, Government Research Grant Foundation, and the University of Turku (Finland).

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

Patients undergoing bariatric surgery for obesity showed significant declines in the use of lipid-lowering and antidiabetic medications up to 15 years after the procedure compared with patients with obesity who did not have such an operation. However, these declines didn’t extend to cardiovascular medication use.

“In this study, undergoing bariatric surgery was associated with a substantial and long-lasting reduction in the use of lipid-lowering and antidiabetic medications, compared with no surgery for obesity, while for cardiovascular medications this reduction was only transient,” the authors report in research published in JAMA Surgery.

“The results can aid in informed decision-making when considering bariatric surgery for patients with morbid obesity and inform patients and professionals about the expected long-term effects of medication use for obesity-related comorbidities,” they write.

The study “highlights the benefits of mandated databases that report metabolic bariatric surgery, obesity-related comorbidities, and medications,” writes Paulina Salminen, MD, in an accompanying editorial.

However, key limitations include a lack of weight data, which is important in light of previous studies showing that suboptimal weight loss after bariatric surgery is linked to a higher incidence of type 2 diabetes, dyslipidemia, and hypertension, note Dr. Salminen, of the department of digestive surgery, University Hospital, Turku, Finland, and colleagues.
 

Swedish, Finnish obesity data probed

When significant weight loss is achieved, bariatric surgery has been well documented to be associated with improvements in a variety of comorbidities, quality of life, and even life expectancy.

Key comorbidities shown to improve with the surgery include hyperlipidemia, cardiovascular disease, and type 2 diabetes.

However, data are lacking on the association between bariatric surgery and the use of medications for those conditions, particularly compared with people with obesity who don’t have bariatric surgery.

To investigate, first author Joonas H. Kauppila, MD, PhD, of Upper Gastrointestinal Surgery, Karolinska University Hospital, Stockholm, and colleagues conducted a population-based cohort study, evaluating data on 26,396 patients who underwent bariatric surgery with gastric bypass or sleeve gastrectomy in Sweden between 2005 and 2020 or Finland between 1995 and 2018.

Overall, 66.4% of patients were women and their median age was 50.

They were compared with five times as many matched controls with obesity who had not had bariatric surgery from the same population databases, representing a total of 131,980 patients who were matched based on age, country, sex, calendar year, and medication use.  

In terms of lipid-lowering medication, rates of use after bariatric surgery decreased from 20.3% at baseline to 12.9% after 2 years and bounced back somewhat to 17.6% after 15 years. Comparatively, in the no surgery group, baseline lipid-lowering medication use of 21.0% increased to 44.6% after 15 years, more than twice the rate of usage in the bariatric surgery group in the same period.

Antidiabetic medications were used by 27.7% of patients in the bariatric surgery group at baseline, with a drop to 10.0% after 2 years, followed by an increase to 23.5% after 15 years. In the no surgery group, the rate of antidiabetic medication use steadily increased from 27.7% at baseline to 54.2% after 15 years, which again was nearly double the rate of antidiabetic medication use in the bariatric surgery group at 15 years.

Meanwhile, cardiovascular medications were used by 60.2% of patients receiving bariatric surgery at baseline, with the rate decreasing to 43.2% after 2 years but increasing to 74.6% after 15 years. Among the nonbariatric surgery patients, use of cardiovascular medications increased from 54.4% at baseline to 83.3% after 15 years.
 

Causes?

As for the cause of the lack of any decline in use of cardiovascular medications versus other medications in the surgery patients, the authors speculate that the effect “may be related to aging and regain of weight over time after bariatric surgery, a phenomenon caused by hormonal, dietary, physical, and behavioral factors.”

“In contrast, as expected, a gradual increase in the use of all three medication groups was observed over time among the patients treated with no surgery for obesity,” they note.

The lower medication use with bariatric surgery can also translate to economic benefits, the authors add.

“Economically, the long-lasting reductions in medication use for hyperlipidemia, cardiovascular morbidity, and diabetes suggest that surgical treatment of morbid obesity may infer savings in medication expenses for patients, health care, and society,” they report.

“Future research may focus on subgroups that are most likely to benefit from bariatric surgery, including resolution and severity of comorbidities,” they continue.

In their editorial, Dr. Salminen and colleagues note that previous research has shown remission of dyslipidemia in up to 70% of patients after bariatric surgery that was independent of weight loss, which appears to support the sustained reduction in lipid-lowering medications following surgery observed in the current study, suggesting some benefits on lipids beyond weight loss.

Other limitations, however, include that the bariatric surgery group in the study was older and had more comorbidities than those in previous bariatric surgery studies.

“Future studies should assess this in a younger cohort with less disease at baseline and differentiation within cardiovascular disease regarding at least hypertension, ischemic heart disease, and heart failure,” the authors conclude.

The authors have reported no relevant financial relationships. Dr. Salminen has reported receiving grants from the Sigrid Jusélius Foundation, Academy of Finland, Government Research Grant Foundation, and the University of Turku (Finland).

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

Adding the immunotherapy cemiplimab to chemotherapy for patients with advanced non–small cell lung cancer (NSCLC) not only improved overall survival but also led to quality-of-life benefits, new data show.

In the trial, patients who received the PD-1 inhibitor plus platinum-doublet chemotherapy in the first-line setting reported significant improvements in pain symptoms and delay in time to deterioration, as well as improvements in disease-related symptoms, such as dyspnea, constipation, nausea, and vomiting.

Overall, “the findings support the concept that the superior efficacy and favorable safety profile of cemiplimab plus chemotherapy translate to better patient-reported outcomes compared with chemotherapy alone in patients with advanced non–small cell lung cancer, “ corresponding author Tamta Makharadze, MD, of LTD High Technology Hospital Med Center in Batumi, Georgia, said in a press release.

The delays reported in time to definitive clinically meaningful deterioration “are particularly pertinent, given the anticipated continued improvements in cancer survivorship among patients with advanced NSCLC,” the authors explained.

The research was published online May 8 in Cancer.

Quality of life is especially important for patients with advanced NSCLC, for whom the benefits of improved survival must be weighed against the potential drawbacks of treatment toxicities, which can severely impact quality of life, the authors noted.

In the initial multinational phase 3 EMPOWER-Lung 3 trial, Dr. Makharadze and colleagues randomly assigned 466 patients with stage IIIB, IIIC, or stage IV NSCLC to receive either 350 mg of cemiplimab (Libtayo, Regeneron Pharmaceuticals) every 3 weeks along with investigator’s choice of platinum‐doublet chemotherapy or placebo plus chemotherapy. Investigator’s choice of chemotherapy was either paclitaxel plus carboplatin or cisplatin, pemetrexed plus carboplatin, or cisplatin.

The researchers found that the addition of cemiplimab to chemotherapy was associated with a significant, almost 9-month improvement in overall survival. While the trial also highlighted significant improvements in quality of life, functioning, and most symptoms with cemiplimab in comparison with placebo, the current study provides more details on these patient-reported quality-of-life outcomes.

In the latest analysis, Dr. Makharadze and colleagues evaluated data on the 312 patients in the cemiplimab arm and the 154 in the placebo arm. The median age of the patients was 63 years, and most (83.9%) were men.

Patients in the cemiplimab arm reported significant improvements in pain symptoms from baseline, as measured with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life–Core 30 (QLQ‐C30) score (–4.98; P = .004).

Patients who were treated with cemiplimab also reported a significant delay in time to definitive clinically meaningful deterioration (hazard ratio [HR], 0.39; P < .0001).

Significant delays in the time to deterioration in other functioning and symptom scales favored the cemiplimab group, including dyspnea (HR, 0.54), nausea/vomiting (HR, 0.39), and constipation (HR, 0.48).

The cemiplimab group also reported significantly delayed time to deterioration in physical (HR, 0.62) and emotional functioning (HR, 0.52) compared with the placebo arm as well as significant overall improvements from baseline in global health status/quality of life scores.

No significant improvements in patient-reported outcomes favoring the placebo group were observed on any quality-of-life metric evaluated using the symptom scales.

As for study limitations, the authors said that although about 86% of patients in both arms completed at least one question at baseline and post baseline, “the results may have overrepresented the patients who did well in both treatment arms because patients who progressed no longer completed the questionnaires.”

Nevertheless, the results “show that the favorable efficacy achieved with cemiplimab plus chemotherapy over placebo plus chemotherapy is accompanied by significant overall improvement in pain and significant delay in [time to definitive clinically meaningful deterioration] in multiple patient‐reported cancer‐related and lung cancer–specific functions and symptoms,” the authors concluded.

The study was sponsored by Regeneron Pharmaceuticals and Sanofi.
 

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

Adding the immunotherapy cemiplimab to chemotherapy for patients with advanced non–small cell lung cancer (NSCLC) not only improved overall survival but also led to quality-of-life benefits, new data show.

In the trial, patients who received the PD-1 inhibitor plus platinum-doublet chemotherapy in the first-line setting reported significant improvements in pain symptoms and delay in time to deterioration, as well as improvements in disease-related symptoms, such as dyspnea, constipation, nausea, and vomiting.

Overall, “the findings support the concept that the superior efficacy and favorable safety profile of cemiplimab plus chemotherapy translate to better patient-reported outcomes compared with chemotherapy alone in patients with advanced non–small cell lung cancer, “ corresponding author Tamta Makharadze, MD, of LTD High Technology Hospital Med Center in Batumi, Georgia, said in a press release.

The delays reported in time to definitive clinically meaningful deterioration “are particularly pertinent, given the anticipated continued improvements in cancer survivorship among patients with advanced NSCLC,” the authors explained.

The research was published online May 8 in Cancer.

Quality of life is especially important for patients with advanced NSCLC, for whom the benefits of improved survival must be weighed against the potential drawbacks of treatment toxicities, which can severely impact quality of life, the authors noted.

In the initial multinational phase 3 EMPOWER-Lung 3 trial, Dr. Makharadze and colleagues randomly assigned 466 patients with stage IIIB, IIIC, or stage IV NSCLC to receive either 350 mg of cemiplimab (Libtayo, Regeneron Pharmaceuticals) every 3 weeks along with investigator’s choice of platinum‐doublet chemotherapy or placebo plus chemotherapy. Investigator’s choice of chemotherapy was either paclitaxel plus carboplatin or cisplatin, pemetrexed plus carboplatin, or cisplatin.

The researchers found that the addition of cemiplimab to chemotherapy was associated with a significant, almost 9-month improvement in overall survival. While the trial also highlighted significant improvements in quality of life, functioning, and most symptoms with cemiplimab in comparison with placebo, the current study provides more details on these patient-reported quality-of-life outcomes.

In the latest analysis, Dr. Makharadze and colleagues evaluated data on the 312 patients in the cemiplimab arm and the 154 in the placebo arm. The median age of the patients was 63 years, and most (83.9%) were men.

Patients in the cemiplimab arm reported significant improvements in pain symptoms from baseline, as measured with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life–Core 30 (QLQ‐C30) score (–4.98; P = .004).

Patients who were treated with cemiplimab also reported a significant delay in time to definitive clinically meaningful deterioration (hazard ratio [HR], 0.39; P < .0001).

Significant delays in the time to deterioration in other functioning and symptom scales favored the cemiplimab group, including dyspnea (HR, 0.54), nausea/vomiting (HR, 0.39), and constipation (HR, 0.48).

The cemiplimab group also reported significantly delayed time to deterioration in physical (HR, 0.62) and emotional functioning (HR, 0.52) compared with the placebo arm as well as significant overall improvements from baseline in global health status/quality of life scores.

No significant improvements in patient-reported outcomes favoring the placebo group were observed on any quality-of-life metric evaluated using the symptom scales.

As for study limitations, the authors said that although about 86% of patients in both arms completed at least one question at baseline and post baseline, “the results may have overrepresented the patients who did well in both treatment arms because patients who progressed no longer completed the questionnaires.”

Nevertheless, the results “show that the favorable efficacy achieved with cemiplimab plus chemotherapy over placebo plus chemotherapy is accompanied by significant overall improvement in pain and significant delay in [time to definitive clinically meaningful deterioration] in multiple patient‐reported cancer‐related and lung cancer–specific functions and symptoms,” the authors concluded.

The study was sponsored by Regeneron Pharmaceuticals and Sanofi.
 

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

Adding the immunotherapy cemiplimab to chemotherapy for patients with advanced non–small cell lung cancer (NSCLC) not only improved overall survival but also led to quality-of-life benefits, new data show.

In the trial, patients who received the PD-1 inhibitor plus platinum-doublet chemotherapy in the first-line setting reported significant improvements in pain symptoms and delay in time to deterioration, as well as improvements in disease-related symptoms, such as dyspnea, constipation, nausea, and vomiting.

Overall, “the findings support the concept that the superior efficacy and favorable safety profile of cemiplimab plus chemotherapy translate to better patient-reported outcomes compared with chemotherapy alone in patients with advanced non–small cell lung cancer, “ corresponding author Tamta Makharadze, MD, of LTD High Technology Hospital Med Center in Batumi, Georgia, said in a press release.

The delays reported in time to definitive clinically meaningful deterioration “are particularly pertinent, given the anticipated continued improvements in cancer survivorship among patients with advanced NSCLC,” the authors explained.

The research was published online May 8 in Cancer.

Quality of life is especially important for patients with advanced NSCLC, for whom the benefits of improved survival must be weighed against the potential drawbacks of treatment toxicities, which can severely impact quality of life, the authors noted.

In the initial multinational phase 3 EMPOWER-Lung 3 trial, Dr. Makharadze and colleagues randomly assigned 466 patients with stage IIIB, IIIC, or stage IV NSCLC to receive either 350 mg of cemiplimab (Libtayo, Regeneron Pharmaceuticals) every 3 weeks along with investigator’s choice of platinum‐doublet chemotherapy or placebo plus chemotherapy. Investigator’s choice of chemotherapy was either paclitaxel plus carboplatin or cisplatin, pemetrexed plus carboplatin, or cisplatin.

The researchers found that the addition of cemiplimab to chemotherapy was associated with a significant, almost 9-month improvement in overall survival. While the trial also highlighted significant improvements in quality of life, functioning, and most symptoms with cemiplimab in comparison with placebo, the current study provides more details on these patient-reported quality-of-life outcomes.

In the latest analysis, Dr. Makharadze and colleagues evaluated data on the 312 patients in the cemiplimab arm and the 154 in the placebo arm. The median age of the patients was 63 years, and most (83.9%) were men.

Patients in the cemiplimab arm reported significant improvements in pain symptoms from baseline, as measured with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life–Core 30 (QLQ‐C30) score (–4.98; P = .004).

Patients who were treated with cemiplimab also reported a significant delay in time to definitive clinically meaningful deterioration (hazard ratio [HR], 0.39; P < .0001).

Significant delays in the time to deterioration in other functioning and symptom scales favored the cemiplimab group, including dyspnea (HR, 0.54), nausea/vomiting (HR, 0.39), and constipation (HR, 0.48).

The cemiplimab group also reported significantly delayed time to deterioration in physical (HR, 0.62) and emotional functioning (HR, 0.52) compared with the placebo arm as well as significant overall improvements from baseline in global health status/quality of life scores.

No significant improvements in patient-reported outcomes favoring the placebo group were observed on any quality-of-life metric evaluated using the symptom scales.

As for study limitations, the authors said that although about 86% of patients in both arms completed at least one question at baseline and post baseline, “the results may have overrepresented the patients who did well in both treatment arms because patients who progressed no longer completed the questionnaires.”

Nevertheless, the results “show that the favorable efficacy achieved with cemiplimab plus chemotherapy over placebo plus chemotherapy is accompanied by significant overall improvement in pain and significant delay in [time to definitive clinically meaningful deterioration] in multiple patient‐reported cancer‐related and lung cancer–specific functions and symptoms,” the authors concluded.

The study was sponsored by Regeneron Pharmaceuticals and Sanofi.
 

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