Conference Coverage

WASHINGTON — When the American College of Rheumatology (ACR) released its updated guideline for management of lupus nephritis (LN) at its 2024 Annual Meeting, they included recommendations for managing pediatric LN for the first time. 

The pediatric recommendations use the same classification criteria, outcome measures, and treatments as in adults — including the first-line triple therapy recommendation — but there remain important differences between pediatric and adult LN, Mary Beth Son, MD, clinical chief of immunology and section chief of rheumatology at Boston Children’s Hospital in Massachusetts, and an associate professor of pediatrics at Harvard Medical School, also in Boston, told attendees. 

“In general, kids and adolescents with lupus are sicker,” Son said. They are more likely to have renal manifestations and neuropsychiatric lupus at diagnosis, compared with adults. Further, “although the disease is the same, it’s happening to kids and adolescents who are undergoing critical periods of growth and development.” 

Medication risk profiles also shift for younger patients, Son noted. 

“Importantly, they’re at risk for higher cumulative dosing of both glucocorticoids and cyclophosphamide,” Son said. “When we give an adolescent a course of cyclophosphamide, we have to be aware that this might be the first of a few courses over the course of the lifetime disease, and with increasing numbers of cyclophosphamide courses, you have increased risk for infertility and malignancy.” 

Son also acknowledged challenges of pediatric literature, including differences in definitions of pediatric lupus, very few randomized controlled trials, and fewer pediatric studies in general, with fewer participants. Given these research gaps, the guideline panels included pediatric rheumatologists and nephrologists, and the patient panel included several patients with childhood-onset disease.

Son also addressed differences in pediatric drug development. Dosing studies also do not always directly translate from adults to children because children have larger drug volume distribution and differences in drug clearance, and they may need different formulations, she said. Children tend to tolerate medications better than adults because they usually have fewer comorbidities, but the assessment of a drug’s safety must take its impact on growth and development into consideration.

During a press conference after the session where the guideline was presented, Linda Hiraki, MD, ScD, a clinician-scientist in rheumatology at the Hospital for Sick Children, Toronto, Ontario, Canada, said the panel took into consideration that pediatric patients receive their diagnosis during a critical time of development, so considerations of medication risks include the fact that children “have much more life to live.”

 

Triple Therapy Recommended

As with adults, the pediatric LN guideline recommends a triple therapy approach: glucocorticoids plus mycophenolate mofetil and belimumab, in addition to the usual renin-angiotensin-aldosterone system inhibitors and hydroxychloroquine. But Son acknowledged limitations of applying the new guideline to children. For one, voclosporin has not been studied in or approved for pediatric patients, although there exists modest evidence for other calcineurin inhibitors, mainly tacrolimus, in children.

“The other important consideration is that the lower dose of prednisone that’s being offered by the guidelines of 40 mg per day as a starting dose has not been studied in pediatric lupus nephritis patients,” Son said. “However, I would offer that, given that we know that kids get higher doses and longer courses, it’s even more important to consider a lower dose to begin with in the setting of other immunosuppressants.”

 

Good Practice Statements for Pediatric LN

Son also reviewed three good practice statements for pediatric LN. First, “glucocorticoid regimens should use pediatric-appropriate doses for children, as reduction of human glucocorticoid dosing is critically important given the early age of pediatric lupus onset and attendant comorbidities,” she said.

That statement is based on both common sense and some literature, including awareness that children are more likely to receive higher doses of steroids and that children’s higher damage scores are driven in part by steroid-related toxicity, such as avascular necrosis and cataracts. In addition, glucocorticoids can have profound effects on body mass index, mood, and height attainment.

“This is during a period of emerging self-identity and struggles with appearance; steroids exacerbate that” as well as mood issues already associated with puberty, Son said.

The second good practice statement recommends that clinicians monitor patients “for delayed pubertal onset and decreased growth velocity that can result from disease activity and glucocorticoid treatment and consider referral to pediatric endocrinology if indicated.” The third states that “a structured, intentional transition from pediatric to adult rheumatology care is indicated to avoid poor outcomes during this vulnerable period.” 

During the press conference, Hiraki said that pediatric rheumatologists already recognize the need for discussions about transfer to adult care to begin very early, even years before patients are ready to transfer.

“The transition from being a pediatric patient to being an adult patient is very challenging for a number of reasons,” starting with loss of insurance coverage, added Bonnie Bermas, MD, a professor of internal medicine at UT Southwestern Medical Center in Dallas, Texas. When adult rheumatologists take on these patients, they may not have had care for 2 or 3 years, she said. 

Rebecca Sadun, MD, PhD, an associate professor of pediatrics in rheumatology at Duke University School of Medicine, Durham, North Carolina, and vice-chair of the Systemic Lupus Erythematosus Committee for the Childhood Arthritis and Rheumatology Research Alliance, was not involved in the guideline development process but reviewed the new guideline. 

“We appreciate that the ACR took care to involve pediatric rheumatologists, pediatric nephrologists, and patients with childhood-onset lupus in the development of the newest lupus nephritis treatment guidelines,” she said in an interview. She also noted, however, that “the dearth of pediatric-specific clinical trial data means that we continue to wonder when it is appropriate to extrapolate from adult data regarding the efficacy, safety, and dosing of certain medications, including steroids and voclosporin.” She also noted that voclosporin use can increase pill burden and therefore be difficult to use in pediatrics.

“Children, adolescents, and young adults are a unique population with unique challenges, including significant struggles with adherence to complex medication regimens,” she said. Sadun drew attention to two themes from the guideline that she found particularly applicable to management of pediatric LN.

“First, we must remain wary of the serious consequences of long-term, high-dose glucocorticoids, and we should continue to look towards steroid-sparing strategies that will reduce reliance on glucocorticoids,” Sadun said. “Second, we are likely to see better outcomes, including better renal response, when we take advantage of combination immunosuppression earlier in the disease course.”

Son, Bermas, and Sadun had no disclosures. Hiraki has consulted for Janssen. The guideline development did not involve outside funding.

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

WASHINGTON — When the American College of Rheumatology (ACR) released its updated guideline for management of lupus nephritis (LN) at its 2024 Annual Meeting, they included recommendations for managing pediatric LN for the first time. 

The pediatric recommendations use the same classification criteria, outcome measures, and treatments as in adults — including the first-line triple therapy recommendation — but there remain important differences between pediatric and adult LN, Mary Beth Son, MD, clinical chief of immunology and section chief of rheumatology at Boston Children’s Hospital in Massachusetts, and an associate professor of pediatrics at Harvard Medical School, also in Boston, told attendees. 

“In general, kids and adolescents with lupus are sicker,” Son said. They are more likely to have renal manifestations and neuropsychiatric lupus at diagnosis, compared with adults. Further, “although the disease is the same, it’s happening to kids and adolescents who are undergoing critical periods of growth and development.” 

Medication risk profiles also shift for younger patients, Son noted. 

“Importantly, they’re at risk for higher cumulative dosing of both glucocorticoids and cyclophosphamide,” Son said. “When we give an adolescent a course of cyclophosphamide, we have to be aware that this might be the first of a few courses over the course of the lifetime disease, and with increasing numbers of cyclophosphamide courses, you have increased risk for infertility and malignancy.” 

Son also acknowledged challenges of pediatric literature, including differences in definitions of pediatric lupus, very few randomized controlled trials, and fewer pediatric studies in general, with fewer participants. Given these research gaps, the guideline panels included pediatric rheumatologists and nephrologists, and the patient panel included several patients with childhood-onset disease.

Son also addressed differences in pediatric drug development. Dosing studies also do not always directly translate from adults to children because children have larger drug volume distribution and differences in drug clearance, and they may need different formulations, she said. Children tend to tolerate medications better than adults because they usually have fewer comorbidities, but the assessment of a drug’s safety must take its impact on growth and development into consideration.

During a press conference after the session where the guideline was presented, Linda Hiraki, MD, ScD, a clinician-scientist in rheumatology at the Hospital for Sick Children, Toronto, Ontario, Canada, said the panel took into consideration that pediatric patients receive their diagnosis during a critical time of development, so considerations of medication risks include the fact that children “have much more life to live.”

 

Triple Therapy Recommended

As with adults, the pediatric LN guideline recommends a triple therapy approach: glucocorticoids plus mycophenolate mofetil and belimumab, in addition to the usual renin-angiotensin-aldosterone system inhibitors and hydroxychloroquine. But Son acknowledged limitations of applying the new guideline to children. For one, voclosporin has not been studied in or approved for pediatric patients, although there exists modest evidence for other calcineurin inhibitors, mainly tacrolimus, in children.

“The other important consideration is that the lower dose of prednisone that’s being offered by the guidelines of 40 mg per day as a starting dose has not been studied in pediatric lupus nephritis patients,” Son said. “However, I would offer that, given that we know that kids get higher doses and longer courses, it’s even more important to consider a lower dose to begin with in the setting of other immunosuppressants.”

 

Good Practice Statements for Pediatric LN

Son also reviewed three good practice statements for pediatric LN. First, “glucocorticoid regimens should use pediatric-appropriate doses for children, as reduction of human glucocorticoid dosing is critically important given the early age of pediatric lupus onset and attendant comorbidities,” she said.

That statement is based on both common sense and some literature, including awareness that children are more likely to receive higher doses of steroids and that children’s higher damage scores are driven in part by steroid-related toxicity, such as avascular necrosis and cataracts. In addition, glucocorticoids can have profound effects on body mass index, mood, and height attainment.

“This is during a period of emerging self-identity and struggles with appearance; steroids exacerbate that” as well as mood issues already associated with puberty, Son said.

The second good practice statement recommends that clinicians monitor patients “for delayed pubertal onset and decreased growth velocity that can result from disease activity and glucocorticoid treatment and consider referral to pediatric endocrinology if indicated.” The third states that “a structured, intentional transition from pediatric to adult rheumatology care is indicated to avoid poor outcomes during this vulnerable period.” 

During the press conference, Hiraki said that pediatric rheumatologists already recognize the need for discussions about transfer to adult care to begin very early, even years before patients are ready to transfer.

“The transition from being a pediatric patient to being an adult patient is very challenging for a number of reasons,” starting with loss of insurance coverage, added Bonnie Bermas, MD, a professor of internal medicine at UT Southwestern Medical Center in Dallas, Texas. When adult rheumatologists take on these patients, they may not have had care for 2 or 3 years, she said. 

Rebecca Sadun, MD, PhD, an associate professor of pediatrics in rheumatology at Duke University School of Medicine, Durham, North Carolina, and vice-chair of the Systemic Lupus Erythematosus Committee for the Childhood Arthritis and Rheumatology Research Alliance, was not involved in the guideline development process but reviewed the new guideline. 

“We appreciate that the ACR took care to involve pediatric rheumatologists, pediatric nephrologists, and patients with childhood-onset lupus in the development of the newest lupus nephritis treatment guidelines,” she said in an interview. She also noted, however, that “the dearth of pediatric-specific clinical trial data means that we continue to wonder when it is appropriate to extrapolate from adult data regarding the efficacy, safety, and dosing of certain medications, including steroids and voclosporin.” She also noted that voclosporin use can increase pill burden and therefore be difficult to use in pediatrics.

“Children, adolescents, and young adults are a unique population with unique challenges, including significant struggles with adherence to complex medication regimens,” she said. Sadun drew attention to two themes from the guideline that she found particularly applicable to management of pediatric LN.

“First, we must remain wary of the serious consequences of long-term, high-dose glucocorticoids, and we should continue to look towards steroid-sparing strategies that will reduce reliance on glucocorticoids,” Sadun said. “Second, we are likely to see better outcomes, including better renal response, when we take advantage of combination immunosuppression earlier in the disease course.”

Son, Bermas, and Sadun had no disclosures. Hiraki has consulted for Janssen. The guideline development did not involve outside funding.

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

WASHINGTON — When the American College of Rheumatology (ACR) released its updated guideline for management of lupus nephritis (LN) at its 2024 Annual Meeting, they included recommendations for managing pediatric LN for the first time. 

The pediatric recommendations use the same classification criteria, outcome measures, and treatments as in adults — including the first-line triple therapy recommendation — but there remain important differences between pediatric and adult LN, Mary Beth Son, MD, clinical chief of immunology and section chief of rheumatology at Boston Children’s Hospital in Massachusetts, and an associate professor of pediatrics at Harvard Medical School, also in Boston, told attendees. 

“In general, kids and adolescents with lupus are sicker,” Son said. They are more likely to have renal manifestations and neuropsychiatric lupus at diagnosis, compared with adults. Further, “although the disease is the same, it’s happening to kids and adolescents who are undergoing critical periods of growth and development.” 

Medication risk profiles also shift for younger patients, Son noted. 

“Importantly, they’re at risk for higher cumulative dosing of both glucocorticoids and cyclophosphamide,” Son said. “When we give an adolescent a course of cyclophosphamide, we have to be aware that this might be the first of a few courses over the course of the lifetime disease, and with increasing numbers of cyclophosphamide courses, you have increased risk for infertility and malignancy.” 

Son also acknowledged challenges of pediatric literature, including differences in definitions of pediatric lupus, very few randomized controlled trials, and fewer pediatric studies in general, with fewer participants. Given these research gaps, the guideline panels included pediatric rheumatologists and nephrologists, and the patient panel included several patients with childhood-onset disease.

Son also addressed differences in pediatric drug development. Dosing studies also do not always directly translate from adults to children because children have larger drug volume distribution and differences in drug clearance, and they may need different formulations, she said. Children tend to tolerate medications better than adults because they usually have fewer comorbidities, but the assessment of a drug’s safety must take its impact on growth and development into consideration.

During a press conference after the session where the guideline was presented, Linda Hiraki, MD, ScD, a clinician-scientist in rheumatology at the Hospital for Sick Children, Toronto, Ontario, Canada, said the panel took into consideration that pediatric patients receive their diagnosis during a critical time of development, so considerations of medication risks include the fact that children “have much more life to live.”

 

Triple Therapy Recommended

As with adults, the pediatric LN guideline recommends a triple therapy approach: glucocorticoids plus mycophenolate mofetil and belimumab, in addition to the usual renin-angiotensin-aldosterone system inhibitors and hydroxychloroquine. But Son acknowledged limitations of applying the new guideline to children. For one, voclosporin has not been studied in or approved for pediatric patients, although there exists modest evidence for other calcineurin inhibitors, mainly tacrolimus, in children.

“The other important consideration is that the lower dose of prednisone that’s being offered by the guidelines of 40 mg per day as a starting dose has not been studied in pediatric lupus nephritis patients,” Son said. “However, I would offer that, given that we know that kids get higher doses and longer courses, it’s even more important to consider a lower dose to begin with in the setting of other immunosuppressants.”

 

Good Practice Statements for Pediatric LN

Son also reviewed three good practice statements for pediatric LN. First, “glucocorticoid regimens should use pediatric-appropriate doses for children, as reduction of human glucocorticoid dosing is critically important given the early age of pediatric lupus onset and attendant comorbidities,” she said.

That statement is based on both common sense and some literature, including awareness that children are more likely to receive higher doses of steroids and that children’s higher damage scores are driven in part by steroid-related toxicity, such as avascular necrosis and cataracts. In addition, glucocorticoids can have profound effects on body mass index, mood, and height attainment.

“This is during a period of emerging self-identity and struggles with appearance; steroids exacerbate that” as well as mood issues already associated with puberty, Son said.

The second good practice statement recommends that clinicians monitor patients “for delayed pubertal onset and decreased growth velocity that can result from disease activity and glucocorticoid treatment and consider referral to pediatric endocrinology if indicated.” The third states that “a structured, intentional transition from pediatric to adult rheumatology care is indicated to avoid poor outcomes during this vulnerable period.” 

During the press conference, Hiraki said that pediatric rheumatologists already recognize the need for discussions about transfer to adult care to begin very early, even years before patients are ready to transfer.

“The transition from being a pediatric patient to being an adult patient is very challenging for a number of reasons,” starting with loss of insurance coverage, added Bonnie Bermas, MD, a professor of internal medicine at UT Southwestern Medical Center in Dallas, Texas. When adult rheumatologists take on these patients, they may not have had care for 2 or 3 years, she said. 

Rebecca Sadun, MD, PhD, an associate professor of pediatrics in rheumatology at Duke University School of Medicine, Durham, North Carolina, and vice-chair of the Systemic Lupus Erythematosus Committee for the Childhood Arthritis and Rheumatology Research Alliance, was not involved in the guideline development process but reviewed the new guideline. 

“We appreciate that the ACR took care to involve pediatric rheumatologists, pediatric nephrologists, and patients with childhood-onset lupus in the development of the newest lupus nephritis treatment guidelines,” she said in an interview. She also noted, however, that “the dearth of pediatric-specific clinical trial data means that we continue to wonder when it is appropriate to extrapolate from adult data regarding the efficacy, safety, and dosing of certain medications, including steroids and voclosporin.” She also noted that voclosporin use can increase pill burden and therefore be difficult to use in pediatrics.

“Children, adolescents, and young adults are a unique population with unique challenges, including significant struggles with adherence to complex medication regimens,” she said. Sadun drew attention to two themes from the guideline that she found particularly applicable to management of pediatric LN.

“First, we must remain wary of the serious consequences of long-term, high-dose glucocorticoids, and we should continue to look towards steroid-sparing strategies that will reduce reliance on glucocorticoids,” Sadun said. “Second, we are likely to see better outcomes, including better renal response, when we take advantage of combination immunosuppression earlier in the disease course.”

Son, Bermas, and Sadun had no disclosures. Hiraki has consulted for Janssen. The guideline development did not involve outside funding.

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

Treatment with the oral Bruton tyrosine kinase (BTK) inhibitor acalabrutinib in combination with venetoclax was associated with improved progression-free survival, compared with standard-of-care chemoimmunotherapy in frontline treatment of chronic lymphocytic leukemia (CLL), according to a prespecified interim analysis of the AMPLIFY trial.

In fit, adult patients without del(17p) or TP53 mutations, the acalabrutinib-venetoclax combination, with or without obinutuzumab, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared with a combination of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab, reported principal investigator Jennifer R. Brown, MD, PhD,who presented the results at the American Society of Hematology (ASH) 2024 Annual Meeting.

Patients with CLL have several frontline treatment options, which include chemoimmunotherapy for low-risk disease as well as venetoclax plus the first-generation BTK inhibitor ibrutinib.

While fixed-duration venetoclax plus ibrutinib can result in deep, durable responses, cardiac toxicity remains a concern, particularly in older patients, explained Brown, director of the CLL Center of the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts, during a press conference.

Acalabrutinib is a highly selective second-generation BTK inhibitor with improved safety and tolerability, compared with ibrutinib. Brown and colleagues wanted to see whether this second-generation BTK inhibitor alongside venetoclax provided a clinical benefit and fewer cardiac toxicities as a frontline option in this patient population.

“AMPLIFY provides the first phase 3 evidence of fixed-duration therapy with a combination of venetoclax and a second-generation BTK inhibitor in patients with treatment-naive CLL,” Brown said. And these results “show the promise of a new all-oral fixed-duration therapy approach, which would allow patients to take breaks from treatment, reducing the risk of long-term adverse events and drug resistance,” Brown, also from Harvard Medical School, Boston, added in a press release.

 

Study Details

AMPLIFY randomized 867 patients (median age, 61 years) to three treatment arms: Acalabrutinib in combination with venetoclax alone (n = 291), acalabrutinib and venetoclax with obinutuzumab (n = 286), or the investigator’s choice of chemoimmunotherapy — a combination of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab (n = 290). The median follow-up was 41 months.

Compared with 66.5% in the chemoimmunotherapy arm, 83.1% of patients in the acalabrutinib-venetoclax arm and 76.5% of the acalabrutinib-venetoclax-obinutuzumab arm reached the primary endpoint of 36-month progression-free survival (hazard ratios [HRs] of 0.65 and 0.42, respectively). Median progression-free survival was not reached in the two acalabrutinib arms, compared with 47.6 months in the chemotherapy arm.

More than half of all participants (58.6%) had unmutated immunoglobulin heavy-chain variable region gene (IGHV) status. In a subgroup analysis, patients on either acalabrutinib regimen experienced a significant improvement in progression-free survival compared with those on chemoimmunotherapy, regardless of IGHV status.

It was “particularly noticeable” in the acalabrutinib-venetoclax-obinutuzumab arm (HR, 0.35) that patients with unmutated IGHV were doing as well as those with mutated IGHV, “suggesting that the addition of obinutuzumab may overcome the adverse impact of unmutated IGHV,” Brown said.

Patients also demonstrated a robust response in both investigational arms with an overall response rate of 92.8% for acalabrutinib-venetoclax and 92.7% for acalabrutinib-venetoclax-obinutuzumab, compared with 75.2% for chemoimmunotherapy (P < .0001 for both).

In addition, compared with chemoimmunotherapy, acalabrutinib-venetoclax was associated with a significant improvement in overall survival (HR, 0.33; 95% CI, 0.18-0.56). Acalabrutinib-venetoclax-obinutuzumab was associated with better overall survival (HR, 0.78), but the findings were not statistically significant.

When considering COVID-19 deaths, overall survival findings were significant for both acalabrutinib regimens, Brown reported.

COVID-19 deaths were observed in 10 patients in the acalabrutinib-venetoclax arm, 25 in the acalabrutinib-venetoclax-obinutuzumab arm, and 21 in the chemoimmunotherapy arm.

In terms of safety, both acalabrutinib treatment regimens demonstrated “tolerable safety profiles with a low incidence of cardiac adverse events typically associated with BTK inhibitors, including atrial fibrillation or hypertension,” she reported.

Any serious adverse events were observed in 24.7% of the acalabrutinib-venetoclax patients, 38.4% of those receiving acalabrutinib-venetoclax-obinutuzumab, and 27.4% on chemoimmunotherapy. Serious adverse events leading to death occurred in 3.4%, 6.0%, and 3.5% of patients in the three groups, respectively, and adverse events leading to death occurred in about 8%, 20%, and 10.8%, respectively, of patients.

The most common adverse event was neutropenia, with grade 3 or higher neutropenia occurring in 32.3% of patients in the acalabrutinib-venetoclax arm and 46.1% in the acalabrutinib-venetoclax-obinutuzumab group, compared with 43.2% of patients with chemoimmunotherapy.

As for cardiac events, 9.3% of patients in the acalabrutinib-venetoclax group experienced an event of any grade compared with 12% in the acalabrutinib-venetoclax-obinutuzumab group and 3.5% in the chemoimmunotherapy group.

 

To Add or Not to Add Obinutuzumab

Asked how clinicians might decide between the two acalabrutinib regimens, Brown said, “if you add the obinutuzumab, it does add more work for the patient,” and it adds more toxicity.

But, she noted, it might optimize progression-free survival.

“I think when physicians are considering whether to use the two- or the three-drug regimen, they have to take account of the patient in front of them,” Brown said. “The acalabrutinib-venetoclax regimen is a very well-tolerated oral regimen, which is really going to be suitable for anyone, and I think, easy to use in the community.”

The fact that there were more COVID-19 deaths in the obinutuzumab arm, compared with the acalabrutinib-venetoclax arm, suggests more immunosuppression in the three-drug regimen, said session moderator Deborah M. Stephens, DO, associate professor of medicine and director of the Chronic Lymphocytic Leukemia and Richter’s Program at the University of North Carolina School of Medicine in Chapel Hill.

This finding could “call into question whether acalabrutinib-venetoclax may have a better risk/benefit ratio when compared to acalabrutinib-venetoclax-obinutuzumab,” she wrote in an email.

Overall, “AMPLIFY is an important trial, and these data will likely be submitted to the US FDA and regulatory bodies of other involved countries to gain approval of the acalabrutinib + venetoclax +/− obinutuzumab regimen,” Stephens added.

“Notably, this is another in a string of phase 3 trials showing that survival is prolonged with targeted agents compared to chemoimmunotherapy,” indicating that standard chemoimmunotherapy “should be considered obsolete as a control arm for phase 3 studies in the frontline treatment of CLL,” said Stephens.

Alexey Danilov, MD, PhD, another CLL specialist from City of Hope, Duarte, California, who was also presenting at the press conference, said, “I don’t see a full justification to use the acalabrutinib-venetoclax-obinutuzumab regimen across the board in all patients, even though progression-free is better. I do think that, unfortunately, this benefit is offset by increased frequency of adverse events.”

Although it looks like “the majority of patients will be very good candidates for acalabrutinib-venetoclax, with impressive progression-free survival, I think we will still have to define who these patients are,” he added.

However, overall, he was enthusiastic. “This is anticipated to get approval as the first oral doublet front line therapy of CLL, and I think many patients do — in my clinic at least — prefer the idea of finite duration therapy to continuous BTK inhibitors.”

The study was funded by AstraZeneca. Brown disclosed consulting with Acerta/AstraZeneca, Genentech/Roche, AbbVie, and multiple other companies. Danilov disclosed consulting with AstraZeneca, Genentech, AbbVie, among others. Stephens had no relevant disclosures.

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

Treatment with the oral Bruton tyrosine kinase (BTK) inhibitor acalabrutinib in combination with venetoclax was associated with improved progression-free survival, compared with standard-of-care chemoimmunotherapy in frontline treatment of chronic lymphocytic leukemia (CLL), according to a prespecified interim analysis of the AMPLIFY trial.

In fit, adult patients without del(17p) or TP53 mutations, the acalabrutinib-venetoclax combination, with or without obinutuzumab, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared with a combination of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab, reported principal investigator Jennifer R. Brown, MD, PhD,who presented the results at the American Society of Hematology (ASH) 2024 Annual Meeting.

Patients with CLL have several frontline treatment options, which include chemoimmunotherapy for low-risk disease as well as venetoclax plus the first-generation BTK inhibitor ibrutinib.

While fixed-duration venetoclax plus ibrutinib can result in deep, durable responses, cardiac toxicity remains a concern, particularly in older patients, explained Brown, director of the CLL Center of the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts, during a press conference.

Acalabrutinib is a highly selective second-generation BTK inhibitor with improved safety and tolerability, compared with ibrutinib. Brown and colleagues wanted to see whether this second-generation BTK inhibitor alongside venetoclax provided a clinical benefit and fewer cardiac toxicities as a frontline option in this patient population.

“AMPLIFY provides the first phase 3 evidence of fixed-duration therapy with a combination of venetoclax and a second-generation BTK inhibitor in patients with treatment-naive CLL,” Brown said. And these results “show the promise of a new all-oral fixed-duration therapy approach, which would allow patients to take breaks from treatment, reducing the risk of long-term adverse events and drug resistance,” Brown, also from Harvard Medical School, Boston, added in a press release.

 

Study Details

AMPLIFY randomized 867 patients (median age, 61 years) to three treatment arms: Acalabrutinib in combination with venetoclax alone (n = 291), acalabrutinib and venetoclax with obinutuzumab (n = 286), or the investigator’s choice of chemoimmunotherapy — a combination of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab (n = 290). The median follow-up was 41 months.

Compared with 66.5% in the chemoimmunotherapy arm, 83.1% of patients in the acalabrutinib-venetoclax arm and 76.5% of the acalabrutinib-venetoclax-obinutuzumab arm reached the primary endpoint of 36-month progression-free survival (hazard ratios [HRs] of 0.65 and 0.42, respectively). Median progression-free survival was not reached in the two acalabrutinib arms, compared with 47.6 months in the chemotherapy arm.

More than half of all participants (58.6%) had unmutated immunoglobulin heavy-chain variable region gene (IGHV) status. In a subgroup analysis, patients on either acalabrutinib regimen experienced a significant improvement in progression-free survival compared with those on chemoimmunotherapy, regardless of IGHV status.

It was “particularly noticeable” in the acalabrutinib-venetoclax-obinutuzumab arm (HR, 0.35) that patients with unmutated IGHV were doing as well as those with mutated IGHV, “suggesting that the addition of obinutuzumab may overcome the adverse impact of unmutated IGHV,” Brown said.

Patients also demonstrated a robust response in both investigational arms with an overall response rate of 92.8% for acalabrutinib-venetoclax and 92.7% for acalabrutinib-venetoclax-obinutuzumab, compared with 75.2% for chemoimmunotherapy (P < .0001 for both).

In addition, compared with chemoimmunotherapy, acalabrutinib-venetoclax was associated with a significant improvement in overall survival (HR, 0.33; 95% CI, 0.18-0.56). Acalabrutinib-venetoclax-obinutuzumab was associated with better overall survival (HR, 0.78), but the findings were not statistically significant.

When considering COVID-19 deaths, overall survival findings were significant for both acalabrutinib regimens, Brown reported.

COVID-19 deaths were observed in 10 patients in the acalabrutinib-venetoclax arm, 25 in the acalabrutinib-venetoclax-obinutuzumab arm, and 21 in the chemoimmunotherapy arm.

In terms of safety, both acalabrutinib treatment regimens demonstrated “tolerable safety profiles with a low incidence of cardiac adverse events typically associated with BTK inhibitors, including atrial fibrillation or hypertension,” she reported.

Any serious adverse events were observed in 24.7% of the acalabrutinib-venetoclax patients, 38.4% of those receiving acalabrutinib-venetoclax-obinutuzumab, and 27.4% on chemoimmunotherapy. Serious adverse events leading to death occurred in 3.4%, 6.0%, and 3.5% of patients in the three groups, respectively, and adverse events leading to death occurred in about 8%, 20%, and 10.8%, respectively, of patients.

The most common adverse event was neutropenia, with grade 3 or higher neutropenia occurring in 32.3% of patients in the acalabrutinib-venetoclax arm and 46.1% in the acalabrutinib-venetoclax-obinutuzumab group, compared with 43.2% of patients with chemoimmunotherapy.

As for cardiac events, 9.3% of patients in the acalabrutinib-venetoclax group experienced an event of any grade compared with 12% in the acalabrutinib-venetoclax-obinutuzumab group and 3.5% in the chemoimmunotherapy group.

 

To Add or Not to Add Obinutuzumab

Asked how clinicians might decide between the two acalabrutinib regimens, Brown said, “if you add the obinutuzumab, it does add more work for the patient,” and it adds more toxicity.

But, she noted, it might optimize progression-free survival.

“I think when physicians are considering whether to use the two- or the three-drug regimen, they have to take account of the patient in front of them,” Brown said. “The acalabrutinib-venetoclax regimen is a very well-tolerated oral regimen, which is really going to be suitable for anyone, and I think, easy to use in the community.”

The fact that there were more COVID-19 deaths in the obinutuzumab arm, compared with the acalabrutinib-venetoclax arm, suggests more immunosuppression in the three-drug regimen, said session moderator Deborah M. Stephens, DO, associate professor of medicine and director of the Chronic Lymphocytic Leukemia and Richter’s Program at the University of North Carolina School of Medicine in Chapel Hill.

This finding could “call into question whether acalabrutinib-venetoclax may have a better risk/benefit ratio when compared to acalabrutinib-venetoclax-obinutuzumab,” she wrote in an email.

Overall, “AMPLIFY is an important trial, and these data will likely be submitted to the US FDA and regulatory bodies of other involved countries to gain approval of the acalabrutinib + venetoclax +/− obinutuzumab regimen,” Stephens added.

“Notably, this is another in a string of phase 3 trials showing that survival is prolonged with targeted agents compared to chemoimmunotherapy,” indicating that standard chemoimmunotherapy “should be considered obsolete as a control arm for phase 3 studies in the frontline treatment of CLL,” said Stephens.

Alexey Danilov, MD, PhD, another CLL specialist from City of Hope, Duarte, California, who was also presenting at the press conference, said, “I don’t see a full justification to use the acalabrutinib-venetoclax-obinutuzumab regimen across the board in all patients, even though progression-free is better. I do think that, unfortunately, this benefit is offset by increased frequency of adverse events.”

Although it looks like “the majority of patients will be very good candidates for acalabrutinib-venetoclax, with impressive progression-free survival, I think we will still have to define who these patients are,” he added.

However, overall, he was enthusiastic. “This is anticipated to get approval as the first oral doublet front line therapy of CLL, and I think many patients do — in my clinic at least — prefer the idea of finite duration therapy to continuous BTK inhibitors.”

The study was funded by AstraZeneca. Brown disclosed consulting with Acerta/AstraZeneca, Genentech/Roche, AbbVie, and multiple other companies. Danilov disclosed consulting with AstraZeneca, Genentech, AbbVie, among others. Stephens had no relevant disclosures.

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

Treatment with the oral Bruton tyrosine kinase (BTK) inhibitor acalabrutinib in combination with venetoclax was associated with improved progression-free survival, compared with standard-of-care chemoimmunotherapy in frontline treatment of chronic lymphocytic leukemia (CLL), according to a prespecified interim analysis of the AMPLIFY trial.

In fit, adult patients without del(17p) or TP53 mutations, the acalabrutinib-venetoclax combination, with or without obinutuzumab, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared with a combination of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab, reported principal investigator Jennifer R. Brown, MD, PhD,who presented the results at the American Society of Hematology (ASH) 2024 Annual Meeting.

Patients with CLL have several frontline treatment options, which include chemoimmunotherapy for low-risk disease as well as venetoclax plus the first-generation BTK inhibitor ibrutinib.

While fixed-duration venetoclax plus ibrutinib can result in deep, durable responses, cardiac toxicity remains a concern, particularly in older patients, explained Brown, director of the CLL Center of the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts, during a press conference.

Acalabrutinib is a highly selective second-generation BTK inhibitor with improved safety and tolerability, compared with ibrutinib. Brown and colleagues wanted to see whether this second-generation BTK inhibitor alongside venetoclax provided a clinical benefit and fewer cardiac toxicities as a frontline option in this patient population.

“AMPLIFY provides the first phase 3 evidence of fixed-duration therapy with a combination of venetoclax and a second-generation BTK inhibitor in patients with treatment-naive CLL,” Brown said. And these results “show the promise of a new all-oral fixed-duration therapy approach, which would allow patients to take breaks from treatment, reducing the risk of long-term adverse events and drug resistance,” Brown, also from Harvard Medical School, Boston, added in a press release.

 

Study Details

AMPLIFY randomized 867 patients (median age, 61 years) to three treatment arms: Acalabrutinib in combination with venetoclax alone (n = 291), acalabrutinib and venetoclax with obinutuzumab (n = 286), or the investigator’s choice of chemoimmunotherapy — a combination of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab (n = 290). The median follow-up was 41 months.

Compared with 66.5% in the chemoimmunotherapy arm, 83.1% of patients in the acalabrutinib-venetoclax arm and 76.5% of the acalabrutinib-venetoclax-obinutuzumab arm reached the primary endpoint of 36-month progression-free survival (hazard ratios [HRs] of 0.65 and 0.42, respectively). Median progression-free survival was not reached in the two acalabrutinib arms, compared with 47.6 months in the chemotherapy arm.

More than half of all participants (58.6%) had unmutated immunoglobulin heavy-chain variable region gene (IGHV) status. In a subgroup analysis, patients on either acalabrutinib regimen experienced a significant improvement in progression-free survival compared with those on chemoimmunotherapy, regardless of IGHV status.

It was “particularly noticeable” in the acalabrutinib-venetoclax-obinutuzumab arm (HR, 0.35) that patients with unmutated IGHV were doing as well as those with mutated IGHV, “suggesting that the addition of obinutuzumab may overcome the adverse impact of unmutated IGHV,” Brown said.

Patients also demonstrated a robust response in both investigational arms with an overall response rate of 92.8% for acalabrutinib-venetoclax and 92.7% for acalabrutinib-venetoclax-obinutuzumab, compared with 75.2% for chemoimmunotherapy (P < .0001 for both).

In addition, compared with chemoimmunotherapy, acalabrutinib-venetoclax was associated with a significant improvement in overall survival (HR, 0.33; 95% CI, 0.18-0.56). Acalabrutinib-venetoclax-obinutuzumab was associated with better overall survival (HR, 0.78), but the findings were not statistically significant.

When considering COVID-19 deaths, overall survival findings were significant for both acalabrutinib regimens, Brown reported.

COVID-19 deaths were observed in 10 patients in the acalabrutinib-venetoclax arm, 25 in the acalabrutinib-venetoclax-obinutuzumab arm, and 21 in the chemoimmunotherapy arm.

In terms of safety, both acalabrutinib treatment regimens demonstrated “tolerable safety profiles with a low incidence of cardiac adverse events typically associated with BTK inhibitors, including atrial fibrillation or hypertension,” she reported.

Any serious adverse events were observed in 24.7% of the acalabrutinib-venetoclax patients, 38.4% of those receiving acalabrutinib-venetoclax-obinutuzumab, and 27.4% on chemoimmunotherapy. Serious adverse events leading to death occurred in 3.4%, 6.0%, and 3.5% of patients in the three groups, respectively, and adverse events leading to death occurred in about 8%, 20%, and 10.8%, respectively, of patients.

The most common adverse event was neutropenia, with grade 3 or higher neutropenia occurring in 32.3% of patients in the acalabrutinib-venetoclax arm and 46.1% in the acalabrutinib-venetoclax-obinutuzumab group, compared with 43.2% of patients with chemoimmunotherapy.

As for cardiac events, 9.3% of patients in the acalabrutinib-venetoclax group experienced an event of any grade compared with 12% in the acalabrutinib-venetoclax-obinutuzumab group and 3.5% in the chemoimmunotherapy group.

 

To Add or Not to Add Obinutuzumab

Asked how clinicians might decide between the two acalabrutinib regimens, Brown said, “if you add the obinutuzumab, it does add more work for the patient,” and it adds more toxicity.

But, she noted, it might optimize progression-free survival.

“I think when physicians are considering whether to use the two- or the three-drug regimen, they have to take account of the patient in front of them,” Brown said. “The acalabrutinib-venetoclax regimen is a very well-tolerated oral regimen, which is really going to be suitable for anyone, and I think, easy to use in the community.”

The fact that there were more COVID-19 deaths in the obinutuzumab arm, compared with the acalabrutinib-venetoclax arm, suggests more immunosuppression in the three-drug regimen, said session moderator Deborah M. Stephens, DO, associate professor of medicine and director of the Chronic Lymphocytic Leukemia and Richter’s Program at the University of North Carolina School of Medicine in Chapel Hill.

This finding could “call into question whether acalabrutinib-venetoclax may have a better risk/benefit ratio when compared to acalabrutinib-venetoclax-obinutuzumab,” she wrote in an email.

Overall, “AMPLIFY is an important trial, and these data will likely be submitted to the US FDA and regulatory bodies of other involved countries to gain approval of the acalabrutinib + venetoclax +/− obinutuzumab regimen,” Stephens added.

“Notably, this is another in a string of phase 3 trials showing that survival is prolonged with targeted agents compared to chemoimmunotherapy,” indicating that standard chemoimmunotherapy “should be considered obsolete as a control arm for phase 3 studies in the frontline treatment of CLL,” said Stephens.

Alexey Danilov, MD, PhD, another CLL specialist from City of Hope, Duarte, California, who was also presenting at the press conference, said, “I don’t see a full justification to use the acalabrutinib-venetoclax-obinutuzumab regimen across the board in all patients, even though progression-free is better. I do think that, unfortunately, this benefit is offset by increased frequency of adverse events.”

Although it looks like “the majority of patients will be very good candidates for acalabrutinib-venetoclax, with impressive progression-free survival, I think we will still have to define who these patients are,” he added.

However, overall, he was enthusiastic. “This is anticipated to get approval as the first oral doublet front line therapy of CLL, and I think many patients do — in my clinic at least — prefer the idea of finite duration therapy to continuous BTK inhibitors.”

The study was funded by AstraZeneca. Brown disclosed consulting with Acerta/AstraZeneca, Genentech/Roche, AbbVie, and multiple other companies. Danilov disclosed consulting with AstraZeneca, Genentech, AbbVie, among others. Stephens had no relevant disclosures.

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

Glucagon-like peptide 1 (GLP-1) receptor agonists led to a significant reduction in the risk for venous thromboembolism (VTE) among individuals with type 2 diabetes, compared with dipeptidyl peptidase 4 (DPP-4) inhibitors, a recent analysis indicated.

Overall, GLP-1 agonist use was associated with a 20% reduction in VTE, compared with DPP-4 inhibitor use, in those with type 2 diabetes, and this benefit held regardless of people’s obesity status, said study investigator Cho-Han Chiang, MD, a medical resident at Mount Auburn Hospital, Cambridge, Massachusetts, who presented the findings at the American Society of Hematology (ASH) 2024 Annual Meeting.

The incidence of VTE has increased by 20% over the past 10 years, and obesity is a risk factor for VTE, Chiang explained. A growing body of evidence demonstrated that GLP-1s provide a variety of cardiovascular benefits in people with type 2 diabetes, but data on VTE benefits remain more limited.

In the retrospective study, the researchers combed electronic health records from the TriNetX global database, which includes more than 250 million patients, and identified adults with type 2 diabetes who were taking a GLP-1 agonist or a DPP-4 inhibitor.

After excluding anyone with prior VTE or atrial fibrillation as well as those treated with both drugs or with oral anticoagulants, patients on GLP-1s were matched with those on DPP-4 inhibitors based on predetermined variables, including age, sex, race, body mass index (BMI), hemoglobin A1c, use of other antidiabetic agents, and underlying comorbidities. VTE was a composite of pulmonary embolism and deep vein thrombosis.

The researchers also performed a subgroup analysis that stratified patients by obesity status, defined as a BMI ≥ 30.

Within 1 year of GLP-1 or DPP-4 prescription, VTE occurred at a rate of 6.5 cases/1000 person-years in the GLP-1 group vs 7.9 cases/1000 person years in the DPP-4 inhibitor group (hazard ratio [HR], 0.80; P < .001).

The 20% risk reduction in VTE held across various subgroups of BMI, including among those with obesity, Chiang reported.

Among patients with the highest BMI (≥ 40), VTE occurred at a rate of 7.2 cases/1000 person years in the GLP-1 group vs 9.6 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.74). Among patients with the next highest BMI (30-34.9), VTE occurred at a rate of 4.8 cases/1000 person years in the GLP-1 group vs 7.9 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.60). Among those with the lowest BMI (18.5-24.9), VTE occurred significantly less frequently among those in the GLP-1 group — 4.7 cases/1000 person years vs 7.4 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.61).

The lower risk for VTE associated with GLP-1s also held across the individual components of the composite VTE. Pulmonary embolism occurred at a rate of 3.1 cases/1000 person years in the GLP-1 group vs 3.9 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.78), and deep vein thrombosis occurred in 4.2 cases/1000 person years in the GLP-1 group vs 5.0 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.82).

Interestingly, the GLP-1 and DPP-4 curves started diverging within the first 30 days of the index prescription date, said Chiang.

Session moderator Ghadeer Dawwas, PhD, said in an interview that patients with type 2 diabetes are increasingly using GLP-1 agonists because of the cardiovascular benefits associated with the agents, which include lower risks for stroke and heart failure, but the antithrombotic benefits are still debated.

“The current study indicates that GLP-1 agonists may help lower the risk of VTE in patients with type 2 diabetes, irrespective of their baseline body weight,” said Dawwas, a pharmacoepidemiologist and assistant professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee. “However, given the current landscape of evidence and the existence of conflicting data on VTE risk, clinicians should proceed with caution and await further studies to validate these findings before making clinical decisions.”

This study was funded by the National Blood Clot Alliance and Conquer Cancer Foundation. Chiang and Dawwas had no disclosures.

A version of this article appeared on Medscape.com.

Glucagon-like peptide 1 (GLP-1) receptor agonists led to a significant reduction in the risk for venous thromboembolism (VTE) among individuals with type 2 diabetes, compared with dipeptidyl peptidase 4 (DPP-4) inhibitors, a recent analysis indicated.

Overall, GLP-1 agonist use was associated with a 20% reduction in VTE, compared with DPP-4 inhibitor use, in those with type 2 diabetes, and this benefit held regardless of people’s obesity status, said study investigator Cho-Han Chiang, MD, a medical resident at Mount Auburn Hospital, Cambridge, Massachusetts, who presented the findings at the American Society of Hematology (ASH) 2024 Annual Meeting.

The incidence of VTE has increased by 20% over the past 10 years, and obesity is a risk factor for VTE, Chiang explained. A growing body of evidence demonstrated that GLP-1s provide a variety of cardiovascular benefits in people with type 2 diabetes, but data on VTE benefits remain more limited.

In the retrospective study, the researchers combed electronic health records from the TriNetX global database, which includes more than 250 million patients, and identified adults with type 2 diabetes who were taking a GLP-1 agonist or a DPP-4 inhibitor.

After excluding anyone with prior VTE or atrial fibrillation as well as those treated with both drugs or with oral anticoagulants, patients on GLP-1s were matched with those on DPP-4 inhibitors based on predetermined variables, including age, sex, race, body mass index (BMI), hemoglobin A1c, use of other antidiabetic agents, and underlying comorbidities. VTE was a composite of pulmonary embolism and deep vein thrombosis.

The researchers also performed a subgroup analysis that stratified patients by obesity status, defined as a BMI ≥ 30.

Within 1 year of GLP-1 or DPP-4 prescription, VTE occurred at a rate of 6.5 cases/1000 person-years in the GLP-1 group vs 7.9 cases/1000 person years in the DPP-4 inhibitor group (hazard ratio [HR], 0.80; P < .001).

The 20% risk reduction in VTE held across various subgroups of BMI, including among those with obesity, Chiang reported.

Among patients with the highest BMI (≥ 40), VTE occurred at a rate of 7.2 cases/1000 person years in the GLP-1 group vs 9.6 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.74). Among patients with the next highest BMI (30-34.9), VTE occurred at a rate of 4.8 cases/1000 person years in the GLP-1 group vs 7.9 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.60). Among those with the lowest BMI (18.5-24.9), VTE occurred significantly less frequently among those in the GLP-1 group — 4.7 cases/1000 person years vs 7.4 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.61).

The lower risk for VTE associated with GLP-1s also held across the individual components of the composite VTE. Pulmonary embolism occurred at a rate of 3.1 cases/1000 person years in the GLP-1 group vs 3.9 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.78), and deep vein thrombosis occurred in 4.2 cases/1000 person years in the GLP-1 group vs 5.0 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.82).

Interestingly, the GLP-1 and DPP-4 curves started diverging within the first 30 days of the index prescription date, said Chiang.

Session moderator Ghadeer Dawwas, PhD, said in an interview that patients with type 2 diabetes are increasingly using GLP-1 agonists because of the cardiovascular benefits associated with the agents, which include lower risks for stroke and heart failure, but the antithrombotic benefits are still debated.

“The current study indicates that GLP-1 agonists may help lower the risk of VTE in patients with type 2 diabetes, irrespective of their baseline body weight,” said Dawwas, a pharmacoepidemiologist and assistant professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee. “However, given the current landscape of evidence and the existence of conflicting data on VTE risk, clinicians should proceed with caution and await further studies to validate these findings before making clinical decisions.”

This study was funded by the National Blood Clot Alliance and Conquer Cancer Foundation. Chiang and Dawwas had no disclosures.

A version of this article appeared on Medscape.com.

Glucagon-like peptide 1 (GLP-1) receptor agonists led to a significant reduction in the risk for venous thromboembolism (VTE) among individuals with type 2 diabetes, compared with dipeptidyl peptidase 4 (DPP-4) inhibitors, a recent analysis indicated.

Overall, GLP-1 agonist use was associated with a 20% reduction in VTE, compared with DPP-4 inhibitor use, in those with type 2 diabetes, and this benefit held regardless of people’s obesity status, said study investigator Cho-Han Chiang, MD, a medical resident at Mount Auburn Hospital, Cambridge, Massachusetts, who presented the findings at the American Society of Hematology (ASH) 2024 Annual Meeting.

The incidence of VTE has increased by 20% over the past 10 years, and obesity is a risk factor for VTE, Chiang explained. A growing body of evidence demonstrated that GLP-1s provide a variety of cardiovascular benefits in people with type 2 diabetes, but data on VTE benefits remain more limited.

In the retrospective study, the researchers combed electronic health records from the TriNetX global database, which includes more than 250 million patients, and identified adults with type 2 diabetes who were taking a GLP-1 agonist or a DPP-4 inhibitor.

After excluding anyone with prior VTE or atrial fibrillation as well as those treated with both drugs or with oral anticoagulants, patients on GLP-1s were matched with those on DPP-4 inhibitors based on predetermined variables, including age, sex, race, body mass index (BMI), hemoglobin A1c, use of other antidiabetic agents, and underlying comorbidities. VTE was a composite of pulmonary embolism and deep vein thrombosis.

The researchers also performed a subgroup analysis that stratified patients by obesity status, defined as a BMI ≥ 30.

Within 1 year of GLP-1 or DPP-4 prescription, VTE occurred at a rate of 6.5 cases/1000 person-years in the GLP-1 group vs 7.9 cases/1000 person years in the DPP-4 inhibitor group (hazard ratio [HR], 0.80; P < .001).

The 20% risk reduction in VTE held across various subgroups of BMI, including among those with obesity, Chiang reported.

Among patients with the highest BMI (≥ 40), VTE occurred at a rate of 7.2 cases/1000 person years in the GLP-1 group vs 9.6 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.74). Among patients with the next highest BMI (30-34.9), VTE occurred at a rate of 4.8 cases/1000 person years in the GLP-1 group vs 7.9 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.60). Among those with the lowest BMI (18.5-24.9), VTE occurred significantly less frequently among those in the GLP-1 group — 4.7 cases/1000 person years vs 7.4 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.61).

The lower risk for VTE associated with GLP-1s also held across the individual components of the composite VTE. Pulmonary embolism occurred at a rate of 3.1 cases/1000 person years in the GLP-1 group vs 3.9 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.78), and deep vein thrombosis occurred in 4.2 cases/1000 person years in the GLP-1 group vs 5.0 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.82).

Interestingly, the GLP-1 and DPP-4 curves started diverging within the first 30 days of the index prescription date, said Chiang.

Session moderator Ghadeer Dawwas, PhD, said in an interview that patients with type 2 diabetes are increasingly using GLP-1 agonists because of the cardiovascular benefits associated with the agents, which include lower risks for stroke and heart failure, but the antithrombotic benefits are still debated.

“The current study indicates that GLP-1 agonists may help lower the risk of VTE in patients with type 2 diabetes, irrespective of their baseline body weight,” said Dawwas, a pharmacoepidemiologist and assistant professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee. “However, given the current landscape of evidence and the existence of conflicting data on VTE risk, clinicians should proceed with caution and await further studies to validate these findings before making clinical decisions.”

This study was funded by the National Blood Clot Alliance and Conquer Cancer Foundation. Chiang and Dawwas had no disclosures.

A version of this article appeared on Medscape.com.

SAN DIEGO — Incidentally discovered vertebral fractures are common on scans in the general population, while the absolute risk for multiple myeloma (MM) in those with such fractures is “quite modest,” according to findings in a Danish cohort of more than 9000 patients.

The findings suggest that evaluation for underlying MM — as recommended in some clinical guidelines — may be unwarranted in the absence of symptoms or other clinical findings leading to suspicion of underlying MM, Rasmus Rønnemoes, MD, reported during a poster session at the annual American Society of Hematology conference.

“Some guidelines say to evaluate patients with vertebral fractures, including measuring serum M-protein and free light chains, and others say to evaluate only if there is an indication — but without specifying what an indication is,” Rønnemoes, of the Danish Red Blood Cell Center, Copenhagen University Hospital — Rigshospitalet, Denmark, said in an interview. 

To assess the association between vertebral fractures and MM, he and his colleagues studied 9065 individuals from the Danish general population, aged 33-94 years (median, 62 years) who were part of the Copenhagen General Population Study and who had attended a health examination and underwent a CT scan as part of the study. Overall, 1574 (17.4%) had one or more incidentally discovered vertebral fracture on the CT scan, and of those, 875 (9.7%) had a grade 1 fracture as the highest grade and 699 (7.7%) had grade 2-3 fractures.

During a median prospective follow-up of 5.5 years after the scan, 13 were diagnosed with myeloma.

“We did find an increased relative risk of myeloma in these patients, which we thought was quite interesting, but the absolute risk was quite modest,” Rønnemoes said.

The absolute 5-year risk for MM was 0.07% and 0.10% in women and men without vertebral fractures, respectively, and the risk for those with fractures was 0.17% and 0.24% in women and men with grade 1 fractures, respectively, and 0.43% and 0.63% in women and men with grade 2-3 fractures, respectively.

A case-cohort study based on more than 56,000 individuals from the UK Biobank cohort who had undergone a dual-energy x-ray absorptiometry scan as part of that study validated the findings in the Danish population: At median follow-up of 4 years, 49 patients in the validation cohort were diagnosed with myeloma, and the absolute 5-year risk for myeloma was 0.06% and 0.12% in women and men with grade 1 fractures, respectively, and 0.14% and 0.26% in women and men with grade 2-3 fractures, respectively.

Given the apparently modest absolute risk for MM in patients with incidentally discovered fractures in the absence of strong indications or risk, treatment guidelines should consider the potential harms associated with additional work up and a monoclonal gammopathy of undetermined significance diagnosis, Rønnemoes said. 

Such a diagnosis can lead to psychological distress in individuals who may never develop malignant disease, he noted.

“We just hope to bring more value to the guidelines by identifying who should be evaluated,” he said, adding that additional study — perhaps looking more closely at whether only the more severe fractures should prompt additional evaluation — is warranted.

Rønnemoes reported no disclosures.

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

SAN DIEGO — Incidentally discovered vertebral fractures are common on scans in the general population, while the absolute risk for multiple myeloma (MM) in those with such fractures is “quite modest,” according to findings in a Danish cohort of more than 9000 patients.

The findings suggest that evaluation for underlying MM — as recommended in some clinical guidelines — may be unwarranted in the absence of symptoms or other clinical findings leading to suspicion of underlying MM, Rasmus Rønnemoes, MD, reported during a poster session at the annual American Society of Hematology conference.

“Some guidelines say to evaluate patients with vertebral fractures, including measuring serum M-protein and free light chains, and others say to evaluate only if there is an indication — but without specifying what an indication is,” Rønnemoes, of the Danish Red Blood Cell Center, Copenhagen University Hospital — Rigshospitalet, Denmark, said in an interview. 

To assess the association between vertebral fractures and MM, he and his colleagues studied 9065 individuals from the Danish general population, aged 33-94 years (median, 62 years) who were part of the Copenhagen General Population Study and who had attended a health examination and underwent a CT scan as part of the study. Overall, 1574 (17.4%) had one or more incidentally discovered vertebral fracture on the CT scan, and of those, 875 (9.7%) had a grade 1 fracture as the highest grade and 699 (7.7%) had grade 2-3 fractures.

During a median prospective follow-up of 5.5 years after the scan, 13 were diagnosed with myeloma.

“We did find an increased relative risk of myeloma in these patients, which we thought was quite interesting, but the absolute risk was quite modest,” Rønnemoes said.

The absolute 5-year risk for MM was 0.07% and 0.10% in women and men without vertebral fractures, respectively, and the risk for those with fractures was 0.17% and 0.24% in women and men with grade 1 fractures, respectively, and 0.43% and 0.63% in women and men with grade 2-3 fractures, respectively.

A case-cohort study based on more than 56,000 individuals from the UK Biobank cohort who had undergone a dual-energy x-ray absorptiometry scan as part of that study validated the findings in the Danish population: At median follow-up of 4 years, 49 patients in the validation cohort were diagnosed with myeloma, and the absolute 5-year risk for myeloma was 0.06% and 0.12% in women and men with grade 1 fractures, respectively, and 0.14% and 0.26% in women and men with grade 2-3 fractures, respectively.

Given the apparently modest absolute risk for MM in patients with incidentally discovered fractures in the absence of strong indications or risk, treatment guidelines should consider the potential harms associated with additional work up and a monoclonal gammopathy of undetermined significance diagnosis, Rønnemoes said. 

Such a diagnosis can lead to psychological distress in individuals who may never develop malignant disease, he noted.

“We just hope to bring more value to the guidelines by identifying who should be evaluated,” he said, adding that additional study — perhaps looking more closely at whether only the more severe fractures should prompt additional evaluation — is warranted.

Rønnemoes reported no disclosures.

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

SAN DIEGO — Incidentally discovered vertebral fractures are common on scans in the general population, while the absolute risk for multiple myeloma (MM) in those with such fractures is “quite modest,” according to findings in a Danish cohort of more than 9000 patients.

The findings suggest that evaluation for underlying MM — as recommended in some clinical guidelines — may be unwarranted in the absence of symptoms or other clinical findings leading to suspicion of underlying MM, Rasmus Rønnemoes, MD, reported during a poster session at the annual American Society of Hematology conference.

“Some guidelines say to evaluate patients with vertebral fractures, including measuring serum M-protein and free light chains, and others say to evaluate only if there is an indication — but without specifying what an indication is,” Rønnemoes, of the Danish Red Blood Cell Center, Copenhagen University Hospital — Rigshospitalet, Denmark, said in an interview. 

To assess the association between vertebral fractures and MM, he and his colleagues studied 9065 individuals from the Danish general population, aged 33-94 years (median, 62 years) who were part of the Copenhagen General Population Study and who had attended a health examination and underwent a CT scan as part of the study. Overall, 1574 (17.4%) had one or more incidentally discovered vertebral fracture on the CT scan, and of those, 875 (9.7%) had a grade 1 fracture as the highest grade and 699 (7.7%) had grade 2-3 fractures.

During a median prospective follow-up of 5.5 years after the scan, 13 were diagnosed with myeloma.

“We did find an increased relative risk of myeloma in these patients, which we thought was quite interesting, but the absolute risk was quite modest,” Rønnemoes said.

The absolute 5-year risk for MM was 0.07% and 0.10% in women and men without vertebral fractures, respectively, and the risk for those with fractures was 0.17% and 0.24% in women and men with grade 1 fractures, respectively, and 0.43% and 0.63% in women and men with grade 2-3 fractures, respectively.

A case-cohort study based on more than 56,000 individuals from the UK Biobank cohort who had undergone a dual-energy x-ray absorptiometry scan as part of that study validated the findings in the Danish population: At median follow-up of 4 years, 49 patients in the validation cohort were diagnosed with myeloma, and the absolute 5-year risk for myeloma was 0.06% and 0.12% in women and men with grade 1 fractures, respectively, and 0.14% and 0.26% in women and men with grade 2-3 fractures, respectively.

Given the apparently modest absolute risk for MM in patients with incidentally discovered fractures in the absence of strong indications or risk, treatment guidelines should consider the potential harms associated with additional work up and a monoclonal gammopathy of undetermined significance diagnosis, Rønnemoes said. 

Such a diagnosis can lead to psychological distress in individuals who may never develop malignant disease, he noted.

“We just hope to bring more value to the guidelines by identifying who should be evaluated,” he said, adding that additional study — perhaps looking more closely at whether only the more severe fractures should prompt additional evaluation — is warranted.

Rønnemoes reported no disclosures.

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

SAN DIEGO — A new study linked longer duration and deeper intensity of tobacco smoking to more genetic mutations in myelodysplastic syndromes (MDSs), a group of bone marrow cancers that are similar to acute myeloid leukemia.

The prospective National MDS Natural History Study evaluated 1898 patients with recently diagnosed or suspected MDS. An adjusted analysis linked higher number of pack-years to more mutations (P = .006), with those at the 90th percentile with 3.5 times the number of mutations as nonsmokers, researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.

The findings “suggest that smoking potentially contributes to the multistep molecular genetic pathogenesis that ultimately results in diagnosis of the cancer,” said corresponding author Mikkael A. Sekeres, MD, of the Sylvester Comprehensive Cancer Center, University of Miami Health System in Florida, at a news briefing. “The more you smoke, the more likely you are to acquire more mutations and even develop a higher risk of myelodysplastic syndromes. [More smoking] was also associated with progression and survival.”

While numbers are uncertain, an estimated 10,000 or more people in the United States each year are diagnosed with MDS, also known as preleukemia, according to the American Cancer Society. Median survival ranges from 1 to 10.6 years based on risk group, although the cancer society says the statistics are dated and mainly from Europe.

Multiple studies have linked smoking to MDS. The new study aims to understand the possible effects of smoking on genetic mutations.

The research analyzed 1898 patients enrolled from 2016 to 2023 (52% who had ever smoked; 18% current smokers; mean smoking years, 29.8 ± 16.9 years). The patients had diagnoses of MDSs, MDS/myeloproliferative neoplasm overlap, or precursor conditions such as clonal cytopenia of undetermined significance (CCUS).

Smokers were more likely than nonsmokers to be men (68% vs 54%; P < .001) and aged 70-79 years (45% vs 34%; P < .001).

After adjustment for confounders, smokers had more average mutations linked to MDS than nonsmokers (2.0 vs 1.4; P = .04). Those at the 75th percentile of pack-years had 1.8 times as many MDS-linked mutations as nonsmokers.

The 5-year cumulative incidence of disease progression was higher in long-term smokers than in nonsmokers and those with shorter smoking history (mean proportion progressed, 20+ years vs < 20 years smoking/nonsmoking, 27% [19%-36%] vs 18% [13%-24%]; P < .05, respectively).

Also, overall survival was lower in smokers than in nonsmokers for patients with CCUS (hazard ratio [HR], 1.91; 95% CI, 1.03-3.55; P = .04) but not for those with MDS (HR, 1.21; 95% CI, 0.53-1.30; P = .41).

“The data suggests that a patient with a new diagnosis of MDS who also smokes should be counseled to stop smoking,” Sekeres said.

This may seem counterintuitive to patients, he acknowledged. When Sekeres was a medical student, he counseled a female patient with advanced lung cancer to quit smoking. “The patient looked at me like I had three heads and she said: ‘Why should I stop smoking? The cats are already out of the bag. I have lung cancer.’ ”

But the new study points to a possible benefit from quitting smoking while sick. “It appears that smoking contributes to the acquisition of new genetic mutations that can lead to worsening of the myelodysplastic syndromes and even evolution of the cancer into acute myeloid leukemia,” Sekeres said.

He added: “One thing to understand about these cancers of the bone marrow is they can take years or decades to develop. They’re not one-hit wonders. Smoking caused very specific genetic mutations. The cool part of this is that they’re the same genetic mutations smoking has been shown to cause in cancers like lung cancer, so we’re seeing consistency across cancers.”

Sekeres said he himself will counsel patients with MDS or acute myeloid leukemia to stop smoking. “If there’s anything we can do to intervene to prevent myelodysplastic syndrome from evolving into acute leukemia, my word, I sure I’m going to try it.”

In an interview, Peter Greenberg, MD, professor of medicine at Stanford Cancer Center in California, who’s familiar with the study but didn’t take part in the research, said the study suggests that smoking in MDS isn’t just related to exposure to fumes “but appears to be a much more widespread problem” related to its impact on generating hematologic stem cell mutations.

Most clinicians don’t warn patients with MDS about the dangers of smoking because they’re not aware of tobacco’s connection to the disease, Greenberg said. But there’s another reason to bring up smoking, he said: It boosts the risk for cardiovascular disease, which may be partially responsible for decreased survival in smokers.

Sekeres disclosed ties with Kurome, Schrödinger, and Bristol-Myers Squibb. Other authors reported multiple and various relationships with industry. Greenberg had no disclosures.

A version of this article appeared on Medscape.com.

SAN DIEGO — A new study linked longer duration and deeper intensity of tobacco smoking to more genetic mutations in myelodysplastic syndromes (MDSs), a group of bone marrow cancers that are similar to acute myeloid leukemia.

The prospective National MDS Natural History Study evaluated 1898 patients with recently diagnosed or suspected MDS. An adjusted analysis linked higher number of pack-years to more mutations (P = .006), with those at the 90th percentile with 3.5 times the number of mutations as nonsmokers, researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.

The findings “suggest that smoking potentially contributes to the multistep molecular genetic pathogenesis that ultimately results in diagnosis of the cancer,” said corresponding author Mikkael A. Sekeres, MD, of the Sylvester Comprehensive Cancer Center, University of Miami Health System in Florida, at a news briefing. “The more you smoke, the more likely you are to acquire more mutations and even develop a higher risk of myelodysplastic syndromes. [More smoking] was also associated with progression and survival.”

While numbers are uncertain, an estimated 10,000 or more people in the United States each year are diagnosed with MDS, also known as preleukemia, according to the American Cancer Society. Median survival ranges from 1 to 10.6 years based on risk group, although the cancer society says the statistics are dated and mainly from Europe.

Multiple studies have linked smoking to MDS. The new study aims to understand the possible effects of smoking on genetic mutations.

The research analyzed 1898 patients enrolled from 2016 to 2023 (52% who had ever smoked; 18% current smokers; mean smoking years, 29.8 ± 16.9 years). The patients had diagnoses of MDSs, MDS/myeloproliferative neoplasm overlap, or precursor conditions such as clonal cytopenia of undetermined significance (CCUS).

Smokers were more likely than nonsmokers to be men (68% vs 54%; P < .001) and aged 70-79 years (45% vs 34%; P < .001).

After adjustment for confounders, smokers had more average mutations linked to MDS than nonsmokers (2.0 vs 1.4; P = .04). Those at the 75th percentile of pack-years had 1.8 times as many MDS-linked mutations as nonsmokers.

The 5-year cumulative incidence of disease progression was higher in long-term smokers than in nonsmokers and those with shorter smoking history (mean proportion progressed, 20+ years vs < 20 years smoking/nonsmoking, 27% [19%-36%] vs 18% [13%-24%]; P < .05, respectively).

Also, overall survival was lower in smokers than in nonsmokers for patients with CCUS (hazard ratio [HR], 1.91; 95% CI, 1.03-3.55; P = .04) but not for those with MDS (HR, 1.21; 95% CI, 0.53-1.30; P = .41).

“The data suggests that a patient with a new diagnosis of MDS who also smokes should be counseled to stop smoking,” Sekeres said.

This may seem counterintuitive to patients, he acknowledged. When Sekeres was a medical student, he counseled a female patient with advanced lung cancer to quit smoking. “The patient looked at me like I had three heads and she said: ‘Why should I stop smoking? The cats are already out of the bag. I have lung cancer.’ ”

But the new study points to a possible benefit from quitting smoking while sick. “It appears that smoking contributes to the acquisition of new genetic mutations that can lead to worsening of the myelodysplastic syndromes and even evolution of the cancer into acute myeloid leukemia,” Sekeres said.

He added: “One thing to understand about these cancers of the bone marrow is they can take years or decades to develop. They’re not one-hit wonders. Smoking caused very specific genetic mutations. The cool part of this is that they’re the same genetic mutations smoking has been shown to cause in cancers like lung cancer, so we’re seeing consistency across cancers.”

Sekeres said he himself will counsel patients with MDS or acute myeloid leukemia to stop smoking. “If there’s anything we can do to intervene to prevent myelodysplastic syndrome from evolving into acute leukemia, my word, I sure I’m going to try it.”

In an interview, Peter Greenberg, MD, professor of medicine at Stanford Cancer Center in California, who’s familiar with the study but didn’t take part in the research, said the study suggests that smoking in MDS isn’t just related to exposure to fumes “but appears to be a much more widespread problem” related to its impact on generating hematologic stem cell mutations.

Most clinicians don’t warn patients with MDS about the dangers of smoking because they’re not aware of tobacco’s connection to the disease, Greenberg said. But there’s another reason to bring up smoking, he said: It boosts the risk for cardiovascular disease, which may be partially responsible for decreased survival in smokers.

Sekeres disclosed ties with Kurome, Schrödinger, and Bristol-Myers Squibb. Other authors reported multiple and various relationships with industry. Greenberg had no disclosures.

A version of this article appeared on Medscape.com.

SAN DIEGO — A new study linked longer duration and deeper intensity of tobacco smoking to more genetic mutations in myelodysplastic syndromes (MDSs), a group of bone marrow cancers that are similar to acute myeloid leukemia.

The prospective National MDS Natural History Study evaluated 1898 patients with recently diagnosed or suspected MDS. An adjusted analysis linked higher number of pack-years to more mutations (P = .006), with those at the 90th percentile with 3.5 times the number of mutations as nonsmokers, researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.

The findings “suggest that smoking potentially contributes to the multistep molecular genetic pathogenesis that ultimately results in diagnosis of the cancer,” said corresponding author Mikkael A. Sekeres, MD, of the Sylvester Comprehensive Cancer Center, University of Miami Health System in Florida, at a news briefing. “The more you smoke, the more likely you are to acquire more mutations and even develop a higher risk of myelodysplastic syndromes. [More smoking] was also associated with progression and survival.”

While numbers are uncertain, an estimated 10,000 or more people in the United States each year are diagnosed with MDS, also known as preleukemia, according to the American Cancer Society. Median survival ranges from 1 to 10.6 years based on risk group, although the cancer society says the statistics are dated and mainly from Europe.

Multiple studies have linked smoking to MDS. The new study aims to understand the possible effects of smoking on genetic mutations.

The research analyzed 1898 patients enrolled from 2016 to 2023 (52% who had ever smoked; 18% current smokers; mean smoking years, 29.8 ± 16.9 years). The patients had diagnoses of MDSs, MDS/myeloproliferative neoplasm overlap, or precursor conditions such as clonal cytopenia of undetermined significance (CCUS).

Smokers were more likely than nonsmokers to be men (68% vs 54%; P < .001) and aged 70-79 years (45% vs 34%; P < .001).

After adjustment for confounders, smokers had more average mutations linked to MDS than nonsmokers (2.0 vs 1.4; P = .04). Those at the 75th percentile of pack-years had 1.8 times as many MDS-linked mutations as nonsmokers.

The 5-year cumulative incidence of disease progression was higher in long-term smokers than in nonsmokers and those with shorter smoking history (mean proportion progressed, 20+ years vs < 20 years smoking/nonsmoking, 27% [19%-36%] vs 18% [13%-24%]; P < .05, respectively).

Also, overall survival was lower in smokers than in nonsmokers for patients with CCUS (hazard ratio [HR], 1.91; 95% CI, 1.03-3.55; P = .04) but not for those with MDS (HR, 1.21; 95% CI, 0.53-1.30; P = .41).

“The data suggests that a patient with a new diagnosis of MDS who also smokes should be counseled to stop smoking,” Sekeres said.

This may seem counterintuitive to patients, he acknowledged. When Sekeres was a medical student, he counseled a female patient with advanced lung cancer to quit smoking. “The patient looked at me like I had three heads and she said: ‘Why should I stop smoking? The cats are already out of the bag. I have lung cancer.’ ”

But the new study points to a possible benefit from quitting smoking while sick. “It appears that smoking contributes to the acquisition of new genetic mutations that can lead to worsening of the myelodysplastic syndromes and even evolution of the cancer into acute myeloid leukemia,” Sekeres said.

He added: “One thing to understand about these cancers of the bone marrow is they can take years or decades to develop. They’re not one-hit wonders. Smoking caused very specific genetic mutations. The cool part of this is that they’re the same genetic mutations smoking has been shown to cause in cancers like lung cancer, so we’re seeing consistency across cancers.”

Sekeres said he himself will counsel patients with MDS or acute myeloid leukemia to stop smoking. “If there’s anything we can do to intervene to prevent myelodysplastic syndrome from evolving into acute leukemia, my word, I sure I’m going to try it.”

In an interview, Peter Greenberg, MD, professor of medicine at Stanford Cancer Center in California, who’s familiar with the study but didn’t take part in the research, said the study suggests that smoking in MDS isn’t just related to exposure to fumes “but appears to be a much more widespread problem” related to its impact on generating hematologic stem cell mutations.

Most clinicians don’t warn patients with MDS about the dangers of smoking because they’re not aware of tobacco’s connection to the disease, Greenberg said. But there’s another reason to bring up smoking, he said: It boosts the risk for cardiovascular disease, which may be partially responsible for decreased survival in smokers.

Sekeres disclosed ties with Kurome, Schrödinger, and Bristol-Myers Squibb. Other authors reported multiple and various relationships with industry. Greenberg had no disclosures.

A version of this article appeared on Medscape.com.

SAN DIEGO — Significant complications were common in female patients with sickle cell disease (SCD) who underwent fertility preservation (FP) procedures, and 13% required multiple retrieval cycles, a five-center retrospective study found.

Of 46 patients with SCD, complications occurred in 25 of 55 controlled ovarian hyperstimulation cycles, including 29 vaso-occlusive episodes (VOEs), researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.

Of 21 post-retrieval VOEs, 19 required emergency department care or hospitalization.

“Baseline sickle cell disease severity is most likely associated with a patient’s risk of complications from an egg retrieval cycle,” study co-author Sarah Cromack, MD, a reproductive endocrinology and infertility fellow at Northwestern University, Chicago, said in an interview.

“Both hematologists and reproductive endocrinologists can use this information to plan ahead and anticipate possible issues, check blood counts prior to and after egg retrieval to see if transfusion is needed, and plan close follow-up during stimulation and immediately after egg retrieval to evaluate and treat pain.”

 

SCD Accelerates Decline in Ovarian Reserve

Pediatric hematologist Lydia H. Pecker, MD, MS, of Johns Hopkins University School of Medicine, Baltimore, the study’s corresponding author, said in an interview that SCD is “a disease of accelerated aging” that leads to accelerated decline in ovarian reserve. “The common indication for fertility preservation in SCD is before bone marrow transplant or gene therapy,” she said, although FP can also be offered to other patients with SCD.

According to Cromack, researchers launched the study to expand information about SCD and FP in light of sparse data about outcomes.

All the 46 patients had hemoglobin SS (HbSS, 93%) and HbSβ0-thalassemia (7%) and a median age of 23.7 (18-28) years. Almost all (44 patients) underwent FP prior to curative treatments, and all had at least one SCD-related complication, mainly cerebrovascular disease (16), acute chest syndrome (23), and more than two VOEs per year (31).

Median anti-Mullerian hormone (AMH) level (2.1 ng/mL), a measurement of ovarian reserve, was lower than the expected level of 2.8-3.4 ng/mL among women in the age range of the patients, the researchers reported. “This is consistent with previous studies showing lower AMH for age in women with sickle cell disease,” Pecker said.

 

Complications in 45% of Retrieval Cycles

“In terms of success of oocyte cryopreservation, the median number of mature eggs frozen was 11,” said co-author and reproductive endocrinologist Jessica Walter, MD, of Northwestern University, in an interview. “Given the average age of 24 years in the cohort, this would give each patient about a 70% estimated probability of at least one live birth from their cohort of frozen eggs. Thus, patients hoping for more than one child may want to consider more than one cycle of egg freezing.”

The rate of complications was “fairly high” at 45% of all cycles, Walter said. “These were mostly complications from underlying sickle cell disease, including unplanned transfusions and admissions for vaso-occlusive crises. Surprisingly, there were very few cases of ovarian hyperstimulation syndrome in this young patient group, which may be due to a combination of underlying vascular disease, lower peak estradiol levels, and slightly less eggs retrieved then would be expected compared to an age-matched healthy controls.”

Any FP complication was associated with more than three VOEs in the year before controlled ovarian hyperstimulation (mean of three VOEs per patient without complications vs six per patient with complications; P = .036).

 

Higher Than Normal Need for Multiple Cycles

Reproductive endocrinologist H. Irene Su, MD, professor and co-director of the Center for OB/GYN Research Innovations at Moores Cancer Center, University of California San Diego, praised the study as “an important report” in an interview.

Su, who wasn’t involved in the research, said the percentage of patients requiring more than one cycle due to cancellation or low oocyte yield — 13% — is “higher than expected, given the young age of this cohort.”

This could reflect the hypothesis that “sickle cell crises and hypoxia adversely affect the finite number of oocytes in the ovary,” she said.

As for the study findings regarding complications, she said the rate “is very high compared to the general infertility or fertility preservation population. It would be good to learn predictors of these outcomes so that fertility and hematology clinicians can work together to stratify risk and supportive services around FP cycles. It would also be good to know if the post-retrieval VOE were unexpected given the patient’s disease activity prior to FP.”

 

Message: FP in SCD Is Feasible, Acceptable

A.D. Mishkin, MD, MPH, associate professor of psychiatry and liaison to the Blood and Marrow Transplantation Program at NewYork–Presbyterian/Columbia University Irving Medical Center, New York City, said in an interview that the study “establishes the feasibility and acceptability of oocyte harvest and preservation in a population of patients with active ongoing symptoms from SCD. It also indicates their interest in pursuing fertility preservation in the setting of frequent crises and the potential for management of ensuing complications.”

Mishkin, who didn’t take part in the research, highlighted the finding that half the patients got access to FP via public insurance or research funding. “Even in this population where most women had multiple complications in the year prior to FP, and even among patients who needed multiple retrievals, these patients wanted to go through that risk to preserve their fertility,” Mishkin said. “This is an important finding given the very limited access many individuals have to FP due to its high cost and limited insurance coverage, which is also largely state-dependent.”

There’s another factor to consider regarding SCD and FP: The potential danger of pregnancy.

Corresponding author Pecker noted that “pregnancy is high risk for people with sickle cell disease. There are very high rates of severe maternal mortality and morbidity even in high-income countries. However, some of this is modifiable with routine use of chronic transfusions during pregnancy and with high-quality and integrated expert SCD and expert maternal fetal medicine care during pregnancy.”

The National Institutes of Health supported the research. Pecker reported receiving research funding from Alexion, Novartis, and Aummune and consulting for Novo Nordisk. Other authors reported no disclosures. Su and Mishkin reported no disclosures.

 

A version of this article appeared on Medscape.com.

SAN DIEGO — Significant complications were common in female patients with sickle cell disease (SCD) who underwent fertility preservation (FP) procedures, and 13% required multiple retrieval cycles, a five-center retrospective study found.

Of 46 patients with SCD, complications occurred in 25 of 55 controlled ovarian hyperstimulation cycles, including 29 vaso-occlusive episodes (VOEs), researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.

Of 21 post-retrieval VOEs, 19 required emergency department care or hospitalization.

“Baseline sickle cell disease severity is most likely associated with a patient’s risk of complications from an egg retrieval cycle,” study co-author Sarah Cromack, MD, a reproductive endocrinology and infertility fellow at Northwestern University, Chicago, said in an interview.

“Both hematologists and reproductive endocrinologists can use this information to plan ahead and anticipate possible issues, check blood counts prior to and after egg retrieval to see if transfusion is needed, and plan close follow-up during stimulation and immediately after egg retrieval to evaluate and treat pain.”

 

SCD Accelerates Decline in Ovarian Reserve

Pediatric hematologist Lydia H. Pecker, MD, MS, of Johns Hopkins University School of Medicine, Baltimore, the study’s corresponding author, said in an interview that SCD is “a disease of accelerated aging” that leads to accelerated decline in ovarian reserve. “The common indication for fertility preservation in SCD is before bone marrow transplant or gene therapy,” she said, although FP can also be offered to other patients with SCD.

According to Cromack, researchers launched the study to expand information about SCD and FP in light of sparse data about outcomes.

All the 46 patients had hemoglobin SS (HbSS, 93%) and HbSβ0-thalassemia (7%) and a median age of 23.7 (18-28) years. Almost all (44 patients) underwent FP prior to curative treatments, and all had at least one SCD-related complication, mainly cerebrovascular disease (16), acute chest syndrome (23), and more than two VOEs per year (31).

Median anti-Mullerian hormone (AMH) level (2.1 ng/mL), a measurement of ovarian reserve, was lower than the expected level of 2.8-3.4 ng/mL among women in the age range of the patients, the researchers reported. “This is consistent with previous studies showing lower AMH for age in women with sickle cell disease,” Pecker said.

 

Complications in 45% of Retrieval Cycles

“In terms of success of oocyte cryopreservation, the median number of mature eggs frozen was 11,” said co-author and reproductive endocrinologist Jessica Walter, MD, of Northwestern University, in an interview. “Given the average age of 24 years in the cohort, this would give each patient about a 70% estimated probability of at least one live birth from their cohort of frozen eggs. Thus, patients hoping for more than one child may want to consider more than one cycle of egg freezing.”

The rate of complications was “fairly high” at 45% of all cycles, Walter said. “These were mostly complications from underlying sickle cell disease, including unplanned transfusions and admissions for vaso-occlusive crises. Surprisingly, there were very few cases of ovarian hyperstimulation syndrome in this young patient group, which may be due to a combination of underlying vascular disease, lower peak estradiol levels, and slightly less eggs retrieved then would be expected compared to an age-matched healthy controls.”

Any FP complication was associated with more than three VOEs in the year before controlled ovarian hyperstimulation (mean of three VOEs per patient without complications vs six per patient with complications; P = .036).

 

Higher Than Normal Need for Multiple Cycles

Reproductive endocrinologist H. Irene Su, MD, professor and co-director of the Center for OB/GYN Research Innovations at Moores Cancer Center, University of California San Diego, praised the study as “an important report” in an interview.

Su, who wasn’t involved in the research, said the percentage of patients requiring more than one cycle due to cancellation or low oocyte yield — 13% — is “higher than expected, given the young age of this cohort.”

This could reflect the hypothesis that “sickle cell crises and hypoxia adversely affect the finite number of oocytes in the ovary,” she said.

As for the study findings regarding complications, she said the rate “is very high compared to the general infertility or fertility preservation population. It would be good to learn predictors of these outcomes so that fertility and hematology clinicians can work together to stratify risk and supportive services around FP cycles. It would also be good to know if the post-retrieval VOE were unexpected given the patient’s disease activity prior to FP.”

 

Message: FP in SCD Is Feasible, Acceptable

A.D. Mishkin, MD, MPH, associate professor of psychiatry and liaison to the Blood and Marrow Transplantation Program at NewYork–Presbyterian/Columbia University Irving Medical Center, New York City, said in an interview that the study “establishes the feasibility and acceptability of oocyte harvest and preservation in a population of patients with active ongoing symptoms from SCD. It also indicates their interest in pursuing fertility preservation in the setting of frequent crises and the potential for management of ensuing complications.”

Mishkin, who didn’t take part in the research, highlighted the finding that half the patients got access to FP via public insurance or research funding. “Even in this population where most women had multiple complications in the year prior to FP, and even among patients who needed multiple retrievals, these patients wanted to go through that risk to preserve their fertility,” Mishkin said. “This is an important finding given the very limited access many individuals have to FP due to its high cost and limited insurance coverage, which is also largely state-dependent.”

There’s another factor to consider regarding SCD and FP: The potential danger of pregnancy.

Corresponding author Pecker noted that “pregnancy is high risk for people with sickle cell disease. There are very high rates of severe maternal mortality and morbidity even in high-income countries. However, some of this is modifiable with routine use of chronic transfusions during pregnancy and with high-quality and integrated expert SCD and expert maternal fetal medicine care during pregnancy.”

The National Institutes of Health supported the research. Pecker reported receiving research funding from Alexion, Novartis, and Aummune and consulting for Novo Nordisk. Other authors reported no disclosures. Su and Mishkin reported no disclosures.

 

A version of this article appeared on Medscape.com.

SAN DIEGO — Significant complications were common in female patients with sickle cell disease (SCD) who underwent fertility preservation (FP) procedures, and 13% required multiple retrieval cycles, a five-center retrospective study found.

Of 46 patients with SCD, complications occurred in 25 of 55 controlled ovarian hyperstimulation cycles, including 29 vaso-occlusive episodes (VOEs), researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.

Of 21 post-retrieval VOEs, 19 required emergency department care or hospitalization.

“Baseline sickle cell disease severity is most likely associated with a patient’s risk of complications from an egg retrieval cycle,” study co-author Sarah Cromack, MD, a reproductive endocrinology and infertility fellow at Northwestern University, Chicago, said in an interview.

“Both hematologists and reproductive endocrinologists can use this information to plan ahead and anticipate possible issues, check blood counts prior to and after egg retrieval to see if transfusion is needed, and plan close follow-up during stimulation and immediately after egg retrieval to evaluate and treat pain.”

 

SCD Accelerates Decline in Ovarian Reserve

Pediatric hematologist Lydia H. Pecker, MD, MS, of Johns Hopkins University School of Medicine, Baltimore, the study’s corresponding author, said in an interview that SCD is “a disease of accelerated aging” that leads to accelerated decline in ovarian reserve. “The common indication for fertility preservation in SCD is before bone marrow transplant or gene therapy,” she said, although FP can also be offered to other patients with SCD.

According to Cromack, researchers launched the study to expand information about SCD and FP in light of sparse data about outcomes.

All the 46 patients had hemoglobin SS (HbSS, 93%) and HbSβ0-thalassemia (7%) and a median age of 23.7 (18-28) years. Almost all (44 patients) underwent FP prior to curative treatments, and all had at least one SCD-related complication, mainly cerebrovascular disease (16), acute chest syndrome (23), and more than two VOEs per year (31).

Median anti-Mullerian hormone (AMH) level (2.1 ng/mL), a measurement of ovarian reserve, was lower than the expected level of 2.8-3.4 ng/mL among women in the age range of the patients, the researchers reported. “This is consistent with previous studies showing lower AMH for age in women with sickle cell disease,” Pecker said.

 

Complications in 45% of Retrieval Cycles

“In terms of success of oocyte cryopreservation, the median number of mature eggs frozen was 11,” said co-author and reproductive endocrinologist Jessica Walter, MD, of Northwestern University, in an interview. “Given the average age of 24 years in the cohort, this would give each patient about a 70% estimated probability of at least one live birth from their cohort of frozen eggs. Thus, patients hoping for more than one child may want to consider more than one cycle of egg freezing.”

The rate of complications was “fairly high” at 45% of all cycles, Walter said. “These were mostly complications from underlying sickle cell disease, including unplanned transfusions and admissions for vaso-occlusive crises. Surprisingly, there were very few cases of ovarian hyperstimulation syndrome in this young patient group, which may be due to a combination of underlying vascular disease, lower peak estradiol levels, and slightly less eggs retrieved then would be expected compared to an age-matched healthy controls.”

Any FP complication was associated with more than three VOEs in the year before controlled ovarian hyperstimulation (mean of three VOEs per patient without complications vs six per patient with complications; P = .036).

 

Higher Than Normal Need for Multiple Cycles

Reproductive endocrinologist H. Irene Su, MD, professor and co-director of the Center for OB/GYN Research Innovations at Moores Cancer Center, University of California San Diego, praised the study as “an important report” in an interview.

Su, who wasn’t involved in the research, said the percentage of patients requiring more than one cycle due to cancellation or low oocyte yield — 13% — is “higher than expected, given the young age of this cohort.”

This could reflect the hypothesis that “sickle cell crises and hypoxia adversely affect the finite number of oocytes in the ovary,” she said.

As for the study findings regarding complications, she said the rate “is very high compared to the general infertility or fertility preservation population. It would be good to learn predictors of these outcomes so that fertility and hematology clinicians can work together to stratify risk and supportive services around FP cycles. It would also be good to know if the post-retrieval VOE were unexpected given the patient’s disease activity prior to FP.”

 

Message: FP in SCD Is Feasible, Acceptable

A.D. Mishkin, MD, MPH, associate professor of psychiatry and liaison to the Blood and Marrow Transplantation Program at NewYork–Presbyterian/Columbia University Irving Medical Center, New York City, said in an interview that the study “establishes the feasibility and acceptability of oocyte harvest and preservation in a population of patients with active ongoing symptoms from SCD. It also indicates their interest in pursuing fertility preservation in the setting of frequent crises and the potential for management of ensuing complications.”

Mishkin, who didn’t take part in the research, highlighted the finding that half the patients got access to FP via public insurance or research funding. “Even in this population where most women had multiple complications in the year prior to FP, and even among patients who needed multiple retrievals, these patients wanted to go through that risk to preserve their fertility,” Mishkin said. “This is an important finding given the very limited access many individuals have to FP due to its high cost and limited insurance coverage, which is also largely state-dependent.”

There’s another factor to consider regarding SCD and FP: The potential danger of pregnancy.

Corresponding author Pecker noted that “pregnancy is high risk for people with sickle cell disease. There are very high rates of severe maternal mortality and morbidity even in high-income countries. However, some of this is modifiable with routine use of chronic transfusions during pregnancy and with high-quality and integrated expert SCD and expert maternal fetal medicine care during pregnancy.”

The National Institutes of Health supported the research. Pecker reported receiving research funding from Alexion, Novartis, and Aummune and consulting for Novo Nordisk. Other authors reported no disclosures. Su and Mishkin reported no disclosures.

 

A version of this article appeared on Medscape.com.

For younger, fit patients with mantle cell lymphoma (MCL), adding the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib to standard induction therapy with bendamustine/rituximab followed by cytarabine/rituximab adds toxicity without improving efficacy, results of the phase 2 ECOG-ACRIN EA4181 trial indicate.

However, treating patients with bendamustine/rituximab plus acalabrutinib might be preferred to either option with cytarabine.

Although the results showed that the bendamustine/rituximab plus acalabrutinib regimen was not superior to standard induction therapy with or without acalabrutinib, it was the least toxic option. 

Standard induction therapy can be still be considered the standard for this patient population, but eliminating cytarabine represents “an appealing option to avoid high-dose cytarabine,” said study investigator Nina Wagner-Johnston, MD, from Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland, during a presentation of the findings at the American Society of Hematology 2024 annual meeting. 

The bendamustine/rituximab plus acalabrutinib regimen, where acalabrutinib replaced high-dose cytarabine, is “the most intriguing arm of the study,” Marcus Messmer, MD, with the Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, said in an interview. 

“The results suggest that bendamustine/rituximab plus acalabrutinib may be equivalent in efficacy to [standard induction] with less toxicity,” said Messmer, who was not involved in the study. 

Unfortunately, the study was not designed to show noninferiority of bendamustine/rituximab plus acalabrutinib compared to standard induction therapy, and the bendamustine/rituximab plus acalabrutinib arm was stopped early because of a lack of a superiority signal, Messmer added.

 

Inside the Findings

MCL is a rare and aggressive B-cell lymphoma that poses unique treatment challenges, particularly in younger patients, for whom the treatment “landscape is shifting rapidly,” Wagner-Johnston explained.

Wagner-Johnston noted that the optimal induction regimen for fit, younger patients with MCL is unclear, although the mainstay of treatment is intensive chemoimmunotherapy with cytarabine.

The standard bendamustine/rituximab followed by cytarabine/rituximab induction regimen is associated with high complete remission and undetectable measurable residual disease, with evidence of improved progression-free survival, she noted. 

“And we know that BTK inhibitors, in combination with chemoimmunotherapy, are highly effective in MCL and that achieving molecular remission or undetectable measurable residual disease is an independent predictor of long-term outcomes in patients. All of these features were key when designing ECOG-ACRIN EA 4181,” Wagner-Johnston told attendees. 

The study enrolled 369 patients, 18-70 years old, with untreated MCL, ECOG performance score 0-2, and adequate organ and marrow function. Study participants were randomized 1:1:1 to the standard induction control arm or to one of two experimental arms. These included the control arm of induction therapy with three cycles of bendamustine/rituximab followed by three cycles of cytarabine/rituximab, the standard induction plus acalabrutinib across both cycles, or six cycles of bendamustine/rituximab with acalabrutinib.

In the standard induction plus acalabrutinib arm, acalabrutinib was dosed continuously at 100 mg twice daily during the initial cycles, and during weeks 1 and 3 of the latter cycles.

The primary analysis focused on 260 patients with an end-of-treatment sample sent for measurable residual disease testing. Roughly 90% of patients completed study treatment, with no differences between treatment arms. 

The primary outcome was a composite of PET/CT complete molecular remission and peripheral blood undetectable measurable residual disease. In the control arm, 82% of patients achieved the primary outcome, as did 82% of patients in the standard induction plus acalabrutinib arm and 78% in the bendamustine/rituximab plus acalabrutinib arm. 

“Notably, neither of the experimental arms were superior to the standard-of-care arm across the board,” Wagner-Johnston said. Overall response rates were “quite high,” with complete response rates of more than 90%, with no differences between the arms. 

Similarly, no significant difference was seen in progression-free survival or overall survival between treatment arms. At a medium follow up of roughly 28 months, the 12-month progression-free survival rate was 90%-92% across the three groups.

The team also evaluated progression-free survival by measurable residual disease status, regardless of whether patients completed protocol therapy. “Not surprisingly,” said Wagner-Johnston, progression-free survival was superior for those with undetectable measurable residual disease, compared with those with detectable levels — but again there was no differences between treatment arms. 

Grades 3-5 treatment-related adverse events occurred in at least 5% of patients and were mostly hematologic. 

The bendamustine/rituximab plus acalabrutinib was associated with significantly less hematologic toxicity, with a febrile neutropenia rate of 4.0% vs 8.9% in the standard induction arm and 9.3% in the standard induction plus acalabrutinib arm. 

Grades 3-5 treatment-related anemia rates were much lower in the bendamustine/rituximab plus acalabrutinib arm (3.0% vs 18.5% for standard induction and 24.8% for standard plus cytarabine). Similarly, the bendamustine/rituximab plus acalabrutinib arm had lower rates of treatment-related grade 3 or higher thrombocytopenia (6.0% vs 44.4% and 51.2%, respectively). 

Across all three treatment groups, rates of neurotoxicity, renal toxicity, bleeding/hemorrhage, and cardiac toxicity were low.

Treatment discontinuations due to adverse events were also low (7%) across the arms, with five treatment-related deaths reported. 

“Standard high-dose cytarabine requires inpatient administration and carries risk of neurologic and hematologic toxicity, making it particularly difficult to give in a community setting,” Marcus said in an interview. “This study, along with updated results from the TRIANGLE study, suggests that we are moving away from high-dose cytotoxic therapy and toward targeted therapy in frontline management of mantle cell lymphoma.”

The study was supported by the National Cancer Institute. Wagner-Johnston has received research founding from Genentech, Merck, and AstraZenecca and consults for Beigene. Marcus had no relevant disclosures.

A version of this article appeared on Medscape.com.

For younger, fit patients with mantle cell lymphoma (MCL), adding the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib to standard induction therapy with bendamustine/rituximab followed by cytarabine/rituximab adds toxicity without improving efficacy, results of the phase 2 ECOG-ACRIN EA4181 trial indicate.

However, treating patients with bendamustine/rituximab plus acalabrutinib might be preferred to either option with cytarabine.

Although the results showed that the bendamustine/rituximab plus acalabrutinib regimen was not superior to standard induction therapy with or without acalabrutinib, it was the least toxic option. 

Standard induction therapy can be still be considered the standard for this patient population, but eliminating cytarabine represents “an appealing option to avoid high-dose cytarabine,” said study investigator Nina Wagner-Johnston, MD, from Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland, during a presentation of the findings at the American Society of Hematology 2024 annual meeting. 

The bendamustine/rituximab plus acalabrutinib regimen, where acalabrutinib replaced high-dose cytarabine, is “the most intriguing arm of the study,” Marcus Messmer, MD, with the Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, said in an interview. 

“The results suggest that bendamustine/rituximab plus acalabrutinib may be equivalent in efficacy to [standard induction] with less toxicity,” said Messmer, who was not involved in the study. 

Unfortunately, the study was not designed to show noninferiority of bendamustine/rituximab plus acalabrutinib compared to standard induction therapy, and the bendamustine/rituximab plus acalabrutinib arm was stopped early because of a lack of a superiority signal, Messmer added.

 

Inside the Findings

MCL is a rare and aggressive B-cell lymphoma that poses unique treatment challenges, particularly in younger patients, for whom the treatment “landscape is shifting rapidly,” Wagner-Johnston explained.

Wagner-Johnston noted that the optimal induction regimen for fit, younger patients with MCL is unclear, although the mainstay of treatment is intensive chemoimmunotherapy with cytarabine.

The standard bendamustine/rituximab followed by cytarabine/rituximab induction regimen is associated with high complete remission and undetectable measurable residual disease, with evidence of improved progression-free survival, she noted. 

“And we know that BTK inhibitors, in combination with chemoimmunotherapy, are highly effective in MCL and that achieving molecular remission or undetectable measurable residual disease is an independent predictor of long-term outcomes in patients. All of these features were key when designing ECOG-ACRIN EA 4181,” Wagner-Johnston told attendees. 

The study enrolled 369 patients, 18-70 years old, with untreated MCL, ECOG performance score 0-2, and adequate organ and marrow function. Study participants were randomized 1:1:1 to the standard induction control arm or to one of two experimental arms. These included the control arm of induction therapy with three cycles of bendamustine/rituximab followed by three cycles of cytarabine/rituximab, the standard induction plus acalabrutinib across both cycles, or six cycles of bendamustine/rituximab with acalabrutinib.

In the standard induction plus acalabrutinib arm, acalabrutinib was dosed continuously at 100 mg twice daily during the initial cycles, and during weeks 1 and 3 of the latter cycles.

The primary analysis focused on 260 patients with an end-of-treatment sample sent for measurable residual disease testing. Roughly 90% of patients completed study treatment, with no differences between treatment arms. 

The primary outcome was a composite of PET/CT complete molecular remission and peripheral blood undetectable measurable residual disease. In the control arm, 82% of patients achieved the primary outcome, as did 82% of patients in the standard induction plus acalabrutinib arm and 78% in the bendamustine/rituximab plus acalabrutinib arm. 

“Notably, neither of the experimental arms were superior to the standard-of-care arm across the board,” Wagner-Johnston said. Overall response rates were “quite high,” with complete response rates of more than 90%, with no differences between the arms. 

Similarly, no significant difference was seen in progression-free survival or overall survival between treatment arms. At a medium follow up of roughly 28 months, the 12-month progression-free survival rate was 90%-92% across the three groups.

The team also evaluated progression-free survival by measurable residual disease status, regardless of whether patients completed protocol therapy. “Not surprisingly,” said Wagner-Johnston, progression-free survival was superior for those with undetectable measurable residual disease, compared with those with detectable levels — but again there was no differences between treatment arms. 

Grades 3-5 treatment-related adverse events occurred in at least 5% of patients and were mostly hematologic. 

The bendamustine/rituximab plus acalabrutinib was associated with significantly less hematologic toxicity, with a febrile neutropenia rate of 4.0% vs 8.9% in the standard induction arm and 9.3% in the standard induction plus acalabrutinib arm. 

Grades 3-5 treatment-related anemia rates were much lower in the bendamustine/rituximab plus acalabrutinib arm (3.0% vs 18.5% for standard induction and 24.8% for standard plus cytarabine). Similarly, the bendamustine/rituximab plus acalabrutinib arm had lower rates of treatment-related grade 3 or higher thrombocytopenia (6.0% vs 44.4% and 51.2%, respectively). 

Across all three treatment groups, rates of neurotoxicity, renal toxicity, bleeding/hemorrhage, and cardiac toxicity were low.

Treatment discontinuations due to adverse events were also low (7%) across the arms, with five treatment-related deaths reported. 

“Standard high-dose cytarabine requires inpatient administration and carries risk of neurologic and hematologic toxicity, making it particularly difficult to give in a community setting,” Marcus said in an interview. “This study, along with updated results from the TRIANGLE study, suggests that we are moving away from high-dose cytotoxic therapy and toward targeted therapy in frontline management of mantle cell lymphoma.”

The study was supported by the National Cancer Institute. Wagner-Johnston has received research founding from Genentech, Merck, and AstraZenecca and consults for Beigene. Marcus had no relevant disclosures.

A version of this article appeared on Medscape.com.

For younger, fit patients with mantle cell lymphoma (MCL), adding the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib to standard induction therapy with bendamustine/rituximab followed by cytarabine/rituximab adds toxicity without improving efficacy, results of the phase 2 ECOG-ACRIN EA4181 trial indicate.

However, treating patients with bendamustine/rituximab plus acalabrutinib might be preferred to either option with cytarabine.

Although the results showed that the bendamustine/rituximab plus acalabrutinib regimen was not superior to standard induction therapy with or without acalabrutinib, it was the least toxic option. 

Standard induction therapy can be still be considered the standard for this patient population, but eliminating cytarabine represents “an appealing option to avoid high-dose cytarabine,” said study investigator Nina Wagner-Johnston, MD, from Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland, during a presentation of the findings at the American Society of Hematology 2024 annual meeting. 

The bendamustine/rituximab plus acalabrutinib regimen, where acalabrutinib replaced high-dose cytarabine, is “the most intriguing arm of the study,” Marcus Messmer, MD, with the Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, said in an interview. 

“The results suggest that bendamustine/rituximab plus acalabrutinib may be equivalent in efficacy to [standard induction] with less toxicity,” said Messmer, who was not involved in the study. 

Unfortunately, the study was not designed to show noninferiority of bendamustine/rituximab plus acalabrutinib compared to standard induction therapy, and the bendamustine/rituximab plus acalabrutinib arm was stopped early because of a lack of a superiority signal, Messmer added.

 

Inside the Findings

MCL is a rare and aggressive B-cell lymphoma that poses unique treatment challenges, particularly in younger patients, for whom the treatment “landscape is shifting rapidly,” Wagner-Johnston explained.

Wagner-Johnston noted that the optimal induction regimen for fit, younger patients with MCL is unclear, although the mainstay of treatment is intensive chemoimmunotherapy with cytarabine.

The standard bendamustine/rituximab followed by cytarabine/rituximab induction regimen is associated with high complete remission and undetectable measurable residual disease, with evidence of improved progression-free survival, she noted. 

“And we know that BTK inhibitors, in combination with chemoimmunotherapy, are highly effective in MCL and that achieving molecular remission or undetectable measurable residual disease is an independent predictor of long-term outcomes in patients. All of these features were key when designing ECOG-ACRIN EA 4181,” Wagner-Johnston told attendees. 

The study enrolled 369 patients, 18-70 years old, with untreated MCL, ECOG performance score 0-2, and adequate organ and marrow function. Study participants were randomized 1:1:1 to the standard induction control arm or to one of two experimental arms. These included the control arm of induction therapy with three cycles of bendamustine/rituximab followed by three cycles of cytarabine/rituximab, the standard induction plus acalabrutinib across both cycles, or six cycles of bendamustine/rituximab with acalabrutinib.

In the standard induction plus acalabrutinib arm, acalabrutinib was dosed continuously at 100 mg twice daily during the initial cycles, and during weeks 1 and 3 of the latter cycles.

The primary analysis focused on 260 patients with an end-of-treatment sample sent for measurable residual disease testing. Roughly 90% of patients completed study treatment, with no differences between treatment arms. 

The primary outcome was a composite of PET/CT complete molecular remission and peripheral blood undetectable measurable residual disease. In the control arm, 82% of patients achieved the primary outcome, as did 82% of patients in the standard induction plus acalabrutinib arm and 78% in the bendamustine/rituximab plus acalabrutinib arm. 

“Notably, neither of the experimental arms were superior to the standard-of-care arm across the board,” Wagner-Johnston said. Overall response rates were “quite high,” with complete response rates of more than 90%, with no differences between the arms. 

Similarly, no significant difference was seen in progression-free survival or overall survival between treatment arms. At a medium follow up of roughly 28 months, the 12-month progression-free survival rate was 90%-92% across the three groups.

The team also evaluated progression-free survival by measurable residual disease status, regardless of whether patients completed protocol therapy. “Not surprisingly,” said Wagner-Johnston, progression-free survival was superior for those with undetectable measurable residual disease, compared with those with detectable levels — but again there was no differences between treatment arms. 

Grades 3-5 treatment-related adverse events occurred in at least 5% of patients and were mostly hematologic. 

The bendamustine/rituximab plus acalabrutinib was associated with significantly less hematologic toxicity, with a febrile neutropenia rate of 4.0% vs 8.9% in the standard induction arm and 9.3% in the standard induction plus acalabrutinib arm. 

Grades 3-5 treatment-related anemia rates were much lower in the bendamustine/rituximab plus acalabrutinib arm (3.0% vs 18.5% for standard induction and 24.8% for standard plus cytarabine). Similarly, the bendamustine/rituximab plus acalabrutinib arm had lower rates of treatment-related grade 3 or higher thrombocytopenia (6.0% vs 44.4% and 51.2%, respectively). 

Across all three treatment groups, rates of neurotoxicity, renal toxicity, bleeding/hemorrhage, and cardiac toxicity were low.

Treatment discontinuations due to adverse events were also low (7%) across the arms, with five treatment-related deaths reported. 

“Standard high-dose cytarabine requires inpatient administration and carries risk of neurologic and hematologic toxicity, making it particularly difficult to give in a community setting,” Marcus said in an interview. “This study, along with updated results from the TRIANGLE study, suggests that we are moving away from high-dose cytotoxic therapy and toward targeted therapy in frontline management of mantle cell lymphoma.”

The study was supported by the National Cancer Institute. Wagner-Johnston has received research founding from Genentech, Merck, and AstraZenecca and consults for Beigene. Marcus had no relevant disclosures.

A version of this article appeared on Medscape.com.

Patients with diffuse large B-cell lymphoma (DLBCL) continue to show superior progression-free survival at 5 years with first-line pola-R-CHP, compared with the R-CHOP regimen, according to updated results of the phase 3 POLARIX study.

These findings “confirm pola-R-CHP as the standard of care for patients with previously untreated intermediate- or high-risk DLBCL,” said lead investigator Gilles Salles, MD, PhD, who presented the extended results at the American Society of Hematology (ASH) 2024 Annual Meeting.

Pola-R-CHP is a modified version of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in which vincristine is replaced with polatuzumab vedotin. The modified regimen was approved by the Food and Drug Administration in April 2023 on the basis of 2-year results from the same study.

In POLARIX, researchers randomized 879 previously untreated adult patients with CD20-positive DLBCL (median age, 66 years) to six to eight 21-day cycles of treatment with either pola-R-CHP or R-CHOP. The primary endpoint was progression-free survival, and secondary endpoints included complete remission and overall survival.

The initial 2-year results — progression-free survival of 76.7% for pola-R-CHP vs 70.2% for R-CHOP — “were the first in 20 years” showing benefits for patients with DLBCL, said Salles, from Memorial Sloan Kettering Cancer Center, New York City.

In the current analysis, there were 879 patients in the global intention-to-treat population — 440 who received pola-R-CHP and 439 who received R-CHOP — and 873 in the safety analysis.

At the 5-year follow-up, Salles and colleagues observed a sustained and significant progression-free survival benefit in patients treated with pola-R-CHP, compared with those who received R-CHOP (64.9% vs 59.1%; hazard ratio [HR], 0.77).

Patients receiving the modified regimen also demonstrated significantly higher rates of complete remission at 5 years (71.8% vs 66.5%; HR, 0.75). These data tell us that for patients who reach complete remission at the end of treatment, the vast majority are still in remission at 5 years, said Salles.

For patients who did progress, those treated with pola-R-CHP had fewer subsequent therapies than those treated with R-CHOP. This included radiotherapy (9.5% vs 14.1%), systemic therapy (20.0% vs 28.2%), platinum-based therapy (9.8% vs 15.5%), stem cell transplant (5.0% vs 8.4%), chimeric antigen receptor T-cell therapy (2.3% vs 4.1%), and bispecifics (1.4% vs 2.1%).

The 5-year overall survival, a secondary endpoint, was numerically better but not significantly so among patients treated with pola-R-CHP (82.3% vs 79.5%; HR, 0.85).

In a competing risk analysis, the cumulative incidence of lymphoma-related deaths at 5 years was 9.1% with pola-R-CHP vs 12.2% with R-CHOP. The probability of non-lymphoma–related deaths, including death due to study treatment, was similar between the two groups at 5 years — 8.56% with pola-R-CHP vs 8.93% with R-CHOP.

An exploratory analysis of progression-free survival and overall survival in subgroups of the patient population, including those with high-risk disease, showed a trend in favor of pola-R-CHP in almost all cases, but Salles warned that the analysis was underpowered.

“I think that interpreting this data to decide the care of the patient should be done very cautiously,” he said.

The researchers did not observe any new safety signals, with pola-R-CHP continuing to show a favorable benefit-risk profile. Looking at adverse events of all grades, Salles noted slightly less peripheral neuropathy with pola-R-CHP (50.3% vs 52.4%), slightly more infection (47.9% vs 44.0%), as well as a favorable trend for pola-R-CHP regarding cardiac arrhythmia (3.6% vs 5.2%) and carcinogenicity (1.0% vs 2.4%), and “very slight and tiny differences” in neutropenia (48.5% vs 45.8%), anemia (33.3% vs 30.1%), and thrombocytopenia (18.0% vs 17.3%).

While the researchers concluded that the study findings confirm pola-R-CHP as the standard of care for patients with previously untreated intermediate- or high-risk DLBCL, Ajay Major, MD, had some reservations.

The results confirm “a small but significant benefit” in progression-free survival and no significant difference in overall survival, but there is some question as to whether pola-R-CHP is appropriate for all-comers with intermediate- or high-risk DLBCL, noted Major, a lymphoma specialist and assistant professor of medicine at the University of Colorado School of Medicine, Aurora, who was not involved in this analysis.

“The subgroup analysis in POLARIX for efficacy of pola-R-CHP based on cell of origin is not adequately powered, and further dedicated on this question studies are needed,” Major said in an interview.

One study presented at the meeting by Major’s group concluded that cell of origin is a strong predictor of the activity of pola-containing therapy in patients with relapsed/refractory large B-cell lymphoma, while another analysis of POLARIX showed progression-free survival and overall survival benefits of pola-R-CHP over R-CHOP in patients with the activated B-cell subtype of DLBCL but not those with the germinal center B-cell subtype, Major noted.

“I think many oncologists will extrapolate from these other data sources and preferentially use pola-R-CHP in patients with activated B-cell or non-germinal center DLBCL,” he predicted.

The study was funded by F. Hoffmann–La Roche/Genentech. Salles reported disclosures with the following companies: BeiGene (consultancy), AbbVie (consultancy, research funding), Genentech/Roche (consultancy, research funding), Incyte (consultancy), and BMS/Celgene (consultancy), among others. Major reported conflicts of interest with Roche/Genentech (consultancy), GSK (research funding), and Incyte (research funding).

A version of this article appeared on Medscape.com.

Patients with diffuse large B-cell lymphoma (DLBCL) continue to show superior progression-free survival at 5 years with first-line pola-R-CHP, compared with the R-CHOP regimen, according to updated results of the phase 3 POLARIX study.

These findings “confirm pola-R-CHP as the standard of care for patients with previously untreated intermediate- or high-risk DLBCL,” said lead investigator Gilles Salles, MD, PhD, who presented the extended results at the American Society of Hematology (ASH) 2024 Annual Meeting.

Pola-R-CHP is a modified version of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in which vincristine is replaced with polatuzumab vedotin. The modified regimen was approved by the Food and Drug Administration in April 2023 on the basis of 2-year results from the same study.

In POLARIX, researchers randomized 879 previously untreated adult patients with CD20-positive DLBCL (median age, 66 years) to six to eight 21-day cycles of treatment with either pola-R-CHP or R-CHOP. The primary endpoint was progression-free survival, and secondary endpoints included complete remission and overall survival.

The initial 2-year results — progression-free survival of 76.7% for pola-R-CHP vs 70.2% for R-CHOP — “were the first in 20 years” showing benefits for patients with DLBCL, said Salles, from Memorial Sloan Kettering Cancer Center, New York City.

In the current analysis, there were 879 patients in the global intention-to-treat population — 440 who received pola-R-CHP and 439 who received R-CHOP — and 873 in the safety analysis.

At the 5-year follow-up, Salles and colleagues observed a sustained and significant progression-free survival benefit in patients treated with pola-R-CHP, compared with those who received R-CHOP (64.9% vs 59.1%; hazard ratio [HR], 0.77).

Patients receiving the modified regimen also demonstrated significantly higher rates of complete remission at 5 years (71.8% vs 66.5%; HR, 0.75). These data tell us that for patients who reach complete remission at the end of treatment, the vast majority are still in remission at 5 years, said Salles.

For patients who did progress, those treated with pola-R-CHP had fewer subsequent therapies than those treated with R-CHOP. This included radiotherapy (9.5% vs 14.1%), systemic therapy (20.0% vs 28.2%), platinum-based therapy (9.8% vs 15.5%), stem cell transplant (5.0% vs 8.4%), chimeric antigen receptor T-cell therapy (2.3% vs 4.1%), and bispecifics (1.4% vs 2.1%).

The 5-year overall survival, a secondary endpoint, was numerically better but not significantly so among patients treated with pola-R-CHP (82.3% vs 79.5%; HR, 0.85).

In a competing risk analysis, the cumulative incidence of lymphoma-related deaths at 5 years was 9.1% with pola-R-CHP vs 12.2% with R-CHOP. The probability of non-lymphoma–related deaths, including death due to study treatment, was similar between the two groups at 5 years — 8.56% with pola-R-CHP vs 8.93% with R-CHOP.

An exploratory analysis of progression-free survival and overall survival in subgroups of the patient population, including those with high-risk disease, showed a trend in favor of pola-R-CHP in almost all cases, but Salles warned that the analysis was underpowered.

“I think that interpreting this data to decide the care of the patient should be done very cautiously,” he said.

The researchers did not observe any new safety signals, with pola-R-CHP continuing to show a favorable benefit-risk profile. Looking at adverse events of all grades, Salles noted slightly less peripheral neuropathy with pola-R-CHP (50.3% vs 52.4%), slightly more infection (47.9% vs 44.0%), as well as a favorable trend for pola-R-CHP regarding cardiac arrhythmia (3.6% vs 5.2%) and carcinogenicity (1.0% vs 2.4%), and “very slight and tiny differences” in neutropenia (48.5% vs 45.8%), anemia (33.3% vs 30.1%), and thrombocytopenia (18.0% vs 17.3%).

While the researchers concluded that the study findings confirm pola-R-CHP as the standard of care for patients with previously untreated intermediate- or high-risk DLBCL, Ajay Major, MD, had some reservations.

The results confirm “a small but significant benefit” in progression-free survival and no significant difference in overall survival, but there is some question as to whether pola-R-CHP is appropriate for all-comers with intermediate- or high-risk DLBCL, noted Major, a lymphoma specialist and assistant professor of medicine at the University of Colorado School of Medicine, Aurora, who was not involved in this analysis.

“The subgroup analysis in POLARIX for efficacy of pola-R-CHP based on cell of origin is not adequately powered, and further dedicated on this question studies are needed,” Major said in an interview.

One study presented at the meeting by Major’s group concluded that cell of origin is a strong predictor of the activity of pola-containing therapy in patients with relapsed/refractory large B-cell lymphoma, while another analysis of POLARIX showed progression-free survival and overall survival benefits of pola-R-CHP over R-CHOP in patients with the activated B-cell subtype of DLBCL but not those with the germinal center B-cell subtype, Major noted.

“I think many oncologists will extrapolate from these other data sources and preferentially use pola-R-CHP in patients with activated B-cell or non-germinal center DLBCL,” he predicted.

The study was funded by F. Hoffmann–La Roche/Genentech. Salles reported disclosures with the following companies: BeiGene (consultancy), AbbVie (consultancy, research funding), Genentech/Roche (consultancy, research funding), Incyte (consultancy), and BMS/Celgene (consultancy), among others. Major reported conflicts of interest with Roche/Genentech (consultancy), GSK (research funding), and Incyte (research funding).

A version of this article appeared on Medscape.com.

Patients with diffuse large B-cell lymphoma (DLBCL) continue to show superior progression-free survival at 5 years with first-line pola-R-CHP, compared with the R-CHOP regimen, according to updated results of the phase 3 POLARIX study.

These findings “confirm pola-R-CHP as the standard of care for patients with previously untreated intermediate- or high-risk DLBCL,” said lead investigator Gilles Salles, MD, PhD, who presented the extended results at the American Society of Hematology (ASH) 2024 Annual Meeting.

Pola-R-CHP is a modified version of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in which vincristine is replaced with polatuzumab vedotin. The modified regimen was approved by the Food and Drug Administration in April 2023 on the basis of 2-year results from the same study.

In POLARIX, researchers randomized 879 previously untreated adult patients with CD20-positive DLBCL (median age, 66 years) to six to eight 21-day cycles of treatment with either pola-R-CHP or R-CHOP. The primary endpoint was progression-free survival, and secondary endpoints included complete remission and overall survival.

The initial 2-year results — progression-free survival of 76.7% for pola-R-CHP vs 70.2% for R-CHOP — “were the first in 20 years” showing benefits for patients with DLBCL, said Salles, from Memorial Sloan Kettering Cancer Center, New York City.

In the current analysis, there were 879 patients in the global intention-to-treat population — 440 who received pola-R-CHP and 439 who received R-CHOP — and 873 in the safety analysis.

At the 5-year follow-up, Salles and colleagues observed a sustained and significant progression-free survival benefit in patients treated with pola-R-CHP, compared with those who received R-CHOP (64.9% vs 59.1%; hazard ratio [HR], 0.77).

Patients receiving the modified regimen also demonstrated significantly higher rates of complete remission at 5 years (71.8% vs 66.5%; HR, 0.75). These data tell us that for patients who reach complete remission at the end of treatment, the vast majority are still in remission at 5 years, said Salles.

For patients who did progress, those treated with pola-R-CHP had fewer subsequent therapies than those treated with R-CHOP. This included radiotherapy (9.5% vs 14.1%), systemic therapy (20.0% vs 28.2%), platinum-based therapy (9.8% vs 15.5%), stem cell transplant (5.0% vs 8.4%), chimeric antigen receptor T-cell therapy (2.3% vs 4.1%), and bispecifics (1.4% vs 2.1%).

The 5-year overall survival, a secondary endpoint, was numerically better but not significantly so among patients treated with pola-R-CHP (82.3% vs 79.5%; HR, 0.85).

In a competing risk analysis, the cumulative incidence of lymphoma-related deaths at 5 years was 9.1% with pola-R-CHP vs 12.2% with R-CHOP. The probability of non-lymphoma–related deaths, including death due to study treatment, was similar between the two groups at 5 years — 8.56% with pola-R-CHP vs 8.93% with R-CHOP.

An exploratory analysis of progression-free survival and overall survival in subgroups of the patient population, including those with high-risk disease, showed a trend in favor of pola-R-CHP in almost all cases, but Salles warned that the analysis was underpowered.

“I think that interpreting this data to decide the care of the patient should be done very cautiously,” he said.

The researchers did not observe any new safety signals, with pola-R-CHP continuing to show a favorable benefit-risk profile. Looking at adverse events of all grades, Salles noted slightly less peripheral neuropathy with pola-R-CHP (50.3% vs 52.4%), slightly more infection (47.9% vs 44.0%), as well as a favorable trend for pola-R-CHP regarding cardiac arrhythmia (3.6% vs 5.2%) and carcinogenicity (1.0% vs 2.4%), and “very slight and tiny differences” in neutropenia (48.5% vs 45.8%), anemia (33.3% vs 30.1%), and thrombocytopenia (18.0% vs 17.3%).

While the researchers concluded that the study findings confirm pola-R-CHP as the standard of care for patients with previously untreated intermediate- or high-risk DLBCL, Ajay Major, MD, had some reservations.

The results confirm “a small but significant benefit” in progression-free survival and no significant difference in overall survival, but there is some question as to whether pola-R-CHP is appropriate for all-comers with intermediate- or high-risk DLBCL, noted Major, a lymphoma specialist and assistant professor of medicine at the University of Colorado School of Medicine, Aurora, who was not involved in this analysis.

“The subgroup analysis in POLARIX for efficacy of pola-R-CHP based on cell of origin is not adequately powered, and further dedicated on this question studies are needed,” Major said in an interview.

One study presented at the meeting by Major’s group concluded that cell of origin is a strong predictor of the activity of pola-containing therapy in patients with relapsed/refractory large B-cell lymphoma, while another analysis of POLARIX showed progression-free survival and overall survival benefits of pola-R-CHP over R-CHOP in patients with the activated B-cell subtype of DLBCL but not those with the germinal center B-cell subtype, Major noted.

“I think many oncologists will extrapolate from these other data sources and preferentially use pola-R-CHP in patients with activated B-cell or non-germinal center DLBCL,” he predicted.

The study was funded by F. Hoffmann–La Roche/Genentech. Salles reported disclosures with the following companies: BeiGene (consultancy), AbbVie (consultancy, research funding), Genentech/Roche (consultancy, research funding), Incyte (consultancy), and BMS/Celgene (consultancy), among others. Major reported conflicts of interest with Roche/Genentech (consultancy), GSK (research funding), and Incyte (research funding).

A version of this article appeared on Medscape.com.

LOS ANGELES — A mattress designed to detect seizures in individuals with epilepsy who are lying face down and quickly reposition them onto their side could significantly reduce the risk for sudden unexpected death in epilepsy (SUDEP), says one of the experts involved in its development.

When used along with a seizure detection device, Jong Woo Lee, MD, PhD, associate professor of neurology, Harvard Medical School, and Brigham and Women’s Hospital, both in Boston, Massachusetts, estimates the smart mattress could cut SUDEP by more than 50%.

In addition, early results from an observational study are backing this up, he said.

The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.

 

Most SUDEP Cases Found Face Down

SUDEP is the leading cause of death in children with epilepsy and in otherwise healthy adult patients with epilepsy. When his fifth patient died of SUDEP, Lee decided it was time to try to tackle the high mortality rate associated with these unexpected deaths. “I desperately wanted to help, ” he said.

About 70% of SUDEP occurs during sleep, and victims are found face down, or in the prone position, 90% of the time, said Lee.

“Of course, the best way to prevent SUDEP is not to have a seizure, but once you have a seizure and once you’re face down, your risk for death goes up by somewhere between 30 and 100 times,” he explained.

Lee was convinced SUDEP could be prevented by simple interventions that stimulate the patient and turn them over. He noted the incidence of sudden infant death syndrome, “which has similar characteristics” to SUDEP, has been reduced by up to 75% through campaigns that simply advise placing babies on their backs.

“Most of SUDEP happens because your arousal system is knocked out and you just don’t take the breath that you’re supposed to. Just the act of turning people over and vibrating the bed will stimulate them,” he said.

However, it’s crucial that this be done quickly, said Lee. “When you look at patients who died on video and see the EEGs, everybody took their last breath within 3 minutes.”

Because the window of opportunity is so short, “we think that seizure detection devices alone are not going to really be effective because you just can’t get there or react within those 3 minutes.”

There are currently no products that detect the prone position or have the ability to reposition a patient quickly into the recovery sideways position.

Lee and his colleagues developed a smart system that can be embedded in a mattress that detects when someone is having a seizure, determines if that person is face down, and if so, safely stimulates and repositions them.

The mattress is made up of a series of programmable inflatable blocks or “cells” that have pressure, vibration, temperature, and humidity sensors embedded within. “Based on the pressure readings, we can figure out whether the patient is right side up, on their right side, on their left side, or face down,” said Lee.

If the person is face down, he or she can be repositioned within a matter of seconds. “Each of the cells can lift 1000 pounds,” he said. The mattress is “very comfortable,” said Lee, who has tried it out himself.

Eighteen normative control participants have been enrolled for development and training purposes. To date, 10 of these individuals, aged 18-53 years, weighing 100-182 lb, and with a height of 5 ft 2 in to 6 ft 1 in, underwent extensive formal testing on the prototype bed.

Researchers found the mattress responded quickly to different body positions and weights. “We were able to reposition everybody in around 20 seconds,” said Lee.

The overall accuracy of detecting the prone position was 96.8%. There were no cases of a supine or prone position being mistaken for each other.

Researchers are refining the algorithm to improve the accuracy for detecting the prone position and expect to have a completely functional prototype within a few years.

 

Big Step Forward

Commenting on the research, Daniel M. Goldenholz, MD, PhD, assistant professor, Division of Epilepsy, Harvard Beth Israel Deaconess Medical Center, Boston, said the study “is a big step forward in the race to provide an actionable tool to prevent SUDEP.”

The technology “appears to mostly be doing what it’s intended to do, with relatively minor technical errors being made,” he said.

However, it is not clear if this technology can truly save lives, said Goldenholz. “The data we have suggests that lying face down in bed after a seizure is correlated with SUDEP, but that does not mean that if we can simply flip people over, they for sure won’t die.”

Even if the new technology “works perfectly,” it’s still an open question, said Goldenholz. If it does save lives, “this will be a major breakthrough, and one that has been needed for a long time.”

However, even if it does not, he congratulates the team for trying to determine if reducing the prone position can help prevent SUDEP. He would like to see more “high-risk, high-reward” studies in the epilepsy field. “We are in so much need of new innovations.”

He said he was “personally very inspired” by this work. “People are dying from this terrible disease, and this team is building what they hope might save lives.”

The study was funded by the National Institutes of Health. The mattress is being developed by Soterya. Lee reported no equity in Soterya. Goldenholz reported no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

LOS ANGELES — A mattress designed to detect seizures in individuals with epilepsy who are lying face down and quickly reposition them onto their side could significantly reduce the risk for sudden unexpected death in epilepsy (SUDEP), says one of the experts involved in its development.

When used along with a seizure detection device, Jong Woo Lee, MD, PhD, associate professor of neurology, Harvard Medical School, and Brigham and Women’s Hospital, both in Boston, Massachusetts, estimates the smart mattress could cut SUDEP by more than 50%.

In addition, early results from an observational study are backing this up, he said.

The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.

 

Most SUDEP Cases Found Face Down

SUDEP is the leading cause of death in children with epilepsy and in otherwise healthy adult patients with epilepsy. When his fifth patient died of SUDEP, Lee decided it was time to try to tackle the high mortality rate associated with these unexpected deaths. “I desperately wanted to help, ” he said.

About 70% of SUDEP occurs during sleep, and victims are found face down, or in the prone position, 90% of the time, said Lee.

“Of course, the best way to prevent SUDEP is not to have a seizure, but once you have a seizure and once you’re face down, your risk for death goes up by somewhere between 30 and 100 times,” he explained.

Lee was convinced SUDEP could be prevented by simple interventions that stimulate the patient and turn them over. He noted the incidence of sudden infant death syndrome, “which has similar characteristics” to SUDEP, has been reduced by up to 75% through campaigns that simply advise placing babies on their backs.

“Most of SUDEP happens because your arousal system is knocked out and you just don’t take the breath that you’re supposed to. Just the act of turning people over and vibrating the bed will stimulate them,” he said.

However, it’s crucial that this be done quickly, said Lee. “When you look at patients who died on video and see the EEGs, everybody took their last breath within 3 minutes.”

Because the window of opportunity is so short, “we think that seizure detection devices alone are not going to really be effective because you just can’t get there or react within those 3 minutes.”

There are currently no products that detect the prone position or have the ability to reposition a patient quickly into the recovery sideways position.

Lee and his colleagues developed a smart system that can be embedded in a mattress that detects when someone is having a seizure, determines if that person is face down, and if so, safely stimulates and repositions them.

The mattress is made up of a series of programmable inflatable blocks or “cells” that have pressure, vibration, temperature, and humidity sensors embedded within. “Based on the pressure readings, we can figure out whether the patient is right side up, on their right side, on their left side, or face down,” said Lee.

If the person is face down, he or she can be repositioned within a matter of seconds. “Each of the cells can lift 1000 pounds,” he said. The mattress is “very comfortable,” said Lee, who has tried it out himself.

Eighteen normative control participants have been enrolled for development and training purposes. To date, 10 of these individuals, aged 18-53 years, weighing 100-182 lb, and with a height of 5 ft 2 in to 6 ft 1 in, underwent extensive formal testing on the prototype bed.

Researchers found the mattress responded quickly to different body positions and weights. “We were able to reposition everybody in around 20 seconds,” said Lee.

The overall accuracy of detecting the prone position was 96.8%. There were no cases of a supine or prone position being mistaken for each other.

Researchers are refining the algorithm to improve the accuracy for detecting the prone position and expect to have a completely functional prototype within a few years.

 

Big Step Forward

Commenting on the research, Daniel M. Goldenholz, MD, PhD, assistant professor, Division of Epilepsy, Harvard Beth Israel Deaconess Medical Center, Boston, said the study “is a big step forward in the race to provide an actionable tool to prevent SUDEP.”

The technology “appears to mostly be doing what it’s intended to do, with relatively minor technical errors being made,” he said.

However, it is not clear if this technology can truly save lives, said Goldenholz. “The data we have suggests that lying face down in bed after a seizure is correlated with SUDEP, but that does not mean that if we can simply flip people over, they for sure won’t die.”

Even if the new technology “works perfectly,” it’s still an open question, said Goldenholz. If it does save lives, “this will be a major breakthrough, and one that has been needed for a long time.”

However, even if it does not, he congratulates the team for trying to determine if reducing the prone position can help prevent SUDEP. He would like to see more “high-risk, high-reward” studies in the epilepsy field. “We are in so much need of new innovations.”

He said he was “personally very inspired” by this work. “People are dying from this terrible disease, and this team is building what they hope might save lives.”

The study was funded by the National Institutes of Health. The mattress is being developed by Soterya. Lee reported no equity in Soterya. Goldenholz reported no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

LOS ANGELES — A mattress designed to detect seizures in individuals with epilepsy who are lying face down and quickly reposition them onto their side could significantly reduce the risk for sudden unexpected death in epilepsy (SUDEP), says one of the experts involved in its development.

When used along with a seizure detection device, Jong Woo Lee, MD, PhD, associate professor of neurology, Harvard Medical School, and Brigham and Women’s Hospital, both in Boston, Massachusetts, estimates the smart mattress could cut SUDEP by more than 50%.

In addition, early results from an observational study are backing this up, he said.

The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.

 

Most SUDEP Cases Found Face Down

SUDEP is the leading cause of death in children with epilepsy and in otherwise healthy adult patients with epilepsy. When his fifth patient died of SUDEP, Lee decided it was time to try to tackle the high mortality rate associated with these unexpected deaths. “I desperately wanted to help, ” he said.

About 70% of SUDEP occurs during sleep, and victims are found face down, or in the prone position, 90% of the time, said Lee.

“Of course, the best way to prevent SUDEP is not to have a seizure, but once you have a seizure and once you’re face down, your risk for death goes up by somewhere between 30 and 100 times,” he explained.

Lee was convinced SUDEP could be prevented by simple interventions that stimulate the patient and turn them over. He noted the incidence of sudden infant death syndrome, “which has similar characteristics” to SUDEP, has been reduced by up to 75% through campaigns that simply advise placing babies on their backs.

“Most of SUDEP happens because your arousal system is knocked out and you just don’t take the breath that you’re supposed to. Just the act of turning people over and vibrating the bed will stimulate them,” he said.

However, it’s crucial that this be done quickly, said Lee. “When you look at patients who died on video and see the EEGs, everybody took their last breath within 3 minutes.”

Because the window of opportunity is so short, “we think that seizure detection devices alone are not going to really be effective because you just can’t get there or react within those 3 minutes.”

There are currently no products that detect the prone position or have the ability to reposition a patient quickly into the recovery sideways position.

Lee and his colleagues developed a smart system that can be embedded in a mattress that detects when someone is having a seizure, determines if that person is face down, and if so, safely stimulates and repositions them.

The mattress is made up of a series of programmable inflatable blocks or “cells” that have pressure, vibration, temperature, and humidity sensors embedded within. “Based on the pressure readings, we can figure out whether the patient is right side up, on their right side, on their left side, or face down,” said Lee.

If the person is face down, he or she can be repositioned within a matter of seconds. “Each of the cells can lift 1000 pounds,” he said. The mattress is “very comfortable,” said Lee, who has tried it out himself.

Eighteen normative control participants have been enrolled for development and training purposes. To date, 10 of these individuals, aged 18-53 years, weighing 100-182 lb, and with a height of 5 ft 2 in to 6 ft 1 in, underwent extensive formal testing on the prototype bed.

Researchers found the mattress responded quickly to different body positions and weights. “We were able to reposition everybody in around 20 seconds,” said Lee.

The overall accuracy of detecting the prone position was 96.8%. There were no cases of a supine or prone position being mistaken for each other.

Researchers are refining the algorithm to improve the accuracy for detecting the prone position and expect to have a completely functional prototype within a few years.

 

Big Step Forward

Commenting on the research, Daniel M. Goldenholz, MD, PhD, assistant professor, Division of Epilepsy, Harvard Beth Israel Deaconess Medical Center, Boston, said the study “is a big step forward in the race to provide an actionable tool to prevent SUDEP.”

The technology “appears to mostly be doing what it’s intended to do, with relatively minor technical errors being made,” he said.

However, it is not clear if this technology can truly save lives, said Goldenholz. “The data we have suggests that lying face down in bed after a seizure is correlated with SUDEP, but that does not mean that if we can simply flip people over, they for sure won’t die.”

Even if the new technology “works perfectly,” it’s still an open question, said Goldenholz. If it does save lives, “this will be a major breakthrough, and one that has been needed for a long time.”

However, even if it does not, he congratulates the team for trying to determine if reducing the prone position can help prevent SUDEP. He would like to see more “high-risk, high-reward” studies in the epilepsy field. “We are in so much need of new innovations.”

He said he was “personally very inspired” by this work. “People are dying from this terrible disease, and this team is building what they hope might save lives.”

The study was funded by the National Institutes of Health. The mattress is being developed by Soterya. Lee reported no equity in Soterya. Goldenholz reported no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

LOS ANGELES — Individuals with both uncontrolled epilepsy and sleep apnea are at significantly higher risk for mortality than those with epilepsy alone, according to a new analysis of over 2 million patient-years drawn from the Komodo Health Claims Database.

“A 10-year-old with uncontrolled epilepsy and central sleep apnea is about 200 times more likely to die than a general population 10-year-old. That’s comparable to a 10-year-old with {epilepsy and} congestive heart failure. Noncentral sleep apnea is comparable to being paralyzed. It’s a huge risk factor,” said poster presenter Dan Lloyd, advanced analytics lead at UCB, which sponsored the research.

The ordering of sleep apnea tests for patients with epilepsy is widely variable, according to Stefanie Dedeurwaerdere, PhD, who is the innovation and value creation lead at UCB. “Some doctors do that as a general practice, and some don’t. There’s no coherency in the way these studies are requested for epilepsy patients. We want to create some awareness around this topic,” she said, and added that treatment of sleep apnea may improve epileptic seizures.

The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.

The study included mortality rates between January 2018 and December 2022, with a total of 2,355,410 patient-years and 968,993 patients, with an age distribution of 19.1% age 1 to less than 18 years, 23.7% age 18-35 years, and 57.2% age 36 years or older. Sleep apnea prevalences were 0.7% for central sleep apnea (CSA), 14.0% for obstructive sleep apnea (OSA), and 85.3% with no sleep apnea.

Among those aged 1-18 years, the standardized mortality ratio (SMR) for those with uncontrolled epilepsy was 27.7. For those with comorbid OSA, the SMR was 74.2, and for comorbid CSA, the SMR was 135.9. The association was less pronounced in older groups, dipping to 7.0, 11.3, and 19.5 in those aged 18-35 years, and 3.3, 3.1, and 2.8 among those aged 36 years or older.

Among the 1-18 age group, SMRs for other comorbidities included 132.3 for heart failure, 74.9 for hemiplegia/paraplegia, 55.3 for cerebrovascular disease, and 44.6 for chronic pulmonary disease.

Asked for comment, Gordon Buchanan, MD, PhD, welcomed the new work. “The results did not surprise me. I study sleep, epilepsy, and [sudden unexplained death in epilepsy (SUDEP)] in particular ... and every time I speak on these topics, someone asks me about risk of SUDEP in patients with sleep apnea. It’s great to finally have some data,” said Buchanan, a professor of neurology at the University of Iowa, Iowa City.

The authors found that patients undergoing continuous positive airway pressure (CPAP)/bi-level positive airway pressure therapy had a higher mortality risk than those not undergoing CPAP therapy but cautioned that uncontrolled confounders may be contributing to the effect.

Buchanan wondered if treatment with CPAP would be associated with a decreased mortality risk. “I think that would be interesting, but I know that, especially in children, it can be difficult to get them to remain compliant with CPAP. I think that would be interesting to know, if pushing harder to get the kids to comply with CPAP would reduce mortality,” he said.

The specific finding of heightened mortality associated with CSA is interesting, according to Buchanan. “We think of seizures propagating through the brain, maybe through direct synaptic connections or through spreading depolarization. So I think it would make sense that it would hit central regions that would then lead to sleep apnea.” 

The relationship between OSA and epilepsy is likely complex. Epilepsy medications and special diets may influence body composition, which could in turn affect the risk for OSA, as could medications associated with psychiatric comorbidities, according to Buchanan.

The study is retrospective and based on claims data. It does not prove causation, and claims data do not fully capture mortality, which may lead to conservative SMR estimates. The researchers did not control for socioeconomic status, treatment status, and other comorbidities or conditions.

Lloyd and Dedeurwaerdere are employees of UCB, which sponsored the study. Buchanan had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

LOS ANGELES — Individuals with both uncontrolled epilepsy and sleep apnea are at significantly higher risk for mortality than those with epilepsy alone, according to a new analysis of over 2 million patient-years drawn from the Komodo Health Claims Database.

“A 10-year-old with uncontrolled epilepsy and central sleep apnea is about 200 times more likely to die than a general population 10-year-old. That’s comparable to a 10-year-old with {epilepsy and} congestive heart failure. Noncentral sleep apnea is comparable to being paralyzed. It’s a huge risk factor,” said poster presenter Dan Lloyd, advanced analytics lead at UCB, which sponsored the research.

The ordering of sleep apnea tests for patients with epilepsy is widely variable, according to Stefanie Dedeurwaerdere, PhD, who is the innovation and value creation lead at UCB. “Some doctors do that as a general practice, and some don’t. There’s no coherency in the way these studies are requested for epilepsy patients. We want to create some awareness around this topic,” she said, and added that treatment of sleep apnea may improve epileptic seizures.

The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.

The study included mortality rates between January 2018 and December 2022, with a total of 2,355,410 patient-years and 968,993 patients, with an age distribution of 19.1% age 1 to less than 18 years, 23.7% age 18-35 years, and 57.2% age 36 years or older. Sleep apnea prevalences were 0.7% for central sleep apnea (CSA), 14.0% for obstructive sleep apnea (OSA), and 85.3% with no sleep apnea.

Among those aged 1-18 years, the standardized mortality ratio (SMR) for those with uncontrolled epilepsy was 27.7. For those with comorbid OSA, the SMR was 74.2, and for comorbid CSA, the SMR was 135.9. The association was less pronounced in older groups, dipping to 7.0, 11.3, and 19.5 in those aged 18-35 years, and 3.3, 3.1, and 2.8 among those aged 36 years or older.

Among the 1-18 age group, SMRs for other comorbidities included 132.3 for heart failure, 74.9 for hemiplegia/paraplegia, 55.3 for cerebrovascular disease, and 44.6 for chronic pulmonary disease.

Asked for comment, Gordon Buchanan, MD, PhD, welcomed the new work. “The results did not surprise me. I study sleep, epilepsy, and [sudden unexplained death in epilepsy (SUDEP)] in particular ... and every time I speak on these topics, someone asks me about risk of SUDEP in patients with sleep apnea. It’s great to finally have some data,” said Buchanan, a professor of neurology at the University of Iowa, Iowa City.

The authors found that patients undergoing continuous positive airway pressure (CPAP)/bi-level positive airway pressure therapy had a higher mortality risk than those not undergoing CPAP therapy but cautioned that uncontrolled confounders may be contributing to the effect.

Buchanan wondered if treatment with CPAP would be associated with a decreased mortality risk. “I think that would be interesting, but I know that, especially in children, it can be difficult to get them to remain compliant with CPAP. I think that would be interesting to know, if pushing harder to get the kids to comply with CPAP would reduce mortality,” he said.

The specific finding of heightened mortality associated with CSA is interesting, according to Buchanan. “We think of seizures propagating through the brain, maybe through direct synaptic connections or through spreading depolarization. So I think it would make sense that it would hit central regions that would then lead to sleep apnea.” 

The relationship between OSA and epilepsy is likely complex. Epilepsy medications and special diets may influence body composition, which could in turn affect the risk for OSA, as could medications associated with psychiatric comorbidities, according to Buchanan.

The study is retrospective and based on claims data. It does not prove causation, and claims data do not fully capture mortality, which may lead to conservative SMR estimates. The researchers did not control for socioeconomic status, treatment status, and other comorbidities or conditions.

Lloyd and Dedeurwaerdere are employees of UCB, which sponsored the study. Buchanan had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

LOS ANGELES — Individuals with both uncontrolled epilepsy and sleep apnea are at significantly higher risk for mortality than those with epilepsy alone, according to a new analysis of over 2 million patient-years drawn from the Komodo Health Claims Database.

“A 10-year-old with uncontrolled epilepsy and central sleep apnea is about 200 times more likely to die than a general population 10-year-old. That’s comparable to a 10-year-old with {epilepsy and} congestive heart failure. Noncentral sleep apnea is comparable to being paralyzed. It’s a huge risk factor,” said poster presenter Dan Lloyd, advanced analytics lead at UCB, which sponsored the research.

The ordering of sleep apnea tests for patients with epilepsy is widely variable, according to Stefanie Dedeurwaerdere, PhD, who is the innovation and value creation lead at UCB. “Some doctors do that as a general practice, and some don’t. There’s no coherency in the way these studies are requested for epilepsy patients. We want to create some awareness around this topic,” she said, and added that treatment of sleep apnea may improve epileptic seizures.

The findings were presented at the American Epilepsy Society (AES) 78th Annual Meeting 2024.

The study included mortality rates between January 2018 and December 2022, with a total of 2,355,410 patient-years and 968,993 patients, with an age distribution of 19.1% age 1 to less than 18 years, 23.7% age 18-35 years, and 57.2% age 36 years or older. Sleep apnea prevalences were 0.7% for central sleep apnea (CSA), 14.0% for obstructive sleep apnea (OSA), and 85.3% with no sleep apnea.

Among those aged 1-18 years, the standardized mortality ratio (SMR) for those with uncontrolled epilepsy was 27.7. For those with comorbid OSA, the SMR was 74.2, and for comorbid CSA, the SMR was 135.9. The association was less pronounced in older groups, dipping to 7.0, 11.3, and 19.5 in those aged 18-35 years, and 3.3, 3.1, and 2.8 among those aged 36 years or older.

Among the 1-18 age group, SMRs for other comorbidities included 132.3 for heart failure, 74.9 for hemiplegia/paraplegia, 55.3 for cerebrovascular disease, and 44.6 for chronic pulmonary disease.

Asked for comment, Gordon Buchanan, MD, PhD, welcomed the new work. “The results did not surprise me. I study sleep, epilepsy, and [sudden unexplained death in epilepsy (SUDEP)] in particular ... and every time I speak on these topics, someone asks me about risk of SUDEP in patients with sleep apnea. It’s great to finally have some data,” said Buchanan, a professor of neurology at the University of Iowa, Iowa City.

The authors found that patients undergoing continuous positive airway pressure (CPAP)/bi-level positive airway pressure therapy had a higher mortality risk than those not undergoing CPAP therapy but cautioned that uncontrolled confounders may be contributing to the effect.

Buchanan wondered if treatment with CPAP would be associated with a decreased mortality risk. “I think that would be interesting, but I know that, especially in children, it can be difficult to get them to remain compliant with CPAP. I think that would be interesting to know, if pushing harder to get the kids to comply with CPAP would reduce mortality,” he said.

The specific finding of heightened mortality associated with CSA is interesting, according to Buchanan. “We think of seizures propagating through the brain, maybe through direct synaptic connections or through spreading depolarization. So I think it would make sense that it would hit central regions that would then lead to sleep apnea.” 

The relationship between OSA and epilepsy is likely complex. Epilepsy medications and special diets may influence body composition, which could in turn affect the risk for OSA, as could medications associated with psychiatric comorbidities, according to Buchanan.

The study is retrospective and based on claims data. It does not prove causation, and claims data do not fully capture mortality, which may lead to conservative SMR estimates. The researchers did not control for socioeconomic status, treatment status, and other comorbidities or conditions.

Lloyd and Dedeurwaerdere are employees of UCB, which sponsored the study. Buchanan had no relevant financial disclosures.

A version of this article appeared on Medscape.com.