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Update Coming for Thyroid Disease in Pregnancy Guidelines
CHICAGO — A preview of much-anticipated updates to guidelines on managing thyroid disease in pregnancy shows key changes to recommendations in the evolving field, ranging from consideration of the chance of spontaneous normalization of thyroid levels during pregnancy to a heightened emphasis on shared decision-making and the nuances can factor into personalized treatment.
The guidelines, expected to be published in early 2025, have not been updated since 2017, and with substantial advances and evidence from countless studies since then, the new guidelines were developed with a goal to start afresh, said ATA Thyroid and Pregnancy Guidelines Task Force cochair Tim IM Korevaar, MD, PhD, in presenting the final draft guidelines at the American Thyroid Association (ATA) 2024 Meeting.
“Obviously, we’re not going to ignore the 2017 guidelines, which have been a very good resource for us so far, but we really wanted to start from scratch and follow a ‘blank canvas’ approach in optimizing the evidence,” said Korevaar, an endocrinologist and obstetric internist with the Division of Pharmacology and Vascular Medicine & Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
The guidelines, developed through a collaborative effort involving a wide variety of related medical societies, involved 14 systematic literature reviews. While the pregnancy issues covered by the guidelines is extensive, key highlights include:
Management in Preconception
Beginning with preconception, a key change in the guidelines will be that patients with euthyroid thyroid peroxidase (TPO) antibodies, which can be indicative of thyroid dysfunction, routine treatment with levothyroxine is not recommended, based on new evidence from randomized trials of high-risk patients showing no clear benefit from the treatment.
“In these trials, and across analyses, there was absolutely no beneficial effect of levothyroxine in these patients [with euthyroid TPO antibody positivity],” he said.
With evidence showing, however, that TPO antibody positivity can lead to subclinical or overt hypothyroidism within 1 or 2 years, the guidelines will recommend that TPO antibody–positive patients do have thyroid stimulating hormone (TSH) levels tested every 3-6 months until pregnancy, and existing recommendations to test during pregnancy among those patients remain in place, Korevaar reported.
In terms of preconception subclinical hypothyroidism, the guidelines will emphasize the existing recommendation “to always strive to reassess” thyroid levels, and if subclinical hypothyroidism does persist, to treat with low-dose levothyroxine.
During Pregnancy
During pregnancy, the new proposed recommendations will reflect the important change that three key risk factors, including age over 30 years, having at least two prior pregnancies, and morbid obesity (body mass index [BMI] at least 40 kg/m2), previously considered a risk for thyroid dysfunction in pregnancy, should not, on their own, suggest the need for thyroid testing, based on low evidence of an increased risk in pregnancy.
Research on the issue includes a recent study from Korevaar’s team showing these factors to in fact have low predictability of thyroid dysfunction.
“We deemed that these risk differences weren’t really clinically meaningful (in predicting risk), and so we have removed to maternal age, BMI, and parity as risk factors for thyroid testing indications in pregnancy,” Korevaar said.
Factors considered a risk, resulting in recommended testing at presentation include a history of subclinical or clinical hypo- or hyperthyroidism, postpartum thyroiditis, known thyroid antibody positivity, symptoms of thyroid dysfunction or goiter, and other factors.
Treatment for Subclinical Hypothyroidism in Pregnancy
Whereas current guidelines recommend TPO antibody status in determining when to consider treatment for subclinical hypothyroidism, the new proposed guideline will instead recommend treatment based on the timing of the diagnosis of the subclinical hypothyroidism, with consideration of treatment during the first trimester, but not in the second or third trimester, based on newer evidence of the absolute risk for pregnancy complications and randomized trial data.
“The recommendations are now to no longer based on TPO antibody status, but instead according to the timing of the diagnosis of subclinical hypothyroidism,” Korevaar said.
Based on the collective data, “due to the low risk, we do not recommend for routine levothyroxine treatment in the second or third trimester groups with TSH levels under 10 mU/L now.”
“However, for subclinical hypothyroidism diagnosed in the first trimester, the recommendation would be that you can consider levothyroxine treatment,” he said.
While a clear indication for treatment in any trimester is the presence of overt hypothyroidism, or TSH levels over 10 mU/L, Korevaar underscored the importance of considering nuances of the recommendations that may warrant flexibility, for instance among patients with borderline TSH levels.
Spontaneous Normalization of Thyroid Levels in Pregnancy
Another new recommendation addresses the issue of spontaneous normalization of abnormal thyroid function during pregnancy, with several large studies showing a large proportion of subclinical hypothyroidism cases spontaneously revert to euthyroidism by the third trimester — despite no treatment having been provided.
Under the important proposed recommendation, retesting of subclinical hypothyroidism is suggested within 3 weeks.
“The data shows that a large proportion of patients spontaneously revert to euthyroidism,” Korevaar said.
“Upon identifying subclinical hypothyroidism in the first trimester, there will be essentially two options that clinicians can discuss with their patient — one would be to consider confirmatory tests in 3 weeks or to discuss the starting the lower dose levothyroxine in the first trimester,” he said.
In terms of overt hypothyroidism, likewise, if patients have a TSH levels below 6 mU/L in pregnancy, “you can either consider doing confirmatory testing within 3 weeks, or discussing with the patient starting levothyroxine treatment,” Korevaar added.
Overt Hyperthyroidism
For overt hyperthyroidism, no significant changes from current guidelines are being proposed, with the key exception of a heightened emphasis on the need for shared decision-making with patients, Korevaar said.
“We want to emphasize shared decision-making especially for women who have Graves’ disease prior to pregnancy, because the antithyroid treatment modalities, primarily methimazole (MMI) and propylthiouracil (PTU), have different advantages and disadvantages for an upcoming pregnancy,” he said.
“If you help a patient become involved in the decision-making process, that can also be very helpful in managing the disease and following-up on the pregnancy.”
Under the recommendations, PTU remains the preferred drug in overt hyperthyroidism, due to a more favorable profile in terms of potential birth defects vs MMI, with research showing a higher absolute risk of 3% vs 5%.
The guidelines further suggest the option of stopping the antithyroid medications upon a positive pregnancy test, with the exception of high-risk patients.
Korevaar noted that, if the treatment is stopped early in pregnancy, relapse is not likely to occur until after approximately 3 months, or 12 weeks, at which time, the high-risk teratogenic period, which is between week 5 and week 15, will have passed.
Current guidelines regarding whether to stop treatment in higher-risk hyperthyroid patients are recommended to remain unchanged.
Thyroid Nodules and Cancer
Recommendations regarding thyroid nodules and cancer during pregnancy are also expected to remain largely similar to those in the 2017 guidelines, with the exception of an emphasis on simply considering how the patient would normally be managed outside of pregnancy.
For instance, regarding the question of whether treatment can be withheld for 9 months during pregnancy. “A lot of times, the answer is yes,” Korevaar said.
Other topics that will be largely unchanged include issues of universal screening, definitions of normal and abnormal TSH and free T4 reference ranges and isolated hypothyroxinemia.
Steps Forward in Improving Updates, Readability
In addition to recommendation updates, the new guidelines are being revised to better reflect more recent evidence-based developments and user-friendliness.
“We have now made the step to a more systematic and replicable methodology to ensure for easier updates with a shorter interval,” Korevaar told this news organization.
“Furthermore, since 2006, the ATA guideline documents have followed a question-and-answer format, lacked recommendation tables and had none or only a few graphic illustrations,” he added.
“We are now further developing the typical outline of the guidelines to improve the readability and dissemination of the guideline document.”
Korevaar’s disclosures include lectureship fees from IBSA, Merck, and Berlin Chemie.
A version of this article first appeared on Medscape.com.
CHICAGO — A preview of much-anticipated updates to guidelines on managing thyroid disease in pregnancy shows key changes to recommendations in the evolving field, ranging from consideration of the chance of spontaneous normalization of thyroid levels during pregnancy to a heightened emphasis on shared decision-making and the nuances can factor into personalized treatment.
The guidelines, expected to be published in early 2025, have not been updated since 2017, and with substantial advances and evidence from countless studies since then, the new guidelines were developed with a goal to start afresh, said ATA Thyroid and Pregnancy Guidelines Task Force cochair Tim IM Korevaar, MD, PhD, in presenting the final draft guidelines at the American Thyroid Association (ATA) 2024 Meeting.
“Obviously, we’re not going to ignore the 2017 guidelines, which have been a very good resource for us so far, but we really wanted to start from scratch and follow a ‘blank canvas’ approach in optimizing the evidence,” said Korevaar, an endocrinologist and obstetric internist with the Division of Pharmacology and Vascular Medicine & Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
The guidelines, developed through a collaborative effort involving a wide variety of related medical societies, involved 14 systematic literature reviews. While the pregnancy issues covered by the guidelines is extensive, key highlights include:
Management in Preconception
Beginning with preconception, a key change in the guidelines will be that patients with euthyroid thyroid peroxidase (TPO) antibodies, which can be indicative of thyroid dysfunction, routine treatment with levothyroxine is not recommended, based on new evidence from randomized trials of high-risk patients showing no clear benefit from the treatment.
“In these trials, and across analyses, there was absolutely no beneficial effect of levothyroxine in these patients [with euthyroid TPO antibody positivity],” he said.
With evidence showing, however, that TPO antibody positivity can lead to subclinical or overt hypothyroidism within 1 or 2 years, the guidelines will recommend that TPO antibody–positive patients do have thyroid stimulating hormone (TSH) levels tested every 3-6 months until pregnancy, and existing recommendations to test during pregnancy among those patients remain in place, Korevaar reported.
In terms of preconception subclinical hypothyroidism, the guidelines will emphasize the existing recommendation “to always strive to reassess” thyroid levels, and if subclinical hypothyroidism does persist, to treat with low-dose levothyroxine.
During Pregnancy
During pregnancy, the new proposed recommendations will reflect the important change that three key risk factors, including age over 30 years, having at least two prior pregnancies, and morbid obesity (body mass index [BMI] at least 40 kg/m2), previously considered a risk for thyroid dysfunction in pregnancy, should not, on their own, suggest the need for thyroid testing, based on low evidence of an increased risk in pregnancy.
Research on the issue includes a recent study from Korevaar’s team showing these factors to in fact have low predictability of thyroid dysfunction.
“We deemed that these risk differences weren’t really clinically meaningful (in predicting risk), and so we have removed to maternal age, BMI, and parity as risk factors for thyroid testing indications in pregnancy,” Korevaar said.
Factors considered a risk, resulting in recommended testing at presentation include a history of subclinical or clinical hypo- or hyperthyroidism, postpartum thyroiditis, known thyroid antibody positivity, symptoms of thyroid dysfunction or goiter, and other factors.
Treatment for Subclinical Hypothyroidism in Pregnancy
Whereas current guidelines recommend TPO antibody status in determining when to consider treatment for subclinical hypothyroidism, the new proposed guideline will instead recommend treatment based on the timing of the diagnosis of the subclinical hypothyroidism, with consideration of treatment during the first trimester, but not in the second or third trimester, based on newer evidence of the absolute risk for pregnancy complications and randomized trial data.
“The recommendations are now to no longer based on TPO antibody status, but instead according to the timing of the diagnosis of subclinical hypothyroidism,” Korevaar said.
Based on the collective data, “due to the low risk, we do not recommend for routine levothyroxine treatment in the second or third trimester groups with TSH levels under 10 mU/L now.”
“However, for subclinical hypothyroidism diagnosed in the first trimester, the recommendation would be that you can consider levothyroxine treatment,” he said.
While a clear indication for treatment in any trimester is the presence of overt hypothyroidism, or TSH levels over 10 mU/L, Korevaar underscored the importance of considering nuances of the recommendations that may warrant flexibility, for instance among patients with borderline TSH levels.
Spontaneous Normalization of Thyroid Levels in Pregnancy
Another new recommendation addresses the issue of spontaneous normalization of abnormal thyroid function during pregnancy, with several large studies showing a large proportion of subclinical hypothyroidism cases spontaneously revert to euthyroidism by the third trimester — despite no treatment having been provided.
Under the important proposed recommendation, retesting of subclinical hypothyroidism is suggested within 3 weeks.
“The data shows that a large proportion of patients spontaneously revert to euthyroidism,” Korevaar said.
“Upon identifying subclinical hypothyroidism in the first trimester, there will be essentially two options that clinicians can discuss with their patient — one would be to consider confirmatory tests in 3 weeks or to discuss the starting the lower dose levothyroxine in the first trimester,” he said.
In terms of overt hypothyroidism, likewise, if patients have a TSH levels below 6 mU/L in pregnancy, “you can either consider doing confirmatory testing within 3 weeks, or discussing with the patient starting levothyroxine treatment,” Korevaar added.
Overt Hyperthyroidism
For overt hyperthyroidism, no significant changes from current guidelines are being proposed, with the key exception of a heightened emphasis on the need for shared decision-making with patients, Korevaar said.
“We want to emphasize shared decision-making especially for women who have Graves’ disease prior to pregnancy, because the antithyroid treatment modalities, primarily methimazole (MMI) and propylthiouracil (PTU), have different advantages and disadvantages for an upcoming pregnancy,” he said.
“If you help a patient become involved in the decision-making process, that can also be very helpful in managing the disease and following-up on the pregnancy.”
Under the recommendations, PTU remains the preferred drug in overt hyperthyroidism, due to a more favorable profile in terms of potential birth defects vs MMI, with research showing a higher absolute risk of 3% vs 5%.
The guidelines further suggest the option of stopping the antithyroid medications upon a positive pregnancy test, with the exception of high-risk patients.
Korevaar noted that, if the treatment is stopped early in pregnancy, relapse is not likely to occur until after approximately 3 months, or 12 weeks, at which time, the high-risk teratogenic period, which is between week 5 and week 15, will have passed.
Current guidelines regarding whether to stop treatment in higher-risk hyperthyroid patients are recommended to remain unchanged.
Thyroid Nodules and Cancer
Recommendations regarding thyroid nodules and cancer during pregnancy are also expected to remain largely similar to those in the 2017 guidelines, with the exception of an emphasis on simply considering how the patient would normally be managed outside of pregnancy.
For instance, regarding the question of whether treatment can be withheld for 9 months during pregnancy. “A lot of times, the answer is yes,” Korevaar said.
Other topics that will be largely unchanged include issues of universal screening, definitions of normal and abnormal TSH and free T4 reference ranges and isolated hypothyroxinemia.
Steps Forward in Improving Updates, Readability
In addition to recommendation updates, the new guidelines are being revised to better reflect more recent evidence-based developments and user-friendliness.
“We have now made the step to a more systematic and replicable methodology to ensure for easier updates with a shorter interval,” Korevaar told this news organization.
“Furthermore, since 2006, the ATA guideline documents have followed a question-and-answer format, lacked recommendation tables and had none or only a few graphic illustrations,” he added.
“We are now further developing the typical outline of the guidelines to improve the readability and dissemination of the guideline document.”
Korevaar’s disclosures include lectureship fees from IBSA, Merck, and Berlin Chemie.
A version of this article first appeared on Medscape.com.
CHICAGO — A preview of much-anticipated updates to guidelines on managing thyroid disease in pregnancy shows key changes to recommendations in the evolving field, ranging from consideration of the chance of spontaneous normalization of thyroid levels during pregnancy to a heightened emphasis on shared decision-making and the nuances can factor into personalized treatment.
The guidelines, expected to be published in early 2025, have not been updated since 2017, and with substantial advances and evidence from countless studies since then, the new guidelines were developed with a goal to start afresh, said ATA Thyroid and Pregnancy Guidelines Task Force cochair Tim IM Korevaar, MD, PhD, in presenting the final draft guidelines at the American Thyroid Association (ATA) 2024 Meeting.
“Obviously, we’re not going to ignore the 2017 guidelines, which have been a very good resource for us so far, but we really wanted to start from scratch and follow a ‘blank canvas’ approach in optimizing the evidence,” said Korevaar, an endocrinologist and obstetric internist with the Division of Pharmacology and Vascular Medicine & Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
The guidelines, developed through a collaborative effort involving a wide variety of related medical societies, involved 14 systematic literature reviews. While the pregnancy issues covered by the guidelines is extensive, key highlights include:
Management in Preconception
Beginning with preconception, a key change in the guidelines will be that patients with euthyroid thyroid peroxidase (TPO) antibodies, which can be indicative of thyroid dysfunction, routine treatment with levothyroxine is not recommended, based on new evidence from randomized trials of high-risk patients showing no clear benefit from the treatment.
“In these trials, and across analyses, there was absolutely no beneficial effect of levothyroxine in these patients [with euthyroid TPO antibody positivity],” he said.
With evidence showing, however, that TPO antibody positivity can lead to subclinical or overt hypothyroidism within 1 or 2 years, the guidelines will recommend that TPO antibody–positive patients do have thyroid stimulating hormone (TSH) levels tested every 3-6 months until pregnancy, and existing recommendations to test during pregnancy among those patients remain in place, Korevaar reported.
In terms of preconception subclinical hypothyroidism, the guidelines will emphasize the existing recommendation “to always strive to reassess” thyroid levels, and if subclinical hypothyroidism does persist, to treat with low-dose levothyroxine.
During Pregnancy
During pregnancy, the new proposed recommendations will reflect the important change that three key risk factors, including age over 30 years, having at least two prior pregnancies, and morbid obesity (body mass index [BMI] at least 40 kg/m2), previously considered a risk for thyroid dysfunction in pregnancy, should not, on their own, suggest the need for thyroid testing, based on low evidence of an increased risk in pregnancy.
Research on the issue includes a recent study from Korevaar’s team showing these factors to in fact have low predictability of thyroid dysfunction.
“We deemed that these risk differences weren’t really clinically meaningful (in predicting risk), and so we have removed to maternal age, BMI, and parity as risk factors for thyroid testing indications in pregnancy,” Korevaar said.
Factors considered a risk, resulting in recommended testing at presentation include a history of subclinical or clinical hypo- or hyperthyroidism, postpartum thyroiditis, known thyroid antibody positivity, symptoms of thyroid dysfunction or goiter, and other factors.
Treatment for Subclinical Hypothyroidism in Pregnancy
Whereas current guidelines recommend TPO antibody status in determining when to consider treatment for subclinical hypothyroidism, the new proposed guideline will instead recommend treatment based on the timing of the diagnosis of the subclinical hypothyroidism, with consideration of treatment during the first trimester, but not in the second or third trimester, based on newer evidence of the absolute risk for pregnancy complications and randomized trial data.
“The recommendations are now to no longer based on TPO antibody status, but instead according to the timing of the diagnosis of subclinical hypothyroidism,” Korevaar said.
Based on the collective data, “due to the low risk, we do not recommend for routine levothyroxine treatment in the second or third trimester groups with TSH levels under 10 mU/L now.”
“However, for subclinical hypothyroidism diagnosed in the first trimester, the recommendation would be that you can consider levothyroxine treatment,” he said.
While a clear indication for treatment in any trimester is the presence of overt hypothyroidism, or TSH levels over 10 mU/L, Korevaar underscored the importance of considering nuances of the recommendations that may warrant flexibility, for instance among patients with borderline TSH levels.
Spontaneous Normalization of Thyroid Levels in Pregnancy
Another new recommendation addresses the issue of spontaneous normalization of abnormal thyroid function during pregnancy, with several large studies showing a large proportion of subclinical hypothyroidism cases spontaneously revert to euthyroidism by the third trimester — despite no treatment having been provided.
Under the important proposed recommendation, retesting of subclinical hypothyroidism is suggested within 3 weeks.
“The data shows that a large proportion of patients spontaneously revert to euthyroidism,” Korevaar said.
“Upon identifying subclinical hypothyroidism in the first trimester, there will be essentially two options that clinicians can discuss with their patient — one would be to consider confirmatory tests in 3 weeks or to discuss the starting the lower dose levothyroxine in the first trimester,” he said.
In terms of overt hypothyroidism, likewise, if patients have a TSH levels below 6 mU/L in pregnancy, “you can either consider doing confirmatory testing within 3 weeks, or discussing with the patient starting levothyroxine treatment,” Korevaar added.
Overt Hyperthyroidism
For overt hyperthyroidism, no significant changes from current guidelines are being proposed, with the key exception of a heightened emphasis on the need for shared decision-making with patients, Korevaar said.
“We want to emphasize shared decision-making especially for women who have Graves’ disease prior to pregnancy, because the antithyroid treatment modalities, primarily methimazole (MMI) and propylthiouracil (PTU), have different advantages and disadvantages for an upcoming pregnancy,” he said.
“If you help a patient become involved in the decision-making process, that can also be very helpful in managing the disease and following-up on the pregnancy.”
Under the recommendations, PTU remains the preferred drug in overt hyperthyroidism, due to a more favorable profile in terms of potential birth defects vs MMI, with research showing a higher absolute risk of 3% vs 5%.
The guidelines further suggest the option of stopping the antithyroid medications upon a positive pregnancy test, with the exception of high-risk patients.
Korevaar noted that, if the treatment is stopped early in pregnancy, relapse is not likely to occur until after approximately 3 months, or 12 weeks, at which time, the high-risk teratogenic period, which is between week 5 and week 15, will have passed.
Current guidelines regarding whether to stop treatment in higher-risk hyperthyroid patients are recommended to remain unchanged.
Thyroid Nodules and Cancer
Recommendations regarding thyroid nodules and cancer during pregnancy are also expected to remain largely similar to those in the 2017 guidelines, with the exception of an emphasis on simply considering how the patient would normally be managed outside of pregnancy.
For instance, regarding the question of whether treatment can be withheld for 9 months during pregnancy. “A lot of times, the answer is yes,” Korevaar said.
Other topics that will be largely unchanged include issues of universal screening, definitions of normal and abnormal TSH and free T4 reference ranges and isolated hypothyroxinemia.
Steps Forward in Improving Updates, Readability
In addition to recommendation updates, the new guidelines are being revised to better reflect more recent evidence-based developments and user-friendliness.
“We have now made the step to a more systematic and replicable methodology to ensure for easier updates with a shorter interval,” Korevaar told this news organization.
“Furthermore, since 2006, the ATA guideline documents have followed a question-and-answer format, lacked recommendation tables and had none or only a few graphic illustrations,” he added.
“We are now further developing the typical outline of the guidelines to improve the readability and dissemination of the guideline document.”
Korevaar’s disclosures include lectureship fees from IBSA, Merck, and Berlin Chemie.
A version of this article first appeared on Medscape.com.
FROM ATA 2024
Myeloma: Isa-KRd Induction Shows High MRD Responses
“We found that this induction induced exceptionally high response and minimal residual disease (MRD) negativity rates,” said first author Aurore Perrot, MD, PhD, an associate professor of hematology at the University of Toulouse in France, in presenting the findings at the annual meeting of the International Myeloma Society (IMS).
“These rates are the highest reported to date regarding MRD negativity,” she said.
The results from a first interim analysis offer encouraging groundwork in the trial that is investigating the tailoring of subsequent therapeutic choices in patients with newly diagnosed MM based on MRD status after six cycles of induction therapy.
In the standard treatment regimen of induction therapy followed by up-front autologous stem cell transplant (ASCT), the use of ever-improving quadruplet regimens is bolstering prognoses, while the role of up-front ASCT continues to be debated, Perrot explained. She noted that no prospective trials have compared up-front transplant vs no transplant following a quadruplet regimen.
In reporting on the initial findings from the induction phase of the phase 3 IFM 2020-02 MIDAS study, Perrot described results among 791 transplant-eligible patients with newly diagnosed MM and a median age of 59 who were enrolled at 72 centers between December 2021 and July 2023.
The patients were treated with six cycles of 28 days of the Isa-KRd regimen, consisting of isatuximab 10 mg/kg (weekly for 4 weeks then biweekly), carfilzomib 20 mg/m2 on day 1 cycle 1, then 56 mg/m2 (days 1, 8, and 15), lenalidomide 25 mg/d (from day 1 to day 21), and dexamethasone at 40 mg/wk.
Overall, MM was classified as International Staging System (ISS) III in 120 patients (15%) and revised-ISS III in 76 (10%) patients.
Of 757 patients undergoing cytogenetics, 8% were considered high risk on the basis of a linear predictor score > 1, while the t(11;14) translocation, a chromosomal abnormality, was present in 26% of patients.
Extramedullary disease was present in five patients, while 53 (7%) had circulating plasma cells.
All 791 patients initiated Isa-KRd induction, and most (766, 97%) had at least one peripheral stem cell mobilization course, with 761 having at least one apheresis. The median number of CD34+ cells collected was 7.106/kg.
The peripheral stem cells collected allowed for potential tandem transplants in 719 patients. In total, 757 patients completed six cycles of Isa-KRd, with an overall response rate of 95%.
In the intent-to-treat (ITT) population, a very good partial response or better was achieved in 92% of patients following induction, with a rate of 99% in the per-protocol [PP] population.
Of 751 patients in the post-induction ITT population, the MRD negativity rates were 63% at the threshold of 10−5 and 47% at the threshold of 10−6, with corresponding rates of 66% and 50%, respectively, in the PP population.
The rates of near-complete response and complete response were 64% and 66% in the ITT population, and 69% and 71% in the PP population.
Of note, no significant differences were observed in prognostic subgroups, with a trend for a higher MRD negative rate among poorer prognostic groups, Perrot said.
However, notable variability was observed in terms of MRD negativity at 10−5 after induction among some cytogenic groups, with an MRD negativity rate as high as 81% among patients with the t(4;14) translocation vs 62% among those without the abnormality (P = .002), while it was only 40% among patients with the t(11;14) translocation vs 64% without (P < .0001).
“This is the first time we have observed this correlation between the MRD negativity and these cytogenetic subgroups,” Perrot noted.
“For the moment, we are not saying that patients with the t(11;14) translocation have a poor prognosis,” she added. “But just that the early assessment of MRD shows the lower negativity rates.”
Safety
Seven patients experienced disease progression and five died during induction, with one dying from disease progression, two deaths related to cardiac adverse events (AEs), and two related to other AEs.
In terms of safety, the most common grade 3-4 AEs were neutropenia (25%), thrombocytopenia (5%), and infections (7%).
Peripheral neuropathy was reported among 13% of patients at any grade, and less than 1% grade 3-4.
“Our findings confirm that six cycles of Isa-KRd induce exceptionally high response and MRD negativity rates, not only at a sensitivity of 10−5 but also at 10−6,” Perrot said.
She noted that, in comparison, the MRD negativity rate at 10−5 in the related CASSIOPEIA, GRIFFIN, and IsKia trials were 35%, 22%, and 45%, respectively.
“A longer follow-up is needed to better interpret the significance of achieving MRD negativity in patients with different cytogenetic abnormalities,” Perrot added.
“Importantly, the Isa-KRd induction ensures successful stem cell collection, with no new safety signals,” she said.
The Isa-KRd regimen is not yet approved, hence only used in clinical trials, but Perrot told this publication the current evidence should help change that.
“The IsKia trial is comparing KRd and Isa-KRd, and Sanofi should try to approve the combo,” she said. “We hope the Midas data will support this approval.”
Questions Aplenty Moving Ahead
While the results are just the first from the ongoing trial, interest in the study and its design is high, Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, told this publication.
“To have a large trial algorithm that is based on response and in particular MRD is novel and reflects the power of MRD in myeloma,” said Mikhael, a professor of applied cancer research and drug discovery at the Translational Genomics Research Institute, City of Hope Cancer Center, Phoenix, Arizona.
“Although the results are preliminary, these kinds of trials can inform our approach to MRD testing and may result in more personalized and effective treatments for patients,” he said. “This may include the potential to de-escalate or even stop therapies that have historically been given for longer or provide more intense therapies for patients with inadequate response.”
“We know the biology of myeloma is ‘one size fits all’, so the design of our trials should reflect that heterogeneity.”
Further commenting on the research, the meeting discussant Sagar Lonial, MD, professor and chair of the Department of Hematology and Medical Oncology and the Anne and Bernard Gray Professor in Cancer at the Winship Cancer Institute of Emory University, Atlanta, Georgia, offered cautious optimism.
Referencing the tale of Midas in Greek mythology as having a “be careful what you wish for” lesson, Lonial pondered that, likewise, a question that may be considered regarding MRD is “whether this is in fact a gift — or could this be a curse that’s going to get us into trouble at some point down the road. I don’t know the answer.”
Some cautionary lessons include prior research indicating that patients with high-risk disease may achieve a complete remission early — but they lose remission earlier down the road, he noted.
Other considerations as the research moves forward: “Recognizing that MRD may in fact be more important than genetics — which is a premise of the current trial,” Lonial pondered. “Does MRD override genetics, or do they travel together?”
The study is ongoing, with future results expected in terms of ASCT vs no ASCT for patients with high and low risk, as well as single vs tandem ASCT.
The trial received financial support from Amgen, Bristol-Myers Squibb, and Sanofi. Perrot reported ties with Amgen, Bristol Myers Squibb, and Sanofi. Mikhael disclosed ties with Amgen, Bristol Myers Squibb, and Sanofi. Lonial reported relationships with Celgene, Bristol-Myers Squibb, Amgen, and Sanofi.
A version of this article first appeared on Medscape.com.
“We found that this induction induced exceptionally high response and minimal residual disease (MRD) negativity rates,” said first author Aurore Perrot, MD, PhD, an associate professor of hematology at the University of Toulouse in France, in presenting the findings at the annual meeting of the International Myeloma Society (IMS).
“These rates are the highest reported to date regarding MRD negativity,” she said.
The results from a first interim analysis offer encouraging groundwork in the trial that is investigating the tailoring of subsequent therapeutic choices in patients with newly diagnosed MM based on MRD status after six cycles of induction therapy.
In the standard treatment regimen of induction therapy followed by up-front autologous stem cell transplant (ASCT), the use of ever-improving quadruplet regimens is bolstering prognoses, while the role of up-front ASCT continues to be debated, Perrot explained. She noted that no prospective trials have compared up-front transplant vs no transplant following a quadruplet regimen.
In reporting on the initial findings from the induction phase of the phase 3 IFM 2020-02 MIDAS study, Perrot described results among 791 transplant-eligible patients with newly diagnosed MM and a median age of 59 who were enrolled at 72 centers between December 2021 and July 2023.
The patients were treated with six cycles of 28 days of the Isa-KRd regimen, consisting of isatuximab 10 mg/kg (weekly for 4 weeks then biweekly), carfilzomib 20 mg/m2 on day 1 cycle 1, then 56 mg/m2 (days 1, 8, and 15), lenalidomide 25 mg/d (from day 1 to day 21), and dexamethasone at 40 mg/wk.
Overall, MM was classified as International Staging System (ISS) III in 120 patients (15%) and revised-ISS III in 76 (10%) patients.
Of 757 patients undergoing cytogenetics, 8% were considered high risk on the basis of a linear predictor score > 1, while the t(11;14) translocation, a chromosomal abnormality, was present in 26% of patients.
Extramedullary disease was present in five patients, while 53 (7%) had circulating plasma cells.
All 791 patients initiated Isa-KRd induction, and most (766, 97%) had at least one peripheral stem cell mobilization course, with 761 having at least one apheresis. The median number of CD34+ cells collected was 7.106/kg.
The peripheral stem cells collected allowed for potential tandem transplants in 719 patients. In total, 757 patients completed six cycles of Isa-KRd, with an overall response rate of 95%.
In the intent-to-treat (ITT) population, a very good partial response or better was achieved in 92% of patients following induction, with a rate of 99% in the per-protocol [PP] population.
Of 751 patients in the post-induction ITT population, the MRD negativity rates were 63% at the threshold of 10−5 and 47% at the threshold of 10−6, with corresponding rates of 66% and 50%, respectively, in the PP population.
The rates of near-complete response and complete response were 64% and 66% in the ITT population, and 69% and 71% in the PP population.
Of note, no significant differences were observed in prognostic subgroups, with a trend for a higher MRD negative rate among poorer prognostic groups, Perrot said.
However, notable variability was observed in terms of MRD negativity at 10−5 after induction among some cytogenic groups, with an MRD negativity rate as high as 81% among patients with the t(4;14) translocation vs 62% among those without the abnormality (P = .002), while it was only 40% among patients with the t(11;14) translocation vs 64% without (P < .0001).
“This is the first time we have observed this correlation between the MRD negativity and these cytogenetic subgroups,” Perrot noted.
“For the moment, we are not saying that patients with the t(11;14) translocation have a poor prognosis,” she added. “But just that the early assessment of MRD shows the lower negativity rates.”
Safety
Seven patients experienced disease progression and five died during induction, with one dying from disease progression, two deaths related to cardiac adverse events (AEs), and two related to other AEs.
In terms of safety, the most common grade 3-4 AEs were neutropenia (25%), thrombocytopenia (5%), and infections (7%).
Peripheral neuropathy was reported among 13% of patients at any grade, and less than 1% grade 3-4.
“Our findings confirm that six cycles of Isa-KRd induce exceptionally high response and MRD negativity rates, not only at a sensitivity of 10−5 but also at 10−6,” Perrot said.
She noted that, in comparison, the MRD negativity rate at 10−5 in the related CASSIOPEIA, GRIFFIN, and IsKia trials were 35%, 22%, and 45%, respectively.
“A longer follow-up is needed to better interpret the significance of achieving MRD negativity in patients with different cytogenetic abnormalities,” Perrot added.
“Importantly, the Isa-KRd induction ensures successful stem cell collection, with no new safety signals,” she said.
The Isa-KRd regimen is not yet approved, hence only used in clinical trials, but Perrot told this publication the current evidence should help change that.
“The IsKia trial is comparing KRd and Isa-KRd, and Sanofi should try to approve the combo,” she said. “We hope the Midas data will support this approval.”
Questions Aplenty Moving Ahead
While the results are just the first from the ongoing trial, interest in the study and its design is high, Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, told this publication.
“To have a large trial algorithm that is based on response and in particular MRD is novel and reflects the power of MRD in myeloma,” said Mikhael, a professor of applied cancer research and drug discovery at the Translational Genomics Research Institute, City of Hope Cancer Center, Phoenix, Arizona.
“Although the results are preliminary, these kinds of trials can inform our approach to MRD testing and may result in more personalized and effective treatments for patients,” he said. “This may include the potential to de-escalate or even stop therapies that have historically been given for longer or provide more intense therapies for patients with inadequate response.”
“We know the biology of myeloma is ‘one size fits all’, so the design of our trials should reflect that heterogeneity.”
Further commenting on the research, the meeting discussant Sagar Lonial, MD, professor and chair of the Department of Hematology and Medical Oncology and the Anne and Bernard Gray Professor in Cancer at the Winship Cancer Institute of Emory University, Atlanta, Georgia, offered cautious optimism.
Referencing the tale of Midas in Greek mythology as having a “be careful what you wish for” lesson, Lonial pondered that, likewise, a question that may be considered regarding MRD is “whether this is in fact a gift — or could this be a curse that’s going to get us into trouble at some point down the road. I don’t know the answer.”
Some cautionary lessons include prior research indicating that patients with high-risk disease may achieve a complete remission early — but they lose remission earlier down the road, he noted.
Other considerations as the research moves forward: “Recognizing that MRD may in fact be more important than genetics — which is a premise of the current trial,” Lonial pondered. “Does MRD override genetics, or do they travel together?”
The study is ongoing, with future results expected in terms of ASCT vs no ASCT for patients with high and low risk, as well as single vs tandem ASCT.
The trial received financial support from Amgen, Bristol-Myers Squibb, and Sanofi. Perrot reported ties with Amgen, Bristol Myers Squibb, and Sanofi. Mikhael disclosed ties with Amgen, Bristol Myers Squibb, and Sanofi. Lonial reported relationships with Celgene, Bristol-Myers Squibb, Amgen, and Sanofi.
A version of this article first appeared on Medscape.com.
“We found that this induction induced exceptionally high response and minimal residual disease (MRD) negativity rates,” said first author Aurore Perrot, MD, PhD, an associate professor of hematology at the University of Toulouse in France, in presenting the findings at the annual meeting of the International Myeloma Society (IMS).
“These rates are the highest reported to date regarding MRD negativity,” she said.
The results from a first interim analysis offer encouraging groundwork in the trial that is investigating the tailoring of subsequent therapeutic choices in patients with newly diagnosed MM based on MRD status after six cycles of induction therapy.
In the standard treatment regimen of induction therapy followed by up-front autologous stem cell transplant (ASCT), the use of ever-improving quadruplet regimens is bolstering prognoses, while the role of up-front ASCT continues to be debated, Perrot explained. She noted that no prospective trials have compared up-front transplant vs no transplant following a quadruplet regimen.
In reporting on the initial findings from the induction phase of the phase 3 IFM 2020-02 MIDAS study, Perrot described results among 791 transplant-eligible patients with newly diagnosed MM and a median age of 59 who were enrolled at 72 centers between December 2021 and July 2023.
The patients were treated with six cycles of 28 days of the Isa-KRd regimen, consisting of isatuximab 10 mg/kg (weekly for 4 weeks then biweekly), carfilzomib 20 mg/m2 on day 1 cycle 1, then 56 mg/m2 (days 1, 8, and 15), lenalidomide 25 mg/d (from day 1 to day 21), and dexamethasone at 40 mg/wk.
Overall, MM was classified as International Staging System (ISS) III in 120 patients (15%) and revised-ISS III in 76 (10%) patients.
Of 757 patients undergoing cytogenetics, 8% were considered high risk on the basis of a linear predictor score > 1, while the t(11;14) translocation, a chromosomal abnormality, was present in 26% of patients.
Extramedullary disease was present in five patients, while 53 (7%) had circulating plasma cells.
All 791 patients initiated Isa-KRd induction, and most (766, 97%) had at least one peripheral stem cell mobilization course, with 761 having at least one apheresis. The median number of CD34+ cells collected was 7.106/kg.
The peripheral stem cells collected allowed for potential tandem transplants in 719 patients. In total, 757 patients completed six cycles of Isa-KRd, with an overall response rate of 95%.
In the intent-to-treat (ITT) population, a very good partial response or better was achieved in 92% of patients following induction, with a rate of 99% in the per-protocol [PP] population.
Of 751 patients in the post-induction ITT population, the MRD negativity rates were 63% at the threshold of 10−5 and 47% at the threshold of 10−6, with corresponding rates of 66% and 50%, respectively, in the PP population.
The rates of near-complete response and complete response were 64% and 66% in the ITT population, and 69% and 71% in the PP population.
Of note, no significant differences were observed in prognostic subgroups, with a trend for a higher MRD negative rate among poorer prognostic groups, Perrot said.
However, notable variability was observed in terms of MRD negativity at 10−5 after induction among some cytogenic groups, with an MRD negativity rate as high as 81% among patients with the t(4;14) translocation vs 62% among those without the abnormality (P = .002), while it was only 40% among patients with the t(11;14) translocation vs 64% without (P < .0001).
“This is the first time we have observed this correlation between the MRD negativity and these cytogenetic subgroups,” Perrot noted.
“For the moment, we are not saying that patients with the t(11;14) translocation have a poor prognosis,” she added. “But just that the early assessment of MRD shows the lower negativity rates.”
Safety
Seven patients experienced disease progression and five died during induction, with one dying from disease progression, two deaths related to cardiac adverse events (AEs), and two related to other AEs.
In terms of safety, the most common grade 3-4 AEs were neutropenia (25%), thrombocytopenia (5%), and infections (7%).
Peripheral neuropathy was reported among 13% of patients at any grade, and less than 1% grade 3-4.
“Our findings confirm that six cycles of Isa-KRd induce exceptionally high response and MRD negativity rates, not only at a sensitivity of 10−5 but also at 10−6,” Perrot said.
She noted that, in comparison, the MRD negativity rate at 10−5 in the related CASSIOPEIA, GRIFFIN, and IsKia trials were 35%, 22%, and 45%, respectively.
“A longer follow-up is needed to better interpret the significance of achieving MRD negativity in patients with different cytogenetic abnormalities,” Perrot added.
“Importantly, the Isa-KRd induction ensures successful stem cell collection, with no new safety signals,” she said.
The Isa-KRd regimen is not yet approved, hence only used in clinical trials, but Perrot told this publication the current evidence should help change that.
“The IsKia trial is comparing KRd and Isa-KRd, and Sanofi should try to approve the combo,” she said. “We hope the Midas data will support this approval.”
Questions Aplenty Moving Ahead
While the results are just the first from the ongoing trial, interest in the study and its design is high, Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, told this publication.
“To have a large trial algorithm that is based on response and in particular MRD is novel and reflects the power of MRD in myeloma,” said Mikhael, a professor of applied cancer research and drug discovery at the Translational Genomics Research Institute, City of Hope Cancer Center, Phoenix, Arizona.
“Although the results are preliminary, these kinds of trials can inform our approach to MRD testing and may result in more personalized and effective treatments for patients,” he said. “This may include the potential to de-escalate or even stop therapies that have historically been given for longer or provide more intense therapies for patients with inadequate response.”
“We know the biology of myeloma is ‘one size fits all’, so the design of our trials should reflect that heterogeneity.”
Further commenting on the research, the meeting discussant Sagar Lonial, MD, professor and chair of the Department of Hematology and Medical Oncology and the Anne and Bernard Gray Professor in Cancer at the Winship Cancer Institute of Emory University, Atlanta, Georgia, offered cautious optimism.
Referencing the tale of Midas in Greek mythology as having a “be careful what you wish for” lesson, Lonial pondered that, likewise, a question that may be considered regarding MRD is “whether this is in fact a gift — or could this be a curse that’s going to get us into trouble at some point down the road. I don’t know the answer.”
Some cautionary lessons include prior research indicating that patients with high-risk disease may achieve a complete remission early — but they lose remission earlier down the road, he noted.
Other considerations as the research moves forward: “Recognizing that MRD may in fact be more important than genetics — which is a premise of the current trial,” Lonial pondered. “Does MRD override genetics, or do they travel together?”
The study is ongoing, with future results expected in terms of ASCT vs no ASCT for patients with high and low risk, as well as single vs tandem ASCT.
The trial received financial support from Amgen, Bristol-Myers Squibb, and Sanofi. Perrot reported ties with Amgen, Bristol Myers Squibb, and Sanofi. Mikhael disclosed ties with Amgen, Bristol Myers Squibb, and Sanofi. Lonial reported relationships with Celgene, Bristol-Myers Squibb, Amgen, and Sanofi.
A version of this article first appeared on Medscape.com.
FROM IMS 2024
Daratumumab Quadruplet Supported Transplant-Ineligible MM
“CEPHEUS is the first phase 3 daratumumab trial with a primary endpoint of MRD negativity,” said first author Saad Z. Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York City, in presenting late-breaking findings at the annual meeting of the International Myeloma Society in Rio de Janeiro, Brazil in late September.
“We found that adding daratumumab to VRd significantly improved depth and duration of response,” Dr. Usmani said. “[The quadruplet regimen] has the potential to improve clinical outcomes for transplant-ineligible or transplant-deferred patients with newly diagnosed MM who can tolerate bortezomib.”
For newly diagnosed patients with MM who are not eligible for a stem cell transplant, the triplet MAIA regimen of daratumumab, lenalidomide, and dexamethasone is a recommended standard of care, having shown a median overall survival of 7.5 years.
However, for those who are transplant eligible, the PERSEUS regimen of D-VRd followed by daratumumab/lenalidomide maintenance, has shown significant progress-free survival benefits compared with the standard of care.
For the ongoing, multicenter, open-label CEPHEUS study, Dr. Usmani and his colleagues investigated the efficacy of the quadruplet D-VRd regimen compared with VRd alone among newly diagnosed patients who are transplant-ineligible or deferred (not planned as initial therapy).
In the trial, 395 adult patients with transplant-ineligible or transplant-deferred newly diagnosed MM all were initially treated with eight 21-day cycles of VRd, followed by 28-day cycles of lenalidomide until disease progression.
The patients were then randomized to VRd either with (n = 197) or without (n = 198) subcutaneous daratumumab.
Those receiving daratumumab received the subcutaneous therapy weekly in cycles 1 and 2, every 3 weeks in cycles 3-8, and every 4 weeks in cycles 9 or more, until disease progression.
The patients had a median age of 70 years; 28.1% had International Staging System stage III disease, and 13.2% had high-risk cytogenetics.
For the primary endpoint, with a median follow-up of 58.7 months, those in the daratumumab group had a significantly higher rate of being MRD-negative (60.9%) than the VRd-only group (39.4%; odds ratio [OR], 2.37; P < .0001).
Likewise, progression-free survival (PFS) was significantly improved with the daratumumab regimen vs VRd (hazard ratio [HR], 0.57; P = .0005).
A median PFS was not reached for daratumumab plus VRd, compared with 52.6 months for the VRd group, while estimated 54-month PFS rates were 68.1% vs 49.5%, respectively.
A complete response or better was achieved among 81.2% in the daratumumab regimen vs 61.6% with VRd alone (P < .0001) and a sustained rate of MRD-negativity was achieved in 48.7% vs 26.3%, respectively (P < .0001).
There was a trend of overall survival in favor of daratumumab plus VRd (HR, 0.85), with an HR of 0.69 in a sensitivity analysis adjusting for deaths related to COVID-19.
Patients in the daratumumab group had a substantially longer median duration of treatment (56.3 months) than the VRd-only group (34.3 months), with the most common reason for treatment discontinuation being disease progression.
The benefit of daratumumab was generally consistent across the study’s prespecified subgroups, and the relative dose intensity of VRd was not affected by combination with daratumumab.
In terms of safety, treatment-emergent adverse events (TEAEs) were consistent with the known profile of daratumumab and VRd, with grade 5 TEAEs comparable between the two groups after adjusting for treatment exposure.
Quality of life, as measured by EORTC QLQ-C30 score, was improved in both arms over time, with no detriment related to treatment with daratumumab.
Of note, frail patients were not included in the trial. Asked in the Q and A why they were excluded, Dr. Usmani explained that “all of these options are wonderful for our patients, and we are entering a phase where quadruplet therapies will become a mainstay for majority of patients.
“But we have to be careful as we think about not overtreating patients or giving too many side effects of therapies, and that’s why it made sense for us to exclude the frail patients.”
Along those lines, he noted that a key concern in the CEPHEUS trial was tolerance of bortezomib.
“Peripheral sensory neuropathy tends to occur in about half of the patients receiving bortezomib, and about half of that number is grade 2 or higher,” he noted in an interview.
“In some patients, the symptoms do not completely resolve. [Therefore], in transplant-ineligible patients, quadruple regimens may be more relevant for the fit or intermediate-fit patients.”
He concluded that “the CEPHEUS trial compliments the MAIA regimen in supporting a daratumumab-based quadruplet or triplet standard-of-care option across transplant-ineligible patients and those deferring transplant.”
Commenting on the study, Philippe Moreau, MD, who is president of the IMS, noted that “the CEPHEUS study is important because [determining] the best treatment upfront for elderly patients is very important.”
“We need confirmation of the very good results achieved with the IMROZ trial, which showed an estimated 5-year PFS of 63.2%, said Dr. Moreau, professor of clinical hematology and head of the translational research program in hematology and oncology at the University Hospital of Nantes, France.
“If we can achieve the same results, we will have the confirmation that quadruplet is probably here to stay,” Dr. Moreau said.
Dr. Usmani disclosed relationships with Abbvie, Amgen, BioPharma, Bristol Myers Squibb, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineOx, and Takeda.
A version of this article first appeared on Medscape.com.
“CEPHEUS is the first phase 3 daratumumab trial with a primary endpoint of MRD negativity,” said first author Saad Z. Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York City, in presenting late-breaking findings at the annual meeting of the International Myeloma Society in Rio de Janeiro, Brazil in late September.
“We found that adding daratumumab to VRd significantly improved depth and duration of response,” Dr. Usmani said. “[The quadruplet regimen] has the potential to improve clinical outcomes for transplant-ineligible or transplant-deferred patients with newly diagnosed MM who can tolerate bortezomib.”
For newly diagnosed patients with MM who are not eligible for a stem cell transplant, the triplet MAIA regimen of daratumumab, lenalidomide, and dexamethasone is a recommended standard of care, having shown a median overall survival of 7.5 years.
However, for those who are transplant eligible, the PERSEUS regimen of D-VRd followed by daratumumab/lenalidomide maintenance, has shown significant progress-free survival benefits compared with the standard of care.
For the ongoing, multicenter, open-label CEPHEUS study, Dr. Usmani and his colleagues investigated the efficacy of the quadruplet D-VRd regimen compared with VRd alone among newly diagnosed patients who are transplant-ineligible or deferred (not planned as initial therapy).
In the trial, 395 adult patients with transplant-ineligible or transplant-deferred newly diagnosed MM all were initially treated with eight 21-day cycles of VRd, followed by 28-day cycles of lenalidomide until disease progression.
The patients were then randomized to VRd either with (n = 197) or without (n = 198) subcutaneous daratumumab.
Those receiving daratumumab received the subcutaneous therapy weekly in cycles 1 and 2, every 3 weeks in cycles 3-8, and every 4 weeks in cycles 9 or more, until disease progression.
The patients had a median age of 70 years; 28.1% had International Staging System stage III disease, and 13.2% had high-risk cytogenetics.
For the primary endpoint, with a median follow-up of 58.7 months, those in the daratumumab group had a significantly higher rate of being MRD-negative (60.9%) than the VRd-only group (39.4%; odds ratio [OR], 2.37; P < .0001).
Likewise, progression-free survival (PFS) was significantly improved with the daratumumab regimen vs VRd (hazard ratio [HR], 0.57; P = .0005).
A median PFS was not reached for daratumumab plus VRd, compared with 52.6 months for the VRd group, while estimated 54-month PFS rates were 68.1% vs 49.5%, respectively.
A complete response or better was achieved among 81.2% in the daratumumab regimen vs 61.6% with VRd alone (P < .0001) and a sustained rate of MRD-negativity was achieved in 48.7% vs 26.3%, respectively (P < .0001).
There was a trend of overall survival in favor of daratumumab plus VRd (HR, 0.85), with an HR of 0.69 in a sensitivity analysis adjusting for deaths related to COVID-19.
Patients in the daratumumab group had a substantially longer median duration of treatment (56.3 months) than the VRd-only group (34.3 months), with the most common reason for treatment discontinuation being disease progression.
The benefit of daratumumab was generally consistent across the study’s prespecified subgroups, and the relative dose intensity of VRd was not affected by combination with daratumumab.
In terms of safety, treatment-emergent adverse events (TEAEs) were consistent with the known profile of daratumumab and VRd, with grade 5 TEAEs comparable between the two groups after adjusting for treatment exposure.
Quality of life, as measured by EORTC QLQ-C30 score, was improved in both arms over time, with no detriment related to treatment with daratumumab.
Of note, frail patients were not included in the trial. Asked in the Q and A why they were excluded, Dr. Usmani explained that “all of these options are wonderful for our patients, and we are entering a phase where quadruplet therapies will become a mainstay for majority of patients.
“But we have to be careful as we think about not overtreating patients or giving too many side effects of therapies, and that’s why it made sense for us to exclude the frail patients.”
Along those lines, he noted that a key concern in the CEPHEUS trial was tolerance of bortezomib.
“Peripheral sensory neuropathy tends to occur in about half of the patients receiving bortezomib, and about half of that number is grade 2 or higher,” he noted in an interview.
“In some patients, the symptoms do not completely resolve. [Therefore], in transplant-ineligible patients, quadruple regimens may be more relevant for the fit or intermediate-fit patients.”
He concluded that “the CEPHEUS trial compliments the MAIA regimen in supporting a daratumumab-based quadruplet or triplet standard-of-care option across transplant-ineligible patients and those deferring transplant.”
Commenting on the study, Philippe Moreau, MD, who is president of the IMS, noted that “the CEPHEUS study is important because [determining] the best treatment upfront for elderly patients is very important.”
“We need confirmation of the very good results achieved with the IMROZ trial, which showed an estimated 5-year PFS of 63.2%, said Dr. Moreau, professor of clinical hematology and head of the translational research program in hematology and oncology at the University Hospital of Nantes, France.
“If we can achieve the same results, we will have the confirmation that quadruplet is probably here to stay,” Dr. Moreau said.
Dr. Usmani disclosed relationships with Abbvie, Amgen, BioPharma, Bristol Myers Squibb, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineOx, and Takeda.
A version of this article first appeared on Medscape.com.
“CEPHEUS is the first phase 3 daratumumab trial with a primary endpoint of MRD negativity,” said first author Saad Z. Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York City, in presenting late-breaking findings at the annual meeting of the International Myeloma Society in Rio de Janeiro, Brazil in late September.
“We found that adding daratumumab to VRd significantly improved depth and duration of response,” Dr. Usmani said. “[The quadruplet regimen] has the potential to improve clinical outcomes for transplant-ineligible or transplant-deferred patients with newly diagnosed MM who can tolerate bortezomib.”
For newly diagnosed patients with MM who are not eligible for a stem cell transplant, the triplet MAIA regimen of daratumumab, lenalidomide, and dexamethasone is a recommended standard of care, having shown a median overall survival of 7.5 years.
However, for those who are transplant eligible, the PERSEUS regimen of D-VRd followed by daratumumab/lenalidomide maintenance, has shown significant progress-free survival benefits compared with the standard of care.
For the ongoing, multicenter, open-label CEPHEUS study, Dr. Usmani and his colleagues investigated the efficacy of the quadruplet D-VRd regimen compared with VRd alone among newly diagnosed patients who are transplant-ineligible or deferred (not planned as initial therapy).
In the trial, 395 adult patients with transplant-ineligible or transplant-deferred newly diagnosed MM all were initially treated with eight 21-day cycles of VRd, followed by 28-day cycles of lenalidomide until disease progression.
The patients were then randomized to VRd either with (n = 197) or without (n = 198) subcutaneous daratumumab.
Those receiving daratumumab received the subcutaneous therapy weekly in cycles 1 and 2, every 3 weeks in cycles 3-8, and every 4 weeks in cycles 9 or more, until disease progression.
The patients had a median age of 70 years; 28.1% had International Staging System stage III disease, and 13.2% had high-risk cytogenetics.
For the primary endpoint, with a median follow-up of 58.7 months, those in the daratumumab group had a significantly higher rate of being MRD-negative (60.9%) than the VRd-only group (39.4%; odds ratio [OR], 2.37; P < .0001).
Likewise, progression-free survival (PFS) was significantly improved with the daratumumab regimen vs VRd (hazard ratio [HR], 0.57; P = .0005).
A median PFS was not reached for daratumumab plus VRd, compared with 52.6 months for the VRd group, while estimated 54-month PFS rates were 68.1% vs 49.5%, respectively.
A complete response or better was achieved among 81.2% in the daratumumab regimen vs 61.6% with VRd alone (P < .0001) and a sustained rate of MRD-negativity was achieved in 48.7% vs 26.3%, respectively (P < .0001).
There was a trend of overall survival in favor of daratumumab plus VRd (HR, 0.85), with an HR of 0.69 in a sensitivity analysis adjusting for deaths related to COVID-19.
Patients in the daratumumab group had a substantially longer median duration of treatment (56.3 months) than the VRd-only group (34.3 months), with the most common reason for treatment discontinuation being disease progression.
The benefit of daratumumab was generally consistent across the study’s prespecified subgroups, and the relative dose intensity of VRd was not affected by combination with daratumumab.
In terms of safety, treatment-emergent adverse events (TEAEs) were consistent with the known profile of daratumumab and VRd, with grade 5 TEAEs comparable between the two groups after adjusting for treatment exposure.
Quality of life, as measured by EORTC QLQ-C30 score, was improved in both arms over time, with no detriment related to treatment with daratumumab.
Of note, frail patients were not included in the trial. Asked in the Q and A why they were excluded, Dr. Usmani explained that “all of these options are wonderful for our patients, and we are entering a phase where quadruplet therapies will become a mainstay for majority of patients.
“But we have to be careful as we think about not overtreating patients or giving too many side effects of therapies, and that’s why it made sense for us to exclude the frail patients.”
Along those lines, he noted that a key concern in the CEPHEUS trial was tolerance of bortezomib.
“Peripheral sensory neuropathy tends to occur in about half of the patients receiving bortezomib, and about half of that number is grade 2 or higher,” he noted in an interview.
“In some patients, the symptoms do not completely resolve. [Therefore], in transplant-ineligible patients, quadruple regimens may be more relevant for the fit or intermediate-fit patients.”
He concluded that “the CEPHEUS trial compliments the MAIA regimen in supporting a daratumumab-based quadruplet or triplet standard-of-care option across transplant-ineligible patients and those deferring transplant.”
Commenting on the study, Philippe Moreau, MD, who is president of the IMS, noted that “the CEPHEUS study is important because [determining] the best treatment upfront for elderly patients is very important.”
“We need confirmation of the very good results achieved with the IMROZ trial, which showed an estimated 5-year PFS of 63.2%, said Dr. Moreau, professor of clinical hematology and head of the translational research program in hematology and oncology at the University Hospital of Nantes, France.
“If we can achieve the same results, we will have the confirmation that quadruplet is probably here to stay,” Dr. Moreau said.
Dr. Usmani disclosed relationships with Abbvie, Amgen, BioPharma, Bristol Myers Squibb, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineOx, and Takeda.
A version of this article first appeared on Medscape.com.
FROM IMS 2024
Myeloma: Daratumumab Plus Lenalidomide Improves MRD Outcomes
“To date, no randomized trial has directly compared daratumumab-based maintenance therapy vs standard of care lenalidomide maintenance, which is the focus of our trial,” said first author Ashraf Z. Badros, MD, a professor of medicine at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, in presenting the findings at the International Myeloma Society (IMS) 2024.
“These results support the addition of daratumumab not only to induction/consolidation but also to standard of care lenalidomide maintenance for these patients,” he said of the study, which was published concurrently in the journal Blood.
Despite ongoing advancements in regimens for induction, consolidation, and maintenance posttransplant, most patients with MM eventually relapse, driving continuing efforts to optimize treatment strategies and improve long-term outcomes.
While daratumumab, an anti-CD38 monoclonal antibody, is approved in induction and consolidation with ASCT for patients with newly diagnosed MM, the authors sought to investigate the potential benefits of adding it to the standard-of-care therapy lenalidomide in maintenance therapy.
For the phase 3 AURIGA trial, they recruited 200 patients with newly diagnosed MM within 12 months of induction therapy and 6 months of ASCT.
The patients, who were all anti-CD38 naive, received at least four induction cycles, had at least a very good partial response, and were MRD positive following ASCT.
They were randomized 1:1 to receive 28-day lenalidomide maintenance cycles either with (n = 99) or without (n = 101) subcutaneous daratumumab for at least 36 cycles or until disease progression, unacceptable toxicity, or withdrawal.
The patients had similar baseline demographic characteristics; their median age was about 62 years, and 25.3% in the daratumumab and 23.5% in the no-daratumumab group had ISS stage III disease. At the time of diagnosis, 23.9% and 16.9%, respectively, had high cytogenic risk.
Overall, patients received a median of five induction cycles prior to entering the study.
For the primary endpoint, the rate of conversion from MRD positive to MRD negative (at a sensitivity of 10-5 using next-generation sequencing) by 12 months was significantly higher in the daratumumab group than in the lenalidomide-only group, at 50.5% vs 18.8% (odds ratio [OR], 4.51; P < .0001).
A similar benefit with the daratumumab group was observed across all clinically relevant subgroups, including patients with high-risk disease.
The MRD-negative conversion rate was similar at the 10-6 threshold (23.2% vs 5%; OR, 5.97; P = .0002).
At a median follow-up of 32.3 months, the overall rates of MRD negativity were 60.6% and 27.7%, with and without daratumumab, respectively (OR, 4.12; P < .0001)
The achievement of complete response or better also was significantly greater with daratumumab (75.8% vs 61.4%; OR, 2.00; P = .0255).
Likewise, PFS favored daratumumab (hazard ratio, 0.53), and the estimated 30-month PFS rates were 82.7% and 66.4%, respectively.
The daratumumab group received more maintenance cycles than the lenalidomide-only group (median of 33 vs 21.5), and it had higher rates of completion of 12 cycles (88.5% vs 78.6%). Dr. Badros noted that the main reason for discontinuation of therapy in the no-daratumumab arm was disease progression.
Consistent with previous studies, daratumumab was associated with more grade 3/4 treatment-emergent adverse events (TEAEs), occurring in 74.0% patients vs 67.3% patients not receiving daratumumab, including infections (18.8% vs 13.3%), cytopenia (54.2% vs 46.9%), and neutropenia (46.9% vs 41.8%). Dr. Badros noted the significantly longer time of treatment in the daratumumab arm (30 months vs 20 months).
Serious TEAEs occurred in 30.2% daratumumab patients and 22.4% no-daratumumab patients, and fatal TEAEs occurred in 2.1% and 1.0% patients, respectively.
“Overall, there were no new safety concerns for daratumumab,” he said.
The authors noted that the requirement that patients be anti-CD38 naive was partially because of “the D-VRd [daratumumab combined with bortezomib, lenalidomide, and dexamethasone] regimen gaining popularity and increased utilization in the myeloma community for transplant-eligible patients with NDMM, even before the publication of the long-term results of the randomized GRIFFIN and PERSEUS studies.”
A key question, remarked Joseph Mikhael, MD, who is chief medical officer of the International Myeloma Foundation, from the audience, is how applicable the findings are in the modern environment, where most patients now have indeed had prior anti-CD38 treatment.
In response, Dr. Badros explained that “I think this is an important study because it is probably one of the few studies that separates the impact of daratumumab-lenalidomide without prior daratumumab use.”
Dr. Badros noted that results from the PERSEUS trial, of D-VRd, show MRD-positive to MRD-negative conversion rates that are similar to the current trial; “therefore, I really don’t think that using daratumumab up front will prevent using it as maintenance,” he said. “If anything, it actually improves outcomes.”
The findings from continuous treatment “are an important reminder that high-risk patients do not do well if you stop treatment,” he said.
Further commenting on the research at the meeting, María-Victoria Mateos, MD, PhD, an associate professor of medicine at the University of Salamanca in Spain, noted that “the unmet need in maintenance is to upgrade the quality of the response and to increase the conversion of MRD-positivity to MRD negative in order to delay the progression of the disease and prolong the overall survival.”
Regarding the AURIGA trial, “this is very interesting data about the role of daratumumab-lenalidomide maintenance in patients who are MRD positive after autologous stem cell transplantation.”
“What is more important is we are progressing in response-adaptive therapy, and we are generating very useful information to possibly make the majority of patients become MRD negative.
“Developing early endpoints as surrogate markers for long-term outcomes and overall survival is critically important,” she added. “Otherwise, trials may continue for more than 15 years.”
The study was sponsored by Janssen Biotech. Dr. Badros reported relationships with Bristol-Myers Squibb, BeiGene, Roche, Jansen, and GSK. Mateos disclosed ties with AbbVie, Amgen, Bristol-Myers Squibb, GSK, Kite, Johnson & Johnson, Oncopeptides, Pfizer, Regeneron, Roche, and Sanofi.
A version of this article first appeared on Medscape.com.
“To date, no randomized trial has directly compared daratumumab-based maintenance therapy vs standard of care lenalidomide maintenance, which is the focus of our trial,” said first author Ashraf Z. Badros, MD, a professor of medicine at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, in presenting the findings at the International Myeloma Society (IMS) 2024.
“These results support the addition of daratumumab not only to induction/consolidation but also to standard of care lenalidomide maintenance for these patients,” he said of the study, which was published concurrently in the journal Blood.
Despite ongoing advancements in regimens for induction, consolidation, and maintenance posttransplant, most patients with MM eventually relapse, driving continuing efforts to optimize treatment strategies and improve long-term outcomes.
While daratumumab, an anti-CD38 monoclonal antibody, is approved in induction and consolidation with ASCT for patients with newly diagnosed MM, the authors sought to investigate the potential benefits of adding it to the standard-of-care therapy lenalidomide in maintenance therapy.
For the phase 3 AURIGA trial, they recruited 200 patients with newly diagnosed MM within 12 months of induction therapy and 6 months of ASCT.
The patients, who were all anti-CD38 naive, received at least four induction cycles, had at least a very good partial response, and were MRD positive following ASCT.
They were randomized 1:1 to receive 28-day lenalidomide maintenance cycles either with (n = 99) or without (n = 101) subcutaneous daratumumab for at least 36 cycles or until disease progression, unacceptable toxicity, or withdrawal.
The patients had similar baseline demographic characteristics; their median age was about 62 years, and 25.3% in the daratumumab and 23.5% in the no-daratumumab group had ISS stage III disease. At the time of diagnosis, 23.9% and 16.9%, respectively, had high cytogenic risk.
Overall, patients received a median of five induction cycles prior to entering the study.
For the primary endpoint, the rate of conversion from MRD positive to MRD negative (at a sensitivity of 10-5 using next-generation sequencing) by 12 months was significantly higher in the daratumumab group than in the lenalidomide-only group, at 50.5% vs 18.8% (odds ratio [OR], 4.51; P < .0001).
A similar benefit with the daratumumab group was observed across all clinically relevant subgroups, including patients with high-risk disease.
The MRD-negative conversion rate was similar at the 10-6 threshold (23.2% vs 5%; OR, 5.97; P = .0002).
At a median follow-up of 32.3 months, the overall rates of MRD negativity were 60.6% and 27.7%, with and without daratumumab, respectively (OR, 4.12; P < .0001)
The achievement of complete response or better also was significantly greater with daratumumab (75.8% vs 61.4%; OR, 2.00; P = .0255).
Likewise, PFS favored daratumumab (hazard ratio, 0.53), and the estimated 30-month PFS rates were 82.7% and 66.4%, respectively.
The daratumumab group received more maintenance cycles than the lenalidomide-only group (median of 33 vs 21.5), and it had higher rates of completion of 12 cycles (88.5% vs 78.6%). Dr. Badros noted that the main reason for discontinuation of therapy in the no-daratumumab arm was disease progression.
Consistent with previous studies, daratumumab was associated with more grade 3/4 treatment-emergent adverse events (TEAEs), occurring in 74.0% patients vs 67.3% patients not receiving daratumumab, including infections (18.8% vs 13.3%), cytopenia (54.2% vs 46.9%), and neutropenia (46.9% vs 41.8%). Dr. Badros noted the significantly longer time of treatment in the daratumumab arm (30 months vs 20 months).
Serious TEAEs occurred in 30.2% daratumumab patients and 22.4% no-daratumumab patients, and fatal TEAEs occurred in 2.1% and 1.0% patients, respectively.
“Overall, there were no new safety concerns for daratumumab,” he said.
The authors noted that the requirement that patients be anti-CD38 naive was partially because of “the D-VRd [daratumumab combined with bortezomib, lenalidomide, and dexamethasone] regimen gaining popularity and increased utilization in the myeloma community for transplant-eligible patients with NDMM, even before the publication of the long-term results of the randomized GRIFFIN and PERSEUS studies.”
A key question, remarked Joseph Mikhael, MD, who is chief medical officer of the International Myeloma Foundation, from the audience, is how applicable the findings are in the modern environment, where most patients now have indeed had prior anti-CD38 treatment.
In response, Dr. Badros explained that “I think this is an important study because it is probably one of the few studies that separates the impact of daratumumab-lenalidomide without prior daratumumab use.”
Dr. Badros noted that results from the PERSEUS trial, of D-VRd, show MRD-positive to MRD-negative conversion rates that are similar to the current trial; “therefore, I really don’t think that using daratumumab up front will prevent using it as maintenance,” he said. “If anything, it actually improves outcomes.”
The findings from continuous treatment “are an important reminder that high-risk patients do not do well if you stop treatment,” he said.
Further commenting on the research at the meeting, María-Victoria Mateos, MD, PhD, an associate professor of medicine at the University of Salamanca in Spain, noted that “the unmet need in maintenance is to upgrade the quality of the response and to increase the conversion of MRD-positivity to MRD negative in order to delay the progression of the disease and prolong the overall survival.”
Regarding the AURIGA trial, “this is very interesting data about the role of daratumumab-lenalidomide maintenance in patients who are MRD positive after autologous stem cell transplantation.”
“What is more important is we are progressing in response-adaptive therapy, and we are generating very useful information to possibly make the majority of patients become MRD negative.
“Developing early endpoints as surrogate markers for long-term outcomes and overall survival is critically important,” she added. “Otherwise, trials may continue for more than 15 years.”
The study was sponsored by Janssen Biotech. Dr. Badros reported relationships with Bristol-Myers Squibb, BeiGene, Roche, Jansen, and GSK. Mateos disclosed ties with AbbVie, Amgen, Bristol-Myers Squibb, GSK, Kite, Johnson & Johnson, Oncopeptides, Pfizer, Regeneron, Roche, and Sanofi.
A version of this article first appeared on Medscape.com.
“To date, no randomized trial has directly compared daratumumab-based maintenance therapy vs standard of care lenalidomide maintenance, which is the focus of our trial,” said first author Ashraf Z. Badros, MD, a professor of medicine at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, in presenting the findings at the International Myeloma Society (IMS) 2024.
“These results support the addition of daratumumab not only to induction/consolidation but also to standard of care lenalidomide maintenance for these patients,” he said of the study, which was published concurrently in the journal Blood.
Despite ongoing advancements in regimens for induction, consolidation, and maintenance posttransplant, most patients with MM eventually relapse, driving continuing efforts to optimize treatment strategies and improve long-term outcomes.
While daratumumab, an anti-CD38 monoclonal antibody, is approved in induction and consolidation with ASCT for patients with newly diagnosed MM, the authors sought to investigate the potential benefits of adding it to the standard-of-care therapy lenalidomide in maintenance therapy.
For the phase 3 AURIGA trial, they recruited 200 patients with newly diagnosed MM within 12 months of induction therapy and 6 months of ASCT.
The patients, who were all anti-CD38 naive, received at least four induction cycles, had at least a very good partial response, and were MRD positive following ASCT.
They were randomized 1:1 to receive 28-day lenalidomide maintenance cycles either with (n = 99) or without (n = 101) subcutaneous daratumumab for at least 36 cycles or until disease progression, unacceptable toxicity, or withdrawal.
The patients had similar baseline demographic characteristics; their median age was about 62 years, and 25.3% in the daratumumab and 23.5% in the no-daratumumab group had ISS stage III disease. At the time of diagnosis, 23.9% and 16.9%, respectively, had high cytogenic risk.
Overall, patients received a median of five induction cycles prior to entering the study.
For the primary endpoint, the rate of conversion from MRD positive to MRD negative (at a sensitivity of 10-5 using next-generation sequencing) by 12 months was significantly higher in the daratumumab group than in the lenalidomide-only group, at 50.5% vs 18.8% (odds ratio [OR], 4.51; P < .0001).
A similar benefit with the daratumumab group was observed across all clinically relevant subgroups, including patients with high-risk disease.
The MRD-negative conversion rate was similar at the 10-6 threshold (23.2% vs 5%; OR, 5.97; P = .0002).
At a median follow-up of 32.3 months, the overall rates of MRD negativity were 60.6% and 27.7%, with and without daratumumab, respectively (OR, 4.12; P < .0001)
The achievement of complete response or better also was significantly greater with daratumumab (75.8% vs 61.4%; OR, 2.00; P = .0255).
Likewise, PFS favored daratumumab (hazard ratio, 0.53), and the estimated 30-month PFS rates were 82.7% and 66.4%, respectively.
The daratumumab group received more maintenance cycles than the lenalidomide-only group (median of 33 vs 21.5), and it had higher rates of completion of 12 cycles (88.5% vs 78.6%). Dr. Badros noted that the main reason for discontinuation of therapy in the no-daratumumab arm was disease progression.
Consistent with previous studies, daratumumab was associated with more grade 3/4 treatment-emergent adverse events (TEAEs), occurring in 74.0% patients vs 67.3% patients not receiving daratumumab, including infections (18.8% vs 13.3%), cytopenia (54.2% vs 46.9%), and neutropenia (46.9% vs 41.8%). Dr. Badros noted the significantly longer time of treatment in the daratumumab arm (30 months vs 20 months).
Serious TEAEs occurred in 30.2% daratumumab patients and 22.4% no-daratumumab patients, and fatal TEAEs occurred in 2.1% and 1.0% patients, respectively.
“Overall, there were no new safety concerns for daratumumab,” he said.
The authors noted that the requirement that patients be anti-CD38 naive was partially because of “the D-VRd [daratumumab combined with bortezomib, lenalidomide, and dexamethasone] regimen gaining popularity and increased utilization in the myeloma community for transplant-eligible patients with NDMM, even before the publication of the long-term results of the randomized GRIFFIN and PERSEUS studies.”
A key question, remarked Joseph Mikhael, MD, who is chief medical officer of the International Myeloma Foundation, from the audience, is how applicable the findings are in the modern environment, where most patients now have indeed had prior anti-CD38 treatment.
In response, Dr. Badros explained that “I think this is an important study because it is probably one of the few studies that separates the impact of daratumumab-lenalidomide without prior daratumumab use.”
Dr. Badros noted that results from the PERSEUS trial, of D-VRd, show MRD-positive to MRD-negative conversion rates that are similar to the current trial; “therefore, I really don’t think that using daratumumab up front will prevent using it as maintenance,” he said. “If anything, it actually improves outcomes.”
The findings from continuous treatment “are an important reminder that high-risk patients do not do well if you stop treatment,” he said.
Further commenting on the research at the meeting, María-Victoria Mateos, MD, PhD, an associate professor of medicine at the University of Salamanca in Spain, noted that “the unmet need in maintenance is to upgrade the quality of the response and to increase the conversion of MRD-positivity to MRD negative in order to delay the progression of the disease and prolong the overall survival.”
Regarding the AURIGA trial, “this is very interesting data about the role of daratumumab-lenalidomide maintenance in patients who are MRD positive after autologous stem cell transplantation.”
“What is more important is we are progressing in response-adaptive therapy, and we are generating very useful information to possibly make the majority of patients become MRD negative.
“Developing early endpoints as surrogate markers for long-term outcomes and overall survival is critically important,” she added. “Otherwise, trials may continue for more than 15 years.”
The study was sponsored by Janssen Biotech. Dr. Badros reported relationships with Bristol-Myers Squibb, BeiGene, Roche, Jansen, and GSK. Mateos disclosed ties with AbbVie, Amgen, Bristol-Myers Squibb, GSK, Kite, Johnson & Johnson, Oncopeptides, Pfizer, Regeneron, Roche, and Sanofi.
A version of this article first appeared on Medscape.com.
FROM IMS 2024
SGLT2 Inhibitor Reduces Risk for Neurodegenerative Diseases in T2D
MADRID — Patients with type 2 diabetes treated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) show significant reductions in the risk of developing neurodegenerative disorders including Alzheimer’s disease, vascular dementia, and Parkinson’s disease, compared with those treated with other antidiabetic drugs, results from a large population-based cohort show.
“This was the largest nationwide population-based longitudinal cohort study to investigate the association between the use of SGLT2 inhibitors and the incidence of all-cause dementia and Parkinson’s disease,” said first author Hae Kyung Kim, MD, of the Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea, in presenting the findings at the annual meeting of the European Association for the Study of Diabetes.
Type 2 diabetes is known to increase the risk for neurodegenerative diseases such as dementia or Alzheimer’s disease, said Dr. Kim. Key factors attributed to the risk include shared pathophysiological mechanisms such as central nervous system insulin resistance and reduced cerebral glucose metabolism.
While research is lacking on the role of antidiabetic drugs in the treatment of neurodegenerative diseases, the researcher noted that “SGLT2 inhibitors, which have shown significant cardiorenal benefits and enhanced energy metabolism through ketogenesis, offer promise.”
To further investigate, Dr. Kim and her colleagues conducted the retrospective study, evaluating data on more than 1.3 million enrollees in Korea’s National Health Insurance Service Database who were aged 40 years or older, diagnosed with type 2 diabetes, and had initiated antidiabetic drugs between September 2014 and December 2019.
In the propensity score analysis, 358,862 patients were matched 1:1, in groups of 179,431 participants each, based on whether they were treated with SGLT2is or other oral antidiabetic drugs. Patients with a history of neurodegenerative disease, cancer, or use of glucagon-like peptide 1 receptor agonists were excluded.
The patients had a mean age of 57.8 years, 57.9% were men, and 6837 had incident dementia or Parkinson’s disease events reported.
With a mean follow-up of 2.88 years, after adjustment for key variables, those treated with SGLT2is had a 19% reduced risk of developing Alzheimer’s disease (adjusted hazard ratio [aHR], 0.81), a 31% reduced risk for vascular dementia (aHR, 0.69), and a 20% reduced risk for Parkinson’s disease (aHR, 0.80) compared with the non-SGLT2i group.
Furthermore, those receiving SGLT2i treatment had a 21% reduced risk for all-cause dementia (aHR, 0.79) and a 22% reduced risk for all-cause dementia and Parkinson’s disease compared with the oral antidiabetic drug group (aHR, 0.78) with a 6-month drug use lag period.
The association was observed regardless of SGLT2i exposure duration. Subgroup analyses indicated that the reductions in neurodegenerative disorders among those receiving SGLT2is were not associated with factors including age, sex, body mass index, blood pressure, glucose, lipid profiles, kidney function, health behaviors, comorbidities, diabetic complications, or other medication use.
Dr. Kim speculated that mechanisms underlying the reduced dementia risk could include SGLT2i effects of mitigating the common severe risk factors of type 2 diabetes and neurodegenerative diseases, including hypertension, heart failure, and chronic kidney disease, and improving hyperperfusion in the heart and cerebral vascular insufficiency.
Commenting on the study to this news organization, Erik H. Serné, MD, of the VU University Medical Centre, Amsterdam, the Netherlands, who comoderated the session, noted that “people with type 2 diabetes have a 50%-100% increased risk of developing dementia, particularly Alzheimer’s disease and vascular dementia.”
“The increasing prevalence of both conditions poses significant public health challenges, highlighting the need for effective prevention strategies and interventions.”
Currently, treatments for dementia are limited, with most primarily addressing symptoms and not the underlying cause of the neurodegenerative disease, he said.
He noted that, in addition to the effects mentioned by Dr. Kim, SGLT2is are also speculated to provide potential neuroprotective effects through improved glycemic control and insulin sensitivity, reduced inflammation and oxidative stress, enhanced mitochondrial function and energy metabolism, and reduced beta-amyloid and tau pathology.
“These mechanisms collectively may reduce the risk of cognitive decline, particularly in diabetic patients, and warrant further investigation in clinical trials to solidify the neuroprotective role of SGLT2 inhibitors,” said Dr. Serné.
In addition to their benefits in type 2 diabetes, SGLT2is “now offer hope in the prevention of dementia, a disease that has very limited therapeutic options thus far. The current data [presented by Dr. Kim] seem to corroborate this,” he added.
Dr. Kim and Dr. Serné had no disclosures to report.
A version of this article first appeared on Medscape.com.
MADRID — Patients with type 2 diabetes treated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) show significant reductions in the risk of developing neurodegenerative disorders including Alzheimer’s disease, vascular dementia, and Parkinson’s disease, compared with those treated with other antidiabetic drugs, results from a large population-based cohort show.
“This was the largest nationwide population-based longitudinal cohort study to investigate the association between the use of SGLT2 inhibitors and the incidence of all-cause dementia and Parkinson’s disease,” said first author Hae Kyung Kim, MD, of the Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea, in presenting the findings at the annual meeting of the European Association for the Study of Diabetes.
Type 2 diabetes is known to increase the risk for neurodegenerative diseases such as dementia or Alzheimer’s disease, said Dr. Kim. Key factors attributed to the risk include shared pathophysiological mechanisms such as central nervous system insulin resistance and reduced cerebral glucose metabolism.
While research is lacking on the role of antidiabetic drugs in the treatment of neurodegenerative diseases, the researcher noted that “SGLT2 inhibitors, which have shown significant cardiorenal benefits and enhanced energy metabolism through ketogenesis, offer promise.”
To further investigate, Dr. Kim and her colleagues conducted the retrospective study, evaluating data on more than 1.3 million enrollees in Korea’s National Health Insurance Service Database who were aged 40 years or older, diagnosed with type 2 diabetes, and had initiated antidiabetic drugs between September 2014 and December 2019.
In the propensity score analysis, 358,862 patients were matched 1:1, in groups of 179,431 participants each, based on whether they were treated with SGLT2is or other oral antidiabetic drugs. Patients with a history of neurodegenerative disease, cancer, or use of glucagon-like peptide 1 receptor agonists were excluded.
The patients had a mean age of 57.8 years, 57.9% were men, and 6837 had incident dementia or Parkinson’s disease events reported.
With a mean follow-up of 2.88 years, after adjustment for key variables, those treated with SGLT2is had a 19% reduced risk of developing Alzheimer’s disease (adjusted hazard ratio [aHR], 0.81), a 31% reduced risk for vascular dementia (aHR, 0.69), and a 20% reduced risk for Parkinson’s disease (aHR, 0.80) compared with the non-SGLT2i group.
Furthermore, those receiving SGLT2i treatment had a 21% reduced risk for all-cause dementia (aHR, 0.79) and a 22% reduced risk for all-cause dementia and Parkinson’s disease compared with the oral antidiabetic drug group (aHR, 0.78) with a 6-month drug use lag period.
The association was observed regardless of SGLT2i exposure duration. Subgroup analyses indicated that the reductions in neurodegenerative disorders among those receiving SGLT2is were not associated with factors including age, sex, body mass index, blood pressure, glucose, lipid profiles, kidney function, health behaviors, comorbidities, diabetic complications, or other medication use.
Dr. Kim speculated that mechanisms underlying the reduced dementia risk could include SGLT2i effects of mitigating the common severe risk factors of type 2 diabetes and neurodegenerative diseases, including hypertension, heart failure, and chronic kidney disease, and improving hyperperfusion in the heart and cerebral vascular insufficiency.
Commenting on the study to this news organization, Erik H. Serné, MD, of the VU University Medical Centre, Amsterdam, the Netherlands, who comoderated the session, noted that “people with type 2 diabetes have a 50%-100% increased risk of developing dementia, particularly Alzheimer’s disease and vascular dementia.”
“The increasing prevalence of both conditions poses significant public health challenges, highlighting the need for effective prevention strategies and interventions.”
Currently, treatments for dementia are limited, with most primarily addressing symptoms and not the underlying cause of the neurodegenerative disease, he said.
He noted that, in addition to the effects mentioned by Dr. Kim, SGLT2is are also speculated to provide potential neuroprotective effects through improved glycemic control and insulin sensitivity, reduced inflammation and oxidative stress, enhanced mitochondrial function and energy metabolism, and reduced beta-amyloid and tau pathology.
“These mechanisms collectively may reduce the risk of cognitive decline, particularly in diabetic patients, and warrant further investigation in clinical trials to solidify the neuroprotective role of SGLT2 inhibitors,” said Dr. Serné.
In addition to their benefits in type 2 diabetes, SGLT2is “now offer hope in the prevention of dementia, a disease that has very limited therapeutic options thus far. The current data [presented by Dr. Kim] seem to corroborate this,” he added.
Dr. Kim and Dr. Serné had no disclosures to report.
A version of this article first appeared on Medscape.com.
MADRID — Patients with type 2 diabetes treated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) show significant reductions in the risk of developing neurodegenerative disorders including Alzheimer’s disease, vascular dementia, and Parkinson’s disease, compared with those treated with other antidiabetic drugs, results from a large population-based cohort show.
“This was the largest nationwide population-based longitudinal cohort study to investigate the association between the use of SGLT2 inhibitors and the incidence of all-cause dementia and Parkinson’s disease,” said first author Hae Kyung Kim, MD, of the Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea, in presenting the findings at the annual meeting of the European Association for the Study of Diabetes.
Type 2 diabetes is known to increase the risk for neurodegenerative diseases such as dementia or Alzheimer’s disease, said Dr. Kim. Key factors attributed to the risk include shared pathophysiological mechanisms such as central nervous system insulin resistance and reduced cerebral glucose metabolism.
While research is lacking on the role of antidiabetic drugs in the treatment of neurodegenerative diseases, the researcher noted that “SGLT2 inhibitors, which have shown significant cardiorenal benefits and enhanced energy metabolism through ketogenesis, offer promise.”
To further investigate, Dr. Kim and her colleagues conducted the retrospective study, evaluating data on more than 1.3 million enrollees in Korea’s National Health Insurance Service Database who were aged 40 years or older, diagnosed with type 2 diabetes, and had initiated antidiabetic drugs between September 2014 and December 2019.
In the propensity score analysis, 358,862 patients were matched 1:1, in groups of 179,431 participants each, based on whether they were treated with SGLT2is or other oral antidiabetic drugs. Patients with a history of neurodegenerative disease, cancer, or use of glucagon-like peptide 1 receptor agonists were excluded.
The patients had a mean age of 57.8 years, 57.9% were men, and 6837 had incident dementia or Parkinson’s disease events reported.
With a mean follow-up of 2.88 years, after adjustment for key variables, those treated with SGLT2is had a 19% reduced risk of developing Alzheimer’s disease (adjusted hazard ratio [aHR], 0.81), a 31% reduced risk for vascular dementia (aHR, 0.69), and a 20% reduced risk for Parkinson’s disease (aHR, 0.80) compared with the non-SGLT2i group.
Furthermore, those receiving SGLT2i treatment had a 21% reduced risk for all-cause dementia (aHR, 0.79) and a 22% reduced risk for all-cause dementia and Parkinson’s disease compared with the oral antidiabetic drug group (aHR, 0.78) with a 6-month drug use lag period.
The association was observed regardless of SGLT2i exposure duration. Subgroup analyses indicated that the reductions in neurodegenerative disorders among those receiving SGLT2is were not associated with factors including age, sex, body mass index, blood pressure, glucose, lipid profiles, kidney function, health behaviors, comorbidities, diabetic complications, or other medication use.
Dr. Kim speculated that mechanisms underlying the reduced dementia risk could include SGLT2i effects of mitigating the common severe risk factors of type 2 diabetes and neurodegenerative diseases, including hypertension, heart failure, and chronic kidney disease, and improving hyperperfusion in the heart and cerebral vascular insufficiency.
Commenting on the study to this news organization, Erik H. Serné, MD, of the VU University Medical Centre, Amsterdam, the Netherlands, who comoderated the session, noted that “people with type 2 diabetes have a 50%-100% increased risk of developing dementia, particularly Alzheimer’s disease and vascular dementia.”
“The increasing prevalence of both conditions poses significant public health challenges, highlighting the need for effective prevention strategies and interventions.”
Currently, treatments for dementia are limited, with most primarily addressing symptoms and not the underlying cause of the neurodegenerative disease, he said.
He noted that, in addition to the effects mentioned by Dr. Kim, SGLT2is are also speculated to provide potential neuroprotective effects through improved glycemic control and insulin sensitivity, reduced inflammation and oxidative stress, enhanced mitochondrial function and energy metabolism, and reduced beta-amyloid and tau pathology.
“These mechanisms collectively may reduce the risk of cognitive decline, particularly in diabetic patients, and warrant further investigation in clinical trials to solidify the neuroprotective role of SGLT2 inhibitors,” said Dr. Serné.
In addition to their benefits in type 2 diabetes, SGLT2is “now offer hope in the prevention of dementia, a disease that has very limited therapeutic options thus far. The current data [presented by Dr. Kim] seem to corroborate this,” he added.
Dr. Kim and Dr. Serné had no disclosures to report.
A version of this article first appeared on Medscape.com.
FROM EASD 2024
After Rapid Weight Loss, Monitor Antiobesity Drug Dosing
A patient who developed atrial fibrillation resulting from the failure to adjust the levothyroxine dose after rapid, significant weight loss while on the antiobesity drug tirzepatide (Zepbound) serves as a key reminder in managing patients experiencing rapid weight loss, either from antiobesity medications or any other means: Patients taking medications with weight-based dosing need to have their doses closely monitored.
“Failing to monitor and adjust dosing of these [and other] medications during a period of rapid weight loss may lead to supratherapeutic — even toxic — levels, as was seen in this [case],” underscore the authors of an editorial regarding the Teachable Moment case, published in JAMA Internal Medicine.
Toxicities from excessive doses can have a range of detrimental effects. In terms of thyroid medicine, the failure to adjust levothyroxine treatment for hypothyroidism in cases of rapid weight loss can lead to thyrotoxicosis, and in older patients in particular, a resulting thyrotropin level < 0.1 mIU/L is associated with as much as a threefold increased risk for atrial fibrillation, as observed in the report.
Case Demonstrates Risks
The case involved a 62-year-old man with obesity, hypothyroidism, and type 1 diabetes who presented to the emergency department with palpitations, excessive sweating, confusion, fever, and hand tremors. Upon being diagnosed with atrial fibrillation, the patient was immediately treated.
His medical history revealed the underlying culprit: Six months earlier, the patient had started treatment with the gastric inhibitory polypeptide (GIP)/glucagon-like peptide (GLP) 1 dual agonist tirzepatide. As is typical with the drug, the patient’s weight quickly plummeted, dropping from a starting body mass index of 44.4 down to 31.2 after 6 months and a decrease in body weight from 132 kg to 93 kg (a loss of 39 kg [approximately 86 lb]).
When he was prescribed tirzepatide, 2.5 mg weekly, for obesity, the patient had been recommended to increase the dose every 4 weeks as tolerated and, importantly, to have a follow-up visit in a month. But because he lived in different states seasonally, the follow-up never occurred.
Upon his emergency department visit, the patient’s thyrotropin level had dropped from 1.9 mIU/L at the first visit 6 months earlier to 0.001 mIU/L (well within the atrial fibrillation risk range), and his free thyroxine level (fT4) was 7.26 ng/ dL — substantially outside of the normal range of about 0.9-1.7 ng/dL for adults.
“The patient had 4-times higher fT4 levels of the upper limit,” first author Kagan E. Karakus, MD, of the Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, told this news organization. “That is why he had experienced the adverse event of atrial fibrillation.”
Thyrotoxicosis Symptoms Can Be ‘Insidious,’ Levothyroxine Should Be Monitored
Although tirzepatide has not been approved by the US Food and Drug Administration for the treatment of type 1 diabetes, obesity is on the rise among patients with this disorder and recent research has shown a more than 10% reduction in body weight in 6 months and significant reductions in A1c with various doses.
Of note, in the current case, although the patient’s levothyroxine dose was not adjusted, his insulin dose was gradually self-decreased during his tirzepatide treatment to prevent hypoglycemia.
“If insulin treatment is excessive in diabetes, it causes hypoglycemia, [and] people with type 1 diabetes will recognize the signs of hypoglycemia related to excessive insulin earlier,” Dr. Karakus said.
If symptoms appear, patients can reduce their insulin doses on their own; however, the symptoms of thyrotoxicosis caused by excessive levothyroxine can be more insidious compared with hypoglycemia, he explained.
“Although patients can change their insulin doses, they cannot change the levothyroxine doses since it requires a blood test [thyroid-stimulating hormone; TSH] and a new prescription of the new dose.”
The key lesson is that “following levothyroxine treatment initiation or dose adjustment, 4-6 weeks is the optimal duration to recheck [the] thyrotropin level and adjust the dose as needed,” Dr. Karakus said.
Key Medications to Monitor
Other common outpatient medications that should be closely monitored in patients experiencing rapid weight loss, by any method, range from anticoagulants, anticonvulsants, and antituberculosis drugs to antibiotics and antifungals, the authors note.
Of note, medications with a narrow therapeutic index include phenytoin, warfarin, lithium carbonate, digoxin theophylline, tacrolimus, valproic acid, carbamazepine, and cyclosporine.
The failure to make necessary dose adjustments “is seen more often since the newer antiobesity drugs reduce a great amount of weight within months, almost as rapidly as bariatric surgery,” Dr. Karakus said.
“It is very important for physicians to be aware of the weight-based medications and narrow therapeutic index medications since their doses should be adjusted carefully, especially during weight loss,” he added.
Furthermore, “the patient should also know that weight reduction medication may cause adverse effects like nausea, vomiting and also may affect metabolism of other medications such that some medication doses should be adjusted regularly.”
In the editorial published with the study, Tyrone A. Johnson, MD, of the Department of Medicine, University of California, San Francisco, and colleagues note that the need for close monitoring is particularly important with older patients, who, in addition to having a higher likelihood of comorbidities, commonly have polypharmacy that could increase the potential for adverse effects.
Another key area concern is the emergence of direct-to-consumer avenues for GLP-1/GIP agonists for the many who either cannot afford or do not have access to the drugs, providing further opportunities for treatment without appropriate clinical oversight, they add.
Overall, the case “highlights the potential dangers underlying under-supervised prescribing of GLP-1/GIP receptor agonists and affirms the need for strong partnerships between patients and their clinicians during their use,” they wrote.
“These medications are best used in collaboration with continuity care teams, in context of a patient’s entire health, and in comprehensive risk-benefit assessment throughout the entire duration of treatment.”
A Caveat: Subclinical Levothyroxine Dosing
Commenting on the study, Matthew Ettleson, MD, a clinical instructor of medicine in the Section of Endocrinology, Diabetes, & Metabolism, University of Chicago, noted the important caveat that patients with hypothyroidism are commonly on subclinical doses, with varying dose adjustment needs.
“The patient in the case was clearly on a replacement level dose. However, many patients are on low doses of levothyroxine (75 µg or lower) for subclinical hypothyroidism, and, in general, I think the risks are lower with patients with subclinical hypothyroidism on lower doses of levothyroxine,” he told this news organization.
Because of that, “frequent TSH monitoring may be excessive in this population,” he said. “I would hesitate to empirically lower the dose with weight loss, unless it was clear that the patient was unlikely to follow up.
“Checking TSH at a more frequent interval and adjusting the dose accordingly should be adequate to prevent situations like this case.”
Dr. Karakus, Dr. Ettleson, and the editorial authors had no relevant disclosures to report.
A version of this article appeared on Medscape.com.
A patient who developed atrial fibrillation resulting from the failure to adjust the levothyroxine dose after rapid, significant weight loss while on the antiobesity drug tirzepatide (Zepbound) serves as a key reminder in managing patients experiencing rapid weight loss, either from antiobesity medications or any other means: Patients taking medications with weight-based dosing need to have their doses closely monitored.
“Failing to monitor and adjust dosing of these [and other] medications during a period of rapid weight loss may lead to supratherapeutic — even toxic — levels, as was seen in this [case],” underscore the authors of an editorial regarding the Teachable Moment case, published in JAMA Internal Medicine.
Toxicities from excessive doses can have a range of detrimental effects. In terms of thyroid medicine, the failure to adjust levothyroxine treatment for hypothyroidism in cases of rapid weight loss can lead to thyrotoxicosis, and in older patients in particular, a resulting thyrotropin level < 0.1 mIU/L is associated with as much as a threefold increased risk for atrial fibrillation, as observed in the report.
Case Demonstrates Risks
The case involved a 62-year-old man with obesity, hypothyroidism, and type 1 diabetes who presented to the emergency department with palpitations, excessive sweating, confusion, fever, and hand tremors. Upon being diagnosed with atrial fibrillation, the patient was immediately treated.
His medical history revealed the underlying culprit: Six months earlier, the patient had started treatment with the gastric inhibitory polypeptide (GIP)/glucagon-like peptide (GLP) 1 dual agonist tirzepatide. As is typical with the drug, the patient’s weight quickly plummeted, dropping from a starting body mass index of 44.4 down to 31.2 after 6 months and a decrease in body weight from 132 kg to 93 kg (a loss of 39 kg [approximately 86 lb]).
When he was prescribed tirzepatide, 2.5 mg weekly, for obesity, the patient had been recommended to increase the dose every 4 weeks as tolerated and, importantly, to have a follow-up visit in a month. But because he lived in different states seasonally, the follow-up never occurred.
Upon his emergency department visit, the patient’s thyrotropin level had dropped from 1.9 mIU/L at the first visit 6 months earlier to 0.001 mIU/L (well within the atrial fibrillation risk range), and his free thyroxine level (fT4) was 7.26 ng/ dL — substantially outside of the normal range of about 0.9-1.7 ng/dL for adults.
“The patient had 4-times higher fT4 levels of the upper limit,” first author Kagan E. Karakus, MD, of the Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, told this news organization. “That is why he had experienced the adverse event of atrial fibrillation.”
Thyrotoxicosis Symptoms Can Be ‘Insidious,’ Levothyroxine Should Be Monitored
Although tirzepatide has not been approved by the US Food and Drug Administration for the treatment of type 1 diabetes, obesity is on the rise among patients with this disorder and recent research has shown a more than 10% reduction in body weight in 6 months and significant reductions in A1c with various doses.
Of note, in the current case, although the patient’s levothyroxine dose was not adjusted, his insulin dose was gradually self-decreased during his tirzepatide treatment to prevent hypoglycemia.
“If insulin treatment is excessive in diabetes, it causes hypoglycemia, [and] people with type 1 diabetes will recognize the signs of hypoglycemia related to excessive insulin earlier,” Dr. Karakus said.
If symptoms appear, patients can reduce their insulin doses on their own; however, the symptoms of thyrotoxicosis caused by excessive levothyroxine can be more insidious compared with hypoglycemia, he explained.
“Although patients can change their insulin doses, they cannot change the levothyroxine doses since it requires a blood test [thyroid-stimulating hormone; TSH] and a new prescription of the new dose.”
The key lesson is that “following levothyroxine treatment initiation or dose adjustment, 4-6 weeks is the optimal duration to recheck [the] thyrotropin level and adjust the dose as needed,” Dr. Karakus said.
Key Medications to Monitor
Other common outpatient medications that should be closely monitored in patients experiencing rapid weight loss, by any method, range from anticoagulants, anticonvulsants, and antituberculosis drugs to antibiotics and antifungals, the authors note.
Of note, medications with a narrow therapeutic index include phenytoin, warfarin, lithium carbonate, digoxin theophylline, tacrolimus, valproic acid, carbamazepine, and cyclosporine.
The failure to make necessary dose adjustments “is seen more often since the newer antiobesity drugs reduce a great amount of weight within months, almost as rapidly as bariatric surgery,” Dr. Karakus said.
“It is very important for physicians to be aware of the weight-based medications and narrow therapeutic index medications since their doses should be adjusted carefully, especially during weight loss,” he added.
Furthermore, “the patient should also know that weight reduction medication may cause adverse effects like nausea, vomiting and also may affect metabolism of other medications such that some medication doses should be adjusted regularly.”
In the editorial published with the study, Tyrone A. Johnson, MD, of the Department of Medicine, University of California, San Francisco, and colleagues note that the need for close monitoring is particularly important with older patients, who, in addition to having a higher likelihood of comorbidities, commonly have polypharmacy that could increase the potential for adverse effects.
Another key area concern is the emergence of direct-to-consumer avenues for GLP-1/GIP agonists for the many who either cannot afford or do not have access to the drugs, providing further opportunities for treatment without appropriate clinical oversight, they add.
Overall, the case “highlights the potential dangers underlying under-supervised prescribing of GLP-1/GIP receptor agonists and affirms the need for strong partnerships between patients and their clinicians during their use,” they wrote.
“These medications are best used in collaboration with continuity care teams, in context of a patient’s entire health, and in comprehensive risk-benefit assessment throughout the entire duration of treatment.”
A Caveat: Subclinical Levothyroxine Dosing
Commenting on the study, Matthew Ettleson, MD, a clinical instructor of medicine in the Section of Endocrinology, Diabetes, & Metabolism, University of Chicago, noted the important caveat that patients with hypothyroidism are commonly on subclinical doses, with varying dose adjustment needs.
“The patient in the case was clearly on a replacement level dose. However, many patients are on low doses of levothyroxine (75 µg or lower) for subclinical hypothyroidism, and, in general, I think the risks are lower with patients with subclinical hypothyroidism on lower doses of levothyroxine,” he told this news organization.
Because of that, “frequent TSH monitoring may be excessive in this population,” he said. “I would hesitate to empirically lower the dose with weight loss, unless it was clear that the patient was unlikely to follow up.
“Checking TSH at a more frequent interval and adjusting the dose accordingly should be adequate to prevent situations like this case.”
Dr. Karakus, Dr. Ettleson, and the editorial authors had no relevant disclosures to report.
A version of this article appeared on Medscape.com.
A patient who developed atrial fibrillation resulting from the failure to adjust the levothyroxine dose after rapid, significant weight loss while on the antiobesity drug tirzepatide (Zepbound) serves as a key reminder in managing patients experiencing rapid weight loss, either from antiobesity medications or any other means: Patients taking medications with weight-based dosing need to have their doses closely monitored.
“Failing to monitor and adjust dosing of these [and other] medications during a period of rapid weight loss may lead to supratherapeutic — even toxic — levels, as was seen in this [case],” underscore the authors of an editorial regarding the Teachable Moment case, published in JAMA Internal Medicine.
Toxicities from excessive doses can have a range of detrimental effects. In terms of thyroid medicine, the failure to adjust levothyroxine treatment for hypothyroidism in cases of rapid weight loss can lead to thyrotoxicosis, and in older patients in particular, a resulting thyrotropin level < 0.1 mIU/L is associated with as much as a threefold increased risk for atrial fibrillation, as observed in the report.
Case Demonstrates Risks
The case involved a 62-year-old man with obesity, hypothyroidism, and type 1 diabetes who presented to the emergency department with palpitations, excessive sweating, confusion, fever, and hand tremors. Upon being diagnosed with atrial fibrillation, the patient was immediately treated.
His medical history revealed the underlying culprit: Six months earlier, the patient had started treatment with the gastric inhibitory polypeptide (GIP)/glucagon-like peptide (GLP) 1 dual agonist tirzepatide. As is typical with the drug, the patient’s weight quickly plummeted, dropping from a starting body mass index of 44.4 down to 31.2 after 6 months and a decrease in body weight from 132 kg to 93 kg (a loss of 39 kg [approximately 86 lb]).
When he was prescribed tirzepatide, 2.5 mg weekly, for obesity, the patient had been recommended to increase the dose every 4 weeks as tolerated and, importantly, to have a follow-up visit in a month. But because he lived in different states seasonally, the follow-up never occurred.
Upon his emergency department visit, the patient’s thyrotropin level had dropped from 1.9 mIU/L at the first visit 6 months earlier to 0.001 mIU/L (well within the atrial fibrillation risk range), and his free thyroxine level (fT4) was 7.26 ng/ dL — substantially outside of the normal range of about 0.9-1.7 ng/dL for adults.
“The patient had 4-times higher fT4 levels of the upper limit,” first author Kagan E. Karakus, MD, of the Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, told this news organization. “That is why he had experienced the adverse event of atrial fibrillation.”
Thyrotoxicosis Symptoms Can Be ‘Insidious,’ Levothyroxine Should Be Monitored
Although tirzepatide has not been approved by the US Food and Drug Administration for the treatment of type 1 diabetes, obesity is on the rise among patients with this disorder and recent research has shown a more than 10% reduction in body weight in 6 months and significant reductions in A1c with various doses.
Of note, in the current case, although the patient’s levothyroxine dose was not adjusted, his insulin dose was gradually self-decreased during his tirzepatide treatment to prevent hypoglycemia.
“If insulin treatment is excessive in diabetes, it causes hypoglycemia, [and] people with type 1 diabetes will recognize the signs of hypoglycemia related to excessive insulin earlier,” Dr. Karakus said.
If symptoms appear, patients can reduce their insulin doses on their own; however, the symptoms of thyrotoxicosis caused by excessive levothyroxine can be more insidious compared with hypoglycemia, he explained.
“Although patients can change their insulin doses, they cannot change the levothyroxine doses since it requires a blood test [thyroid-stimulating hormone; TSH] and a new prescription of the new dose.”
The key lesson is that “following levothyroxine treatment initiation or dose adjustment, 4-6 weeks is the optimal duration to recheck [the] thyrotropin level and adjust the dose as needed,” Dr. Karakus said.
Key Medications to Monitor
Other common outpatient medications that should be closely monitored in patients experiencing rapid weight loss, by any method, range from anticoagulants, anticonvulsants, and antituberculosis drugs to antibiotics and antifungals, the authors note.
Of note, medications with a narrow therapeutic index include phenytoin, warfarin, lithium carbonate, digoxin theophylline, tacrolimus, valproic acid, carbamazepine, and cyclosporine.
The failure to make necessary dose adjustments “is seen more often since the newer antiobesity drugs reduce a great amount of weight within months, almost as rapidly as bariatric surgery,” Dr. Karakus said.
“It is very important for physicians to be aware of the weight-based medications and narrow therapeutic index medications since their doses should be adjusted carefully, especially during weight loss,” he added.
Furthermore, “the patient should also know that weight reduction medication may cause adverse effects like nausea, vomiting and also may affect metabolism of other medications such that some medication doses should be adjusted regularly.”
In the editorial published with the study, Tyrone A. Johnson, MD, of the Department of Medicine, University of California, San Francisco, and colleagues note that the need for close monitoring is particularly important with older patients, who, in addition to having a higher likelihood of comorbidities, commonly have polypharmacy that could increase the potential for adverse effects.
Another key area concern is the emergence of direct-to-consumer avenues for GLP-1/GIP agonists for the many who either cannot afford or do not have access to the drugs, providing further opportunities for treatment without appropriate clinical oversight, they add.
Overall, the case “highlights the potential dangers underlying under-supervised prescribing of GLP-1/GIP receptor agonists and affirms the need for strong partnerships between patients and their clinicians during their use,” they wrote.
“These medications are best used in collaboration with continuity care teams, in context of a patient’s entire health, and in comprehensive risk-benefit assessment throughout the entire duration of treatment.”
A Caveat: Subclinical Levothyroxine Dosing
Commenting on the study, Matthew Ettleson, MD, a clinical instructor of medicine in the Section of Endocrinology, Diabetes, & Metabolism, University of Chicago, noted the important caveat that patients with hypothyroidism are commonly on subclinical doses, with varying dose adjustment needs.
“The patient in the case was clearly on a replacement level dose. However, many patients are on low doses of levothyroxine (75 µg or lower) for subclinical hypothyroidism, and, in general, I think the risks are lower with patients with subclinical hypothyroidism on lower doses of levothyroxine,” he told this news organization.
Because of that, “frequent TSH monitoring may be excessive in this population,” he said. “I would hesitate to empirically lower the dose with weight loss, unless it was clear that the patient was unlikely to follow up.
“Checking TSH at a more frequent interval and adjusting the dose accordingly should be adequate to prevent situations like this case.”
Dr. Karakus, Dr. Ettleson, and the editorial authors had no relevant disclosures to report.
A version of this article appeared on Medscape.com.
LBCL: CAR T Benefits Both Young and Old
“This real-world study demonstrates that CD19 CAR-T cell therapy is feasible in a population of patients aged 75 years and older,” said senior author Pierre Bories, MD, PhD, of the Institute for Cancer Strasbourg-Europe, in Alsace, France. He presented the findings at the annual meeting of the European Hematology Association, held in Madrid, Spain.
Patients with R/R LBCL are often older, with many aged over 75, yet patients in those age groups are frequently underrepresented in clinical trials of CD19-directed CAR T-cell therapy, which has significantly improved outcomes for patients with R/R LBCL.
To further investigate differences in outcomes between older and younger patients with R/R LBCL treated with CAR-T cell therapy, Dr. Bories and colleagues conducted a retrospective analysis of 1,524 patients in the French DESCAR-T registry who were treated at treated at 31 centers in France and had at least two previous infusions of CAR-T cell therapy between April 2018 and September 2023.
Of the patients, 69.8% (n = 1065) were treated with axicabtagene ciloleucel (axi-cel), while 30.1% (n = 459) were treated with tisagenlecleucel (tisa-cel).
Among those patients, 125 were 75 years old or older, with a median age of 76, and the remaining 1399 were under the age of 75, with a median age of 62.
The two age groups had significant differences in terms of characteristics including gender, LBCL subset, number of prior lines of therapy, performance status, age-adjusted International Prognostic Index (IPI), rate of patients receiving a bridging therapy, response to the bridging therapy, and LDH at time of infusion.
Compared with patients aged 75 or younger, those who were 75 years or older had a higher hematopoietic cell transplantation–specific comorbidity index (HCT-CI) score, (31.2% high HCT-CI versus 16.8%, respectively; P < .001).
Patients over 75 also had fewer prior transplants than those under 75 (4.8% versus 21.8%, respectively; P < .001), and they more commonly received tisa-cel CAR-T cell therapy (43.2% versus 28.9%, respectively; P < .001).
Among 1457 patients with response data available, with a median follow-up of 12.7 months, there were no significant differences in terms of the best overall response rate (ORR) and complete response rates (CRR) between the two age groups, with rates of 74.8% for ORR and 62.6% for CRR among those 75 or older, compared with 78.0% and 60.8%, respectively, in the under 75 group (P = .425 and P = .699, respectively).
Likewise, the estimated median overall survival (OS) was 18.3 months in the 75 and older group and 24.0 months in the under 75 group (P = .12).
There were also no significant difference in terms of the estimated median progression-free survival, of 8.2 months in the 75 and older group versus 6.1 months in the under 75 group (P = .73).
In terms of safety, there were no significant differences in terms of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) among patients 75 and older versus under 75, with 7.3% versus 7.4% developing CRS, respectively (P = .97), and 9.8% versus 12.4% developing ICANS (P = .39).
There were no significant differences between the age groups regarding ICU admissions, which occurred in about 24% of the cohorts, or the need for mechanical ventilation, which was necessary in about 3% of the entire cohort.
Of note, the overall rates of non-relapse mortality were more common in the 75 years and older group, among whom 19.5% of deaths were not related to lymphoma progression or relapse, compared with 8.1% in the under 75 group (P < .0001).
Early mortalities not related to relapse, defined as occurring before day 28 post-infusion, occurred among 3 patients aged 75 and older (2.4% of all patients 75 and older, representing 12.0% of all non-relapse mortality cases) compared with 16 patients under 75 (1.2% of those patients and 13.1% of all non-relapse mortality).
Infection was the main cause of non-relapse mortality in both groups, representing the cause in 57.7% of those under 75 and 54.2% of those aged 75 and older.
Patients 75 and older had a significantly higher risk of non-relapse mortality from infection (P = .0003), CRS (P = .022) or other causes, compared with those under 75 (P = .0004), but not from ICANS (P = .524).
“Our findings show a higher non-relapse mortality in this older population, which mainly relied on late infectious events, occurring after 28 days,” Dr. Bories said.
“There was also a higher rate of non-relapse mortality from infections, CRS or other causes in those 75 or older, but that did not translate to a lower overall survival in our patient sample,” he said.
Asked at the session about the implications of the higher infection risk in elderly patients, Dr. Bories said, “I think this deserves special attention and we have to be more careful with frail patients.
“This should obviously encourage the use of prophylaxis for a longer period of time.”
Dr. Bories noted that he and his team are currently conducting a more detailed propensity-matched comparison between axi-cel and tisa-cel in an older population.
The findings are consistent with those of other studies, among the latest including a 2024 real-world multicenter study of 172 diffuse LBCL (DLBCL) patients treated with CAR-T cell therapy (mostly axi-cel).
That study showed comparable median progression-free and OS rates between those over and under the age of 70, however, in contrast to the current study, that study showed no significant differences in non-relapse mortality.
The ORR in that study also did not differ between age groups, exceeding 75%.
Of note, in that study, tisa‐cel treatment was associated with an approximately 60% higher risk of relapse and/or death compared with axi‐cel treatment, which the authors report was driven primarily by less favorable survival outcomes among tisa‐cel patients younger than age 70 years.
“In this context, some reports showed that axi‐cel may offer enhanced effectiveness compared to tisa‐cel in patients aged 65 and older, despite higher rates of neurotoxicity,” they wrote.
Nevertheless, the study’s overall findings indicate that “CAR T-cell therapy should be not withheld for elderly patients with r/r DLBCL,” the authors concluded.
Low CAR T Utilization in Elderly Patients
Overall, utilization of CAR-T cell therapy among older patients reportedly remains low, as demonstrated in one recent real-world study on the issue, involving 551 older patients with DLBCL.
The study showed that 19% of patients aged 65-69 and 22% of those aged 70-74 years received CAR-T cell therapy, compared with only 13% of those aged 75 and older.
“While CAR T-cell therapy in older patients is associated with favorable event-free survival comparable to outcomes in younger patients, CAR T-cell usage is low in older patients with DLBCL, which suggests an unmet need for more accessible, effective, and tolerable therapy,” reported first author Dia Chihara, MD, PhD, of the Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, in Houston, Texas, and colleagues.
Noting that “the use of current CAR-T cell therapy products seemed to be limited to selected patients,” the authors added that “this may change in the future with next-generation CAR T-cell therapy products.”
Dr. Bories disclosed relationships with Kite Gilead, Novartis, BMD-Celgene, Abbvie, Servier, Janssen and the BMS foundation.
“This real-world study demonstrates that CD19 CAR-T cell therapy is feasible in a population of patients aged 75 years and older,” said senior author Pierre Bories, MD, PhD, of the Institute for Cancer Strasbourg-Europe, in Alsace, France. He presented the findings at the annual meeting of the European Hematology Association, held in Madrid, Spain.
Patients with R/R LBCL are often older, with many aged over 75, yet patients in those age groups are frequently underrepresented in clinical trials of CD19-directed CAR T-cell therapy, which has significantly improved outcomes for patients with R/R LBCL.
To further investigate differences in outcomes between older and younger patients with R/R LBCL treated with CAR-T cell therapy, Dr. Bories and colleagues conducted a retrospective analysis of 1,524 patients in the French DESCAR-T registry who were treated at treated at 31 centers in France and had at least two previous infusions of CAR-T cell therapy between April 2018 and September 2023.
Of the patients, 69.8% (n = 1065) were treated with axicabtagene ciloleucel (axi-cel), while 30.1% (n = 459) were treated with tisagenlecleucel (tisa-cel).
Among those patients, 125 were 75 years old or older, with a median age of 76, and the remaining 1399 were under the age of 75, with a median age of 62.
The two age groups had significant differences in terms of characteristics including gender, LBCL subset, number of prior lines of therapy, performance status, age-adjusted International Prognostic Index (IPI), rate of patients receiving a bridging therapy, response to the bridging therapy, and LDH at time of infusion.
Compared with patients aged 75 or younger, those who were 75 years or older had a higher hematopoietic cell transplantation–specific comorbidity index (HCT-CI) score, (31.2% high HCT-CI versus 16.8%, respectively; P < .001).
Patients over 75 also had fewer prior transplants than those under 75 (4.8% versus 21.8%, respectively; P < .001), and they more commonly received tisa-cel CAR-T cell therapy (43.2% versus 28.9%, respectively; P < .001).
Among 1457 patients with response data available, with a median follow-up of 12.7 months, there were no significant differences in terms of the best overall response rate (ORR) and complete response rates (CRR) between the two age groups, with rates of 74.8% for ORR and 62.6% for CRR among those 75 or older, compared with 78.0% and 60.8%, respectively, in the under 75 group (P = .425 and P = .699, respectively).
Likewise, the estimated median overall survival (OS) was 18.3 months in the 75 and older group and 24.0 months in the under 75 group (P = .12).
There were also no significant difference in terms of the estimated median progression-free survival, of 8.2 months in the 75 and older group versus 6.1 months in the under 75 group (P = .73).
In terms of safety, there were no significant differences in terms of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) among patients 75 and older versus under 75, with 7.3% versus 7.4% developing CRS, respectively (P = .97), and 9.8% versus 12.4% developing ICANS (P = .39).
There were no significant differences between the age groups regarding ICU admissions, which occurred in about 24% of the cohorts, or the need for mechanical ventilation, which was necessary in about 3% of the entire cohort.
Of note, the overall rates of non-relapse mortality were more common in the 75 years and older group, among whom 19.5% of deaths were not related to lymphoma progression or relapse, compared with 8.1% in the under 75 group (P < .0001).
Early mortalities not related to relapse, defined as occurring before day 28 post-infusion, occurred among 3 patients aged 75 and older (2.4% of all patients 75 and older, representing 12.0% of all non-relapse mortality cases) compared with 16 patients under 75 (1.2% of those patients and 13.1% of all non-relapse mortality).
Infection was the main cause of non-relapse mortality in both groups, representing the cause in 57.7% of those under 75 and 54.2% of those aged 75 and older.
Patients 75 and older had a significantly higher risk of non-relapse mortality from infection (P = .0003), CRS (P = .022) or other causes, compared with those under 75 (P = .0004), but not from ICANS (P = .524).
“Our findings show a higher non-relapse mortality in this older population, which mainly relied on late infectious events, occurring after 28 days,” Dr. Bories said.
“There was also a higher rate of non-relapse mortality from infections, CRS or other causes in those 75 or older, but that did not translate to a lower overall survival in our patient sample,” he said.
Asked at the session about the implications of the higher infection risk in elderly patients, Dr. Bories said, “I think this deserves special attention and we have to be more careful with frail patients.
“This should obviously encourage the use of prophylaxis for a longer period of time.”
Dr. Bories noted that he and his team are currently conducting a more detailed propensity-matched comparison between axi-cel and tisa-cel in an older population.
The findings are consistent with those of other studies, among the latest including a 2024 real-world multicenter study of 172 diffuse LBCL (DLBCL) patients treated with CAR-T cell therapy (mostly axi-cel).
That study showed comparable median progression-free and OS rates between those over and under the age of 70, however, in contrast to the current study, that study showed no significant differences in non-relapse mortality.
The ORR in that study also did not differ between age groups, exceeding 75%.
Of note, in that study, tisa‐cel treatment was associated with an approximately 60% higher risk of relapse and/or death compared with axi‐cel treatment, which the authors report was driven primarily by less favorable survival outcomes among tisa‐cel patients younger than age 70 years.
“In this context, some reports showed that axi‐cel may offer enhanced effectiveness compared to tisa‐cel in patients aged 65 and older, despite higher rates of neurotoxicity,” they wrote.
Nevertheless, the study’s overall findings indicate that “CAR T-cell therapy should be not withheld for elderly patients with r/r DLBCL,” the authors concluded.
Low CAR T Utilization in Elderly Patients
Overall, utilization of CAR-T cell therapy among older patients reportedly remains low, as demonstrated in one recent real-world study on the issue, involving 551 older patients with DLBCL.
The study showed that 19% of patients aged 65-69 and 22% of those aged 70-74 years received CAR-T cell therapy, compared with only 13% of those aged 75 and older.
“While CAR T-cell therapy in older patients is associated with favorable event-free survival comparable to outcomes in younger patients, CAR T-cell usage is low in older patients with DLBCL, which suggests an unmet need for more accessible, effective, and tolerable therapy,” reported first author Dia Chihara, MD, PhD, of the Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, in Houston, Texas, and colleagues.
Noting that “the use of current CAR-T cell therapy products seemed to be limited to selected patients,” the authors added that “this may change in the future with next-generation CAR T-cell therapy products.”
Dr. Bories disclosed relationships with Kite Gilead, Novartis, BMD-Celgene, Abbvie, Servier, Janssen and the BMS foundation.
“This real-world study demonstrates that CD19 CAR-T cell therapy is feasible in a population of patients aged 75 years and older,” said senior author Pierre Bories, MD, PhD, of the Institute for Cancer Strasbourg-Europe, in Alsace, France. He presented the findings at the annual meeting of the European Hematology Association, held in Madrid, Spain.
Patients with R/R LBCL are often older, with many aged over 75, yet patients in those age groups are frequently underrepresented in clinical trials of CD19-directed CAR T-cell therapy, which has significantly improved outcomes for patients with R/R LBCL.
To further investigate differences in outcomes between older and younger patients with R/R LBCL treated with CAR-T cell therapy, Dr. Bories and colleagues conducted a retrospective analysis of 1,524 patients in the French DESCAR-T registry who were treated at treated at 31 centers in France and had at least two previous infusions of CAR-T cell therapy between April 2018 and September 2023.
Of the patients, 69.8% (n = 1065) were treated with axicabtagene ciloleucel (axi-cel), while 30.1% (n = 459) were treated with tisagenlecleucel (tisa-cel).
Among those patients, 125 were 75 years old or older, with a median age of 76, and the remaining 1399 were under the age of 75, with a median age of 62.
The two age groups had significant differences in terms of characteristics including gender, LBCL subset, number of prior lines of therapy, performance status, age-adjusted International Prognostic Index (IPI), rate of patients receiving a bridging therapy, response to the bridging therapy, and LDH at time of infusion.
Compared with patients aged 75 or younger, those who were 75 years or older had a higher hematopoietic cell transplantation–specific comorbidity index (HCT-CI) score, (31.2% high HCT-CI versus 16.8%, respectively; P < .001).
Patients over 75 also had fewer prior transplants than those under 75 (4.8% versus 21.8%, respectively; P < .001), and they more commonly received tisa-cel CAR-T cell therapy (43.2% versus 28.9%, respectively; P < .001).
Among 1457 patients with response data available, with a median follow-up of 12.7 months, there were no significant differences in terms of the best overall response rate (ORR) and complete response rates (CRR) between the two age groups, with rates of 74.8% for ORR and 62.6% for CRR among those 75 or older, compared with 78.0% and 60.8%, respectively, in the under 75 group (P = .425 and P = .699, respectively).
Likewise, the estimated median overall survival (OS) was 18.3 months in the 75 and older group and 24.0 months in the under 75 group (P = .12).
There were also no significant difference in terms of the estimated median progression-free survival, of 8.2 months in the 75 and older group versus 6.1 months in the under 75 group (P = .73).
In terms of safety, there were no significant differences in terms of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) among patients 75 and older versus under 75, with 7.3% versus 7.4% developing CRS, respectively (P = .97), and 9.8% versus 12.4% developing ICANS (P = .39).
There were no significant differences between the age groups regarding ICU admissions, which occurred in about 24% of the cohorts, or the need for mechanical ventilation, which was necessary in about 3% of the entire cohort.
Of note, the overall rates of non-relapse mortality were more common in the 75 years and older group, among whom 19.5% of deaths were not related to lymphoma progression or relapse, compared with 8.1% in the under 75 group (P < .0001).
Early mortalities not related to relapse, defined as occurring before day 28 post-infusion, occurred among 3 patients aged 75 and older (2.4% of all patients 75 and older, representing 12.0% of all non-relapse mortality cases) compared with 16 patients under 75 (1.2% of those patients and 13.1% of all non-relapse mortality).
Infection was the main cause of non-relapse mortality in both groups, representing the cause in 57.7% of those under 75 and 54.2% of those aged 75 and older.
Patients 75 and older had a significantly higher risk of non-relapse mortality from infection (P = .0003), CRS (P = .022) or other causes, compared with those under 75 (P = .0004), but not from ICANS (P = .524).
“Our findings show a higher non-relapse mortality in this older population, which mainly relied on late infectious events, occurring after 28 days,” Dr. Bories said.
“There was also a higher rate of non-relapse mortality from infections, CRS or other causes in those 75 or older, but that did not translate to a lower overall survival in our patient sample,” he said.
Asked at the session about the implications of the higher infection risk in elderly patients, Dr. Bories said, “I think this deserves special attention and we have to be more careful with frail patients.
“This should obviously encourage the use of prophylaxis for a longer period of time.”
Dr. Bories noted that he and his team are currently conducting a more detailed propensity-matched comparison between axi-cel and tisa-cel in an older population.
The findings are consistent with those of other studies, among the latest including a 2024 real-world multicenter study of 172 diffuse LBCL (DLBCL) patients treated with CAR-T cell therapy (mostly axi-cel).
That study showed comparable median progression-free and OS rates between those over and under the age of 70, however, in contrast to the current study, that study showed no significant differences in non-relapse mortality.
The ORR in that study also did not differ between age groups, exceeding 75%.
Of note, in that study, tisa‐cel treatment was associated with an approximately 60% higher risk of relapse and/or death compared with axi‐cel treatment, which the authors report was driven primarily by less favorable survival outcomes among tisa‐cel patients younger than age 70 years.
“In this context, some reports showed that axi‐cel may offer enhanced effectiveness compared to tisa‐cel in patients aged 65 and older, despite higher rates of neurotoxicity,” they wrote.
Nevertheless, the study’s overall findings indicate that “CAR T-cell therapy should be not withheld for elderly patients with r/r DLBCL,” the authors concluded.
Low CAR T Utilization in Elderly Patients
Overall, utilization of CAR-T cell therapy among older patients reportedly remains low, as demonstrated in one recent real-world study on the issue, involving 551 older patients with DLBCL.
The study showed that 19% of patients aged 65-69 and 22% of those aged 70-74 years received CAR-T cell therapy, compared with only 13% of those aged 75 and older.
“While CAR T-cell therapy in older patients is associated with favorable event-free survival comparable to outcomes in younger patients, CAR T-cell usage is low in older patients with DLBCL, which suggests an unmet need for more accessible, effective, and tolerable therapy,” reported first author Dia Chihara, MD, PhD, of the Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, in Houston, Texas, and colleagues.
Noting that “the use of current CAR-T cell therapy products seemed to be limited to selected patients,” the authors added that “this may change in the future with next-generation CAR T-cell therapy products.”
Dr. Bories disclosed relationships with Kite Gilead, Novartis, BMD-Celgene, Abbvie, Servier, Janssen and the BMS foundation.
FROM EHA 2024
Hemophilia: Novel Tx Also Cuts Bleeding in Kids
“In this study, once-weekly efanesoctocog alfa provided high sustained factor VIII activity and highly efficacious protection against bleeding episodes in children with severe hemophilia A, a population in which this goal has been difficult to achieve without burdensome treatment regimens,” report the authors in the study, published in The New England Journal of Medicine.
The results are from the phase 3, open-label XTEND-Kids study, in which first author Lynn Malec, MD, medical director of the Comprehensive Center for Bleeding Disorders and associate professor of medicine and pediatrics at The Medical College of Wisconsin, in Milwaukee, and colleagues enrolled 74 male pediatric patients with hemophilia A, including 38 under the age of 6 and 36 ages 6-12.
The participants received prophylaxis with once-weekly efanesoctocog alfa (50 IU per kg of body weight), for 52 weeks.
Prior to the treatment period, all patients had received factor VIII replacement therapy, with the exception of one who received the therapy on demand. Most (70%) received extended half-life products, such as doses twice a week or every 3 days, and the remaining 30% received standard half-life products, with dose regimens ranging from every 2 days to twice a week.
Over the course of the year-long study, none of the patients developed factor VIII inhibitors, neutralizing antibodies, a common complication in hemophilia A that prevents factor VIII replacement treatment from working to form clots.
In addition, no serious adverse events occurred that were determined to be related to efanesoctocog alfa.
“No inhibitors to factor VIII developed, most adverse events were not serious, and no adverse events led to discontinuation of efanesoctocog alfa,” the authors report.
In terms of efficacy, among 73 patients who were treated according to the protocol, the median annualized bleeding rate was 0.00 and the model-based mean rate was 0.61.
Overall, 47 patients (64%) experienced no treated bleeding episodes during the study, 65 (88%) had no spontaneous bleeding episodes, and 61 (82%) had no episodes of bleeding into joints.
Of 43 bleeding episodes, most (41; 95%) resolved with a single injection of efanesoctocog alfa.
Of note, “shortening the weekly administration interval was not deemed to be necessary in any patient during this study,” the authors add.
In comparison, other studies of children receiving other factor VIII products, including damoctocog alfa pegol, rurioctocog alfa pegol, and efmoroctocog alfa, show higher annualized bleeding rates of 2.9, 2.0, and 1.96, respectively, and studies showed the percentages of patients with no bleeding with those products were 23%, 38%, and 46%, respectively, compared with the 64% in the current study of efanesoctocog alfa.
“Although these clinical study results cannot be directly compared because of the differences in patient populations and study designs, the XTEND-Kids study showed favorable bleeding protection with efanesoctocog alfa prophylaxis as compared with these extended half-life factor VIII products,” the authors report.
Data on the once-weekly monoclonal antibody emicizumab, which has the important benefit of being administered subcutaneously instead of intravenously, is limited in children under age 12 with severe hemophilia A and without factor VIII inhibitors, the authors note.
However, the mean annualized bleeding rate with efanesoctocog alfa appears improved compared with that observed in a small Japanese study of 13 children who received emicizumab prophylaxis every 2 weeks or every 4 weeks, which showed annualized rates of treated bleeding episodes of 1.3 and 0.7 with the respective emicizumab regimens.
Results Compare With Findings in Adults
The results are similar to those reported among adults in the previous XTEND-1 phase 3 study, which was the basis for US Food and Drug Administration (FDA) approval of the drug in 2023 for routine prevention and on-demand treatment for the control of bleeding episodes, in addition to perioperative surgery for adults.
That approval was extended to children as well at the time, based on earlier interim results from the XTEND-Kids trial.
The annualized bleeding rate among adult patients treated with efanesoctocog alfa decreased from 2.96 to 0.69 over the 52 weeks, which was a significantly greater improvement compared with prestudy prophylaxis with conventional factor VIII prophylaxis (P < .001).
In children and adults alike, the decreased bleeding events were accompanied by improvements in physical health, pain, and joint health.
“Weekly prophylaxis with efanesoctocog alfa has the potential to provide long-term preservation of joint health,” the authors conclude.
Commenting in an editorial published concurrently with the study, Pratima Chowdary, MD, of the Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, England, underscored the need for a longer duration of prophylaxis, particularly in children.
“In children, the factor VIII protein has a shorter half-life than in adults, and intravenous administration of coagulation factors is particularly challenging, owing to poor venous access,” she explains.
“In this context, a notable outcome in [the study] is the achievement of once-weekly prophylaxis in children with sustained factor VIII levels through the week, which augurs well for protection in the context of delayed or missed doses.”
Dr. Chowdary adds that limitations include that “the study participants had pre-existing tolerance of factor VIII, because only those with previous exposure to factor VIII and without inhibitors were eligible for enrollment.”
“As such, immunogenicity needs to be assessed in other patients, especially those with no previous treatment with factor VIII.”
Further commenting to this news organization, Dr. Chowdary emphasized “the key takeaway for patients with hemophilia is that the notion of a single, lifelong treatment is outdated.”
“Regular reviews and adjustments to prophylaxis are necessary to ensure optimal control of hemophilia, aiming for zero bleeds each year,” Dr. Chowdary noted.
Furthermore, “the treatment regimen to achieve this must also align with the life goals of both patients and their parents,” she said.
The study was supported by Sanofi and Sobi. The authors’ and Dr. Chowdary’s disclosures are published with the study and editorial, respectively.
“In this study, once-weekly efanesoctocog alfa provided high sustained factor VIII activity and highly efficacious protection against bleeding episodes in children with severe hemophilia A, a population in which this goal has been difficult to achieve without burdensome treatment regimens,” report the authors in the study, published in The New England Journal of Medicine.
The results are from the phase 3, open-label XTEND-Kids study, in which first author Lynn Malec, MD, medical director of the Comprehensive Center for Bleeding Disorders and associate professor of medicine and pediatrics at The Medical College of Wisconsin, in Milwaukee, and colleagues enrolled 74 male pediatric patients with hemophilia A, including 38 under the age of 6 and 36 ages 6-12.
The participants received prophylaxis with once-weekly efanesoctocog alfa (50 IU per kg of body weight), for 52 weeks.
Prior to the treatment period, all patients had received factor VIII replacement therapy, with the exception of one who received the therapy on demand. Most (70%) received extended half-life products, such as doses twice a week or every 3 days, and the remaining 30% received standard half-life products, with dose regimens ranging from every 2 days to twice a week.
Over the course of the year-long study, none of the patients developed factor VIII inhibitors, neutralizing antibodies, a common complication in hemophilia A that prevents factor VIII replacement treatment from working to form clots.
In addition, no serious adverse events occurred that were determined to be related to efanesoctocog alfa.
“No inhibitors to factor VIII developed, most adverse events were not serious, and no adverse events led to discontinuation of efanesoctocog alfa,” the authors report.
In terms of efficacy, among 73 patients who were treated according to the protocol, the median annualized bleeding rate was 0.00 and the model-based mean rate was 0.61.
Overall, 47 patients (64%) experienced no treated bleeding episodes during the study, 65 (88%) had no spontaneous bleeding episodes, and 61 (82%) had no episodes of bleeding into joints.
Of 43 bleeding episodes, most (41; 95%) resolved with a single injection of efanesoctocog alfa.
Of note, “shortening the weekly administration interval was not deemed to be necessary in any patient during this study,” the authors add.
In comparison, other studies of children receiving other factor VIII products, including damoctocog alfa pegol, rurioctocog alfa pegol, and efmoroctocog alfa, show higher annualized bleeding rates of 2.9, 2.0, and 1.96, respectively, and studies showed the percentages of patients with no bleeding with those products were 23%, 38%, and 46%, respectively, compared with the 64% in the current study of efanesoctocog alfa.
“Although these clinical study results cannot be directly compared because of the differences in patient populations and study designs, the XTEND-Kids study showed favorable bleeding protection with efanesoctocog alfa prophylaxis as compared with these extended half-life factor VIII products,” the authors report.
Data on the once-weekly monoclonal antibody emicizumab, which has the important benefit of being administered subcutaneously instead of intravenously, is limited in children under age 12 with severe hemophilia A and without factor VIII inhibitors, the authors note.
However, the mean annualized bleeding rate with efanesoctocog alfa appears improved compared with that observed in a small Japanese study of 13 children who received emicizumab prophylaxis every 2 weeks or every 4 weeks, which showed annualized rates of treated bleeding episodes of 1.3 and 0.7 with the respective emicizumab regimens.
Results Compare With Findings in Adults
The results are similar to those reported among adults in the previous XTEND-1 phase 3 study, which was the basis for US Food and Drug Administration (FDA) approval of the drug in 2023 for routine prevention and on-demand treatment for the control of bleeding episodes, in addition to perioperative surgery for adults.
That approval was extended to children as well at the time, based on earlier interim results from the XTEND-Kids trial.
The annualized bleeding rate among adult patients treated with efanesoctocog alfa decreased from 2.96 to 0.69 over the 52 weeks, which was a significantly greater improvement compared with prestudy prophylaxis with conventional factor VIII prophylaxis (P < .001).
In children and adults alike, the decreased bleeding events were accompanied by improvements in physical health, pain, and joint health.
“Weekly prophylaxis with efanesoctocog alfa has the potential to provide long-term preservation of joint health,” the authors conclude.
Commenting in an editorial published concurrently with the study, Pratima Chowdary, MD, of the Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, England, underscored the need for a longer duration of prophylaxis, particularly in children.
“In children, the factor VIII protein has a shorter half-life than in adults, and intravenous administration of coagulation factors is particularly challenging, owing to poor venous access,” she explains.
“In this context, a notable outcome in [the study] is the achievement of once-weekly prophylaxis in children with sustained factor VIII levels through the week, which augurs well for protection in the context of delayed or missed doses.”
Dr. Chowdary adds that limitations include that “the study participants had pre-existing tolerance of factor VIII, because only those with previous exposure to factor VIII and without inhibitors were eligible for enrollment.”
“As such, immunogenicity needs to be assessed in other patients, especially those with no previous treatment with factor VIII.”
Further commenting to this news organization, Dr. Chowdary emphasized “the key takeaway for patients with hemophilia is that the notion of a single, lifelong treatment is outdated.”
“Regular reviews and adjustments to prophylaxis are necessary to ensure optimal control of hemophilia, aiming for zero bleeds each year,” Dr. Chowdary noted.
Furthermore, “the treatment regimen to achieve this must also align with the life goals of both patients and their parents,” she said.
The study was supported by Sanofi and Sobi. The authors’ and Dr. Chowdary’s disclosures are published with the study and editorial, respectively.
“In this study, once-weekly efanesoctocog alfa provided high sustained factor VIII activity and highly efficacious protection against bleeding episodes in children with severe hemophilia A, a population in which this goal has been difficult to achieve without burdensome treatment regimens,” report the authors in the study, published in The New England Journal of Medicine.
The results are from the phase 3, open-label XTEND-Kids study, in which first author Lynn Malec, MD, medical director of the Comprehensive Center for Bleeding Disorders and associate professor of medicine and pediatrics at The Medical College of Wisconsin, in Milwaukee, and colleagues enrolled 74 male pediatric patients with hemophilia A, including 38 under the age of 6 and 36 ages 6-12.
The participants received prophylaxis with once-weekly efanesoctocog alfa (50 IU per kg of body weight), for 52 weeks.
Prior to the treatment period, all patients had received factor VIII replacement therapy, with the exception of one who received the therapy on demand. Most (70%) received extended half-life products, such as doses twice a week or every 3 days, and the remaining 30% received standard half-life products, with dose regimens ranging from every 2 days to twice a week.
Over the course of the year-long study, none of the patients developed factor VIII inhibitors, neutralizing antibodies, a common complication in hemophilia A that prevents factor VIII replacement treatment from working to form clots.
In addition, no serious adverse events occurred that were determined to be related to efanesoctocog alfa.
“No inhibitors to factor VIII developed, most adverse events were not serious, and no adverse events led to discontinuation of efanesoctocog alfa,” the authors report.
In terms of efficacy, among 73 patients who were treated according to the protocol, the median annualized bleeding rate was 0.00 and the model-based mean rate was 0.61.
Overall, 47 patients (64%) experienced no treated bleeding episodes during the study, 65 (88%) had no spontaneous bleeding episodes, and 61 (82%) had no episodes of bleeding into joints.
Of 43 bleeding episodes, most (41; 95%) resolved with a single injection of efanesoctocog alfa.
Of note, “shortening the weekly administration interval was not deemed to be necessary in any patient during this study,” the authors add.
In comparison, other studies of children receiving other factor VIII products, including damoctocog alfa pegol, rurioctocog alfa pegol, and efmoroctocog alfa, show higher annualized bleeding rates of 2.9, 2.0, and 1.96, respectively, and studies showed the percentages of patients with no bleeding with those products were 23%, 38%, and 46%, respectively, compared with the 64% in the current study of efanesoctocog alfa.
“Although these clinical study results cannot be directly compared because of the differences in patient populations and study designs, the XTEND-Kids study showed favorable bleeding protection with efanesoctocog alfa prophylaxis as compared with these extended half-life factor VIII products,” the authors report.
Data on the once-weekly monoclonal antibody emicizumab, which has the important benefit of being administered subcutaneously instead of intravenously, is limited in children under age 12 with severe hemophilia A and without factor VIII inhibitors, the authors note.
However, the mean annualized bleeding rate with efanesoctocog alfa appears improved compared with that observed in a small Japanese study of 13 children who received emicizumab prophylaxis every 2 weeks or every 4 weeks, which showed annualized rates of treated bleeding episodes of 1.3 and 0.7 with the respective emicizumab regimens.
Results Compare With Findings in Adults
The results are similar to those reported among adults in the previous XTEND-1 phase 3 study, which was the basis for US Food and Drug Administration (FDA) approval of the drug in 2023 for routine prevention and on-demand treatment for the control of bleeding episodes, in addition to perioperative surgery for adults.
That approval was extended to children as well at the time, based on earlier interim results from the XTEND-Kids trial.
The annualized bleeding rate among adult patients treated with efanesoctocog alfa decreased from 2.96 to 0.69 over the 52 weeks, which was a significantly greater improvement compared with prestudy prophylaxis with conventional factor VIII prophylaxis (P < .001).
In children and adults alike, the decreased bleeding events were accompanied by improvements in physical health, pain, and joint health.
“Weekly prophylaxis with efanesoctocog alfa has the potential to provide long-term preservation of joint health,” the authors conclude.
Commenting in an editorial published concurrently with the study, Pratima Chowdary, MD, of the Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, England, underscored the need for a longer duration of prophylaxis, particularly in children.
“In children, the factor VIII protein has a shorter half-life than in adults, and intravenous administration of coagulation factors is particularly challenging, owing to poor venous access,” she explains.
“In this context, a notable outcome in [the study] is the achievement of once-weekly prophylaxis in children with sustained factor VIII levels through the week, which augurs well for protection in the context of delayed or missed doses.”
Dr. Chowdary adds that limitations include that “the study participants had pre-existing tolerance of factor VIII, because only those with previous exposure to factor VIII and without inhibitors were eligible for enrollment.”
“As such, immunogenicity needs to be assessed in other patients, especially those with no previous treatment with factor VIII.”
Further commenting to this news organization, Dr. Chowdary emphasized “the key takeaway for patients with hemophilia is that the notion of a single, lifelong treatment is outdated.”
“Regular reviews and adjustments to prophylaxis are necessary to ensure optimal control of hemophilia, aiming for zero bleeds each year,” Dr. Chowdary noted.
Furthermore, “the treatment regimen to achieve this must also align with the life goals of both patients and their parents,” she said.
The study was supported by Sanofi and Sobi. The authors’ and Dr. Chowdary’s disclosures are published with the study and editorial, respectively.
What Should Be Prioritized in Managing Early Diabetes?
ORLANDO, FLORIDA — What to prioritize first in managing early diabetes? That was the question debated on an expert panel at the American Diabetes Association (ADA) 84th Scientific Sessions, with impassioned responses ranging from a plea to “treat obesity first,” to a James Carville–inspired counterpoint of “it’s the glucose, stupid.”
With a focus on preventing complications and inducing remission rounding out the four positions argued,
“In clinical decision-making [for early diabetes], we are faced with weighing each of these variables for the individual patient, and while all are good options, strong arguments can be made for prioritizing each — with the potential of each choice to influence or improve all of the others,” Dr. Retnakaran told this news organization.
Which to Prioritize First?
Making the obesity first argument, Ania M. Jastreboff, MD, PhD, associate professor and director of the Yale Obesity Research Center at Yale School of Medicine, New Haven, Connecticut, noted the striking statistic that nearly 90% of people with type 2 diabetes have overweight or obesity and discussed the ever-expanding data showing the benefits of drugs including glucagon-like peptide 1 (GLP-1) receptor agonists not just in weight loss but also in kidney, cardiovascular, and, as presented at the meeting, sleep apnea improvement.
She contrasted the experiences of two patients with obesity: One treated for the obesity upon type 2 diagnosis — who had a quick normalization of lipids and hypertension soon after the obesity treatment — and the other presenting after 10 years with type 2 diabetes — who was on therapy for hypertension and hyperlipidemia but not for obesity and whose diseases were not as easily treated by that point.
“Why are we treating all the downstream effects and we’re not treating the disease that is potentially the root cause of all these other diseases?” Dr. Jastreboff said.
Complications?
Arguing in favor of focusing on complications, Roopa Mehta, MD, PhD, with the department of endocrinology and metabolism at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City, made the case that stakes don’t get any higher in diabetes than when it comes the looming threat of potentially fatal complications.
Acute myocardial infarction, stroke, amputation, and end-stage renal disease are all on the list of unwanted outcomes and need to be considered even in the earliest stages, as data show early onset type 2 diabetes is linked to life expectancy.
“The main goal of management has always been to prevent complications,” she noted. Citing ADA guidelines, Dr. Mehta underscored the benefits of first- and second-line therapy of metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and GLP-1 receptor agonists for most patients.
Remission?
Discussing the priority of putting patients into disease remission, Roy Taylor, MD, professor of medicine and metabolism at Newcastle University and Newcastle Hospitals NHS in Newcastle upon Tyne, England, and author of the book Life Without Diabetes, focused on an evidence-based alternative to achieving remission — a nonpharmacologic approach that avoids costly and sometimes inaccessible drugs.
In the intervention, described in the DiRECT randomized trial and subsequently in the UK National Health Service Type 2 Diabetes Path to Remission Program, patients with overweight or obesity were placed on a highly restrictive diet of just 800-900 calories a day for 12-20 weeks, followed by maintenance for 12 months, and they not only achieved weight loss but also achieved diabetes remission, in some cases long term.
Acknowledging that “this is not for everyone,” Dr. Taylor asserted that “we have to realize there is a substantial minority of people who want to be healthy but who don’t want to be medicalized,” he said.
“They want their health, and they can do extremely well.”
Glucose?
In taking his self-titled “it’s the glucose, stupid” stand, David M. Nathan, MD, of the Diabetes Center, Massachusetts General Hospital, Harvard Medical School, in Boston, cited extensive evidence showing that early intensive blood glucose control with treatment including sulfonylureas, insulin, or metformin significantly reduced the risk for complications in type 2 diabetes 15 or more years later, including renal failure, blindness, amputation, and myocardial infarctions, in addition to a reduction in diabetes-related death.
“In many of these studies, you saw the benefit even in the setting of weight-gain,” Dr. Nathan underscored.
He further noted the “sobering” findings of the Look AHEAD study, which had to be stopped due to futility when an intensive lifestyle/weight loss intervention showed no significant benefits in terms of cardiovascular disease in people with type 2 diabetes at a median follow-up of 9.6 years.
Ultimately, “diabetes, type 1 and type 2, remains a gluco-centric disease,” Dr. Nathan asserted. “Hyperglycemia is the only universal link between all forms of diabetes and mortality, and the long-term complications of diabetes are intimately associated with hyperglycemia.”
Tackling the Caveats
The ensuing panel discussion did not fail to deliver in delving into key areas of contention, particularly in terms of GLP-1 treatment.
Regarding a lack of data on the potential long-term effects of GLP-1s: “Yes, there are a huge number of studies [on GLP-1 receptor agonists], but they are, in general, over short periods of time and driven by pharma, who get in and get out as quickly as they can and have little in the way of interest to do comparative effectiveness studies,” Dr. Nathan argued.
“Meanwhile, this is like the crack cocaine of medications — patients have to stay on it for a lifetime or they will regain the weight — are you concerned at all about a lifetime of exposure to GLP-1 [drugs]?” he asked the panel.
Dr. Jastreboff responded that the first GLP-1 receptor agonist medications were approved in 2005, nearly 20 years ago, by the US Food and Drug Administration.
“Do I think we need long-term lifetime data? Absolutely,” she said. “We need to do our due diligence, we need to be careful, we need to monitor patients, and when and if there are signals, we need to follow them.”
What about the notorious gastrointestinal side effects of the drugs? “A majority of them are mitigated by slow up-titration,” Dr. Jastreboff noted.
“If patients have nausea, I do not go up [in dose]. I invite patients to tell me if they’re having vomiting because I don’t want anybody to have it, and I can count on one hand how many of my patients do.”
Dr. Mehta added the concern that as the drugs’ popularity soars, “a lot of doctors don’t know when they need to put the brakes on [weight coming off too quickly].”
She underscored that “we are not treating obesity for weight loss or for cosmetic reasons — this is about optimizing health.”
Dr. Jastreboff noted that in her practice, “I down-titrate if they’re losing weight too quickly.”
“If the patient is losing more than 1% per week of their body weight, then I slow down to make sure they’re getting the nutrients that they need, that they have enough energy to exercise, and that they’re prioritizing protein and fruits and vegetables in their diet.
“We just need to go slow, and yes, we need to follow them long term,” she said.
Chiming in from the audience, Julio Rosenstock, MD, a recognized thought leader in type 2 diabetes, offered his own take on the issues, describing Dr. Taylor’s very low–calorie diet suggestion as “not realistic” and Dr. Nathan’s glucose-first argument to be “stuck in the past.”
Based on modern-day evidence, “there is no reason on earth to start [diabetes treatment] with only metformin,” asserted Dr. Rosenstock, director of the Velocity Clinical Research center at Medical City and clinical professor of medicine at the University of Texas Southwestern Medical Center, Dallas.
“We need to start at the very least with metformin and a sodium-glucose cotransporter 2 (SGLT2) inhibitor from day 1, and then, if it’s affordable and there is access, with a GLP-1 receptor agonist,” he said.
“There is nothing better these days than those agents that consistently have shown a reduction of cardiovascular events and slowing of kidney disease progression.”
Overall, however, “I think you are all right,” he added, a sentiment shared by most.
Noting that the discussion as a whole represents a virtual sea change from the evidence-based options that would have been discussed only a decade ago, Dr. Retnakaran summed up his take-home message: “Stay tuned.
“You could easily see things changing in the next decade to come as we get more data and evidence to support what we ultimately should prioritize an early type 2 diabetes, so this is an exciting time.”
Dr. Retnakaran disclosed ties with Novo Nordisk, Boehringer Ingelheim, Novartis, Sanofi, and Eli Lilly. Dr. Jastreboff disclosed ties with Amgen, AstraZeneca, Boehringer Ingelheim, Biohaven, Eli Lilly, Intellihealth, Novo Nordisk, Pfizer, Regeneron, Scholar Rock, Structure Therapeutics, Terms Pharmaceutical, Weight Watchers, and Zealand Pharmaceuticals. Dr. Roopa had relationships with Novo Nordisk, Boehringer Ingelheim, Amgen, AstraZeneca, Eli Lilly, Silanes, and Sanofi. Dr. Taylor received lecture fees from Novartis, Lilly, Abbott, and Nestle Health and research funding from Diabetes UK and is an advisor to Fast800. Dr. Rosenstock reported relationships with Applied Therapeutics, AstraZeneca, Biomea Fusion, Boehringer Ingelheim, Eli Lilly and Company, Hanmi, Merck, Oramed, Structure Therapeutics, Novartis, Novo Nordisk, Pfizer, Ragor, and Sanofi. Dr. Nathan had no disclosures to report.
A version of this article first appeared on Medscape.com.
ORLANDO, FLORIDA — What to prioritize first in managing early diabetes? That was the question debated on an expert panel at the American Diabetes Association (ADA) 84th Scientific Sessions, with impassioned responses ranging from a plea to “treat obesity first,” to a James Carville–inspired counterpoint of “it’s the glucose, stupid.”
With a focus on preventing complications and inducing remission rounding out the four positions argued,
“In clinical decision-making [for early diabetes], we are faced with weighing each of these variables for the individual patient, and while all are good options, strong arguments can be made for prioritizing each — with the potential of each choice to influence or improve all of the others,” Dr. Retnakaran told this news organization.
Which to Prioritize First?
Making the obesity first argument, Ania M. Jastreboff, MD, PhD, associate professor and director of the Yale Obesity Research Center at Yale School of Medicine, New Haven, Connecticut, noted the striking statistic that nearly 90% of people with type 2 diabetes have overweight or obesity and discussed the ever-expanding data showing the benefits of drugs including glucagon-like peptide 1 (GLP-1) receptor agonists not just in weight loss but also in kidney, cardiovascular, and, as presented at the meeting, sleep apnea improvement.
She contrasted the experiences of two patients with obesity: One treated for the obesity upon type 2 diagnosis — who had a quick normalization of lipids and hypertension soon after the obesity treatment — and the other presenting after 10 years with type 2 diabetes — who was on therapy for hypertension and hyperlipidemia but not for obesity and whose diseases were not as easily treated by that point.
“Why are we treating all the downstream effects and we’re not treating the disease that is potentially the root cause of all these other diseases?” Dr. Jastreboff said.
Complications?
Arguing in favor of focusing on complications, Roopa Mehta, MD, PhD, with the department of endocrinology and metabolism at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City, made the case that stakes don’t get any higher in diabetes than when it comes the looming threat of potentially fatal complications.
Acute myocardial infarction, stroke, amputation, and end-stage renal disease are all on the list of unwanted outcomes and need to be considered even in the earliest stages, as data show early onset type 2 diabetes is linked to life expectancy.
“The main goal of management has always been to prevent complications,” she noted. Citing ADA guidelines, Dr. Mehta underscored the benefits of first- and second-line therapy of metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and GLP-1 receptor agonists for most patients.
Remission?
Discussing the priority of putting patients into disease remission, Roy Taylor, MD, professor of medicine and metabolism at Newcastle University and Newcastle Hospitals NHS in Newcastle upon Tyne, England, and author of the book Life Without Diabetes, focused on an evidence-based alternative to achieving remission — a nonpharmacologic approach that avoids costly and sometimes inaccessible drugs.
In the intervention, described in the DiRECT randomized trial and subsequently in the UK National Health Service Type 2 Diabetes Path to Remission Program, patients with overweight or obesity were placed on a highly restrictive diet of just 800-900 calories a day for 12-20 weeks, followed by maintenance for 12 months, and they not only achieved weight loss but also achieved diabetes remission, in some cases long term.
Acknowledging that “this is not for everyone,” Dr. Taylor asserted that “we have to realize there is a substantial minority of people who want to be healthy but who don’t want to be medicalized,” he said.
“They want their health, and they can do extremely well.”
Glucose?
In taking his self-titled “it’s the glucose, stupid” stand, David M. Nathan, MD, of the Diabetes Center, Massachusetts General Hospital, Harvard Medical School, in Boston, cited extensive evidence showing that early intensive blood glucose control with treatment including sulfonylureas, insulin, or metformin significantly reduced the risk for complications in type 2 diabetes 15 or more years later, including renal failure, blindness, amputation, and myocardial infarctions, in addition to a reduction in diabetes-related death.
“In many of these studies, you saw the benefit even in the setting of weight-gain,” Dr. Nathan underscored.
He further noted the “sobering” findings of the Look AHEAD study, which had to be stopped due to futility when an intensive lifestyle/weight loss intervention showed no significant benefits in terms of cardiovascular disease in people with type 2 diabetes at a median follow-up of 9.6 years.
Ultimately, “diabetes, type 1 and type 2, remains a gluco-centric disease,” Dr. Nathan asserted. “Hyperglycemia is the only universal link between all forms of diabetes and mortality, and the long-term complications of diabetes are intimately associated with hyperglycemia.”
Tackling the Caveats
The ensuing panel discussion did not fail to deliver in delving into key areas of contention, particularly in terms of GLP-1 treatment.
Regarding a lack of data on the potential long-term effects of GLP-1s: “Yes, there are a huge number of studies [on GLP-1 receptor agonists], but they are, in general, over short periods of time and driven by pharma, who get in and get out as quickly as they can and have little in the way of interest to do comparative effectiveness studies,” Dr. Nathan argued.
“Meanwhile, this is like the crack cocaine of medications — patients have to stay on it for a lifetime or they will regain the weight — are you concerned at all about a lifetime of exposure to GLP-1 [drugs]?” he asked the panel.
Dr. Jastreboff responded that the first GLP-1 receptor agonist medications were approved in 2005, nearly 20 years ago, by the US Food and Drug Administration.
“Do I think we need long-term lifetime data? Absolutely,” she said. “We need to do our due diligence, we need to be careful, we need to monitor patients, and when and if there are signals, we need to follow them.”
What about the notorious gastrointestinal side effects of the drugs? “A majority of them are mitigated by slow up-titration,” Dr. Jastreboff noted.
“If patients have nausea, I do not go up [in dose]. I invite patients to tell me if they’re having vomiting because I don’t want anybody to have it, and I can count on one hand how many of my patients do.”
Dr. Mehta added the concern that as the drugs’ popularity soars, “a lot of doctors don’t know when they need to put the brakes on [weight coming off too quickly].”
She underscored that “we are not treating obesity for weight loss or for cosmetic reasons — this is about optimizing health.”
Dr. Jastreboff noted that in her practice, “I down-titrate if they’re losing weight too quickly.”
“If the patient is losing more than 1% per week of their body weight, then I slow down to make sure they’re getting the nutrients that they need, that they have enough energy to exercise, and that they’re prioritizing protein and fruits and vegetables in their diet.
“We just need to go slow, and yes, we need to follow them long term,” she said.
Chiming in from the audience, Julio Rosenstock, MD, a recognized thought leader in type 2 diabetes, offered his own take on the issues, describing Dr. Taylor’s very low–calorie diet suggestion as “not realistic” and Dr. Nathan’s glucose-first argument to be “stuck in the past.”
Based on modern-day evidence, “there is no reason on earth to start [diabetes treatment] with only metformin,” asserted Dr. Rosenstock, director of the Velocity Clinical Research center at Medical City and clinical professor of medicine at the University of Texas Southwestern Medical Center, Dallas.
“We need to start at the very least with metformin and a sodium-glucose cotransporter 2 (SGLT2) inhibitor from day 1, and then, if it’s affordable and there is access, with a GLP-1 receptor agonist,” he said.
“There is nothing better these days than those agents that consistently have shown a reduction of cardiovascular events and slowing of kidney disease progression.”
Overall, however, “I think you are all right,” he added, a sentiment shared by most.
Noting that the discussion as a whole represents a virtual sea change from the evidence-based options that would have been discussed only a decade ago, Dr. Retnakaran summed up his take-home message: “Stay tuned.
“You could easily see things changing in the next decade to come as we get more data and evidence to support what we ultimately should prioritize an early type 2 diabetes, so this is an exciting time.”
Dr. Retnakaran disclosed ties with Novo Nordisk, Boehringer Ingelheim, Novartis, Sanofi, and Eli Lilly. Dr. Jastreboff disclosed ties with Amgen, AstraZeneca, Boehringer Ingelheim, Biohaven, Eli Lilly, Intellihealth, Novo Nordisk, Pfizer, Regeneron, Scholar Rock, Structure Therapeutics, Terms Pharmaceutical, Weight Watchers, and Zealand Pharmaceuticals. Dr. Roopa had relationships with Novo Nordisk, Boehringer Ingelheim, Amgen, AstraZeneca, Eli Lilly, Silanes, and Sanofi. Dr. Taylor received lecture fees from Novartis, Lilly, Abbott, and Nestle Health and research funding from Diabetes UK and is an advisor to Fast800. Dr. Rosenstock reported relationships with Applied Therapeutics, AstraZeneca, Biomea Fusion, Boehringer Ingelheim, Eli Lilly and Company, Hanmi, Merck, Oramed, Structure Therapeutics, Novartis, Novo Nordisk, Pfizer, Ragor, and Sanofi. Dr. Nathan had no disclosures to report.
A version of this article first appeared on Medscape.com.
ORLANDO, FLORIDA — What to prioritize first in managing early diabetes? That was the question debated on an expert panel at the American Diabetes Association (ADA) 84th Scientific Sessions, with impassioned responses ranging from a plea to “treat obesity first,” to a James Carville–inspired counterpoint of “it’s the glucose, stupid.”
With a focus on preventing complications and inducing remission rounding out the four positions argued,
“In clinical decision-making [for early diabetes], we are faced with weighing each of these variables for the individual patient, and while all are good options, strong arguments can be made for prioritizing each — with the potential of each choice to influence or improve all of the others,” Dr. Retnakaran told this news organization.
Which to Prioritize First?
Making the obesity first argument, Ania M. Jastreboff, MD, PhD, associate professor and director of the Yale Obesity Research Center at Yale School of Medicine, New Haven, Connecticut, noted the striking statistic that nearly 90% of people with type 2 diabetes have overweight or obesity and discussed the ever-expanding data showing the benefits of drugs including glucagon-like peptide 1 (GLP-1) receptor agonists not just in weight loss but also in kidney, cardiovascular, and, as presented at the meeting, sleep apnea improvement.
She contrasted the experiences of two patients with obesity: One treated for the obesity upon type 2 diagnosis — who had a quick normalization of lipids and hypertension soon after the obesity treatment — and the other presenting after 10 years with type 2 diabetes — who was on therapy for hypertension and hyperlipidemia but not for obesity and whose diseases were not as easily treated by that point.
“Why are we treating all the downstream effects and we’re not treating the disease that is potentially the root cause of all these other diseases?” Dr. Jastreboff said.
Complications?
Arguing in favor of focusing on complications, Roopa Mehta, MD, PhD, with the department of endocrinology and metabolism at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City, made the case that stakes don’t get any higher in diabetes than when it comes the looming threat of potentially fatal complications.
Acute myocardial infarction, stroke, amputation, and end-stage renal disease are all on the list of unwanted outcomes and need to be considered even in the earliest stages, as data show early onset type 2 diabetes is linked to life expectancy.
“The main goal of management has always been to prevent complications,” she noted. Citing ADA guidelines, Dr. Mehta underscored the benefits of first- and second-line therapy of metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and GLP-1 receptor agonists for most patients.
Remission?
Discussing the priority of putting patients into disease remission, Roy Taylor, MD, professor of medicine and metabolism at Newcastle University and Newcastle Hospitals NHS in Newcastle upon Tyne, England, and author of the book Life Without Diabetes, focused on an evidence-based alternative to achieving remission — a nonpharmacologic approach that avoids costly and sometimes inaccessible drugs.
In the intervention, described in the DiRECT randomized trial and subsequently in the UK National Health Service Type 2 Diabetes Path to Remission Program, patients with overweight or obesity were placed on a highly restrictive diet of just 800-900 calories a day for 12-20 weeks, followed by maintenance for 12 months, and they not only achieved weight loss but also achieved diabetes remission, in some cases long term.
Acknowledging that “this is not for everyone,” Dr. Taylor asserted that “we have to realize there is a substantial minority of people who want to be healthy but who don’t want to be medicalized,” he said.
“They want their health, and they can do extremely well.”
Glucose?
In taking his self-titled “it’s the glucose, stupid” stand, David M. Nathan, MD, of the Diabetes Center, Massachusetts General Hospital, Harvard Medical School, in Boston, cited extensive evidence showing that early intensive blood glucose control with treatment including sulfonylureas, insulin, or metformin significantly reduced the risk for complications in type 2 diabetes 15 or more years later, including renal failure, blindness, amputation, and myocardial infarctions, in addition to a reduction in diabetes-related death.
“In many of these studies, you saw the benefit even in the setting of weight-gain,” Dr. Nathan underscored.
He further noted the “sobering” findings of the Look AHEAD study, which had to be stopped due to futility when an intensive lifestyle/weight loss intervention showed no significant benefits in terms of cardiovascular disease in people with type 2 diabetes at a median follow-up of 9.6 years.
Ultimately, “diabetes, type 1 and type 2, remains a gluco-centric disease,” Dr. Nathan asserted. “Hyperglycemia is the only universal link between all forms of diabetes and mortality, and the long-term complications of diabetes are intimately associated with hyperglycemia.”
Tackling the Caveats
The ensuing panel discussion did not fail to deliver in delving into key areas of contention, particularly in terms of GLP-1 treatment.
Regarding a lack of data on the potential long-term effects of GLP-1s: “Yes, there are a huge number of studies [on GLP-1 receptor agonists], but they are, in general, over short periods of time and driven by pharma, who get in and get out as quickly as they can and have little in the way of interest to do comparative effectiveness studies,” Dr. Nathan argued.
“Meanwhile, this is like the crack cocaine of medications — patients have to stay on it for a lifetime or they will regain the weight — are you concerned at all about a lifetime of exposure to GLP-1 [drugs]?” he asked the panel.
Dr. Jastreboff responded that the first GLP-1 receptor agonist medications were approved in 2005, nearly 20 years ago, by the US Food and Drug Administration.
“Do I think we need long-term lifetime data? Absolutely,” she said. “We need to do our due diligence, we need to be careful, we need to monitor patients, and when and if there are signals, we need to follow them.”
What about the notorious gastrointestinal side effects of the drugs? “A majority of them are mitigated by slow up-titration,” Dr. Jastreboff noted.
“If patients have nausea, I do not go up [in dose]. I invite patients to tell me if they’re having vomiting because I don’t want anybody to have it, and I can count on one hand how many of my patients do.”
Dr. Mehta added the concern that as the drugs’ popularity soars, “a lot of doctors don’t know when they need to put the brakes on [weight coming off too quickly].”
She underscored that “we are not treating obesity for weight loss or for cosmetic reasons — this is about optimizing health.”
Dr. Jastreboff noted that in her practice, “I down-titrate if they’re losing weight too quickly.”
“If the patient is losing more than 1% per week of their body weight, then I slow down to make sure they’re getting the nutrients that they need, that they have enough energy to exercise, and that they’re prioritizing protein and fruits and vegetables in their diet.
“We just need to go slow, and yes, we need to follow them long term,” she said.
Chiming in from the audience, Julio Rosenstock, MD, a recognized thought leader in type 2 diabetes, offered his own take on the issues, describing Dr. Taylor’s very low–calorie diet suggestion as “not realistic” and Dr. Nathan’s glucose-first argument to be “stuck in the past.”
Based on modern-day evidence, “there is no reason on earth to start [diabetes treatment] with only metformin,” asserted Dr. Rosenstock, director of the Velocity Clinical Research center at Medical City and clinical professor of medicine at the University of Texas Southwestern Medical Center, Dallas.
“We need to start at the very least with metformin and a sodium-glucose cotransporter 2 (SGLT2) inhibitor from day 1, and then, if it’s affordable and there is access, with a GLP-1 receptor agonist,” he said.
“There is nothing better these days than those agents that consistently have shown a reduction of cardiovascular events and slowing of kidney disease progression.”
Overall, however, “I think you are all right,” he added, a sentiment shared by most.
Noting that the discussion as a whole represents a virtual sea change from the evidence-based options that would have been discussed only a decade ago, Dr. Retnakaran summed up his take-home message: “Stay tuned.
“You could easily see things changing in the next decade to come as we get more data and evidence to support what we ultimately should prioritize an early type 2 diabetes, so this is an exciting time.”
Dr. Retnakaran disclosed ties with Novo Nordisk, Boehringer Ingelheim, Novartis, Sanofi, and Eli Lilly. Dr. Jastreboff disclosed ties with Amgen, AstraZeneca, Boehringer Ingelheim, Biohaven, Eli Lilly, Intellihealth, Novo Nordisk, Pfizer, Regeneron, Scholar Rock, Structure Therapeutics, Terms Pharmaceutical, Weight Watchers, and Zealand Pharmaceuticals. Dr. Roopa had relationships with Novo Nordisk, Boehringer Ingelheim, Amgen, AstraZeneca, Eli Lilly, Silanes, and Sanofi. Dr. Taylor received lecture fees from Novartis, Lilly, Abbott, and Nestle Health and research funding from Diabetes UK and is an advisor to Fast800. Dr. Rosenstock reported relationships with Applied Therapeutics, AstraZeneca, Biomea Fusion, Boehringer Ingelheim, Eli Lilly and Company, Hanmi, Merck, Oramed, Structure Therapeutics, Novartis, Novo Nordisk, Pfizer, Ragor, and Sanofi. Dr. Nathan had no disclosures to report.
A version of this article first appeared on Medscape.com.
Hemophilia: Marstacimab Sustains Long-Term Bleeding Reduction
“In the long-term extension study treatment with marstacimab demonstrates sustained or improved efficacy for treated and total annualized bleeding rates (ABR) in adults and adolescents with hemophilia A or hemophilia B in this data set of patients without inhibitors,” first author Shamsah Kazani, MD, of Pfizer, Cambridge, Massachusetts, said in presenting the findings at the 2024 annual meeting of the European Hematology Association (EHA) in Madrid.
“The majority of the patients from the pivotal study chose to transition into the long-term extension, and we are finding that these patients are highly compliant with their weekly marstacimab dose, with more than 98% compliance,” Dr. Kazani said.
Marstacimab targets the tissue factor pathway inhibitor, a natural anticoagulation protein that prevents the formation of blood clots, and is administered as a once-weekly subcutaneous injection.
The therapy has been granted fast-track and orphan drug status in the United States, in addition to orphan drug status in the European Union for the prevention of hemophilia bleeding episodes.
If approved, the therapy would become the first once-weekly subcutaneous therapy for either hemophilia A or B. Emicizumab, which also is administered subcutaneously, is only approved to prevent or reduce bleeding in hemophilia A.
The latest findings are from an interim analysis of a long-term extension study involving 107 of 116 patients who were in the non-inhibitor cohort in the pivotal BASIS trial. Data from that trial, involving patients aged 12-75 previously showed favorable outcomes in the non-inhibitor cohort receiving marstacimab, and a cohort of patients with inhibitors is ongoing.
Participants entering the extension study were continuing on 150-mg subcutaneous doses of marstacimab, which had been administered in the BASIS study for 12 months after a loading dose of 300 mg.
Of the patients, 89 (83%) were adult and 18 (17%) were adolescents. Overall, they had a mean age of 29 years; 83 (76%) patients had hemophilia A, while 24 (22.4%) had hemophilia B.
Prior to switching to marstacimab treatment, 32 patients had been treated with factor replacement therapy on demand, while 75 received the therapy as routine prophylaxis.
With a mean additional duration of follow-up of 12.5 months in the extension study (range, 1-23.1 months), the overall rate of compliance was very high, at 98.9%.
In the pivotal and extension studies combined, 21% of patients had their marstacimab dose increased from 150 mg to 300 mg weekly, which was an option if patients had 2 or more spontaneous bleeds in a major joint while on the 150-mg dose.
In the hemophilia A and B groups combined, those previously treated with on-demand factor replacement therapy (n = 33) had substantial reductions in estimated ABR for treated bleeds from the baseline of 38.0 prior to initiating marstacimab, to 3.2 after 12 months of the treatment in the trial (P < .001).That reduction was sustained at an ABR of 3.7 after the mean additional 12.5 months in the extension study.
The corresponding estimated ABR rates in the routine prophylaxis group (n = 83) were 7.9 at baseline, 5.1 at the end of the trial, and 2.8 in the extension study analysis interim cutoff.
The authors then further stratified the results based on hemophilia A or B groups: Among patients with hemophilia A (n = 26), the on-demand subgroup had a baseline ABR of 40.6, which dropped substantially to just 3.6 after 12 months on marstacimab in the pivotal trial and was sustained at 5.3 in the extension study.
Similar trends were observed in the hemophilia A group who received routine prophylaxis (n = 65), with an ABR of 9.2 at baseline; 5.3 after the trial, and 3.1 at the extension study interim.
The trends were similar among those with hemophilia B, albeit with lower numbers of patients, consistent with hemophilia B being more rare.
The mean ABR at baseline in the on-demand group of those patients (n = 7) was 28.7, which was reduced to just 1.7 after the 12-months of active marstacimab treatment and sustained at 1.8 by the interim analysis of the extension study.
Of hemophilia B patients previously on routine prophylaxis (n = 18), the mean ABR at baseline was 3.3 and was at 4.7 at the end of the trial. The rate declined to 2.3 in the extension phase.
“We see that these trends of improvement with marstacimab are sustained into the long-term extension study, both in the on-demand group and in the routine prophylaxis groups,” Dr. Kazani said.
Importantly, she noted that marstacimab continued to be well tolerated and safe in the long-term extension study, with no reports of thromboembolic events, which had been a concern with the drug.
Commenting on the study, Margaret Ragni, MD, MPH, a professor of medicine and clinical and translational research in the Division of Hematology/Oncology at the University of Pittsburgh, Pittsburgh, Pennsylvania, noted that marstacimab could represent an important addition in the prevention of bleeds in hemophilia. “[If marstacimab is approved], hemophilia B patients [will] have a drug that can be given subcutaneously weekly to rebalance hemostasis, reducing bleeds, just as hemophilia A patients have with emicizumab.”
Dr. Ragni underscored, however, that caveats include the important point that “neither [marstacimab nor emicizumab] treats bleeds. For that, standard factor replacement therapy or bypass for inhibitors, would be required.”
Also, “a limitation with marstacimab is the lack of weight-dependent dosing. All use one dose [however, in the studies they did use 150 mg or 300 mg]. ... Furthermore, emicizumab can be given weekly, biweekly, or monthly, while that [variation in dosing] is not yet studied with marstacimab.”
And while no thromboembolic events occurred during the trial, Dr. Ragni underscored that “longer-term follow-up is needed.”
The marstacimab long-term extension study is designed to extend to 7 years of follow-up.
The study was sponsored by Pfizer, and Dr. Kazani is an employee of Pfizer. Dr. Ragni reported no disclosures.
“In the long-term extension study treatment with marstacimab demonstrates sustained or improved efficacy for treated and total annualized bleeding rates (ABR) in adults and adolescents with hemophilia A or hemophilia B in this data set of patients without inhibitors,” first author Shamsah Kazani, MD, of Pfizer, Cambridge, Massachusetts, said in presenting the findings at the 2024 annual meeting of the European Hematology Association (EHA) in Madrid.
“The majority of the patients from the pivotal study chose to transition into the long-term extension, and we are finding that these patients are highly compliant with their weekly marstacimab dose, with more than 98% compliance,” Dr. Kazani said.
Marstacimab targets the tissue factor pathway inhibitor, a natural anticoagulation protein that prevents the formation of blood clots, and is administered as a once-weekly subcutaneous injection.
The therapy has been granted fast-track and orphan drug status in the United States, in addition to orphan drug status in the European Union for the prevention of hemophilia bleeding episodes.
If approved, the therapy would become the first once-weekly subcutaneous therapy for either hemophilia A or B. Emicizumab, which also is administered subcutaneously, is only approved to prevent or reduce bleeding in hemophilia A.
The latest findings are from an interim analysis of a long-term extension study involving 107 of 116 patients who were in the non-inhibitor cohort in the pivotal BASIS trial. Data from that trial, involving patients aged 12-75 previously showed favorable outcomes in the non-inhibitor cohort receiving marstacimab, and a cohort of patients with inhibitors is ongoing.
Participants entering the extension study were continuing on 150-mg subcutaneous doses of marstacimab, which had been administered in the BASIS study for 12 months after a loading dose of 300 mg.
Of the patients, 89 (83%) were adult and 18 (17%) were adolescents. Overall, they had a mean age of 29 years; 83 (76%) patients had hemophilia A, while 24 (22.4%) had hemophilia B.
Prior to switching to marstacimab treatment, 32 patients had been treated with factor replacement therapy on demand, while 75 received the therapy as routine prophylaxis.
With a mean additional duration of follow-up of 12.5 months in the extension study (range, 1-23.1 months), the overall rate of compliance was very high, at 98.9%.
In the pivotal and extension studies combined, 21% of patients had their marstacimab dose increased from 150 mg to 300 mg weekly, which was an option if patients had 2 or more spontaneous bleeds in a major joint while on the 150-mg dose.
In the hemophilia A and B groups combined, those previously treated with on-demand factor replacement therapy (n = 33) had substantial reductions in estimated ABR for treated bleeds from the baseline of 38.0 prior to initiating marstacimab, to 3.2 after 12 months of the treatment in the trial (P < .001).That reduction was sustained at an ABR of 3.7 after the mean additional 12.5 months in the extension study.
The corresponding estimated ABR rates in the routine prophylaxis group (n = 83) were 7.9 at baseline, 5.1 at the end of the trial, and 2.8 in the extension study analysis interim cutoff.
The authors then further stratified the results based on hemophilia A or B groups: Among patients with hemophilia A (n = 26), the on-demand subgroup had a baseline ABR of 40.6, which dropped substantially to just 3.6 after 12 months on marstacimab in the pivotal trial and was sustained at 5.3 in the extension study.
Similar trends were observed in the hemophilia A group who received routine prophylaxis (n = 65), with an ABR of 9.2 at baseline; 5.3 after the trial, and 3.1 at the extension study interim.
The trends were similar among those with hemophilia B, albeit with lower numbers of patients, consistent with hemophilia B being more rare.
The mean ABR at baseline in the on-demand group of those patients (n = 7) was 28.7, which was reduced to just 1.7 after the 12-months of active marstacimab treatment and sustained at 1.8 by the interim analysis of the extension study.
Of hemophilia B patients previously on routine prophylaxis (n = 18), the mean ABR at baseline was 3.3 and was at 4.7 at the end of the trial. The rate declined to 2.3 in the extension phase.
“We see that these trends of improvement with marstacimab are sustained into the long-term extension study, both in the on-demand group and in the routine prophylaxis groups,” Dr. Kazani said.
Importantly, she noted that marstacimab continued to be well tolerated and safe in the long-term extension study, with no reports of thromboembolic events, which had been a concern with the drug.
Commenting on the study, Margaret Ragni, MD, MPH, a professor of medicine and clinical and translational research in the Division of Hematology/Oncology at the University of Pittsburgh, Pittsburgh, Pennsylvania, noted that marstacimab could represent an important addition in the prevention of bleeds in hemophilia. “[If marstacimab is approved], hemophilia B patients [will] have a drug that can be given subcutaneously weekly to rebalance hemostasis, reducing bleeds, just as hemophilia A patients have with emicizumab.”
Dr. Ragni underscored, however, that caveats include the important point that “neither [marstacimab nor emicizumab] treats bleeds. For that, standard factor replacement therapy or bypass for inhibitors, would be required.”
Also, “a limitation with marstacimab is the lack of weight-dependent dosing. All use one dose [however, in the studies they did use 150 mg or 300 mg]. ... Furthermore, emicizumab can be given weekly, biweekly, or monthly, while that [variation in dosing] is not yet studied with marstacimab.”
And while no thromboembolic events occurred during the trial, Dr. Ragni underscored that “longer-term follow-up is needed.”
The marstacimab long-term extension study is designed to extend to 7 years of follow-up.
The study was sponsored by Pfizer, and Dr. Kazani is an employee of Pfizer. Dr. Ragni reported no disclosures.
“In the long-term extension study treatment with marstacimab demonstrates sustained or improved efficacy for treated and total annualized bleeding rates (ABR) in adults and adolescents with hemophilia A or hemophilia B in this data set of patients without inhibitors,” first author Shamsah Kazani, MD, of Pfizer, Cambridge, Massachusetts, said in presenting the findings at the 2024 annual meeting of the European Hematology Association (EHA) in Madrid.
“The majority of the patients from the pivotal study chose to transition into the long-term extension, and we are finding that these patients are highly compliant with their weekly marstacimab dose, with more than 98% compliance,” Dr. Kazani said.
Marstacimab targets the tissue factor pathway inhibitor, a natural anticoagulation protein that prevents the formation of blood clots, and is administered as a once-weekly subcutaneous injection.
The therapy has been granted fast-track and orphan drug status in the United States, in addition to orphan drug status in the European Union for the prevention of hemophilia bleeding episodes.
If approved, the therapy would become the first once-weekly subcutaneous therapy for either hemophilia A or B. Emicizumab, which also is administered subcutaneously, is only approved to prevent or reduce bleeding in hemophilia A.
The latest findings are from an interim analysis of a long-term extension study involving 107 of 116 patients who were in the non-inhibitor cohort in the pivotal BASIS trial. Data from that trial, involving patients aged 12-75 previously showed favorable outcomes in the non-inhibitor cohort receiving marstacimab, and a cohort of patients with inhibitors is ongoing.
Participants entering the extension study were continuing on 150-mg subcutaneous doses of marstacimab, which had been administered in the BASIS study for 12 months after a loading dose of 300 mg.
Of the patients, 89 (83%) were adult and 18 (17%) were adolescents. Overall, they had a mean age of 29 years; 83 (76%) patients had hemophilia A, while 24 (22.4%) had hemophilia B.
Prior to switching to marstacimab treatment, 32 patients had been treated with factor replacement therapy on demand, while 75 received the therapy as routine prophylaxis.
With a mean additional duration of follow-up of 12.5 months in the extension study (range, 1-23.1 months), the overall rate of compliance was very high, at 98.9%.
In the pivotal and extension studies combined, 21% of patients had their marstacimab dose increased from 150 mg to 300 mg weekly, which was an option if patients had 2 or more spontaneous bleeds in a major joint while on the 150-mg dose.
In the hemophilia A and B groups combined, those previously treated with on-demand factor replacement therapy (n = 33) had substantial reductions in estimated ABR for treated bleeds from the baseline of 38.0 prior to initiating marstacimab, to 3.2 after 12 months of the treatment in the trial (P < .001).That reduction was sustained at an ABR of 3.7 after the mean additional 12.5 months in the extension study.
The corresponding estimated ABR rates in the routine prophylaxis group (n = 83) were 7.9 at baseline, 5.1 at the end of the trial, and 2.8 in the extension study analysis interim cutoff.
The authors then further stratified the results based on hemophilia A or B groups: Among patients with hemophilia A (n = 26), the on-demand subgroup had a baseline ABR of 40.6, which dropped substantially to just 3.6 after 12 months on marstacimab in the pivotal trial and was sustained at 5.3 in the extension study.
Similar trends were observed in the hemophilia A group who received routine prophylaxis (n = 65), with an ABR of 9.2 at baseline; 5.3 after the trial, and 3.1 at the extension study interim.
The trends were similar among those with hemophilia B, albeit with lower numbers of patients, consistent with hemophilia B being more rare.
The mean ABR at baseline in the on-demand group of those patients (n = 7) was 28.7, which was reduced to just 1.7 after the 12-months of active marstacimab treatment and sustained at 1.8 by the interim analysis of the extension study.
Of hemophilia B patients previously on routine prophylaxis (n = 18), the mean ABR at baseline was 3.3 and was at 4.7 at the end of the trial. The rate declined to 2.3 in the extension phase.
“We see that these trends of improvement with marstacimab are sustained into the long-term extension study, both in the on-demand group and in the routine prophylaxis groups,” Dr. Kazani said.
Importantly, she noted that marstacimab continued to be well tolerated and safe in the long-term extension study, with no reports of thromboembolic events, which had been a concern with the drug.
Commenting on the study, Margaret Ragni, MD, MPH, a professor of medicine and clinical and translational research in the Division of Hematology/Oncology at the University of Pittsburgh, Pittsburgh, Pennsylvania, noted that marstacimab could represent an important addition in the prevention of bleeds in hemophilia. “[If marstacimab is approved], hemophilia B patients [will] have a drug that can be given subcutaneously weekly to rebalance hemostasis, reducing bleeds, just as hemophilia A patients have with emicizumab.”
Dr. Ragni underscored, however, that caveats include the important point that “neither [marstacimab nor emicizumab] treats bleeds. For that, standard factor replacement therapy or bypass for inhibitors, would be required.”
Also, “a limitation with marstacimab is the lack of weight-dependent dosing. All use one dose [however, in the studies they did use 150 mg or 300 mg]. ... Furthermore, emicizumab can be given weekly, biweekly, or monthly, while that [variation in dosing] is not yet studied with marstacimab.”
And while no thromboembolic events occurred during the trial, Dr. Ragni underscored that “longer-term follow-up is needed.”
The marstacimab long-term extension study is designed to extend to 7 years of follow-up.
The study was sponsored by Pfizer, and Dr. Kazani is an employee of Pfizer. Dr. Ragni reported no disclosures.
FROM EHA 2024