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Myeloma: Isatuximab Four-Drug Regimen Boosts MRD Negativity
“This [research] builds on our experience that four-drug combinations with a monoclonal antibody, proteasome inhibitor, immunomodulatory drug and steroids are superior to three-drug combinations,” Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, said in an interview on the study.
“It also demonstrates the value of CD38 antibodies, and specifically isatuximab, in the frontline setting,” said Dr. Mikhael, professor at the Translational Genomics Research Institute (TGen), City of Hope Cancer Center in Goodyear, Ariz.
The findings were presented at the annual meeting of the American Society of Hematology.
The current standard of care for transplant-eligible, newly diagnosed MM consists of the quadruple combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid, followed by high-dose melphalan and autologous stem-cell transplantation (ASCT).
Isatuximab already has approval in combination with the regimen of carfilzomib and dexamethasone (KRd) in the treatment of relapsed or refractory MM patients who have received prior lines of therapy.
To investigate the efficacy and safety of addition of isatuximab in the setting of transplant-eligible, newly diagnosed MM patients, first author Francesca Gay, MD, PhD, of the Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy, and colleagues conducted the multisite, phase-3 Iskia trial, enrolling 302 transplant-eligible newly diagnosed MM patients.
The patients were randomized to groups of 151 each to treatment either with IsaKRd or KRd alone. The treatment regimen for KRd included four cycles in induction including weekly carfilzomib at 56 mg on day 1, 8 and 15, lenalidomide 25 mg at day 1-21, and dexamethasone at 40 mg weekly, and the IsaKRd group included four 28-day cycles of isatuximab 10 mg/kg IV days 1, 8, 15, and 22 in cycle 1, followed by 10 mg/kg days 1, 15 in cycles 2-4.
The induction was followed by stem cell mobilization and collection and high dose chemotherapy, followed by four cycles of full-dose consolidation at the same doses and schedule as induction, followed by a light consolidation phase of 12 28-day cycles of reduced dose KRd.
Patients had a median age of 61 and 60 in the isatuximab versus KRd group, respectively, and characteristics were similar between the two arms.
With the current follow-up of a mean of 21 months, the primary endpoint was met, with the intention-to-treat analysis showing a rate of post-consolidation MRD negativity, as assessed with a next-generation sequencing (NGS) cut-off of 10-5, of 77% with isatuximab versus 67% with KRd alone (OR 1.67; P = .049).
With an NGS cut-off of 10-6, the respective rates were 67% vs. 48% (OR 2.29; P < .001).
“This difference in MRD negativity in the depth of response was seen despite the responses analyzed according to the conventional criteria being comparable in the two arms, with more than 90% of patients achieving at least a very good partial response and more than 70% achieving at least a complete response,” Dr. Gay noted.
For the key secondary endpoint of MRD negativity over time, the rates were also significantly higher with IsaKRd vs. KRd at post-induction (10-5 cut-off, 45% vs. 26%, OR 2.34; P < .001; 10-6 cut-off, 27% vs. 14%, OR 2.36, P = .004).
IsaKRd also had greater MRD negativity post-ASCT (10-5 cutoff 64% vs. 49%; P = .006; 10-6 cutoff, 52% vs. 27%, P < .001) and post-consolidation (10-5 cutoff, 77% vs. 67%; P = .049 and 10-6 cutoff, 67% vs. 48%, P < .001).
The increase in the MRD negativity in the IsaKRd group was observed in all subgroups of patients analyzed at the 10-5 and 10-6 cut-offs.
The improved post-consolidation rate of MRD negativity with IsaKRd was also observed among patients based on all levels of cytogenetic risk, which was not the case in the KRd alone arm, which showed a reduction in MRD negativity among very high-risk patients, Dr. Gay observed.
The study’s other key secondary endpoint of progression-free survival will be presented in the future, when longer-term outcomes are available.
As of the current follow-up, 17% of patients in the IsaKRd group had discontinued the study treatment versus 10% with KRd, with the leading cause of adverse events for 6% and 5%, respectively.
At least one hematologic adverse event occurred in 55% of patients treated with IsaKRd and 44% in the KRd alone group, with the most prominent grade 3-4 adverse events occurring more commonly with IsaKRd being neutropenia (36% vs. 22%) and thrombocytopenia (15% vs. 17%).
Non-hematologic grade 3-4 adverse events occurred in 41% of patients in the IsaKRd group versus 37% in KRd only, which included infections (15% vs. 11%), and gastrointestinal (7% vs. 5%), vascular (5% vs. 10%) and cardiac events (<1% vs. 3%).
Discontinuation for toxicity occurred in similar rates in both groups (6% in IsaKRd vs. 5% in KRd); with four treatment-related deaths occurring with IsaKRd (two COVID, one pneumonia, one pulmonary embolism) and one with KRd (septic shock).
“Treatment was tolerable with a toxicity profile that was similar to that in previous reports,” Dr. Gay said.
“In the context of these highly effective regimens that produce a high rate of response, the 10-6 MRD cutoff might be more informative than other result categories,” she added.
Longer follow-up will provide more insights in survival endpoints, and “the trial can potentially offer the opportunity to explore correlations between depth of MRD negativity and survival endpoints,” Dr. Gay noted.
Further commenting on the study, Irene Ghobrial, MD, of Medical Oncology, with the Dana-Farber Cancer Institute, Boston, said the results are encouraging.
“We’re seeing two phase three trials now showing us that indeed a CD38 antibody in addition to our triplet standards of care are making a huge difference in MRD response,” she said in an interview.
“So, I think the main message here is that the four-drug regimen is the way to go from now on in multiple myeloma.”
The study received funding from Sanofi and Amgen. Dr. Gay disclosed relationships with AbbVie; Bristol Myers Squibb/Celgene; Sanofi; Roche; GlaxoSmithKline; Pfizer; Oncopeptides; Takeda; Janssen; and Amgen. Dr. Mikhael reported ties with Amgen, BMS, Janssen, Sanofi and Takeda.
“This [research] builds on our experience that four-drug combinations with a monoclonal antibody, proteasome inhibitor, immunomodulatory drug and steroids are superior to three-drug combinations,” Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, said in an interview on the study.
“It also demonstrates the value of CD38 antibodies, and specifically isatuximab, in the frontline setting,” said Dr. Mikhael, professor at the Translational Genomics Research Institute (TGen), City of Hope Cancer Center in Goodyear, Ariz.
The findings were presented at the annual meeting of the American Society of Hematology.
The current standard of care for transplant-eligible, newly diagnosed MM consists of the quadruple combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid, followed by high-dose melphalan and autologous stem-cell transplantation (ASCT).
Isatuximab already has approval in combination with the regimen of carfilzomib and dexamethasone (KRd) in the treatment of relapsed or refractory MM patients who have received prior lines of therapy.
To investigate the efficacy and safety of addition of isatuximab in the setting of transplant-eligible, newly diagnosed MM patients, first author Francesca Gay, MD, PhD, of the Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy, and colleagues conducted the multisite, phase-3 Iskia trial, enrolling 302 transplant-eligible newly diagnosed MM patients.
The patients were randomized to groups of 151 each to treatment either with IsaKRd or KRd alone. The treatment regimen for KRd included four cycles in induction including weekly carfilzomib at 56 mg on day 1, 8 and 15, lenalidomide 25 mg at day 1-21, and dexamethasone at 40 mg weekly, and the IsaKRd group included four 28-day cycles of isatuximab 10 mg/kg IV days 1, 8, 15, and 22 in cycle 1, followed by 10 mg/kg days 1, 15 in cycles 2-4.
The induction was followed by stem cell mobilization and collection and high dose chemotherapy, followed by four cycles of full-dose consolidation at the same doses and schedule as induction, followed by a light consolidation phase of 12 28-day cycles of reduced dose KRd.
Patients had a median age of 61 and 60 in the isatuximab versus KRd group, respectively, and characteristics were similar between the two arms.
With the current follow-up of a mean of 21 months, the primary endpoint was met, with the intention-to-treat analysis showing a rate of post-consolidation MRD negativity, as assessed with a next-generation sequencing (NGS) cut-off of 10-5, of 77% with isatuximab versus 67% with KRd alone (OR 1.67; P = .049).
With an NGS cut-off of 10-6, the respective rates were 67% vs. 48% (OR 2.29; P < .001).
“This difference in MRD negativity in the depth of response was seen despite the responses analyzed according to the conventional criteria being comparable in the two arms, with more than 90% of patients achieving at least a very good partial response and more than 70% achieving at least a complete response,” Dr. Gay noted.
For the key secondary endpoint of MRD negativity over time, the rates were also significantly higher with IsaKRd vs. KRd at post-induction (10-5 cut-off, 45% vs. 26%, OR 2.34; P < .001; 10-6 cut-off, 27% vs. 14%, OR 2.36, P = .004).
IsaKRd also had greater MRD negativity post-ASCT (10-5 cutoff 64% vs. 49%; P = .006; 10-6 cutoff, 52% vs. 27%, P < .001) and post-consolidation (10-5 cutoff, 77% vs. 67%; P = .049 and 10-6 cutoff, 67% vs. 48%, P < .001).
The increase in the MRD negativity in the IsaKRd group was observed in all subgroups of patients analyzed at the 10-5 and 10-6 cut-offs.
The improved post-consolidation rate of MRD negativity with IsaKRd was also observed among patients based on all levels of cytogenetic risk, which was not the case in the KRd alone arm, which showed a reduction in MRD negativity among very high-risk patients, Dr. Gay observed.
The study’s other key secondary endpoint of progression-free survival will be presented in the future, when longer-term outcomes are available.
As of the current follow-up, 17% of patients in the IsaKRd group had discontinued the study treatment versus 10% with KRd, with the leading cause of adverse events for 6% and 5%, respectively.
At least one hematologic adverse event occurred in 55% of patients treated with IsaKRd and 44% in the KRd alone group, with the most prominent grade 3-4 adverse events occurring more commonly with IsaKRd being neutropenia (36% vs. 22%) and thrombocytopenia (15% vs. 17%).
Non-hematologic grade 3-4 adverse events occurred in 41% of patients in the IsaKRd group versus 37% in KRd only, which included infections (15% vs. 11%), and gastrointestinal (7% vs. 5%), vascular (5% vs. 10%) and cardiac events (<1% vs. 3%).
Discontinuation for toxicity occurred in similar rates in both groups (6% in IsaKRd vs. 5% in KRd); with four treatment-related deaths occurring with IsaKRd (two COVID, one pneumonia, one pulmonary embolism) and one with KRd (septic shock).
“Treatment was tolerable with a toxicity profile that was similar to that in previous reports,” Dr. Gay said.
“In the context of these highly effective regimens that produce a high rate of response, the 10-6 MRD cutoff might be more informative than other result categories,” she added.
Longer follow-up will provide more insights in survival endpoints, and “the trial can potentially offer the opportunity to explore correlations between depth of MRD negativity and survival endpoints,” Dr. Gay noted.
Further commenting on the study, Irene Ghobrial, MD, of Medical Oncology, with the Dana-Farber Cancer Institute, Boston, said the results are encouraging.
“We’re seeing two phase three trials now showing us that indeed a CD38 antibody in addition to our triplet standards of care are making a huge difference in MRD response,” she said in an interview.
“So, I think the main message here is that the four-drug regimen is the way to go from now on in multiple myeloma.”
The study received funding from Sanofi and Amgen. Dr. Gay disclosed relationships with AbbVie; Bristol Myers Squibb/Celgene; Sanofi; Roche; GlaxoSmithKline; Pfizer; Oncopeptides; Takeda; Janssen; and Amgen. Dr. Mikhael reported ties with Amgen, BMS, Janssen, Sanofi and Takeda.
“This [research] builds on our experience that four-drug combinations with a monoclonal antibody, proteasome inhibitor, immunomodulatory drug and steroids are superior to three-drug combinations,” Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, said in an interview on the study.
“It also demonstrates the value of CD38 antibodies, and specifically isatuximab, in the frontline setting,” said Dr. Mikhael, professor at the Translational Genomics Research Institute (TGen), City of Hope Cancer Center in Goodyear, Ariz.
The findings were presented at the annual meeting of the American Society of Hematology.
The current standard of care for transplant-eligible, newly diagnosed MM consists of the quadruple combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid, followed by high-dose melphalan and autologous stem-cell transplantation (ASCT).
Isatuximab already has approval in combination with the regimen of carfilzomib and dexamethasone (KRd) in the treatment of relapsed or refractory MM patients who have received prior lines of therapy.
To investigate the efficacy and safety of addition of isatuximab in the setting of transplant-eligible, newly diagnosed MM patients, first author Francesca Gay, MD, PhD, of the Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy, and colleagues conducted the multisite, phase-3 Iskia trial, enrolling 302 transplant-eligible newly diagnosed MM patients.
The patients were randomized to groups of 151 each to treatment either with IsaKRd or KRd alone. The treatment regimen for KRd included four cycles in induction including weekly carfilzomib at 56 mg on day 1, 8 and 15, lenalidomide 25 mg at day 1-21, and dexamethasone at 40 mg weekly, and the IsaKRd group included four 28-day cycles of isatuximab 10 mg/kg IV days 1, 8, 15, and 22 in cycle 1, followed by 10 mg/kg days 1, 15 in cycles 2-4.
The induction was followed by stem cell mobilization and collection and high dose chemotherapy, followed by four cycles of full-dose consolidation at the same doses and schedule as induction, followed by a light consolidation phase of 12 28-day cycles of reduced dose KRd.
Patients had a median age of 61 and 60 in the isatuximab versus KRd group, respectively, and characteristics were similar between the two arms.
With the current follow-up of a mean of 21 months, the primary endpoint was met, with the intention-to-treat analysis showing a rate of post-consolidation MRD negativity, as assessed with a next-generation sequencing (NGS) cut-off of 10-5, of 77% with isatuximab versus 67% with KRd alone (OR 1.67; P = .049).
With an NGS cut-off of 10-6, the respective rates were 67% vs. 48% (OR 2.29; P < .001).
“This difference in MRD negativity in the depth of response was seen despite the responses analyzed according to the conventional criteria being comparable in the two arms, with more than 90% of patients achieving at least a very good partial response and more than 70% achieving at least a complete response,” Dr. Gay noted.
For the key secondary endpoint of MRD negativity over time, the rates were also significantly higher with IsaKRd vs. KRd at post-induction (10-5 cut-off, 45% vs. 26%, OR 2.34; P < .001; 10-6 cut-off, 27% vs. 14%, OR 2.36, P = .004).
IsaKRd also had greater MRD negativity post-ASCT (10-5 cutoff 64% vs. 49%; P = .006; 10-6 cutoff, 52% vs. 27%, P < .001) and post-consolidation (10-5 cutoff, 77% vs. 67%; P = .049 and 10-6 cutoff, 67% vs. 48%, P < .001).
The increase in the MRD negativity in the IsaKRd group was observed in all subgroups of patients analyzed at the 10-5 and 10-6 cut-offs.
The improved post-consolidation rate of MRD negativity with IsaKRd was also observed among patients based on all levels of cytogenetic risk, which was not the case in the KRd alone arm, which showed a reduction in MRD negativity among very high-risk patients, Dr. Gay observed.
The study’s other key secondary endpoint of progression-free survival will be presented in the future, when longer-term outcomes are available.
As of the current follow-up, 17% of patients in the IsaKRd group had discontinued the study treatment versus 10% with KRd, with the leading cause of adverse events for 6% and 5%, respectively.
At least one hematologic adverse event occurred in 55% of patients treated with IsaKRd and 44% in the KRd alone group, with the most prominent grade 3-4 adverse events occurring more commonly with IsaKRd being neutropenia (36% vs. 22%) and thrombocytopenia (15% vs. 17%).
Non-hematologic grade 3-4 adverse events occurred in 41% of patients in the IsaKRd group versus 37% in KRd only, which included infections (15% vs. 11%), and gastrointestinal (7% vs. 5%), vascular (5% vs. 10%) and cardiac events (<1% vs. 3%).
Discontinuation for toxicity occurred in similar rates in both groups (6% in IsaKRd vs. 5% in KRd); with four treatment-related deaths occurring with IsaKRd (two COVID, one pneumonia, one pulmonary embolism) and one with KRd (septic shock).
“Treatment was tolerable with a toxicity profile that was similar to that in previous reports,” Dr. Gay said.
“In the context of these highly effective regimens that produce a high rate of response, the 10-6 MRD cutoff might be more informative than other result categories,” she added.
Longer follow-up will provide more insights in survival endpoints, and “the trial can potentially offer the opportunity to explore correlations between depth of MRD negativity and survival endpoints,” Dr. Gay noted.
Further commenting on the study, Irene Ghobrial, MD, of Medical Oncology, with the Dana-Farber Cancer Institute, Boston, said the results are encouraging.
“We’re seeing two phase three trials now showing us that indeed a CD38 antibody in addition to our triplet standards of care are making a huge difference in MRD response,” she said in an interview.
“So, I think the main message here is that the four-drug regimen is the way to go from now on in multiple myeloma.”
The study received funding from Sanofi and Amgen. Dr. Gay disclosed relationships with AbbVie; Bristol Myers Squibb/Celgene; Sanofi; Roche; GlaxoSmithKline; Pfizer; Oncopeptides; Takeda; Janssen; and Amgen. Dr. Mikhael reported ties with Amgen, BMS, Janssen, Sanofi and Takeda.
FROM ASH 2023
Telemedicine in diabetes care associated with worse outcomes
TOPLINE:
Adult patients with type 2 diabetes and complex care needs receiving endocrinology treatment through telemedicine alone show worse glycemic outcomes compared with those receiving treatment either in-person or in mixed-care models.
The findings contrast with some previous studies showing similar glycemic outcomes with telemedicine care vs in-person care for type 2 diabetes management.
The study is believed to be the first to examine telemedicine care outcomes specifically in the endocrinology setting and based on clinical factors that affect treatment complexity.
METHODOLOGY:
- The retrospective cohort study included 3778 adults with type 2 diabetes in a single, large integrated US health system who had received either telemedicine-only, in-person, or a mix of telemedicine and in-person care between May and October 2020.
- Patients were followed up through May 2022 and evaluated for estimated A1c change after 12 months within each treatment cohort, as well as factors associated with any changes.
- Of the patients, 1182 received telemedicine-only, 1049 received in-person, and 1547 received mixed care. Mean ages in the groups ranged from 57 to 63 years, and women made up between 55% and 63%.
TAKEAWAY:
- Over the 12-month evaluation period, patients receiving telemedicine-only care had no significant changes or improvements in adjusted A1c (−0.06; P = .55), those receiving in-person care had an improvement of 0.37% (P < .001), and those receiving mixed care had an improvement of 0.22% (P = .004).
- The glycemic outcome patterns were similar among patients with a baseline A1c of 8% or higher.
- Of those prescribed multiple daily injections vs no insulin, estimated changes in A1c were 0.25% higher for those receiving telemedicine than for those receiving in-person care (P = .03).
- No associations were observed between changes in A1c and comorbidities.
- Regarding reasons for the differences, the authors noted that “the strategies to support glycemic improvement that are available during in-person appointments have not consistently been translated to telemedicine care.”
- Essential components of telemedicine such as self-management education support may not currently be routinely available through telemedicine or at the point-of-care during telemedicine visits, they added.
- “In our prior work in this care setting, practitioners described how inferior availability of glucose data limited their ability to intensify treatment through telemedicine.”
- “Implementation of approaches to overcome these differences, such as team-based virtual care and technological tools to automate blood glucose data sharing, are needed to ensure all patients receive high-quality diabetes care regardless of care modality.”
IN PRACTICE:
“These findings suggest that patients with type 2 diabetes who rely on telemedicine alone to access endocrinology care may require additional support to achieve glycemic goals,” the authors reported.
“Since some patients with barriers to in-person endocrinology care will continue to rely on telemedicine to access care, structured approaches to ensure routine delivery of high-quality team-based diabetes care are needed,” they asserted.
“Translation of successful strategies from clinical trials into routine telemedicine care, especially targeted toward adults with more complex diabetes, is critical to improve clinical outcomes for patients who rely on this care modality.”
SOURCE:
The study was conducted by first author Margaret F. Zupa, MD, of the division of endocrinology and metabolism, University of Pittsburgh School of Medicine, Pennsylvania, and colleagues.
It was published in JAMA Network Open.
LIMITATIONS:
While demographic differences between the groups were included as covariates, the treatment modality cohorts were not balanced based on baseline characteristics that could be confounders.
Various factors, such as treatment complexity, glycemic control, and transportation barriers, could have affected whether patients received care with telemedicine; therefore, causal associations could not be established.
DISCLOSURES:
The study received funding from the National Center for Advancing Translational Sciences, National Institutes of Health, Pittsburgh Foundation, and Fraternal Order of the Eagles Charity Foundation Diabetes Fund. The authors’ disclosures are detailed in the study.
A version of this article appeared on Medscape.com.
TOPLINE:
Adult patients with type 2 diabetes and complex care needs receiving endocrinology treatment through telemedicine alone show worse glycemic outcomes compared with those receiving treatment either in-person or in mixed-care models.
The findings contrast with some previous studies showing similar glycemic outcomes with telemedicine care vs in-person care for type 2 diabetes management.
The study is believed to be the first to examine telemedicine care outcomes specifically in the endocrinology setting and based on clinical factors that affect treatment complexity.
METHODOLOGY:
- The retrospective cohort study included 3778 adults with type 2 diabetes in a single, large integrated US health system who had received either telemedicine-only, in-person, or a mix of telemedicine and in-person care between May and October 2020.
- Patients were followed up through May 2022 and evaluated for estimated A1c change after 12 months within each treatment cohort, as well as factors associated with any changes.
- Of the patients, 1182 received telemedicine-only, 1049 received in-person, and 1547 received mixed care. Mean ages in the groups ranged from 57 to 63 years, and women made up between 55% and 63%.
TAKEAWAY:
- Over the 12-month evaluation period, patients receiving telemedicine-only care had no significant changes or improvements in adjusted A1c (−0.06; P = .55), those receiving in-person care had an improvement of 0.37% (P < .001), and those receiving mixed care had an improvement of 0.22% (P = .004).
- The glycemic outcome patterns were similar among patients with a baseline A1c of 8% or higher.
- Of those prescribed multiple daily injections vs no insulin, estimated changes in A1c were 0.25% higher for those receiving telemedicine than for those receiving in-person care (P = .03).
- No associations were observed between changes in A1c and comorbidities.
- Regarding reasons for the differences, the authors noted that “the strategies to support glycemic improvement that are available during in-person appointments have not consistently been translated to telemedicine care.”
- Essential components of telemedicine such as self-management education support may not currently be routinely available through telemedicine or at the point-of-care during telemedicine visits, they added.
- “In our prior work in this care setting, practitioners described how inferior availability of glucose data limited their ability to intensify treatment through telemedicine.”
- “Implementation of approaches to overcome these differences, such as team-based virtual care and technological tools to automate blood glucose data sharing, are needed to ensure all patients receive high-quality diabetes care regardless of care modality.”
IN PRACTICE:
“These findings suggest that patients with type 2 diabetes who rely on telemedicine alone to access endocrinology care may require additional support to achieve glycemic goals,” the authors reported.
“Since some patients with barriers to in-person endocrinology care will continue to rely on telemedicine to access care, structured approaches to ensure routine delivery of high-quality team-based diabetes care are needed,” they asserted.
“Translation of successful strategies from clinical trials into routine telemedicine care, especially targeted toward adults with more complex diabetes, is critical to improve clinical outcomes for patients who rely on this care modality.”
SOURCE:
The study was conducted by first author Margaret F. Zupa, MD, of the division of endocrinology and metabolism, University of Pittsburgh School of Medicine, Pennsylvania, and colleagues.
It was published in JAMA Network Open.
LIMITATIONS:
While demographic differences between the groups were included as covariates, the treatment modality cohorts were not balanced based on baseline characteristics that could be confounders.
Various factors, such as treatment complexity, glycemic control, and transportation barriers, could have affected whether patients received care with telemedicine; therefore, causal associations could not be established.
DISCLOSURES:
The study received funding from the National Center for Advancing Translational Sciences, National Institutes of Health, Pittsburgh Foundation, and Fraternal Order of the Eagles Charity Foundation Diabetes Fund. The authors’ disclosures are detailed in the study.
A version of this article appeared on Medscape.com.
TOPLINE:
Adult patients with type 2 diabetes and complex care needs receiving endocrinology treatment through telemedicine alone show worse glycemic outcomes compared with those receiving treatment either in-person or in mixed-care models.
The findings contrast with some previous studies showing similar glycemic outcomes with telemedicine care vs in-person care for type 2 diabetes management.
The study is believed to be the first to examine telemedicine care outcomes specifically in the endocrinology setting and based on clinical factors that affect treatment complexity.
METHODOLOGY:
- The retrospective cohort study included 3778 adults with type 2 diabetes in a single, large integrated US health system who had received either telemedicine-only, in-person, or a mix of telemedicine and in-person care between May and October 2020.
- Patients were followed up through May 2022 and evaluated for estimated A1c change after 12 months within each treatment cohort, as well as factors associated with any changes.
- Of the patients, 1182 received telemedicine-only, 1049 received in-person, and 1547 received mixed care. Mean ages in the groups ranged from 57 to 63 years, and women made up between 55% and 63%.
TAKEAWAY:
- Over the 12-month evaluation period, patients receiving telemedicine-only care had no significant changes or improvements in adjusted A1c (−0.06; P = .55), those receiving in-person care had an improvement of 0.37% (P < .001), and those receiving mixed care had an improvement of 0.22% (P = .004).
- The glycemic outcome patterns were similar among patients with a baseline A1c of 8% or higher.
- Of those prescribed multiple daily injections vs no insulin, estimated changes in A1c were 0.25% higher for those receiving telemedicine than for those receiving in-person care (P = .03).
- No associations were observed between changes in A1c and comorbidities.
- Regarding reasons for the differences, the authors noted that “the strategies to support glycemic improvement that are available during in-person appointments have not consistently been translated to telemedicine care.”
- Essential components of telemedicine such as self-management education support may not currently be routinely available through telemedicine or at the point-of-care during telemedicine visits, they added.
- “In our prior work in this care setting, practitioners described how inferior availability of glucose data limited their ability to intensify treatment through telemedicine.”
- “Implementation of approaches to overcome these differences, such as team-based virtual care and technological tools to automate blood glucose data sharing, are needed to ensure all patients receive high-quality diabetes care regardless of care modality.”
IN PRACTICE:
“These findings suggest that patients with type 2 diabetes who rely on telemedicine alone to access endocrinology care may require additional support to achieve glycemic goals,” the authors reported.
“Since some patients with barriers to in-person endocrinology care will continue to rely on telemedicine to access care, structured approaches to ensure routine delivery of high-quality team-based diabetes care are needed,” they asserted.
“Translation of successful strategies from clinical trials into routine telemedicine care, especially targeted toward adults with more complex diabetes, is critical to improve clinical outcomes for patients who rely on this care modality.”
SOURCE:
The study was conducted by first author Margaret F. Zupa, MD, of the division of endocrinology and metabolism, University of Pittsburgh School of Medicine, Pennsylvania, and colleagues.
It was published in JAMA Network Open.
LIMITATIONS:
While demographic differences between the groups were included as covariates, the treatment modality cohorts were not balanced based on baseline characteristics that could be confounders.
Various factors, such as treatment complexity, glycemic control, and transportation barriers, could have affected whether patients received care with telemedicine; therefore, causal associations could not be established.
DISCLOSURES:
The study received funding from the National Center for Advancing Translational Sciences, National Institutes of Health, Pittsburgh Foundation, and Fraternal Order of the Eagles Charity Foundation Diabetes Fund. The authors’ disclosures are detailed in the study.
A version of this article appeared on Medscape.com.
Relapsed DLBCL: With Complete Interim Response, SCT Outperforms CAR T
“In patients with relapsed DLBCL in a complete remission, treatment with auto-HCT is associated with a lower rate of relapse/progression, and a longer progression-free survival [versus CAR T therapy],” said first author Mazyar Shadman, MD, MPH, of the Division of Medical Oncology, University of Washington, Seattle.
“The data support utilization of auto-HCT in patients with relapsed LBCL achieving a complete response,” he said.
The findings were presented at the annual meeting of the American Society of Hematology in San Diego.
While approximately 60% of patients with DLBCL are successfully treated after an initial anthracycline-based and rituximab-containing chemotherapy regimen, those who do not improve have poorer outcomes, and CAR T-cell therapy has emerged as the standard of care for those patients, based on results from the ZUMA-7 and TRANSFORM clinical trials.
But with delays in accessing CAR T quite common, patients will often receive interim chemotherapy while awaiting referral to a CAR T center, and occasionally, usually unexpectedly, some will achieve a partial or complete response.
In previous research involving patients who achieved a partial remission in such interim cases, Dr. Shadman and colleagues demonstrated that auto-HCT had favorable outcomes, compared with those who received CAR T therapy.
For the new retrospective, real-world analysis, the authors compared outcomes with the treatment options among 360 patients between the ages of 18 and 75 who were enrolled in the Center for International Blood & Marrow Transplant Research registry and had received auto-HCT or CAR T therapy after achieving a complete remission following salvage chemotherapy.
Of those receiving CAR-T cell therapy, most (53.2%) received tisagenlecleucel (tisa-cel), followed by axicabtagene ciloleucel (axi-cel, 45.6%) and lisocabtagene maraleucel (liso-cel, 1.3%), between 2018 and 2021, while 281 patients were treated with auto-HCT between 2015 and 2021.
With a median follow-up of 49.7 months (range 3.0-94.4) for auto-HCT and 24.7 months (range 3.3-49.4) for CAR-T, a univariate analysis showed the rate of 2-year progression free survival was 66.2% in the auto-HCT group and 47.8% in the CAR T group (P < .001).
The results also favored auto-HCT for 2-year progression/relapse, with a cumulative incidence of 27.8% with auto-HCT versus 48% with CAR T (P < .001), and the 2-year overall survival was higher with auto-HCT (78.9% vs. 65.6%; P = .037).
After adjustment in multivariable analysis adjusting for relevant clinical variables, auto-HCT versus CAR T remained associated with a lower risk of relapse or progression (HR 2.18; P < .0001) and an improved progression-free survival (HR 1.83; P = .0011), with no significant differences in the risk of treatment-related mortality (HR 0.59; P = .36) or overall survival (HR 1.44; P = .12).
Deaths occurred among 85 patients in the auto-HCT group and 25 in the CAR T cohort, with lymphoma being the main cause of death in both groups (60% and 68%, respectively).
While 37 (13.2%) of auto-HCT patients later received subsequent CAR-T therapy, no patients receiving CAR-T had subsequent auto-HCT.
There were no differences between the CAR-T and auto-HST groups in rates of 2-year treatment-related mortality (4.1% vs. 5.9%; P = .673).
A subanalysis of those who had treatment failure at 12 months, (CAR-T = 57 and auto-HCT = 163) showed that those receiving CAR-T therapy had a higher 2-year relapse rate (46.3% vs. 25%; P < .001); an inferior 2-year progression-free survival rate (48.4% vs. 68.2%; P = .001) compared with auto-HCT, while there were no significant differences between the groups in terms of 2-year overall survival or treatment-related mortality.
After a multivariable analysis adjusting for relevant clinical factors, CAR-T therapy remained associated with higher risk of relapse (HR 2.18; P < .0001) and an inferior progression-free survival (HR 1.83; P = .0011) compared with auto-HCT, with no differences in the risk of treatment-related mortality (HR 0.59; P = .36) or overall survival (HR 1.44; P = .12).
“These results are consistent with our previously reported findings, indicating higher efficacy of auto-HCT compared with CAR T in patients with partial remission,” Dr. Shadman said.
In addition to the study’s being a retrospective analysis, limitations include that more than half of patients in the CAR T cohort received tisa-cel, which could have lower efficacy compared with other approved CAR T therapies, Dr. Shadman noted.
“A repeat analysis by including more patients treated with axi-cel or liso-cel may address this issue in the future,” he said.
Discussing the results in a press briefing, Dr. Shadman underscored that “there is no question the choice of therapy for these DLBCL patients with primary refractory disease should be second-line CAR T therapy — we are not suggesting that those patients should be sent for auto-HCT,” he said.
“What we are saying is, in real-world practice ... patients may need chemotherapy treatment in the interim (awaiting CAR T treatment), and we don’t expect these patients to respond to those cycles because they have already shown us that they don’t do well with chemotherapy — however some do respond and can go into complete remission.”
The question then becomes whether patients at that point will fare better with CAR T or auto-HCT, and the results indicate that “auto-HCT gives those patients a pretty solid remission that looks better than [that with] CAR T therapy.”
Dr. Shadman noted that the results serve to inform or confirm key clinical practices, including “in patients with late relapses, after 12 months, auto-HCT should remain the standard of care.
“In patients with primary refractory disease or early relapse, CAR T should be the goal of therapy and improving access to CAR T should remain a priority.
“In the subset of patients who achieve a CR with interim treatment, a discussion about the possibility of utilizing auto-HCT seems reasonable and can provide another curative option for some patients while keeping CAR-T as a backup treatment plan in case of auto-HCT failure.”
Commenting on the study, Jonathan W. Friedberg, MD, the Samuel Durand Professor of Medicine and director of the Wilmot Cancer Institute, University of Rochester, New York, said, “these findings confirm utility of auto-HCT in patients who achieve a CR.”
However, “the problem is that only a small fraction of patients achieve CR in this situation, and we do not know who they are going to be at time of relapse,” he told this news organization.
He agreed that “given robust randomized trials showing overall survival benefit of CAR-T compared to auto-HCT in patients with high risk relapsed DLBCL, CAR-T treatment should remain the current standard.
“However, these current results help to confirm the strategy for management of low- risk (late) relapses and indicate that auto-HCT still has a place for these patients if they achieve CR with salvage therapy.”
Dr. Shadman reported relationships with ADC therapeutics, Bristol Myers Squibb, Genmab, Lilly, Vincerx, Kite (Gilead), Janssen, Fate Therapeutics, MorphoSys/Incyte, AstraZeneca, BeiGene, Pharmacyclics, Mustang Bio, AbbVie, Genentech, MEI Pharma, Regeneron, and TG Therapeutics. Dr. Friedberg had no disclosures to report.
“In patients with relapsed DLBCL in a complete remission, treatment with auto-HCT is associated with a lower rate of relapse/progression, and a longer progression-free survival [versus CAR T therapy],” said first author Mazyar Shadman, MD, MPH, of the Division of Medical Oncology, University of Washington, Seattle.
“The data support utilization of auto-HCT in patients with relapsed LBCL achieving a complete response,” he said.
The findings were presented at the annual meeting of the American Society of Hematology in San Diego.
While approximately 60% of patients with DLBCL are successfully treated after an initial anthracycline-based and rituximab-containing chemotherapy regimen, those who do not improve have poorer outcomes, and CAR T-cell therapy has emerged as the standard of care for those patients, based on results from the ZUMA-7 and TRANSFORM clinical trials.
But with delays in accessing CAR T quite common, patients will often receive interim chemotherapy while awaiting referral to a CAR T center, and occasionally, usually unexpectedly, some will achieve a partial or complete response.
In previous research involving patients who achieved a partial remission in such interim cases, Dr. Shadman and colleagues demonstrated that auto-HCT had favorable outcomes, compared with those who received CAR T therapy.
For the new retrospective, real-world analysis, the authors compared outcomes with the treatment options among 360 patients between the ages of 18 and 75 who were enrolled in the Center for International Blood & Marrow Transplant Research registry and had received auto-HCT or CAR T therapy after achieving a complete remission following salvage chemotherapy.
Of those receiving CAR-T cell therapy, most (53.2%) received tisagenlecleucel (tisa-cel), followed by axicabtagene ciloleucel (axi-cel, 45.6%) and lisocabtagene maraleucel (liso-cel, 1.3%), between 2018 and 2021, while 281 patients were treated with auto-HCT between 2015 and 2021.
With a median follow-up of 49.7 months (range 3.0-94.4) for auto-HCT and 24.7 months (range 3.3-49.4) for CAR-T, a univariate analysis showed the rate of 2-year progression free survival was 66.2% in the auto-HCT group and 47.8% in the CAR T group (P < .001).
The results also favored auto-HCT for 2-year progression/relapse, with a cumulative incidence of 27.8% with auto-HCT versus 48% with CAR T (P < .001), and the 2-year overall survival was higher with auto-HCT (78.9% vs. 65.6%; P = .037).
After adjustment in multivariable analysis adjusting for relevant clinical variables, auto-HCT versus CAR T remained associated with a lower risk of relapse or progression (HR 2.18; P < .0001) and an improved progression-free survival (HR 1.83; P = .0011), with no significant differences in the risk of treatment-related mortality (HR 0.59; P = .36) or overall survival (HR 1.44; P = .12).
Deaths occurred among 85 patients in the auto-HCT group and 25 in the CAR T cohort, with lymphoma being the main cause of death in both groups (60% and 68%, respectively).
While 37 (13.2%) of auto-HCT patients later received subsequent CAR-T therapy, no patients receiving CAR-T had subsequent auto-HCT.
There were no differences between the CAR-T and auto-HST groups in rates of 2-year treatment-related mortality (4.1% vs. 5.9%; P = .673).
A subanalysis of those who had treatment failure at 12 months, (CAR-T = 57 and auto-HCT = 163) showed that those receiving CAR-T therapy had a higher 2-year relapse rate (46.3% vs. 25%; P < .001); an inferior 2-year progression-free survival rate (48.4% vs. 68.2%; P = .001) compared with auto-HCT, while there were no significant differences between the groups in terms of 2-year overall survival or treatment-related mortality.
After a multivariable analysis adjusting for relevant clinical factors, CAR-T therapy remained associated with higher risk of relapse (HR 2.18; P < .0001) and an inferior progression-free survival (HR 1.83; P = .0011) compared with auto-HCT, with no differences in the risk of treatment-related mortality (HR 0.59; P = .36) or overall survival (HR 1.44; P = .12).
“These results are consistent with our previously reported findings, indicating higher efficacy of auto-HCT compared with CAR T in patients with partial remission,” Dr. Shadman said.
In addition to the study’s being a retrospective analysis, limitations include that more than half of patients in the CAR T cohort received tisa-cel, which could have lower efficacy compared with other approved CAR T therapies, Dr. Shadman noted.
“A repeat analysis by including more patients treated with axi-cel or liso-cel may address this issue in the future,” he said.
Discussing the results in a press briefing, Dr. Shadman underscored that “there is no question the choice of therapy for these DLBCL patients with primary refractory disease should be second-line CAR T therapy — we are not suggesting that those patients should be sent for auto-HCT,” he said.
“What we are saying is, in real-world practice ... patients may need chemotherapy treatment in the interim (awaiting CAR T treatment), and we don’t expect these patients to respond to those cycles because they have already shown us that they don’t do well with chemotherapy — however some do respond and can go into complete remission.”
The question then becomes whether patients at that point will fare better with CAR T or auto-HCT, and the results indicate that “auto-HCT gives those patients a pretty solid remission that looks better than [that with] CAR T therapy.”
Dr. Shadman noted that the results serve to inform or confirm key clinical practices, including “in patients with late relapses, after 12 months, auto-HCT should remain the standard of care.
“In patients with primary refractory disease or early relapse, CAR T should be the goal of therapy and improving access to CAR T should remain a priority.
“In the subset of patients who achieve a CR with interim treatment, a discussion about the possibility of utilizing auto-HCT seems reasonable and can provide another curative option for some patients while keeping CAR-T as a backup treatment plan in case of auto-HCT failure.”
Commenting on the study, Jonathan W. Friedberg, MD, the Samuel Durand Professor of Medicine and director of the Wilmot Cancer Institute, University of Rochester, New York, said, “these findings confirm utility of auto-HCT in patients who achieve a CR.”
However, “the problem is that only a small fraction of patients achieve CR in this situation, and we do not know who they are going to be at time of relapse,” he told this news organization.
He agreed that “given robust randomized trials showing overall survival benefit of CAR-T compared to auto-HCT in patients with high risk relapsed DLBCL, CAR-T treatment should remain the current standard.
“However, these current results help to confirm the strategy for management of low- risk (late) relapses and indicate that auto-HCT still has a place for these patients if they achieve CR with salvage therapy.”
Dr. Shadman reported relationships with ADC therapeutics, Bristol Myers Squibb, Genmab, Lilly, Vincerx, Kite (Gilead), Janssen, Fate Therapeutics, MorphoSys/Incyte, AstraZeneca, BeiGene, Pharmacyclics, Mustang Bio, AbbVie, Genentech, MEI Pharma, Regeneron, and TG Therapeutics. Dr. Friedberg had no disclosures to report.
“In patients with relapsed DLBCL in a complete remission, treatment with auto-HCT is associated with a lower rate of relapse/progression, and a longer progression-free survival [versus CAR T therapy],” said first author Mazyar Shadman, MD, MPH, of the Division of Medical Oncology, University of Washington, Seattle.
“The data support utilization of auto-HCT in patients with relapsed LBCL achieving a complete response,” he said.
The findings were presented at the annual meeting of the American Society of Hematology in San Diego.
While approximately 60% of patients with DLBCL are successfully treated after an initial anthracycline-based and rituximab-containing chemotherapy regimen, those who do not improve have poorer outcomes, and CAR T-cell therapy has emerged as the standard of care for those patients, based on results from the ZUMA-7 and TRANSFORM clinical trials.
But with delays in accessing CAR T quite common, patients will often receive interim chemotherapy while awaiting referral to a CAR T center, and occasionally, usually unexpectedly, some will achieve a partial or complete response.
In previous research involving patients who achieved a partial remission in such interim cases, Dr. Shadman and colleagues demonstrated that auto-HCT had favorable outcomes, compared with those who received CAR T therapy.
For the new retrospective, real-world analysis, the authors compared outcomes with the treatment options among 360 patients between the ages of 18 and 75 who were enrolled in the Center for International Blood & Marrow Transplant Research registry and had received auto-HCT or CAR T therapy after achieving a complete remission following salvage chemotherapy.
Of those receiving CAR-T cell therapy, most (53.2%) received tisagenlecleucel (tisa-cel), followed by axicabtagene ciloleucel (axi-cel, 45.6%) and lisocabtagene maraleucel (liso-cel, 1.3%), between 2018 and 2021, while 281 patients were treated with auto-HCT between 2015 and 2021.
With a median follow-up of 49.7 months (range 3.0-94.4) for auto-HCT and 24.7 months (range 3.3-49.4) for CAR-T, a univariate analysis showed the rate of 2-year progression free survival was 66.2% in the auto-HCT group and 47.8% in the CAR T group (P < .001).
The results also favored auto-HCT for 2-year progression/relapse, with a cumulative incidence of 27.8% with auto-HCT versus 48% with CAR T (P < .001), and the 2-year overall survival was higher with auto-HCT (78.9% vs. 65.6%; P = .037).
After adjustment in multivariable analysis adjusting for relevant clinical variables, auto-HCT versus CAR T remained associated with a lower risk of relapse or progression (HR 2.18; P < .0001) and an improved progression-free survival (HR 1.83; P = .0011), with no significant differences in the risk of treatment-related mortality (HR 0.59; P = .36) or overall survival (HR 1.44; P = .12).
Deaths occurred among 85 patients in the auto-HCT group and 25 in the CAR T cohort, with lymphoma being the main cause of death in both groups (60% and 68%, respectively).
While 37 (13.2%) of auto-HCT patients later received subsequent CAR-T therapy, no patients receiving CAR-T had subsequent auto-HCT.
There were no differences between the CAR-T and auto-HST groups in rates of 2-year treatment-related mortality (4.1% vs. 5.9%; P = .673).
A subanalysis of those who had treatment failure at 12 months, (CAR-T = 57 and auto-HCT = 163) showed that those receiving CAR-T therapy had a higher 2-year relapse rate (46.3% vs. 25%; P < .001); an inferior 2-year progression-free survival rate (48.4% vs. 68.2%; P = .001) compared with auto-HCT, while there were no significant differences between the groups in terms of 2-year overall survival or treatment-related mortality.
After a multivariable analysis adjusting for relevant clinical factors, CAR-T therapy remained associated with higher risk of relapse (HR 2.18; P < .0001) and an inferior progression-free survival (HR 1.83; P = .0011) compared with auto-HCT, with no differences in the risk of treatment-related mortality (HR 0.59; P = .36) or overall survival (HR 1.44; P = .12).
“These results are consistent with our previously reported findings, indicating higher efficacy of auto-HCT compared with CAR T in patients with partial remission,” Dr. Shadman said.
In addition to the study’s being a retrospective analysis, limitations include that more than half of patients in the CAR T cohort received tisa-cel, which could have lower efficacy compared with other approved CAR T therapies, Dr. Shadman noted.
“A repeat analysis by including more patients treated with axi-cel or liso-cel may address this issue in the future,” he said.
Discussing the results in a press briefing, Dr. Shadman underscored that “there is no question the choice of therapy for these DLBCL patients with primary refractory disease should be second-line CAR T therapy — we are not suggesting that those patients should be sent for auto-HCT,” he said.
“What we are saying is, in real-world practice ... patients may need chemotherapy treatment in the interim (awaiting CAR T treatment), and we don’t expect these patients to respond to those cycles because they have already shown us that they don’t do well with chemotherapy — however some do respond and can go into complete remission.”
The question then becomes whether patients at that point will fare better with CAR T or auto-HCT, and the results indicate that “auto-HCT gives those patients a pretty solid remission that looks better than [that with] CAR T therapy.”
Dr. Shadman noted that the results serve to inform or confirm key clinical practices, including “in patients with late relapses, after 12 months, auto-HCT should remain the standard of care.
“In patients with primary refractory disease or early relapse, CAR T should be the goal of therapy and improving access to CAR T should remain a priority.
“In the subset of patients who achieve a CR with interim treatment, a discussion about the possibility of utilizing auto-HCT seems reasonable and can provide another curative option for some patients while keeping CAR-T as a backup treatment plan in case of auto-HCT failure.”
Commenting on the study, Jonathan W. Friedberg, MD, the Samuel Durand Professor of Medicine and director of the Wilmot Cancer Institute, University of Rochester, New York, said, “these findings confirm utility of auto-HCT in patients who achieve a CR.”
However, “the problem is that only a small fraction of patients achieve CR in this situation, and we do not know who they are going to be at time of relapse,” he told this news organization.
He agreed that “given robust randomized trials showing overall survival benefit of CAR-T compared to auto-HCT in patients with high risk relapsed DLBCL, CAR-T treatment should remain the current standard.
“However, these current results help to confirm the strategy for management of low- risk (late) relapses and indicate that auto-HCT still has a place for these patients if they achieve CR with salvage therapy.”
Dr. Shadman reported relationships with ADC therapeutics, Bristol Myers Squibb, Genmab, Lilly, Vincerx, Kite (Gilead), Janssen, Fate Therapeutics, MorphoSys/Incyte, AstraZeneca, BeiGene, Pharmacyclics, Mustang Bio, AbbVie, Genentech, MEI Pharma, Regeneron, and TG Therapeutics. Dr. Friedberg had no disclosures to report.
FROM ASH 2023
Most stop taking weight loss drugs within 1 year
Patients receiving semaglutide for weight loss show a significantly higher rate of continuing the medication at 1 year compared with less effective anti-obesity drugs. However, even among those patients, continuation declines to fewer than half of patients.
“We now have effective US Food and Drug Administration–approved anti-obesity medications; [however], this study shows that in a real-world setting, the vast majority of patients discontinued their prescription fills within the first year,” said first author Hamlet Gasoyan, PhD, lead author of the study and a researcher with Cleveland Clinic’s Center for Value-Based Care Research, said in a press statement.
The study was published online in the journal Obesity.
While breakthrough drugs such as glucagon-like peptide-1 (GLP-1) receptor agonists have shown high efficacy in achieving weight loss while providing a host of other health benefits, their discontinuation has been shown to potentially result in a rapid regaining of weight that was lost, as well as a reversal of the other health benefits, such as cardiometabolic improvements, the study authors wrote.
To evaluate rates of persistence with those along with other weight loss medications and factors associated with discontinuation, Dr. Gasoyan and colleagues conducted a retrospective cohort study, identifying 1911 patients with obesity, who had an initial anti-obesity medication prescription filled between 2015 and 2022 at Cleveland Clinic centers in Ohio and Florida.
Over the study period, 25% of patients filled a prescription for semaglutide, 34% for naltrexone-bupropion, 26% for phentermine-topiramate, 14% for liraglutide, and 0.9% for orlistat.
The patients had a median baseline BMI of 38, with obesity defined as a BMI of 30 or higher.
Medication Continuation Drops After 3 Months
With a median follow-up time of 2.4 years, the rate of persistence to the medications overall dropped from 44% at 3 months to 33% at 6 months and just 19% at 12 months.
In a multivariate analysis, semaglutide was associated with the highest odds of 1-year persistence (adjusted odds ratio [AOR], 4.26), while naltrexone-bupropion had the lowest odds (AOR, 0.68), compared with phentermine-topiramate. The other agents did not have significantly different odds of persistence.
Semaglutide and liraglutide also had the highest persistence rates overall, including at 3 months (63% and 52%, respectively) and 6 months (56% and 37%, respectively).
Those with higher weight loss at 6 months had a higher likelihood of remaining on the weight loss medication at 1 year, with a 1% increase in weight loss at 6 months associated with 6% increased odds of still being persistent at year 1 (adjusted odds ratio, 1.06).
Those who did continue medications at 1 year had a mean of 10% weight loss at 12 months compared with just 2% among individuals who were not persistent (P <.001).
Most patients (84%) in the study were privately insured, and weight loss drug adherence varied significantly based on the insurance carrier.
Studies demonstrating the effects of discontinuing treatment with semaglutide include the STEP 1 trial extension, which showed that 1 year after discontinuation of treatment and lifestyle intervention, participants regained two thirds of their lost weight on average, and the cardiometabolic improvements with the weight loss were reversed.
In light of those findings, “the current scientific knowledge favors using anti-obesity medications longer term for weight loss maintenance if they are well-tolerated and have resulted in clinically meaningful weight loss,” Dr. Gasoyan told this news organization.
Paradoxically, the possible regaining of weight could be a factor in some insurers denying longer-term coverage, he noted.
Discontinuing Medications Means Regaining Appetite
Anne Peters, MD, a professor of medicine at USC’s Keck School of Medicine in Los Angeles and director of the USC Clinical Diabetes Programs, underscored that the possibility of regaining weight with discontinuation of GLP-1 receptor agonists is indeed “a big concern because your appetite comes back in spades when you take away the effect of these hormones,” she told this news organization. “For that reason, I don’t ever tell people to stop cold turkey.”
Regarding the question of how long patients should remain on the medications, Peters said the scenario might be compared to the need for patients with type 1 diabetes to be on insulin, which is a gut hormone.
“These medications are also gut hormones, and some patients may need to also be on them for life to maintain the benefits,” she said.
“If a patient for some reason wishes to come off of the medication, for instance in order to be on less medicine, I have them titrate down and usually there will be a dose where they actually need only a small dose.
“I even have some patients who just take semaglutide once a month who are able to manage to maintain their weight loss,” Dr. Peters noted.
“But the whole goal in people who are overweight or obese is to establish a new set point and maintain whatever that new target weight is.”
Dr. Peters agreed that the loss of insurance coverage for the medications can throw a big wrench into that maintenance, presenting adverse effects of its own by causing a lack of treatment continuity.
“When you lose weight, you lose lean body mass and fat mass, but when you regain, it’s primary fat mass, so if you go on and off these drugs, it can contribute to a loss of lean mass. Therefore, these drugs should not be taken if someone is going to go on and off them repeatedly.”
The study received funding from the National Cancer Institute. Dr. Peters has consulted for Eli Lilly in the past.
A version of this article appeared on Medscape.com.
Patients receiving semaglutide for weight loss show a significantly higher rate of continuing the medication at 1 year compared with less effective anti-obesity drugs. However, even among those patients, continuation declines to fewer than half of patients.
“We now have effective US Food and Drug Administration–approved anti-obesity medications; [however], this study shows that in a real-world setting, the vast majority of patients discontinued their prescription fills within the first year,” said first author Hamlet Gasoyan, PhD, lead author of the study and a researcher with Cleveland Clinic’s Center for Value-Based Care Research, said in a press statement.
The study was published online in the journal Obesity.
While breakthrough drugs such as glucagon-like peptide-1 (GLP-1) receptor agonists have shown high efficacy in achieving weight loss while providing a host of other health benefits, their discontinuation has been shown to potentially result in a rapid regaining of weight that was lost, as well as a reversal of the other health benefits, such as cardiometabolic improvements, the study authors wrote.
To evaluate rates of persistence with those along with other weight loss medications and factors associated with discontinuation, Dr. Gasoyan and colleagues conducted a retrospective cohort study, identifying 1911 patients with obesity, who had an initial anti-obesity medication prescription filled between 2015 and 2022 at Cleveland Clinic centers in Ohio and Florida.
Over the study period, 25% of patients filled a prescription for semaglutide, 34% for naltrexone-bupropion, 26% for phentermine-topiramate, 14% for liraglutide, and 0.9% for orlistat.
The patients had a median baseline BMI of 38, with obesity defined as a BMI of 30 or higher.
Medication Continuation Drops After 3 Months
With a median follow-up time of 2.4 years, the rate of persistence to the medications overall dropped from 44% at 3 months to 33% at 6 months and just 19% at 12 months.
In a multivariate analysis, semaglutide was associated with the highest odds of 1-year persistence (adjusted odds ratio [AOR], 4.26), while naltrexone-bupropion had the lowest odds (AOR, 0.68), compared with phentermine-topiramate. The other agents did not have significantly different odds of persistence.
Semaglutide and liraglutide also had the highest persistence rates overall, including at 3 months (63% and 52%, respectively) and 6 months (56% and 37%, respectively).
Those with higher weight loss at 6 months had a higher likelihood of remaining on the weight loss medication at 1 year, with a 1% increase in weight loss at 6 months associated with 6% increased odds of still being persistent at year 1 (adjusted odds ratio, 1.06).
Those who did continue medications at 1 year had a mean of 10% weight loss at 12 months compared with just 2% among individuals who were not persistent (P <.001).
Most patients (84%) in the study were privately insured, and weight loss drug adherence varied significantly based on the insurance carrier.
Studies demonstrating the effects of discontinuing treatment with semaglutide include the STEP 1 trial extension, which showed that 1 year after discontinuation of treatment and lifestyle intervention, participants regained two thirds of their lost weight on average, and the cardiometabolic improvements with the weight loss were reversed.
In light of those findings, “the current scientific knowledge favors using anti-obesity medications longer term for weight loss maintenance if they are well-tolerated and have resulted in clinically meaningful weight loss,” Dr. Gasoyan told this news organization.
Paradoxically, the possible regaining of weight could be a factor in some insurers denying longer-term coverage, he noted.
Discontinuing Medications Means Regaining Appetite
Anne Peters, MD, a professor of medicine at USC’s Keck School of Medicine in Los Angeles and director of the USC Clinical Diabetes Programs, underscored that the possibility of regaining weight with discontinuation of GLP-1 receptor agonists is indeed “a big concern because your appetite comes back in spades when you take away the effect of these hormones,” she told this news organization. “For that reason, I don’t ever tell people to stop cold turkey.”
Regarding the question of how long patients should remain on the medications, Peters said the scenario might be compared to the need for patients with type 1 diabetes to be on insulin, which is a gut hormone.
“These medications are also gut hormones, and some patients may need to also be on them for life to maintain the benefits,” she said.
“If a patient for some reason wishes to come off of the medication, for instance in order to be on less medicine, I have them titrate down and usually there will be a dose where they actually need only a small dose.
“I even have some patients who just take semaglutide once a month who are able to manage to maintain their weight loss,” Dr. Peters noted.
“But the whole goal in people who are overweight or obese is to establish a new set point and maintain whatever that new target weight is.”
Dr. Peters agreed that the loss of insurance coverage for the medications can throw a big wrench into that maintenance, presenting adverse effects of its own by causing a lack of treatment continuity.
“When you lose weight, you lose lean body mass and fat mass, but when you regain, it’s primary fat mass, so if you go on and off these drugs, it can contribute to a loss of lean mass. Therefore, these drugs should not be taken if someone is going to go on and off them repeatedly.”
The study received funding from the National Cancer Institute. Dr. Peters has consulted for Eli Lilly in the past.
A version of this article appeared on Medscape.com.
Patients receiving semaglutide for weight loss show a significantly higher rate of continuing the medication at 1 year compared with less effective anti-obesity drugs. However, even among those patients, continuation declines to fewer than half of patients.
“We now have effective US Food and Drug Administration–approved anti-obesity medications; [however], this study shows that in a real-world setting, the vast majority of patients discontinued their prescription fills within the first year,” said first author Hamlet Gasoyan, PhD, lead author of the study and a researcher with Cleveland Clinic’s Center for Value-Based Care Research, said in a press statement.
The study was published online in the journal Obesity.
While breakthrough drugs such as glucagon-like peptide-1 (GLP-1) receptor agonists have shown high efficacy in achieving weight loss while providing a host of other health benefits, their discontinuation has been shown to potentially result in a rapid regaining of weight that was lost, as well as a reversal of the other health benefits, such as cardiometabolic improvements, the study authors wrote.
To evaluate rates of persistence with those along with other weight loss medications and factors associated with discontinuation, Dr. Gasoyan and colleagues conducted a retrospective cohort study, identifying 1911 patients with obesity, who had an initial anti-obesity medication prescription filled between 2015 and 2022 at Cleveland Clinic centers in Ohio and Florida.
Over the study period, 25% of patients filled a prescription for semaglutide, 34% for naltrexone-bupropion, 26% for phentermine-topiramate, 14% for liraglutide, and 0.9% for orlistat.
The patients had a median baseline BMI of 38, with obesity defined as a BMI of 30 or higher.
Medication Continuation Drops After 3 Months
With a median follow-up time of 2.4 years, the rate of persistence to the medications overall dropped from 44% at 3 months to 33% at 6 months and just 19% at 12 months.
In a multivariate analysis, semaglutide was associated with the highest odds of 1-year persistence (adjusted odds ratio [AOR], 4.26), while naltrexone-bupropion had the lowest odds (AOR, 0.68), compared with phentermine-topiramate. The other agents did not have significantly different odds of persistence.
Semaglutide and liraglutide also had the highest persistence rates overall, including at 3 months (63% and 52%, respectively) and 6 months (56% and 37%, respectively).
Those with higher weight loss at 6 months had a higher likelihood of remaining on the weight loss medication at 1 year, with a 1% increase in weight loss at 6 months associated with 6% increased odds of still being persistent at year 1 (adjusted odds ratio, 1.06).
Those who did continue medications at 1 year had a mean of 10% weight loss at 12 months compared with just 2% among individuals who were not persistent (P <.001).
Most patients (84%) in the study were privately insured, and weight loss drug adherence varied significantly based on the insurance carrier.
Studies demonstrating the effects of discontinuing treatment with semaglutide include the STEP 1 trial extension, which showed that 1 year after discontinuation of treatment and lifestyle intervention, participants regained two thirds of their lost weight on average, and the cardiometabolic improvements with the weight loss were reversed.
In light of those findings, “the current scientific knowledge favors using anti-obesity medications longer term for weight loss maintenance if they are well-tolerated and have resulted in clinically meaningful weight loss,” Dr. Gasoyan told this news organization.
Paradoxically, the possible regaining of weight could be a factor in some insurers denying longer-term coverage, he noted.
Discontinuing Medications Means Regaining Appetite
Anne Peters, MD, a professor of medicine at USC’s Keck School of Medicine in Los Angeles and director of the USC Clinical Diabetes Programs, underscored that the possibility of regaining weight with discontinuation of GLP-1 receptor agonists is indeed “a big concern because your appetite comes back in spades when you take away the effect of these hormones,” she told this news organization. “For that reason, I don’t ever tell people to stop cold turkey.”
Regarding the question of how long patients should remain on the medications, Peters said the scenario might be compared to the need for patients with type 1 diabetes to be on insulin, which is a gut hormone.
“These medications are also gut hormones, and some patients may need to also be on them for life to maintain the benefits,” she said.
“If a patient for some reason wishes to come off of the medication, for instance in order to be on less medicine, I have them titrate down and usually there will be a dose where they actually need only a small dose.
“I even have some patients who just take semaglutide once a month who are able to manage to maintain their weight loss,” Dr. Peters noted.
“But the whole goal in people who are overweight or obese is to establish a new set point and maintain whatever that new target weight is.”
Dr. Peters agreed that the loss of insurance coverage for the medications can throw a big wrench into that maintenance, presenting adverse effects of its own by causing a lack of treatment continuity.
“When you lose weight, you lose lean body mass and fat mass, but when you regain, it’s primary fat mass, so if you go on and off these drugs, it can contribute to a loss of lean mass. Therefore, these drugs should not be taken if someone is going to go on and off them repeatedly.”
The study received funding from the National Cancer Institute. Dr. Peters has consulted for Eli Lilly in the past.
A version of this article appeared on Medscape.com.
FROM OBESITY
WHO: Smoking cessation reduces risk of type 2 diabetes up to 40%
TOPLINE:
, and quitting even after one has developed type 2 diabetes is important in preventing a worsening of the disease’s many serious comorbidities, according to a new policy brief jointly issued by the World Health Organization, the International Diabetes Federation (IDF), and the University of Newcastle, Callaghan, Australia.
With type 2 diabetes representing one of the most prevalent chronic diseases worldwide and the ninth cause of death globally, the potential to reduce the risk and worsening of the disease by quitting smoking adds to the urgency of smoking cessation as a public health interest.
METHODOLOGY:
- The policy brief summarizes the evidence on the health impacts of type 2 diabetes, tobacco smoking, and the pathophysiology of tobacco use and its role in the development of type 2 diabetes.
- The brief also describes the latest data on newer products that target smokers or potential smokers, including smokeless tobacco, new nicotine and tobacco products, and their relationship with type 2 diabetes. For instance, evidence suggests that even with smokeless tobacco, heavy use or high consumption increases the risk of developing type 2 diabetes, as the products often contain nicotine, known to contribute to the development of type 2 diabetes and related health conditions.
- Evidence on the effectiveness of tobacco control interventions among those with type 2 diabetes is also summarized, including discussion of a systematic review of six studies suggesting that interventions focusing on education and the involvement of health care professionals and pharmacists can be beneficial for people with type 2 diabetes.
TAKEAWAY:
- Smoking exacerbates the known serious complications of diabetic neuropathy and foot ulcers with type 2 diabetes, while further impeding wound healing.
- Smoking also causes damage to retinal blood vessels already at risk with type 2 diabetes, increasing the risk of diabetic retinopathy and vision loss.
- Quitting tobacco use can help prevent those and other major health complications already linked to diabetes, including kidney failure and cardiovascular events.
- Studies show that key misconceptions among smokers with type 2 diabetes that can prevent cessation include concerns about post-cessation weight gain, the influence of peers who smoke, and the psychological aspect of addiction.
- Clinicians are urged to provide advice on how to stop smoking to all tobacco users during the course of a routine consultation or interaction, which can be accomplished in only a few minutes.
IN PRACTICE:
“Health professionals play a vital role in motivating and guiding individuals with type 2 diabetes in their journey to quit tobacco,” Ruediger Krech, MD, director of the Department of Health Promotion at the World Health Organization in Geneva, Switzerland, said in a press statement on the policy brief.
“Simultaneously, governments must take the crucial step of ensuring all indoor public places, workplaces, and public transport are completely smoke-free. These interventions are essential safeguards against the onset and progression of this and many other chronic diseases,” he emphasized.
SOURCE:
The policy brief was jointly developed by the World Health Organization, the International Diabetes Federation, and the University of Newcastle.
The detailed policy brief can be downloaded on the IDF website.
LIMITATIONS:
Research remains limited on some issues, including the effectiveness of tobacco control interventions and smoking cessation methods for people with type 2 diabetes.
Likewise, specific guidelines for smoking cessation in the type 2 diabetes population are lacking. However, the general approaches of building patient motivation, behavioral interventions, and pharmacological treatments are advised.
“These interventions should be at least as intensive as those for the general population, while considering the unique characteristics of the disease and the individual,” the authors asserted.
DISCLOSURES:
The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TOPLINE:
, and quitting even after one has developed type 2 diabetes is important in preventing a worsening of the disease’s many serious comorbidities, according to a new policy brief jointly issued by the World Health Organization, the International Diabetes Federation (IDF), and the University of Newcastle, Callaghan, Australia.
With type 2 diabetes representing one of the most prevalent chronic diseases worldwide and the ninth cause of death globally, the potential to reduce the risk and worsening of the disease by quitting smoking adds to the urgency of smoking cessation as a public health interest.
METHODOLOGY:
- The policy brief summarizes the evidence on the health impacts of type 2 diabetes, tobacco smoking, and the pathophysiology of tobacco use and its role in the development of type 2 diabetes.
- The brief also describes the latest data on newer products that target smokers or potential smokers, including smokeless tobacco, new nicotine and tobacco products, and their relationship with type 2 diabetes. For instance, evidence suggests that even with smokeless tobacco, heavy use or high consumption increases the risk of developing type 2 diabetes, as the products often contain nicotine, known to contribute to the development of type 2 diabetes and related health conditions.
- Evidence on the effectiveness of tobacco control interventions among those with type 2 diabetes is also summarized, including discussion of a systematic review of six studies suggesting that interventions focusing on education and the involvement of health care professionals and pharmacists can be beneficial for people with type 2 diabetes.
TAKEAWAY:
- Smoking exacerbates the known serious complications of diabetic neuropathy and foot ulcers with type 2 diabetes, while further impeding wound healing.
- Smoking also causes damage to retinal blood vessels already at risk with type 2 diabetes, increasing the risk of diabetic retinopathy and vision loss.
- Quitting tobacco use can help prevent those and other major health complications already linked to diabetes, including kidney failure and cardiovascular events.
- Studies show that key misconceptions among smokers with type 2 diabetes that can prevent cessation include concerns about post-cessation weight gain, the influence of peers who smoke, and the psychological aspect of addiction.
- Clinicians are urged to provide advice on how to stop smoking to all tobacco users during the course of a routine consultation or interaction, which can be accomplished in only a few minutes.
IN PRACTICE:
“Health professionals play a vital role in motivating and guiding individuals with type 2 diabetes in their journey to quit tobacco,” Ruediger Krech, MD, director of the Department of Health Promotion at the World Health Organization in Geneva, Switzerland, said in a press statement on the policy brief.
“Simultaneously, governments must take the crucial step of ensuring all indoor public places, workplaces, and public transport are completely smoke-free. These interventions are essential safeguards against the onset and progression of this and many other chronic diseases,” he emphasized.
SOURCE:
The policy brief was jointly developed by the World Health Organization, the International Diabetes Federation, and the University of Newcastle.
The detailed policy brief can be downloaded on the IDF website.
LIMITATIONS:
Research remains limited on some issues, including the effectiveness of tobacco control interventions and smoking cessation methods for people with type 2 diabetes.
Likewise, specific guidelines for smoking cessation in the type 2 diabetes population are lacking. However, the general approaches of building patient motivation, behavioral interventions, and pharmacological treatments are advised.
“These interventions should be at least as intensive as those for the general population, while considering the unique characteristics of the disease and the individual,” the authors asserted.
DISCLOSURES:
The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TOPLINE:
, and quitting even after one has developed type 2 diabetes is important in preventing a worsening of the disease’s many serious comorbidities, according to a new policy brief jointly issued by the World Health Organization, the International Diabetes Federation (IDF), and the University of Newcastle, Callaghan, Australia.
With type 2 diabetes representing one of the most prevalent chronic diseases worldwide and the ninth cause of death globally, the potential to reduce the risk and worsening of the disease by quitting smoking adds to the urgency of smoking cessation as a public health interest.
METHODOLOGY:
- The policy brief summarizes the evidence on the health impacts of type 2 diabetes, tobacco smoking, and the pathophysiology of tobacco use and its role in the development of type 2 diabetes.
- The brief also describes the latest data on newer products that target smokers or potential smokers, including smokeless tobacco, new nicotine and tobacco products, and their relationship with type 2 diabetes. For instance, evidence suggests that even with smokeless tobacco, heavy use or high consumption increases the risk of developing type 2 diabetes, as the products often contain nicotine, known to contribute to the development of type 2 diabetes and related health conditions.
- Evidence on the effectiveness of tobacco control interventions among those with type 2 diabetes is also summarized, including discussion of a systematic review of six studies suggesting that interventions focusing on education and the involvement of health care professionals and pharmacists can be beneficial for people with type 2 diabetes.
TAKEAWAY:
- Smoking exacerbates the known serious complications of diabetic neuropathy and foot ulcers with type 2 diabetes, while further impeding wound healing.
- Smoking also causes damage to retinal blood vessels already at risk with type 2 diabetes, increasing the risk of diabetic retinopathy and vision loss.
- Quitting tobacco use can help prevent those and other major health complications already linked to diabetes, including kidney failure and cardiovascular events.
- Studies show that key misconceptions among smokers with type 2 diabetes that can prevent cessation include concerns about post-cessation weight gain, the influence of peers who smoke, and the psychological aspect of addiction.
- Clinicians are urged to provide advice on how to stop smoking to all tobacco users during the course of a routine consultation or interaction, which can be accomplished in only a few minutes.
IN PRACTICE:
“Health professionals play a vital role in motivating and guiding individuals with type 2 diabetes in their journey to quit tobacco,” Ruediger Krech, MD, director of the Department of Health Promotion at the World Health Organization in Geneva, Switzerland, said in a press statement on the policy brief.
“Simultaneously, governments must take the crucial step of ensuring all indoor public places, workplaces, and public transport are completely smoke-free. These interventions are essential safeguards against the onset and progression of this and many other chronic diseases,” he emphasized.
SOURCE:
The policy brief was jointly developed by the World Health Organization, the International Diabetes Federation, and the University of Newcastle.
The detailed policy brief can be downloaded on the IDF website.
LIMITATIONS:
Research remains limited on some issues, including the effectiveness of tobacco control interventions and smoking cessation methods for people with type 2 diabetes.
Likewise, specific guidelines for smoking cessation in the type 2 diabetes population are lacking. However, the general approaches of building patient motivation, behavioral interventions, and pharmacological treatments are advised.
“These interventions should be at least as intensive as those for the general population, while considering the unique characteristics of the disease and the individual,” the authors asserted.
DISCLOSURES:
The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Newly approved myasthenia gravis drug shows sustained benefits in early responders
PHOENIX – , a new analyses show.
“The information [in the studies] is valuable in making clinical decisions in managing myasthenia gravis, which is a chronic autoimmune condition that requires long-term use of immunosuppressives,” said Xinli Du, MD, PhD, an assistant professor in the department of neurology at Virginia Commonwealth University in Richmond, who was not involved in the research.
“Compared with conventional immunosuppressants, which take 3-9 months to know if the patient will respond, this is definitely a game-changer,” she said.
The research was presented at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM).
FDA approval
Approved by the U.S. Food and Drug Administration in October, the targeted peptide inhibitor of complement component 5 represents the only once-daily self-administered subcutaneous injection for adult patients with acetylcholine receptor autoantibody–positive (AChR+) generalized myasthenia gravis.
The multicenter, phase 3, placebo-controlled RAISE trial demonstrated that zilucoplan was associated with significant improvement in myasthenia gravis–specific outcomes in adult patients with mild to severe AChR+ generalized myasthenia gravis.
Of note, approximately 40% of patients in the zilucoplan phase 2 and 3 clinical trials have a significant response as early as the first week of treatment. For the current post hoc analysis, first author Miriam Freimer, MD, and colleagues took a closer look at the longer-term outcomes in these patients in the ongoing RAISE-XT open-label extension study.
In these two double-blind studies, patients were randomly assigned to receive either daily subcutaneous injections of 0.3 mg/kg zilucoplan or placebo.
Among 93 patients receiving zilucoplan in the two studies, 40 (43%) were identified as early responders based on having at least a 3-point reduction from baseline on the Myasthenia Gravis Activities of Daily Living scale (MG-ADL) within 1 week of treatment, and 31 (33%) qualified based on having at least 5-point reductions in Quantitative Myasthenia Gravis (QMG), at week 1.
Of these early responders, more than 80% meeting the MG-ADL and 85% meeting QMG criteria continued to show a treatment response at each assessment through week 60 in the open-label RAISE-XT trial.
Furthermore, week 1 responders maintained their response for 88.1% of their total treatment time in the MG-ADL group and 88.8% of their total treatment time on treatment in the QMG group, representing a median zilucoplan treatment duration of 450 days.
Of note, the week 1 early responders had no significant differences, compared with the study’s overall population. Participants had a mean age of 49.6 years versus 52.9 years in the overall population. Approximately 40% of patients in both studies were men, and 60%-64% were disease class III as assessed by the Myasthenia Gravis Foundation of America criteria.
“It is very exciting to see such a high response of rapid responders. This means that some patients may be able to avoid steroids or be able to taper them faster than with other accepted treatments for myasthenia gravis,” said Dr. Freimer, director of the division of neuromuscular disorders and the codirector of the Myasthenia Gravis Clinic at the Ohio State University in Columbus.
Impact on fatigue
In a separate post hoc analysis of patients who entered RAISE-XT, the researchers evaluated long-term effects of zilucoplan on fatigue.
Improvements in fatigue were already apparent at the end of the RAISE trial, with the least squares mean (LSM) change from baseline in fatigue assessed after 12 weeks with the Neuro-QOL T-score being –6.26 for zilucoplan (n = 86) compared with an increase of 2.65 for placebo (n = 88; LSM difference, –3.61; nominal P = .0060).
Patients who received placebo in the RAISE trial were able to switch to zilucoplan in the RAISE-XT open-label trail, and among those who did, fatigue, as measured in the T-scores, improved significantly within 1 week of switching.
Fatigue further improved out to week 16 in terms of T-scores for the placebo-switch as well as zilucoplan groups, and the improvements in the scores were sustained through week 60 (mean change from RAISE baseline, –10.71 [n = 42] and –9.15 [n = 42], respectively).
“Fatigue is a challenge for patients with [generalized myasthenia gravis]. Zilucoplan significantly and clinically meaningfully improved myasthenic fatigue versus placebo during RAISE,” the investigators report.
“Further improvements were observed during RAISE-XT and were sustained up to 60 weeks of treatment,” they added.
Favorable safety profile
Zilucoplan continued to show a favorable safety profile in the RAISE-XT trial and was well tolerated in the long term.
The most common adverse reactions (10% or more) in patients with generalized myasthenia gravis were injection-site reactions, upper respiratory tract infection, and diarrhea.
Though additional therapies have also recently entered the market for generalized myasthenia gravis, they are either intravenous or subcutaneous infusions requiring a health care professional to administer them.
“This self-administered medication allows patients to be more independent and can even travel since it is not dependent on an infusion center,” Dr. Freimer noted.
However, similar to the other complement inhibitors, zilucoplan carries a risk for infection, particularly meningitis, Dr. Du noted. “Complement meningitis vaccination protocol and close monitoring for signs of infection are required,” she said.
However, she added, “the rapid action benefits shown as early as week 1 are impressive, and potentially open the door to use as adjunctive therapy in myasthenia gravis crisis.”
“I think zilucoplan definitely adds more excitement to the already active field of myasthenia gravis management,” she said.
The study was funded by UCB Pharma. Dr. Freimer has reports she has served as a paid consultant for argenx, UCB Pharma, and Alexion Pharmaceuticals and reports research support from the National Institutes of Health, UCB Pharma, Jansen Pharmaceuticals, Alnylam, Avidity, and Fulcrum. Dr. Du reports no disclosures.
A version of this article appeared on Medscape.com.
PHOENIX – , a new analyses show.
“The information [in the studies] is valuable in making clinical decisions in managing myasthenia gravis, which is a chronic autoimmune condition that requires long-term use of immunosuppressives,” said Xinli Du, MD, PhD, an assistant professor in the department of neurology at Virginia Commonwealth University in Richmond, who was not involved in the research.
“Compared with conventional immunosuppressants, which take 3-9 months to know if the patient will respond, this is definitely a game-changer,” she said.
The research was presented at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM).
FDA approval
Approved by the U.S. Food and Drug Administration in October, the targeted peptide inhibitor of complement component 5 represents the only once-daily self-administered subcutaneous injection for adult patients with acetylcholine receptor autoantibody–positive (AChR+) generalized myasthenia gravis.
The multicenter, phase 3, placebo-controlled RAISE trial demonstrated that zilucoplan was associated with significant improvement in myasthenia gravis–specific outcomes in adult patients with mild to severe AChR+ generalized myasthenia gravis.
Of note, approximately 40% of patients in the zilucoplan phase 2 and 3 clinical trials have a significant response as early as the first week of treatment. For the current post hoc analysis, first author Miriam Freimer, MD, and colleagues took a closer look at the longer-term outcomes in these patients in the ongoing RAISE-XT open-label extension study.
In these two double-blind studies, patients were randomly assigned to receive either daily subcutaneous injections of 0.3 mg/kg zilucoplan or placebo.
Among 93 patients receiving zilucoplan in the two studies, 40 (43%) were identified as early responders based on having at least a 3-point reduction from baseline on the Myasthenia Gravis Activities of Daily Living scale (MG-ADL) within 1 week of treatment, and 31 (33%) qualified based on having at least 5-point reductions in Quantitative Myasthenia Gravis (QMG), at week 1.
Of these early responders, more than 80% meeting the MG-ADL and 85% meeting QMG criteria continued to show a treatment response at each assessment through week 60 in the open-label RAISE-XT trial.
Furthermore, week 1 responders maintained their response for 88.1% of their total treatment time in the MG-ADL group and 88.8% of their total treatment time on treatment in the QMG group, representing a median zilucoplan treatment duration of 450 days.
Of note, the week 1 early responders had no significant differences, compared with the study’s overall population. Participants had a mean age of 49.6 years versus 52.9 years in the overall population. Approximately 40% of patients in both studies were men, and 60%-64% were disease class III as assessed by the Myasthenia Gravis Foundation of America criteria.
“It is very exciting to see such a high response of rapid responders. This means that some patients may be able to avoid steroids or be able to taper them faster than with other accepted treatments for myasthenia gravis,” said Dr. Freimer, director of the division of neuromuscular disorders and the codirector of the Myasthenia Gravis Clinic at the Ohio State University in Columbus.
Impact on fatigue
In a separate post hoc analysis of patients who entered RAISE-XT, the researchers evaluated long-term effects of zilucoplan on fatigue.
Improvements in fatigue were already apparent at the end of the RAISE trial, with the least squares mean (LSM) change from baseline in fatigue assessed after 12 weeks with the Neuro-QOL T-score being –6.26 for zilucoplan (n = 86) compared with an increase of 2.65 for placebo (n = 88; LSM difference, –3.61; nominal P = .0060).
Patients who received placebo in the RAISE trial were able to switch to zilucoplan in the RAISE-XT open-label trail, and among those who did, fatigue, as measured in the T-scores, improved significantly within 1 week of switching.
Fatigue further improved out to week 16 in terms of T-scores for the placebo-switch as well as zilucoplan groups, and the improvements in the scores were sustained through week 60 (mean change from RAISE baseline, –10.71 [n = 42] and –9.15 [n = 42], respectively).
“Fatigue is a challenge for patients with [generalized myasthenia gravis]. Zilucoplan significantly and clinically meaningfully improved myasthenic fatigue versus placebo during RAISE,” the investigators report.
“Further improvements were observed during RAISE-XT and were sustained up to 60 weeks of treatment,” they added.
Favorable safety profile
Zilucoplan continued to show a favorable safety profile in the RAISE-XT trial and was well tolerated in the long term.
The most common adverse reactions (10% or more) in patients with generalized myasthenia gravis were injection-site reactions, upper respiratory tract infection, and diarrhea.
Though additional therapies have also recently entered the market for generalized myasthenia gravis, they are either intravenous or subcutaneous infusions requiring a health care professional to administer them.
“This self-administered medication allows patients to be more independent and can even travel since it is not dependent on an infusion center,” Dr. Freimer noted.
However, similar to the other complement inhibitors, zilucoplan carries a risk for infection, particularly meningitis, Dr. Du noted. “Complement meningitis vaccination protocol and close monitoring for signs of infection are required,” she said.
However, she added, “the rapid action benefits shown as early as week 1 are impressive, and potentially open the door to use as adjunctive therapy in myasthenia gravis crisis.”
“I think zilucoplan definitely adds more excitement to the already active field of myasthenia gravis management,” she said.
The study was funded by UCB Pharma. Dr. Freimer has reports she has served as a paid consultant for argenx, UCB Pharma, and Alexion Pharmaceuticals and reports research support from the National Institutes of Health, UCB Pharma, Jansen Pharmaceuticals, Alnylam, Avidity, and Fulcrum. Dr. Du reports no disclosures.
A version of this article appeared on Medscape.com.
PHOENIX – , a new analyses show.
“The information [in the studies] is valuable in making clinical decisions in managing myasthenia gravis, which is a chronic autoimmune condition that requires long-term use of immunosuppressives,” said Xinli Du, MD, PhD, an assistant professor in the department of neurology at Virginia Commonwealth University in Richmond, who was not involved in the research.
“Compared with conventional immunosuppressants, which take 3-9 months to know if the patient will respond, this is definitely a game-changer,” she said.
The research was presented at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM).
FDA approval
Approved by the U.S. Food and Drug Administration in October, the targeted peptide inhibitor of complement component 5 represents the only once-daily self-administered subcutaneous injection for adult patients with acetylcholine receptor autoantibody–positive (AChR+) generalized myasthenia gravis.
The multicenter, phase 3, placebo-controlled RAISE trial demonstrated that zilucoplan was associated with significant improvement in myasthenia gravis–specific outcomes in adult patients with mild to severe AChR+ generalized myasthenia gravis.
Of note, approximately 40% of patients in the zilucoplan phase 2 and 3 clinical trials have a significant response as early as the first week of treatment. For the current post hoc analysis, first author Miriam Freimer, MD, and colleagues took a closer look at the longer-term outcomes in these patients in the ongoing RAISE-XT open-label extension study.
In these two double-blind studies, patients were randomly assigned to receive either daily subcutaneous injections of 0.3 mg/kg zilucoplan or placebo.
Among 93 patients receiving zilucoplan in the two studies, 40 (43%) were identified as early responders based on having at least a 3-point reduction from baseline on the Myasthenia Gravis Activities of Daily Living scale (MG-ADL) within 1 week of treatment, and 31 (33%) qualified based on having at least 5-point reductions in Quantitative Myasthenia Gravis (QMG), at week 1.
Of these early responders, more than 80% meeting the MG-ADL and 85% meeting QMG criteria continued to show a treatment response at each assessment through week 60 in the open-label RAISE-XT trial.
Furthermore, week 1 responders maintained their response for 88.1% of their total treatment time in the MG-ADL group and 88.8% of their total treatment time on treatment in the QMG group, representing a median zilucoplan treatment duration of 450 days.
Of note, the week 1 early responders had no significant differences, compared with the study’s overall population. Participants had a mean age of 49.6 years versus 52.9 years in the overall population. Approximately 40% of patients in both studies were men, and 60%-64% were disease class III as assessed by the Myasthenia Gravis Foundation of America criteria.
“It is very exciting to see such a high response of rapid responders. This means that some patients may be able to avoid steroids or be able to taper them faster than with other accepted treatments for myasthenia gravis,” said Dr. Freimer, director of the division of neuromuscular disorders and the codirector of the Myasthenia Gravis Clinic at the Ohio State University in Columbus.
Impact on fatigue
In a separate post hoc analysis of patients who entered RAISE-XT, the researchers evaluated long-term effects of zilucoplan on fatigue.
Improvements in fatigue were already apparent at the end of the RAISE trial, with the least squares mean (LSM) change from baseline in fatigue assessed after 12 weeks with the Neuro-QOL T-score being –6.26 for zilucoplan (n = 86) compared with an increase of 2.65 for placebo (n = 88; LSM difference, –3.61; nominal P = .0060).
Patients who received placebo in the RAISE trial were able to switch to zilucoplan in the RAISE-XT open-label trail, and among those who did, fatigue, as measured in the T-scores, improved significantly within 1 week of switching.
Fatigue further improved out to week 16 in terms of T-scores for the placebo-switch as well as zilucoplan groups, and the improvements in the scores were sustained through week 60 (mean change from RAISE baseline, –10.71 [n = 42] and –9.15 [n = 42], respectively).
“Fatigue is a challenge for patients with [generalized myasthenia gravis]. Zilucoplan significantly and clinically meaningfully improved myasthenic fatigue versus placebo during RAISE,” the investigators report.
“Further improvements were observed during RAISE-XT and were sustained up to 60 weeks of treatment,” they added.
Favorable safety profile
Zilucoplan continued to show a favorable safety profile in the RAISE-XT trial and was well tolerated in the long term.
The most common adverse reactions (10% or more) in patients with generalized myasthenia gravis were injection-site reactions, upper respiratory tract infection, and diarrhea.
Though additional therapies have also recently entered the market for generalized myasthenia gravis, they are either intravenous or subcutaneous infusions requiring a health care professional to administer them.
“This self-administered medication allows patients to be more independent and can even travel since it is not dependent on an infusion center,” Dr. Freimer noted.
However, similar to the other complement inhibitors, zilucoplan carries a risk for infection, particularly meningitis, Dr. Du noted. “Complement meningitis vaccination protocol and close monitoring for signs of infection are required,” she said.
However, she added, “the rapid action benefits shown as early as week 1 are impressive, and potentially open the door to use as adjunctive therapy in myasthenia gravis crisis.”
“I think zilucoplan definitely adds more excitement to the already active field of myasthenia gravis management,” she said.
The study was funded by UCB Pharma. Dr. Freimer has reports she has served as a paid consultant for argenx, UCB Pharma, and Alexion Pharmaceuticals and reports research support from the National Institutes of Health, UCB Pharma, Jansen Pharmaceuticals, Alnylam, Avidity, and Fulcrum. Dr. Du reports no disclosures.
A version of this article appeared on Medscape.com.
At AANEM 2023
Chemotherapy-induced peripheral neuropathy tied to compromised executive function
PHOENIX – , a new finding that may increase the risk for compromised mobility and fall risk.
“Among older cancer survivors treated with chemotherapy, the presence of CIPN was independently associated with reduced executive function,” said study investigator Brendan L. McNeish, MD, of the department of physical medicine and rehabilitation, University of Pittsburgh.
“Importantly, given the emerging relationship of executive function with mobility in this population, stakeholders and clinicians are called to acknowledge that chemotherapy-related mobility declines in CIPN survivors are likely due to both neuromuscular and executive dysfunction,” he said.
The findings were presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
Research gap
Characterized by numbness, tingling, pain, and motor impairment, CIPN affects up to 50% of all patients with cancer that is treated with taxane-, platinum-, or vinca alkaloid–based chemotherapy. The condition is among the leading dose-limiting toxicities, potentially increasing mortality risk.
Though the effects of chemotherapy on cognitive function are well-established, less is known about a potential relationship between this side effect and CIPN, Dr. McNeish said.
“Chemotherapy can be neurotoxic, but few studies have linked neurotoxicity to the central nervous system and peripheral nervous system,” Dr. McNeish said.
To compare cognitive outcomes in patients treated with chemotherapy who did and did not develop CIPN, the investigators conducted a cross-sectional study that included 50 chemotherapy-treated cancer survivors at a single time point post chemotherapy. The mean age of participants was 65.6 years, and 90% were women.
Twenty-two (44%) patients had CIPN on the basis of patient-reported distal paresthesias or numbness that started when chemotherapy was initiated and was present at the time of study enrollment.
Patients with CIPN had a greater decline in executive function, compared with those without the condition, as measured by the Trail Making Test Part B (TMT-B; CIPN-positive, 84.9 sec vs. 59.1 sec, respectively; P = .01) and the Stroop Color and Word Test (SCWT; CIPN-positive, 178.1 sec vs. CIPN-negative, 152.7 sec; P = .04), as well as lower rapid reaction accuracy (CIPN-positive, 60.3% vs. CIPN-negative, 70.6%; P = .01).
The association between CIPN and decreased executive function remained after multivariate adjusting for age, gender, depression, and benzodiazepine use for TMT-B (beta, 18.7; P = .046) and rapid reaction accuracy (beta, -.088; P = .018) but not SCWT (beta, 9.52; P = .233).
Clinical guidance
A recent study by the same investigators showed a link between executive function and balance in cancer survivors (mean age, 65.6 years; 88% women) treated with chemotherapy.
Another study of 116 patients treated with chemotherapy, including 32 who developed CIPN, showed that those with CIPN were nearly three times more likely to report a fall or near fall than were those without CIPN symptoms. In addition, those with CIPN symptoms were also more likely to have received medical care for falls.
Based on the current findings, the research suggests that “current clinical approaches to caring for this growing population [of cancer patients] should not assume that the well-known increased fall risk is solely related to CIPN.”
Dr. McNeish speculated that two potential hypotheses could explain the association between CIPN and reduced executive function in older cancer survivors.
“First, CIPN is associated with other conditions such as depression and anxiety, which are associated with reduced executive function,” he said.
“The second is that cancer-related cognitive dysfunction and CIPN share pathogenic mechanisms of neuronal injury, inflammation, and advanced aging, and thus some patients are vulnerable to both central (cancer-related cognitive function) and peripheral neurotoxicity.”
Either way, Dr. McNeish noted that “all interventions should measure both CIPN and executive function, as one could confound the other.”
Need for increased awareness
Commenting on the study, Ting Bao, MD, co-director of the Leonard P. Zakim Center for Integrative Therapies & Healthy Living at the Dana-Farber Cancer Institute, Boston, said that the findings underscore that “there is a need for increased awareness of the diverse manifestations of chemotherapy-induced neuropathy.”
These include the fact that “neurotoxic chemotherapy impacts both the peripheral and central nervous systems, affecting balance through distinct mechanisms.”
Although treatments routinely recommended for CIPN include duloxetine, tricyclic antidepressants, or gabapentin as well as topical agents such as lidocaine, evidence also shows benefits of nonpharmacologic approaches including exercise, acupuncture, and yoga. Dr. Bao’s own research has suggested that those benefits can extend improved balance and reduced fall risk.
Dr. Bao and colleagues recently conducted a randomized study that included 41 patients with CIPN to receive either yoga or usual care.
“The findings revealed that after eight biweekly sessions of yoga, there was a notable improvement in the far-reach test, which is a predictor of fall risk,” she said.
To validate these findings, the researchers are currently conducting a larger randomized controlled trial, she said.
In the meantime, “further research into the mechanisms and effective treatments for chemotherapy-induced neurotoxicity is essential,” added Dr. Bao.
Dr. McNeish and Dr. Bao report no relevant disclosures.
A version of this article first appeared on Medscape.com.
PHOENIX – , a new finding that may increase the risk for compromised mobility and fall risk.
“Among older cancer survivors treated with chemotherapy, the presence of CIPN was independently associated with reduced executive function,” said study investigator Brendan L. McNeish, MD, of the department of physical medicine and rehabilitation, University of Pittsburgh.
“Importantly, given the emerging relationship of executive function with mobility in this population, stakeholders and clinicians are called to acknowledge that chemotherapy-related mobility declines in CIPN survivors are likely due to both neuromuscular and executive dysfunction,” he said.
The findings were presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
Research gap
Characterized by numbness, tingling, pain, and motor impairment, CIPN affects up to 50% of all patients with cancer that is treated with taxane-, platinum-, or vinca alkaloid–based chemotherapy. The condition is among the leading dose-limiting toxicities, potentially increasing mortality risk.
Though the effects of chemotherapy on cognitive function are well-established, less is known about a potential relationship between this side effect and CIPN, Dr. McNeish said.
“Chemotherapy can be neurotoxic, but few studies have linked neurotoxicity to the central nervous system and peripheral nervous system,” Dr. McNeish said.
To compare cognitive outcomes in patients treated with chemotherapy who did and did not develop CIPN, the investigators conducted a cross-sectional study that included 50 chemotherapy-treated cancer survivors at a single time point post chemotherapy. The mean age of participants was 65.6 years, and 90% were women.
Twenty-two (44%) patients had CIPN on the basis of patient-reported distal paresthesias or numbness that started when chemotherapy was initiated and was present at the time of study enrollment.
Patients with CIPN had a greater decline in executive function, compared with those without the condition, as measured by the Trail Making Test Part B (TMT-B; CIPN-positive, 84.9 sec vs. 59.1 sec, respectively; P = .01) and the Stroop Color and Word Test (SCWT; CIPN-positive, 178.1 sec vs. CIPN-negative, 152.7 sec; P = .04), as well as lower rapid reaction accuracy (CIPN-positive, 60.3% vs. CIPN-negative, 70.6%; P = .01).
The association between CIPN and decreased executive function remained after multivariate adjusting for age, gender, depression, and benzodiazepine use for TMT-B (beta, 18.7; P = .046) and rapid reaction accuracy (beta, -.088; P = .018) but not SCWT (beta, 9.52; P = .233).
Clinical guidance
A recent study by the same investigators showed a link between executive function and balance in cancer survivors (mean age, 65.6 years; 88% women) treated with chemotherapy.
Another study of 116 patients treated with chemotherapy, including 32 who developed CIPN, showed that those with CIPN were nearly three times more likely to report a fall or near fall than were those without CIPN symptoms. In addition, those with CIPN symptoms were also more likely to have received medical care for falls.
Based on the current findings, the research suggests that “current clinical approaches to caring for this growing population [of cancer patients] should not assume that the well-known increased fall risk is solely related to CIPN.”
Dr. McNeish speculated that two potential hypotheses could explain the association between CIPN and reduced executive function in older cancer survivors.
“First, CIPN is associated with other conditions such as depression and anxiety, which are associated with reduced executive function,” he said.
“The second is that cancer-related cognitive dysfunction and CIPN share pathogenic mechanisms of neuronal injury, inflammation, and advanced aging, and thus some patients are vulnerable to both central (cancer-related cognitive function) and peripheral neurotoxicity.”
Either way, Dr. McNeish noted that “all interventions should measure both CIPN and executive function, as one could confound the other.”
Need for increased awareness
Commenting on the study, Ting Bao, MD, co-director of the Leonard P. Zakim Center for Integrative Therapies & Healthy Living at the Dana-Farber Cancer Institute, Boston, said that the findings underscore that “there is a need for increased awareness of the diverse manifestations of chemotherapy-induced neuropathy.”
These include the fact that “neurotoxic chemotherapy impacts both the peripheral and central nervous systems, affecting balance through distinct mechanisms.”
Although treatments routinely recommended for CIPN include duloxetine, tricyclic antidepressants, or gabapentin as well as topical agents such as lidocaine, evidence also shows benefits of nonpharmacologic approaches including exercise, acupuncture, and yoga. Dr. Bao’s own research has suggested that those benefits can extend improved balance and reduced fall risk.
Dr. Bao and colleagues recently conducted a randomized study that included 41 patients with CIPN to receive either yoga or usual care.
“The findings revealed that after eight biweekly sessions of yoga, there was a notable improvement in the far-reach test, which is a predictor of fall risk,” she said.
To validate these findings, the researchers are currently conducting a larger randomized controlled trial, she said.
In the meantime, “further research into the mechanisms and effective treatments for chemotherapy-induced neurotoxicity is essential,” added Dr. Bao.
Dr. McNeish and Dr. Bao report no relevant disclosures.
A version of this article first appeared on Medscape.com.
PHOENIX – , a new finding that may increase the risk for compromised mobility and fall risk.
“Among older cancer survivors treated with chemotherapy, the presence of CIPN was independently associated with reduced executive function,” said study investigator Brendan L. McNeish, MD, of the department of physical medicine and rehabilitation, University of Pittsburgh.
“Importantly, given the emerging relationship of executive function with mobility in this population, stakeholders and clinicians are called to acknowledge that chemotherapy-related mobility declines in CIPN survivors are likely due to both neuromuscular and executive dysfunction,” he said.
The findings were presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
Research gap
Characterized by numbness, tingling, pain, and motor impairment, CIPN affects up to 50% of all patients with cancer that is treated with taxane-, platinum-, or vinca alkaloid–based chemotherapy. The condition is among the leading dose-limiting toxicities, potentially increasing mortality risk.
Though the effects of chemotherapy on cognitive function are well-established, less is known about a potential relationship between this side effect and CIPN, Dr. McNeish said.
“Chemotherapy can be neurotoxic, but few studies have linked neurotoxicity to the central nervous system and peripheral nervous system,” Dr. McNeish said.
To compare cognitive outcomes in patients treated with chemotherapy who did and did not develop CIPN, the investigators conducted a cross-sectional study that included 50 chemotherapy-treated cancer survivors at a single time point post chemotherapy. The mean age of participants was 65.6 years, and 90% were women.
Twenty-two (44%) patients had CIPN on the basis of patient-reported distal paresthesias or numbness that started when chemotherapy was initiated and was present at the time of study enrollment.
Patients with CIPN had a greater decline in executive function, compared with those without the condition, as measured by the Trail Making Test Part B (TMT-B; CIPN-positive, 84.9 sec vs. 59.1 sec, respectively; P = .01) and the Stroop Color and Word Test (SCWT; CIPN-positive, 178.1 sec vs. CIPN-negative, 152.7 sec; P = .04), as well as lower rapid reaction accuracy (CIPN-positive, 60.3% vs. CIPN-negative, 70.6%; P = .01).
The association between CIPN and decreased executive function remained after multivariate adjusting for age, gender, depression, and benzodiazepine use for TMT-B (beta, 18.7; P = .046) and rapid reaction accuracy (beta, -.088; P = .018) but not SCWT (beta, 9.52; P = .233).
Clinical guidance
A recent study by the same investigators showed a link between executive function and balance in cancer survivors (mean age, 65.6 years; 88% women) treated with chemotherapy.
Another study of 116 patients treated with chemotherapy, including 32 who developed CIPN, showed that those with CIPN were nearly three times more likely to report a fall or near fall than were those without CIPN symptoms. In addition, those with CIPN symptoms were also more likely to have received medical care for falls.
Based on the current findings, the research suggests that “current clinical approaches to caring for this growing population [of cancer patients] should not assume that the well-known increased fall risk is solely related to CIPN.”
Dr. McNeish speculated that two potential hypotheses could explain the association between CIPN and reduced executive function in older cancer survivors.
“First, CIPN is associated with other conditions such as depression and anxiety, which are associated with reduced executive function,” he said.
“The second is that cancer-related cognitive dysfunction and CIPN share pathogenic mechanisms of neuronal injury, inflammation, and advanced aging, and thus some patients are vulnerable to both central (cancer-related cognitive function) and peripheral neurotoxicity.”
Either way, Dr. McNeish noted that “all interventions should measure both CIPN and executive function, as one could confound the other.”
Need for increased awareness
Commenting on the study, Ting Bao, MD, co-director of the Leonard P. Zakim Center for Integrative Therapies & Healthy Living at the Dana-Farber Cancer Institute, Boston, said that the findings underscore that “there is a need for increased awareness of the diverse manifestations of chemotherapy-induced neuropathy.”
These include the fact that “neurotoxic chemotherapy impacts both the peripheral and central nervous systems, affecting balance through distinct mechanisms.”
Although treatments routinely recommended for CIPN include duloxetine, tricyclic antidepressants, or gabapentin as well as topical agents such as lidocaine, evidence also shows benefits of nonpharmacologic approaches including exercise, acupuncture, and yoga. Dr. Bao’s own research has suggested that those benefits can extend improved balance and reduced fall risk.
Dr. Bao and colleagues recently conducted a randomized study that included 41 patients with CIPN to receive either yoga or usual care.
“The findings revealed that after eight biweekly sessions of yoga, there was a notable improvement in the far-reach test, which is a predictor of fall risk,” she said.
To validate these findings, the researchers are currently conducting a larger randomized controlled trial, she said.
In the meantime, “further research into the mechanisms and effective treatments for chemotherapy-induced neurotoxicity is essential,” added Dr. Bao.
Dr. McNeish and Dr. Bao report no relevant disclosures.
A version of this article first appeared on Medscape.com.
AT AANEM 2023
First new treatment in 30 years for rare disease is effective, tolerable, convenient
PHOENIX –
“This was the largest study of CIDP that has been performed, with over 600 patients screened and 322 enrolled, and was the first to use an adjudication committee to confirm the diagnosis,” said study investigator Richard Lewis, MD, of the department of neurology, Cedars-Sinai Medical Center, Los Angeles.
Furthermore, “this is the first new treatment for CIDP in over 30 years, so it’s very exciting. It is a brief subcutaneous injection, which should be something that patients will appreciate,” he said.
The study was presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
Filling an unmet need
A rare and often-debilitating autoimmune disorder, CIDP is characterized by weakness and numbness that can result in disability, pain, and fatigue and has been linked to IgG autoantibodies.
Treatments include corticosteroids, intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin, and plasma exchange, but not all patients achieve meaningful benefits and many patients complain about safety risks, costs, and burdensome treatment regimens.
“There is an unmet need for a first-line treatment with long-term efficacy that maintains or improves quality of life, has an early onset of action, is well tolerated, is not dependent on plasma donation, and has greater convenience,” the investigators wrote in their abstract.
Efgartigimod, which is approved in its intravenous and subcutaneous forms for the treatment of myasthenia gravis, is a human IgG1 antibody Fc receptor blocker designed to reduce pathogenic IgG autoantibody levels, which may be drivers of pathogenesis in CIDP.
The therapy is a coformulation of efgartigimod and recombinant human hyaluronidase that allows for rapid subcutaneous administration of larger volumes and is administered as a 90-second subcutaneous injection once weekly.
For the ongoing phase 2 ADHERE trial, 322 patients with a diagnosis of CIDP and active disease who were either treatment naive or receiving standard treatments were withdrawn from their treatments prior to day 1 of a run-in period of up to 12 weeks.
They then entered stage A of the study, an open-label phase in which all were treated with 1,000-mg efgartigimod PH20 SC weekly for up to 12 weeks.
Of those patients, 66% showed evidence of clinical improvement and a rapid onset of effect with the efgartigimod PH20 SC treatment, and 70% of the patients were then entered into stage B, a double-blind randomized phase, with 111 of patients receiving continued efgartigimod PH20 SC weekly and 110 receiving placebo for 48 weeks.
Of those moving on to stage B, more than 70% were on IVIg prior to the time of enrollment.
The study met its primary endpoint, with the efgartigimod PH20 SC groups showing a 61% lower risk for relapse on the basis of time to a first adjusted Inflammatory Neuropathy Cause and Treatment deterioration, compared with placebo (hazard ratio, 0.39; P = .000039).
Clinical benefits were also observed on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) and in measures of mean grip strength in all groups regardless of prior CIDP medication.
Specifically, efgartigimod patients had a mean improvement of 7.7 points on I-RODS and 12.3 kPa on mean grip strength in stage A, which was maintained in stage B. These were partially lost in patients receiving placebo.
In terms of safety, most adverse events were mild or moderate in severity, and no new safety signals were identified with up to 60 weeks of treatment. There were no increased infection rates with increased exposure.
The findings show that “efgartigimod-PH20, given as a 90-second subcutaneous injection once a week, was effective in treating patients with CIDP who had relapsed when taken off their previous treatment (IVIg or corticosteroids),” said Dr. Lewis.
“[The study] then showed that the majority of patients, over 70%, maintained that improvement, compared with placebo, where over 50% relapsed – most within 8 weeks, so the treatment, which reduces circulating immunoglobulin G by over 70%, is effective in treating CIDP,” he added.
Plans for this ongoing trial include recruiting up to 360 patients until 88 events of clinical deterioration have been observed in stage B.
Promising data
Commenting on the study, Karissa Gable, MD, an associate professor of neurology at Duke University, Durham, N.C., said that the “initial data reported from the ADHERE study is very promising and demonstrated significant efficacy.”
The study’s use of an adjudication committee in confirming the diagnosis is particularly notable, she said. “The trial design demonstrated confirmation of diagnosis and activity of disease and response to drug prior to randomization, which is a novel design that is particularly applicable to patients with CIDP given the rate of misdiagnosis and placebo effect found in other trials.”
Dr. Gable agreed that new options are important to address an unmet need in CIDP.
“The current first-line treatments are generally 80%-90% effective, however, there are limited options with respect to the first line treatments due to side effects and comorbid disease in patients,” she explained.
“Other treatments options are needed and so this is an unmet need in patients with CIDP,” Dr. Gable said. “This medication will be likely to be one that will provide a strong alternate option for treatment.”
Overall, “this is a novel mechanism for drug treatment for CIDP and seems to demonstrate efficacy and good safety and tolerability based on the initial report of the data,” Dr. Gable added.
“It will likely be a promising medication to use for these patients to fill the unmet need for treatment of patients with CIDP.”
The study was sponsored by Argenx. Dr. Lewis disclosed relationships with Argenx and other companies involved in neuromuscular disease therapies. Dr. Gable is on the global medical advisory board steering committee for Argenx and she was the principal investigator at her site for the Adhere study. Dr. Gable has served as a consultant for Immunovant and Takeda as well as Sanofi for CIDP and she is on the Takeda speaker bureau for Huyquvia for treatment of CIDP.
A version of this article first appeared on Medscape.com.
PHOENIX –
“This was the largest study of CIDP that has been performed, with over 600 patients screened and 322 enrolled, and was the first to use an adjudication committee to confirm the diagnosis,” said study investigator Richard Lewis, MD, of the department of neurology, Cedars-Sinai Medical Center, Los Angeles.
Furthermore, “this is the first new treatment for CIDP in over 30 years, so it’s very exciting. It is a brief subcutaneous injection, which should be something that patients will appreciate,” he said.
The study was presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
Filling an unmet need
A rare and often-debilitating autoimmune disorder, CIDP is characterized by weakness and numbness that can result in disability, pain, and fatigue and has been linked to IgG autoantibodies.
Treatments include corticosteroids, intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin, and plasma exchange, but not all patients achieve meaningful benefits and many patients complain about safety risks, costs, and burdensome treatment regimens.
“There is an unmet need for a first-line treatment with long-term efficacy that maintains or improves quality of life, has an early onset of action, is well tolerated, is not dependent on plasma donation, and has greater convenience,” the investigators wrote in their abstract.
Efgartigimod, which is approved in its intravenous and subcutaneous forms for the treatment of myasthenia gravis, is a human IgG1 antibody Fc receptor blocker designed to reduce pathogenic IgG autoantibody levels, which may be drivers of pathogenesis in CIDP.
The therapy is a coformulation of efgartigimod and recombinant human hyaluronidase that allows for rapid subcutaneous administration of larger volumes and is administered as a 90-second subcutaneous injection once weekly.
For the ongoing phase 2 ADHERE trial, 322 patients with a diagnosis of CIDP and active disease who were either treatment naive or receiving standard treatments were withdrawn from their treatments prior to day 1 of a run-in period of up to 12 weeks.
They then entered stage A of the study, an open-label phase in which all were treated with 1,000-mg efgartigimod PH20 SC weekly for up to 12 weeks.
Of those patients, 66% showed evidence of clinical improvement and a rapid onset of effect with the efgartigimod PH20 SC treatment, and 70% of the patients were then entered into stage B, a double-blind randomized phase, with 111 of patients receiving continued efgartigimod PH20 SC weekly and 110 receiving placebo for 48 weeks.
Of those moving on to stage B, more than 70% were on IVIg prior to the time of enrollment.
The study met its primary endpoint, with the efgartigimod PH20 SC groups showing a 61% lower risk for relapse on the basis of time to a first adjusted Inflammatory Neuropathy Cause and Treatment deterioration, compared with placebo (hazard ratio, 0.39; P = .000039).
Clinical benefits were also observed on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) and in measures of mean grip strength in all groups regardless of prior CIDP medication.
Specifically, efgartigimod patients had a mean improvement of 7.7 points on I-RODS and 12.3 kPa on mean grip strength in stage A, which was maintained in stage B. These were partially lost in patients receiving placebo.
In terms of safety, most adverse events were mild or moderate in severity, and no new safety signals were identified with up to 60 weeks of treatment. There were no increased infection rates with increased exposure.
The findings show that “efgartigimod-PH20, given as a 90-second subcutaneous injection once a week, was effective in treating patients with CIDP who had relapsed when taken off their previous treatment (IVIg or corticosteroids),” said Dr. Lewis.
“[The study] then showed that the majority of patients, over 70%, maintained that improvement, compared with placebo, where over 50% relapsed – most within 8 weeks, so the treatment, which reduces circulating immunoglobulin G by over 70%, is effective in treating CIDP,” he added.
Plans for this ongoing trial include recruiting up to 360 patients until 88 events of clinical deterioration have been observed in stage B.
Promising data
Commenting on the study, Karissa Gable, MD, an associate professor of neurology at Duke University, Durham, N.C., said that the “initial data reported from the ADHERE study is very promising and demonstrated significant efficacy.”
The study’s use of an adjudication committee in confirming the diagnosis is particularly notable, she said. “The trial design demonstrated confirmation of diagnosis and activity of disease and response to drug prior to randomization, which is a novel design that is particularly applicable to patients with CIDP given the rate of misdiagnosis and placebo effect found in other trials.”
Dr. Gable agreed that new options are important to address an unmet need in CIDP.
“The current first-line treatments are generally 80%-90% effective, however, there are limited options with respect to the first line treatments due to side effects and comorbid disease in patients,” she explained.
“Other treatments options are needed and so this is an unmet need in patients with CIDP,” Dr. Gable said. “This medication will be likely to be one that will provide a strong alternate option for treatment.”
Overall, “this is a novel mechanism for drug treatment for CIDP and seems to demonstrate efficacy and good safety and tolerability based on the initial report of the data,” Dr. Gable added.
“It will likely be a promising medication to use for these patients to fill the unmet need for treatment of patients with CIDP.”
The study was sponsored by Argenx. Dr. Lewis disclosed relationships with Argenx and other companies involved in neuromuscular disease therapies. Dr. Gable is on the global medical advisory board steering committee for Argenx and she was the principal investigator at her site for the Adhere study. Dr. Gable has served as a consultant for Immunovant and Takeda as well as Sanofi for CIDP and she is on the Takeda speaker bureau for Huyquvia for treatment of CIDP.
A version of this article first appeared on Medscape.com.
PHOENIX –
“This was the largest study of CIDP that has been performed, with over 600 patients screened and 322 enrolled, and was the first to use an adjudication committee to confirm the diagnosis,” said study investigator Richard Lewis, MD, of the department of neurology, Cedars-Sinai Medical Center, Los Angeles.
Furthermore, “this is the first new treatment for CIDP in over 30 years, so it’s very exciting. It is a brief subcutaneous injection, which should be something that patients will appreciate,” he said.
The study was presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
Filling an unmet need
A rare and often-debilitating autoimmune disorder, CIDP is characterized by weakness and numbness that can result in disability, pain, and fatigue and has been linked to IgG autoantibodies.
Treatments include corticosteroids, intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin, and plasma exchange, but not all patients achieve meaningful benefits and many patients complain about safety risks, costs, and burdensome treatment regimens.
“There is an unmet need for a first-line treatment with long-term efficacy that maintains or improves quality of life, has an early onset of action, is well tolerated, is not dependent on plasma donation, and has greater convenience,” the investigators wrote in their abstract.
Efgartigimod, which is approved in its intravenous and subcutaneous forms for the treatment of myasthenia gravis, is a human IgG1 antibody Fc receptor blocker designed to reduce pathogenic IgG autoantibody levels, which may be drivers of pathogenesis in CIDP.
The therapy is a coformulation of efgartigimod and recombinant human hyaluronidase that allows for rapid subcutaneous administration of larger volumes and is administered as a 90-second subcutaneous injection once weekly.
For the ongoing phase 2 ADHERE trial, 322 patients with a diagnosis of CIDP and active disease who were either treatment naive or receiving standard treatments were withdrawn from their treatments prior to day 1 of a run-in period of up to 12 weeks.
They then entered stage A of the study, an open-label phase in which all were treated with 1,000-mg efgartigimod PH20 SC weekly for up to 12 weeks.
Of those patients, 66% showed evidence of clinical improvement and a rapid onset of effect with the efgartigimod PH20 SC treatment, and 70% of the patients were then entered into stage B, a double-blind randomized phase, with 111 of patients receiving continued efgartigimod PH20 SC weekly and 110 receiving placebo for 48 weeks.
Of those moving on to stage B, more than 70% were on IVIg prior to the time of enrollment.
The study met its primary endpoint, with the efgartigimod PH20 SC groups showing a 61% lower risk for relapse on the basis of time to a first adjusted Inflammatory Neuropathy Cause and Treatment deterioration, compared with placebo (hazard ratio, 0.39; P = .000039).
Clinical benefits were also observed on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) and in measures of mean grip strength in all groups regardless of prior CIDP medication.
Specifically, efgartigimod patients had a mean improvement of 7.7 points on I-RODS and 12.3 kPa on mean grip strength in stage A, which was maintained in stage B. These were partially lost in patients receiving placebo.
In terms of safety, most adverse events were mild or moderate in severity, and no new safety signals were identified with up to 60 weeks of treatment. There were no increased infection rates with increased exposure.
The findings show that “efgartigimod-PH20, given as a 90-second subcutaneous injection once a week, was effective in treating patients with CIDP who had relapsed when taken off their previous treatment (IVIg or corticosteroids),” said Dr. Lewis.
“[The study] then showed that the majority of patients, over 70%, maintained that improvement, compared with placebo, where over 50% relapsed – most within 8 weeks, so the treatment, which reduces circulating immunoglobulin G by over 70%, is effective in treating CIDP,” he added.
Plans for this ongoing trial include recruiting up to 360 patients until 88 events of clinical deterioration have been observed in stage B.
Promising data
Commenting on the study, Karissa Gable, MD, an associate professor of neurology at Duke University, Durham, N.C., said that the “initial data reported from the ADHERE study is very promising and demonstrated significant efficacy.”
The study’s use of an adjudication committee in confirming the diagnosis is particularly notable, she said. “The trial design demonstrated confirmation of diagnosis and activity of disease and response to drug prior to randomization, which is a novel design that is particularly applicable to patients with CIDP given the rate of misdiagnosis and placebo effect found in other trials.”
Dr. Gable agreed that new options are important to address an unmet need in CIDP.
“The current first-line treatments are generally 80%-90% effective, however, there are limited options with respect to the first line treatments due to side effects and comorbid disease in patients,” she explained.
“Other treatments options are needed and so this is an unmet need in patients with CIDP,” Dr. Gable said. “This medication will be likely to be one that will provide a strong alternate option for treatment.”
Overall, “this is a novel mechanism for drug treatment for CIDP and seems to demonstrate efficacy and good safety and tolerability based on the initial report of the data,” Dr. Gable added.
“It will likely be a promising medication to use for these patients to fill the unmet need for treatment of patients with CIDP.”
The study was sponsored by Argenx. Dr. Lewis disclosed relationships with Argenx and other companies involved in neuromuscular disease therapies. Dr. Gable is on the global medical advisory board steering committee for Argenx and she was the principal investigator at her site for the Adhere study. Dr. Gable has served as a consultant for Immunovant and Takeda as well as Sanofi for CIDP and she is on the Takeda speaker bureau for Huyquvia for treatment of CIDP.
A version of this article first appeared on Medscape.com.
AT AANEM 2023
Duchenne muscular dystrophy gene therapy safe, effective at 4 years
PHOENIX – compared with untreated patients who showed significant decline over the same time period, new research shows.
“Functional assessments demonstrated long-term sustained stabilization of motor function that was clinically meaningful, at ages where functional decline would be expected based on natural history,” the investigators noted in their abstract. Furthermore, the treatment, known as delandistrogene moxeparvovec-rokl (SRP-9001), was well tolerated 4 years post treatment.
The study was presented at the annual meeting of the American Association of Neuromuscular Electrodiagnostic Medicine.
Severe type of DMD
Considered one of the most severe forms of muscular dystrophy, DMD causes progressive muscle wasting stemming from the root genetic cause of missing dystrophin in muscle cells. Often referred to as a molecular “shock absorber,” dystrophin stabilizes the sarcolemma during muscle contractions to prevent degeneration.
SRP-9001, a single-dose recombinant gene therapy administered as an intravenous infusion, was designed to deliver a trimmed down form of dystrophin to compensate for the deficit.
In July, the adeno-associated virus vector (AAV)–based SRP-9001 gene therapy was granted accelerated approval by the Food and Drug Administration for the treatment of ambulatory pediatric patients aged 4-5 years with DMD with a confirmed mutation in the DMD gene.
The therapy is administered over 1-2 hours at a dose of 133 trillion vector genomes per kilogram of body weight.
For Study 101, one of several evaluating the novel therapy, a research team led by senior investigator Jerry Mendell, MD, an attending neurologist at Nationwide Children’s Hospital and professor of pediatrics and neurology at Ohio State University, both in Columbus,evaluated data on four ambulatory male patients aged 4-8 years who received a single IV infusion of the therapy.
All patients also received prednisone 1 mg/kg, 1 day preinfusion and 30 days post infusion.
At 4 years post treatment, there were no new safety events. All treatment-related adverse events occurred mainly within the first 70 days, and all resolved.
The most commonly reported adverse reactions of the gene therapy include vomiting, nausea, increases in liver enzymes, pyrexia (fever), and thrombocytopenia, all of which occurred within 90 days of infusion and been manageable.
Risk mitigation strategies for hepatotoxicity or acute liver injury include pre- and postinfusion monitoring of liver enzymes, the authors noted.
No serious abnormalities were observed in hematologic or chemistry panels, and while three patients had elevated gamma-glutamyl transpeptidase in the first 3 months post treatment, those cases resolved with oral steroid treatment.
Significant improvements in function were observed, with a mean improvement in North Star Ambulatory Assessment (NSAA) scores from baseline of 7.0 points (range, 4-11).
Exploratory analyses further showed that, compared with a propensity score–weighted external control cohort of 21 patients with DMD who did not receive the therapy, those receiving SRP-9001 had a statistically significant difference of 9.4 points in least-squares mean change from baseline to 4 years on the NSAA score (P = .0125).
Similar trends were observed in improvement from baseline in key measures of time to rise, 4-stair climb, and 10- and 100-meter walk/run function tests.
Other reported adverse events include acute serious liver injury, immune-mediated myositis, and myocarditis. Because of the latter risk, the therapy is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.
The current 4-year update on SRP-9001 adds to clinical trial results that have been reported on more than 80 patients treated to date, with favorable results and consistent safety profiles reported at other time points.
Continued FDA approval for the therapy will be contingent upon verification of a clinical benefit in the confirmatory trials, including the EMBARK trial.
Increased function, long-term stability
Discussing the research at the meeting, Craig McDonald, MD, professor and chair of physical medicine & rehabilitation, a professor of pediatrics and study chair of the CINRG Duchenne Natural History Study at University of California Davis Health, noted that top-line results from the ongoing, confirmatory phase 3 EMBARK trial show functional benefits of SRP-9001 not only in 4- to 5-year-olds but also in other older age groups.
“What’s really striking, and in my mind the most impressive, is that when you follow these patients out 3 or 4 years ... you see there is this bump in function followed by long-term stability, whereas the external control cohort predictably shows really quite significant declines in their [NSAA] functional values,” he said in his presentation.
“When you look at each individually treated patient versus their own predicted trajectory using their baseline values on the time function test, each of the patients actually has a really quite impressive stabilization of function over their predicted disease trajectory,” he added.
A caveat that SRP-9001 shares with other gene therapies is the issue of cost – reported in the range of $2 million–$3 million.
In the context of racial and socioeconomic disparities in access to diagnosis and care reported in DMD, Emma Ciafaloni, MD, a professor of neurology and pediatrics at the University of Rochester (N.Y.) Medical Center, underscored the need to consider approval versus access to gene therapies and how to optimize access to the novel treatments.
“We need to consider what the cost is, how it’s going to be accessed, and whether there is a sustainable model,” said Ciafaloni, who was not associated with the study. “There will need to be institutional readiness and support for specialized multidisciplinary clinics for gene therapy.”
She also noted “we need to consider how we can do better on a broader level, because this is not a provider problem or a manufacturer problem — it’s a society problem.”
The study was funded by Sarepta Therapeutics. McDonald reported consulting work for Sarepta Therapeutics and has been an investigator in SRP-9001 research. Ciafaloni reported serving on advisory boards or other relationships with Alexion, Argenx, Biogen, Amicus, Momenta, Medscape, Pfizer, Sanofi/Genzyme, Sarepta, Jansen, NS Pharma, CureSMA, Orphazyme, the Patient-Centered Outcomes Research Institute, PPMD, PTC Therapeutics, and Santhera.
A version of this article first appeared on Medscape.com.
PHOENIX – compared with untreated patients who showed significant decline over the same time period, new research shows.
“Functional assessments demonstrated long-term sustained stabilization of motor function that was clinically meaningful, at ages where functional decline would be expected based on natural history,” the investigators noted in their abstract. Furthermore, the treatment, known as delandistrogene moxeparvovec-rokl (SRP-9001), was well tolerated 4 years post treatment.
The study was presented at the annual meeting of the American Association of Neuromuscular Electrodiagnostic Medicine.
Severe type of DMD
Considered one of the most severe forms of muscular dystrophy, DMD causes progressive muscle wasting stemming from the root genetic cause of missing dystrophin in muscle cells. Often referred to as a molecular “shock absorber,” dystrophin stabilizes the sarcolemma during muscle contractions to prevent degeneration.
SRP-9001, a single-dose recombinant gene therapy administered as an intravenous infusion, was designed to deliver a trimmed down form of dystrophin to compensate for the deficit.
In July, the adeno-associated virus vector (AAV)–based SRP-9001 gene therapy was granted accelerated approval by the Food and Drug Administration for the treatment of ambulatory pediatric patients aged 4-5 years with DMD with a confirmed mutation in the DMD gene.
The therapy is administered over 1-2 hours at a dose of 133 trillion vector genomes per kilogram of body weight.
For Study 101, one of several evaluating the novel therapy, a research team led by senior investigator Jerry Mendell, MD, an attending neurologist at Nationwide Children’s Hospital and professor of pediatrics and neurology at Ohio State University, both in Columbus,evaluated data on four ambulatory male patients aged 4-8 years who received a single IV infusion of the therapy.
All patients also received prednisone 1 mg/kg, 1 day preinfusion and 30 days post infusion.
At 4 years post treatment, there were no new safety events. All treatment-related adverse events occurred mainly within the first 70 days, and all resolved.
The most commonly reported adverse reactions of the gene therapy include vomiting, nausea, increases in liver enzymes, pyrexia (fever), and thrombocytopenia, all of which occurred within 90 days of infusion and been manageable.
Risk mitigation strategies for hepatotoxicity or acute liver injury include pre- and postinfusion monitoring of liver enzymes, the authors noted.
No serious abnormalities were observed in hematologic or chemistry panels, and while three patients had elevated gamma-glutamyl transpeptidase in the first 3 months post treatment, those cases resolved with oral steroid treatment.
Significant improvements in function were observed, with a mean improvement in North Star Ambulatory Assessment (NSAA) scores from baseline of 7.0 points (range, 4-11).
Exploratory analyses further showed that, compared with a propensity score–weighted external control cohort of 21 patients with DMD who did not receive the therapy, those receiving SRP-9001 had a statistically significant difference of 9.4 points in least-squares mean change from baseline to 4 years on the NSAA score (P = .0125).
Similar trends were observed in improvement from baseline in key measures of time to rise, 4-stair climb, and 10- and 100-meter walk/run function tests.
Other reported adverse events include acute serious liver injury, immune-mediated myositis, and myocarditis. Because of the latter risk, the therapy is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.
The current 4-year update on SRP-9001 adds to clinical trial results that have been reported on more than 80 patients treated to date, with favorable results and consistent safety profiles reported at other time points.
Continued FDA approval for the therapy will be contingent upon verification of a clinical benefit in the confirmatory trials, including the EMBARK trial.
Increased function, long-term stability
Discussing the research at the meeting, Craig McDonald, MD, professor and chair of physical medicine & rehabilitation, a professor of pediatrics and study chair of the CINRG Duchenne Natural History Study at University of California Davis Health, noted that top-line results from the ongoing, confirmatory phase 3 EMBARK trial show functional benefits of SRP-9001 not only in 4- to 5-year-olds but also in other older age groups.
“What’s really striking, and in my mind the most impressive, is that when you follow these patients out 3 or 4 years ... you see there is this bump in function followed by long-term stability, whereas the external control cohort predictably shows really quite significant declines in their [NSAA] functional values,” he said in his presentation.
“When you look at each individually treated patient versus their own predicted trajectory using their baseline values on the time function test, each of the patients actually has a really quite impressive stabilization of function over their predicted disease trajectory,” he added.
A caveat that SRP-9001 shares with other gene therapies is the issue of cost – reported in the range of $2 million–$3 million.
In the context of racial and socioeconomic disparities in access to diagnosis and care reported in DMD, Emma Ciafaloni, MD, a professor of neurology and pediatrics at the University of Rochester (N.Y.) Medical Center, underscored the need to consider approval versus access to gene therapies and how to optimize access to the novel treatments.
“We need to consider what the cost is, how it’s going to be accessed, and whether there is a sustainable model,” said Ciafaloni, who was not associated with the study. “There will need to be institutional readiness and support for specialized multidisciplinary clinics for gene therapy.”
She also noted “we need to consider how we can do better on a broader level, because this is not a provider problem or a manufacturer problem — it’s a society problem.”
The study was funded by Sarepta Therapeutics. McDonald reported consulting work for Sarepta Therapeutics and has been an investigator in SRP-9001 research. Ciafaloni reported serving on advisory boards or other relationships with Alexion, Argenx, Biogen, Amicus, Momenta, Medscape, Pfizer, Sanofi/Genzyme, Sarepta, Jansen, NS Pharma, CureSMA, Orphazyme, the Patient-Centered Outcomes Research Institute, PPMD, PTC Therapeutics, and Santhera.
A version of this article first appeared on Medscape.com.
PHOENIX – compared with untreated patients who showed significant decline over the same time period, new research shows.
“Functional assessments demonstrated long-term sustained stabilization of motor function that was clinically meaningful, at ages where functional decline would be expected based on natural history,” the investigators noted in their abstract. Furthermore, the treatment, known as delandistrogene moxeparvovec-rokl (SRP-9001), was well tolerated 4 years post treatment.
The study was presented at the annual meeting of the American Association of Neuromuscular Electrodiagnostic Medicine.
Severe type of DMD
Considered one of the most severe forms of muscular dystrophy, DMD causes progressive muscle wasting stemming from the root genetic cause of missing dystrophin in muscle cells. Often referred to as a molecular “shock absorber,” dystrophin stabilizes the sarcolemma during muscle contractions to prevent degeneration.
SRP-9001, a single-dose recombinant gene therapy administered as an intravenous infusion, was designed to deliver a trimmed down form of dystrophin to compensate for the deficit.
In July, the adeno-associated virus vector (AAV)–based SRP-9001 gene therapy was granted accelerated approval by the Food and Drug Administration for the treatment of ambulatory pediatric patients aged 4-5 years with DMD with a confirmed mutation in the DMD gene.
The therapy is administered over 1-2 hours at a dose of 133 trillion vector genomes per kilogram of body weight.
For Study 101, one of several evaluating the novel therapy, a research team led by senior investigator Jerry Mendell, MD, an attending neurologist at Nationwide Children’s Hospital and professor of pediatrics and neurology at Ohio State University, both in Columbus,evaluated data on four ambulatory male patients aged 4-8 years who received a single IV infusion of the therapy.
All patients also received prednisone 1 mg/kg, 1 day preinfusion and 30 days post infusion.
At 4 years post treatment, there were no new safety events. All treatment-related adverse events occurred mainly within the first 70 days, and all resolved.
The most commonly reported adverse reactions of the gene therapy include vomiting, nausea, increases in liver enzymes, pyrexia (fever), and thrombocytopenia, all of which occurred within 90 days of infusion and been manageable.
Risk mitigation strategies for hepatotoxicity or acute liver injury include pre- and postinfusion monitoring of liver enzymes, the authors noted.
No serious abnormalities were observed in hematologic or chemistry panels, and while three patients had elevated gamma-glutamyl transpeptidase in the first 3 months post treatment, those cases resolved with oral steroid treatment.
Significant improvements in function were observed, with a mean improvement in North Star Ambulatory Assessment (NSAA) scores from baseline of 7.0 points (range, 4-11).
Exploratory analyses further showed that, compared with a propensity score–weighted external control cohort of 21 patients with DMD who did not receive the therapy, those receiving SRP-9001 had a statistically significant difference of 9.4 points in least-squares mean change from baseline to 4 years on the NSAA score (P = .0125).
Similar trends were observed in improvement from baseline in key measures of time to rise, 4-stair climb, and 10- and 100-meter walk/run function tests.
Other reported adverse events include acute serious liver injury, immune-mediated myositis, and myocarditis. Because of the latter risk, the therapy is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.
The current 4-year update on SRP-9001 adds to clinical trial results that have been reported on more than 80 patients treated to date, with favorable results and consistent safety profiles reported at other time points.
Continued FDA approval for the therapy will be contingent upon verification of a clinical benefit in the confirmatory trials, including the EMBARK trial.
Increased function, long-term stability
Discussing the research at the meeting, Craig McDonald, MD, professor and chair of physical medicine & rehabilitation, a professor of pediatrics and study chair of the CINRG Duchenne Natural History Study at University of California Davis Health, noted that top-line results from the ongoing, confirmatory phase 3 EMBARK trial show functional benefits of SRP-9001 not only in 4- to 5-year-olds but also in other older age groups.
“What’s really striking, and in my mind the most impressive, is that when you follow these patients out 3 or 4 years ... you see there is this bump in function followed by long-term stability, whereas the external control cohort predictably shows really quite significant declines in their [NSAA] functional values,” he said in his presentation.
“When you look at each individually treated patient versus their own predicted trajectory using their baseline values on the time function test, each of the patients actually has a really quite impressive stabilization of function over their predicted disease trajectory,” he added.
A caveat that SRP-9001 shares with other gene therapies is the issue of cost – reported in the range of $2 million–$3 million.
In the context of racial and socioeconomic disparities in access to diagnosis and care reported in DMD, Emma Ciafaloni, MD, a professor of neurology and pediatrics at the University of Rochester (N.Y.) Medical Center, underscored the need to consider approval versus access to gene therapies and how to optimize access to the novel treatments.
“We need to consider what the cost is, how it’s going to be accessed, and whether there is a sustainable model,” said Ciafaloni, who was not associated with the study. “There will need to be institutional readiness and support for specialized multidisciplinary clinics for gene therapy.”
She also noted “we need to consider how we can do better on a broader level, because this is not a provider problem or a manufacturer problem — it’s a society problem.”
The study was funded by Sarepta Therapeutics. McDonald reported consulting work for Sarepta Therapeutics and has been an investigator in SRP-9001 research. Ciafaloni reported serving on advisory boards or other relationships with Alexion, Argenx, Biogen, Amicus, Momenta, Medscape, Pfizer, Sanofi/Genzyme, Sarepta, Jansen, NS Pharma, CureSMA, Orphazyme, the Patient-Centered Outcomes Research Institute, PPMD, PTC Therapeutics, and Santhera.
A version of this article first appeared on Medscape.com.
AT AANEM 2023
PD-1 inhibitor improves outcomes in NHL subtype
, while pretreatment mutational profiles offer clues as to which patients may respond to such anti-PD-1 treatments, according to studies presented at the European Society of Medical Oncology (ESMO) Congress 2023.
“We found that toripalimab combined with radiotherapy is safe and has promising efficacy for stage I/II extranodal NK/T cell lymphoma [patients] who have poor response after previous standard chemotherapy,” said first author Ming Jiang, MD, of the department of medical oncology, Cancer Center, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, China.
“This combined strategy can not only improve patient efficacy but also avoid unnecessary medication, and is worth further exploration,” she said in a presentation at ESMO on Oct. 27 in Madrid. The current standard of care for extranodal NK/T cell lymphoma, a subtype of non-Hodgkin lymphoma, is L-asparaginase or pegaspargase-based multi-agent chemotherapy combined with radiotherapy.
However, for patients who fail to respond to first-line treatment, the prognosis is poor: The median progression-free survival of those patients is approximately 4.5 months, with a median overall survival of about 6.4 months, Dr. Jiang explained.
“There is a need to establish a better first-line treatment for this group of patients,” she said.
In the prospective, single-arm, multicenter phase 2 study, Dr. Jiang and her colleagues enrolled patients with stage 1 and 2 extranodal NK/T cell lymphoma who had failed to achieve a complete response following 2-3 cycles of multi-agent chemotherapy.
Of the patients, eight (36.4%) had partial response, eight (36.2%) had stable disease, and six (27.2%) had progressive disease after the chemotherapy.
The patients were treated with toripalimab at 240 mg, once every 3 weeks, plus radiotherapy at a dose of 56 Gy, sequentially with or without two to four cycles of chemotherapy.
Patients who did not have disease progression were then continued with toripalimab for 1 year or until disease progression or intolerable toxicity.
The 22 patients had a median age of 45 (range 26-64) and 14 were male. Most were stage 1 (77.3%; 17) and the remaining were stage 2, while 81% had primary tumor invasion.
For the primary endpoint, at 3 months following radiotherapy, the overall response rate was 90.9%, with 17 patients (77.3%) having a complete response, 3 (13.6%) a partial response, and 2 (9.1%) having progressive disease.
Eight who had responded to previous chemotherapy received two additional chemotherapy cycles after completion of radiotherapy, while the others were treated with toripalimab alone.
With a median follow-up of 23 months (range 3-78), the 2-year progression-free survival was 81.6%, and overall survival was 95.0%.
Two of three patients with a partial response had a recurrence after radiotherapy at 5 and 10 months; one of the complete-response patients had a recurrence at 60 months, and two patients with progressive disease died at 9 months after radiotherapy.
In terms of safety, the most common adverse events during and after radiotherapy included oral mucositis and hypothyroidism. No adverse events of grade 3 or higher were reported.
Dr. Jiang speculated that “radiotherapy could synergize PD-1 inhibitors,” and she urged that “optimal radiotherapy and PD-1 inhibitor administration plans should be further explored.”
Genetic factors
Additional research presented in that ESMO session offered insights into the genetic factors that may play key roles in either response or resistance to anti-PD-1 therapy in peripheral T cell lymphoma (PTCL), of which extranodal NK/T cell lymphoma is a subtype.
The findings are from a genetic analysis of a phase 2 trial that demonstrated benefits the PD-1 inhibitor geptanolimab in patients with PTCL who failed initial chemotherapy.
Specifically, geptanolimab treatment was associated with an objective response rate of 40.4%, a complete response rate of 14.6%, and partial response rate of 25.8%.
Of 44 patients who had been treated with geptanolimab and had next-generation sequencing genetic data available, PD-L1 expression was found to be significantly elevated among those who had a complete or partial response, whereas PD-L1 expression was lower among those who had disease progression, which is consistent with previous research suggesting that low PD-L1 expression is linked to poorer response to anti-PD-1 therapies.
Tumor mutation burden did not exhibit significant prognostic value. However, the authors noted that this may be confounded by variation across PTCL subtypes.
Among other key findings were that JAK3 and EZH2 mutations, which are among the top genes frequently mutated in PTCL and extranodal NK/T cell lymphoma, were consistently associated with low PD-L1 expression (P < .05) and shorter progression-free survival (HR 5.97; P = .027, JAK3, and HR 4.76; P = .027 EZH2).
“Notably, we found JAK3 mutations, which are vital and prevalent in PTCL, reduced PD-L1 levels in vivo and in vitro, which are of great clinical and biological sense,” said the study’s first author, Ning Lou, MD, of the Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College, in Beijing.
Commenting on the study, discussant Olivier Casasnovas, MD, PhD, of the department of hematology, University Hospital Francois Mitterrand in Dijon, France, said that the findings are especially notable in relation to extranodal NK/T cell lymphoma.
“The clinical relevance of anti PD1 is mainly observed in relapsing/recurrent extranodal NK/T cell lymphoma, and much less in other T-cell lymphoma subtypes,” he told this news organization.
“So identifying molecular events associated with the chance of response to a PD1 blocker in relapsing extranodal NK/T cell lymphoma is important as PD1-blockers are recommended to treat [those] patients,” Dr. Casasnovas added.
Furthermore, “the interest of next-generation sequencing to identify JAK3 mutations associated with low level of PDL1 expression and weak response to anti PD1 blockers is important as JAK3 mutated tumors are potentially targetable by JAK inhibitors such as tofacitinib,” he said.
“Obviously this assumption has to be tested in clinical trials but it’s an interesting lead.”
The research on toripalimab additionally shows that “the combination of radiotherapy and PD1 blockers provides a high response rate in patients who are nonresponders to asparaginase-based chemotherapy on the basis of PET evaluation and could be a new option for optimizing the first line treatment of extranodal NK/T cell lymphoma patients,” Dr. Casasnovas added.
The authors and Dr. Casasnovas had no disclosures to report.
, while pretreatment mutational profiles offer clues as to which patients may respond to such anti-PD-1 treatments, according to studies presented at the European Society of Medical Oncology (ESMO) Congress 2023.
“We found that toripalimab combined with radiotherapy is safe and has promising efficacy for stage I/II extranodal NK/T cell lymphoma [patients] who have poor response after previous standard chemotherapy,” said first author Ming Jiang, MD, of the department of medical oncology, Cancer Center, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, China.
“This combined strategy can not only improve patient efficacy but also avoid unnecessary medication, and is worth further exploration,” she said in a presentation at ESMO on Oct. 27 in Madrid. The current standard of care for extranodal NK/T cell lymphoma, a subtype of non-Hodgkin lymphoma, is L-asparaginase or pegaspargase-based multi-agent chemotherapy combined with radiotherapy.
However, for patients who fail to respond to first-line treatment, the prognosis is poor: The median progression-free survival of those patients is approximately 4.5 months, with a median overall survival of about 6.4 months, Dr. Jiang explained.
“There is a need to establish a better first-line treatment for this group of patients,” she said.
In the prospective, single-arm, multicenter phase 2 study, Dr. Jiang and her colleagues enrolled patients with stage 1 and 2 extranodal NK/T cell lymphoma who had failed to achieve a complete response following 2-3 cycles of multi-agent chemotherapy.
Of the patients, eight (36.4%) had partial response, eight (36.2%) had stable disease, and six (27.2%) had progressive disease after the chemotherapy.
The patients were treated with toripalimab at 240 mg, once every 3 weeks, plus radiotherapy at a dose of 56 Gy, sequentially with or without two to four cycles of chemotherapy.
Patients who did not have disease progression were then continued with toripalimab for 1 year or until disease progression or intolerable toxicity.
The 22 patients had a median age of 45 (range 26-64) and 14 were male. Most were stage 1 (77.3%; 17) and the remaining were stage 2, while 81% had primary tumor invasion.
For the primary endpoint, at 3 months following radiotherapy, the overall response rate was 90.9%, with 17 patients (77.3%) having a complete response, 3 (13.6%) a partial response, and 2 (9.1%) having progressive disease.
Eight who had responded to previous chemotherapy received two additional chemotherapy cycles after completion of radiotherapy, while the others were treated with toripalimab alone.
With a median follow-up of 23 months (range 3-78), the 2-year progression-free survival was 81.6%, and overall survival was 95.0%.
Two of three patients with a partial response had a recurrence after radiotherapy at 5 and 10 months; one of the complete-response patients had a recurrence at 60 months, and two patients with progressive disease died at 9 months after radiotherapy.
In terms of safety, the most common adverse events during and after radiotherapy included oral mucositis and hypothyroidism. No adverse events of grade 3 or higher were reported.
Dr. Jiang speculated that “radiotherapy could synergize PD-1 inhibitors,” and she urged that “optimal radiotherapy and PD-1 inhibitor administration plans should be further explored.”
Genetic factors
Additional research presented in that ESMO session offered insights into the genetic factors that may play key roles in either response or resistance to anti-PD-1 therapy in peripheral T cell lymphoma (PTCL), of which extranodal NK/T cell lymphoma is a subtype.
The findings are from a genetic analysis of a phase 2 trial that demonstrated benefits the PD-1 inhibitor geptanolimab in patients with PTCL who failed initial chemotherapy.
Specifically, geptanolimab treatment was associated with an objective response rate of 40.4%, a complete response rate of 14.6%, and partial response rate of 25.8%.
Of 44 patients who had been treated with geptanolimab and had next-generation sequencing genetic data available, PD-L1 expression was found to be significantly elevated among those who had a complete or partial response, whereas PD-L1 expression was lower among those who had disease progression, which is consistent with previous research suggesting that low PD-L1 expression is linked to poorer response to anti-PD-1 therapies.
Tumor mutation burden did not exhibit significant prognostic value. However, the authors noted that this may be confounded by variation across PTCL subtypes.
Among other key findings were that JAK3 and EZH2 mutations, which are among the top genes frequently mutated in PTCL and extranodal NK/T cell lymphoma, were consistently associated with low PD-L1 expression (P < .05) and shorter progression-free survival (HR 5.97; P = .027, JAK3, and HR 4.76; P = .027 EZH2).
“Notably, we found JAK3 mutations, which are vital and prevalent in PTCL, reduced PD-L1 levels in vivo and in vitro, which are of great clinical and biological sense,” said the study’s first author, Ning Lou, MD, of the Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College, in Beijing.
Commenting on the study, discussant Olivier Casasnovas, MD, PhD, of the department of hematology, University Hospital Francois Mitterrand in Dijon, France, said that the findings are especially notable in relation to extranodal NK/T cell lymphoma.
“The clinical relevance of anti PD1 is mainly observed in relapsing/recurrent extranodal NK/T cell lymphoma, and much less in other T-cell lymphoma subtypes,” he told this news organization.
“So identifying molecular events associated with the chance of response to a PD1 blocker in relapsing extranodal NK/T cell lymphoma is important as PD1-blockers are recommended to treat [those] patients,” Dr. Casasnovas added.
Furthermore, “the interest of next-generation sequencing to identify JAK3 mutations associated with low level of PDL1 expression and weak response to anti PD1 blockers is important as JAK3 mutated tumors are potentially targetable by JAK inhibitors such as tofacitinib,” he said.
“Obviously this assumption has to be tested in clinical trials but it’s an interesting lead.”
The research on toripalimab additionally shows that “the combination of radiotherapy and PD1 blockers provides a high response rate in patients who are nonresponders to asparaginase-based chemotherapy on the basis of PET evaluation and could be a new option for optimizing the first line treatment of extranodal NK/T cell lymphoma patients,” Dr. Casasnovas added.
The authors and Dr. Casasnovas had no disclosures to report.
, while pretreatment mutational profiles offer clues as to which patients may respond to such anti-PD-1 treatments, according to studies presented at the European Society of Medical Oncology (ESMO) Congress 2023.
“We found that toripalimab combined with radiotherapy is safe and has promising efficacy for stage I/II extranodal NK/T cell lymphoma [patients] who have poor response after previous standard chemotherapy,” said first author Ming Jiang, MD, of the department of medical oncology, Cancer Center, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, China.
“This combined strategy can not only improve patient efficacy but also avoid unnecessary medication, and is worth further exploration,” she said in a presentation at ESMO on Oct. 27 in Madrid. The current standard of care for extranodal NK/T cell lymphoma, a subtype of non-Hodgkin lymphoma, is L-asparaginase or pegaspargase-based multi-agent chemotherapy combined with radiotherapy.
However, for patients who fail to respond to first-line treatment, the prognosis is poor: The median progression-free survival of those patients is approximately 4.5 months, with a median overall survival of about 6.4 months, Dr. Jiang explained.
“There is a need to establish a better first-line treatment for this group of patients,” she said.
In the prospective, single-arm, multicenter phase 2 study, Dr. Jiang and her colleagues enrolled patients with stage 1 and 2 extranodal NK/T cell lymphoma who had failed to achieve a complete response following 2-3 cycles of multi-agent chemotherapy.
Of the patients, eight (36.4%) had partial response, eight (36.2%) had stable disease, and six (27.2%) had progressive disease after the chemotherapy.
The patients were treated with toripalimab at 240 mg, once every 3 weeks, plus radiotherapy at a dose of 56 Gy, sequentially with or without two to four cycles of chemotherapy.
Patients who did not have disease progression were then continued with toripalimab for 1 year or until disease progression or intolerable toxicity.
The 22 patients had a median age of 45 (range 26-64) and 14 were male. Most were stage 1 (77.3%; 17) and the remaining were stage 2, while 81% had primary tumor invasion.
For the primary endpoint, at 3 months following radiotherapy, the overall response rate was 90.9%, with 17 patients (77.3%) having a complete response, 3 (13.6%) a partial response, and 2 (9.1%) having progressive disease.
Eight who had responded to previous chemotherapy received two additional chemotherapy cycles after completion of radiotherapy, while the others were treated with toripalimab alone.
With a median follow-up of 23 months (range 3-78), the 2-year progression-free survival was 81.6%, and overall survival was 95.0%.
Two of three patients with a partial response had a recurrence after radiotherapy at 5 and 10 months; one of the complete-response patients had a recurrence at 60 months, and two patients with progressive disease died at 9 months after radiotherapy.
In terms of safety, the most common adverse events during and after radiotherapy included oral mucositis and hypothyroidism. No adverse events of grade 3 or higher were reported.
Dr. Jiang speculated that “radiotherapy could synergize PD-1 inhibitors,” and she urged that “optimal radiotherapy and PD-1 inhibitor administration plans should be further explored.”
Genetic factors
Additional research presented in that ESMO session offered insights into the genetic factors that may play key roles in either response or resistance to anti-PD-1 therapy in peripheral T cell lymphoma (PTCL), of which extranodal NK/T cell lymphoma is a subtype.
The findings are from a genetic analysis of a phase 2 trial that demonstrated benefits the PD-1 inhibitor geptanolimab in patients with PTCL who failed initial chemotherapy.
Specifically, geptanolimab treatment was associated with an objective response rate of 40.4%, a complete response rate of 14.6%, and partial response rate of 25.8%.
Of 44 patients who had been treated with geptanolimab and had next-generation sequencing genetic data available, PD-L1 expression was found to be significantly elevated among those who had a complete or partial response, whereas PD-L1 expression was lower among those who had disease progression, which is consistent with previous research suggesting that low PD-L1 expression is linked to poorer response to anti-PD-1 therapies.
Tumor mutation burden did not exhibit significant prognostic value. However, the authors noted that this may be confounded by variation across PTCL subtypes.
Among other key findings were that JAK3 and EZH2 mutations, which are among the top genes frequently mutated in PTCL and extranodal NK/T cell lymphoma, were consistently associated with low PD-L1 expression (P < .05) and shorter progression-free survival (HR 5.97; P = .027, JAK3, and HR 4.76; P = .027 EZH2).
“Notably, we found JAK3 mutations, which are vital and prevalent in PTCL, reduced PD-L1 levels in vivo and in vitro, which are of great clinical and biological sense,” said the study’s first author, Ning Lou, MD, of the Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College, in Beijing.
Commenting on the study, discussant Olivier Casasnovas, MD, PhD, of the department of hematology, University Hospital Francois Mitterrand in Dijon, France, said that the findings are especially notable in relation to extranodal NK/T cell lymphoma.
“The clinical relevance of anti PD1 is mainly observed in relapsing/recurrent extranodal NK/T cell lymphoma, and much less in other T-cell lymphoma subtypes,” he told this news organization.
“So identifying molecular events associated with the chance of response to a PD1 blocker in relapsing extranodal NK/T cell lymphoma is important as PD1-blockers are recommended to treat [those] patients,” Dr. Casasnovas added.
Furthermore, “the interest of next-generation sequencing to identify JAK3 mutations associated with low level of PDL1 expression and weak response to anti PD1 blockers is important as JAK3 mutated tumors are potentially targetable by JAK inhibitors such as tofacitinib,” he said.
“Obviously this assumption has to be tested in clinical trials but it’s an interesting lead.”
The research on toripalimab additionally shows that “the combination of radiotherapy and PD1 blockers provides a high response rate in patients who are nonresponders to asparaginase-based chemotherapy on the basis of PET evaluation and could be a new option for optimizing the first line treatment of extranodal NK/T cell lymphoma patients,” Dr. Casasnovas added.
The authors and Dr. Casasnovas had no disclosures to report.
FROM ESMO 2023