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Chemo-free combo gets high response rate in relapsed or refractory DLBCL
LUGANO, Switzerland – A chemotherapy-free combination of lenalidomide (Revlimid) and the novel anti-CD19 antibody tafasitamab (MOR208) continues to show encouraging clinical activity against relapsed/refractory diffuse large B cell lymphoma, with durable responses and promising progression-free and overall survival, investigators in the phase 2 L-MIND study reported.
After a median follow-up of 17.3 months, the overall response rate (ORR) – the primary endpoint in the single arm trial – was 60%, consisting of 42.5% complete responses (CR) and 17.5% partial responses (PR), reported Giles Salles, MD, PhD, of Claude Bernard University in Lyon, France.
“We see consistently high activity in transplant-ineligible subgroups, patients who have limited treatment options and who have really poor prognosis,” he said at the International Conference on Malignant Lymphoma (15-ICML).
In a preclinical study, a combination of MOR208 and lenalidomide showed synergistic antileukemic and antilymphoma activity both in vivo and in vitro. In addition, both lenalidomide and MOR208 have shown significant activity against relapsed, refractory B-cell non-Hodgkin lymphomas.
At the previous ICML meeting in 2017, Dr. Salles reported early interim results from the study, which showed that among 34 patients evaluable for response, the ORR was 56%, including complete responses in 32% of patients.
The L-MIND investigators enrolled transplant-ineligible patients 18 years and older with relapsed/refractory DLBCL, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function who had disease progression after 1-3 prior lines of therapy.
Patients with primary refractory DLBCL, double-hit or triple-hit DLBCL (i.e., mutations in Myc, BCL2, and/or BCL6), other non-Hodgkin lymphoma histological subtypes, or central nervous system lymphoma involvement were excluded.
Patients received tafasitamab 12 mg/kg intravenously on days 1, 8, 15, and 22 for cycles 1-3 and on days 1 and 15 of cycles 4-12. Lenalidomide 25 mg orally was delivered on days 1-21 of each cycle. Patients with stable disease or better at the end of 12 cycles could be maintained on tafasitamab at the same dose on days 1 and 15.
As noted, the combination was associated with an ORR among 80 patients of 60%, consisting of 34 CR (42.5%) complete responses and 14 (17.5%) PR. An additional 11 patients (13.75%) had stable disease, 13 (16.25%) had disease progression, and eight (10%) were not evaluable because of missing post-baseline tumor assessments.
The median duration of response in the entire cohort was 21.7 months. For patients with a CR, the median duration of response had not been reached at the time of data cutoff. For patients with a PR, the median duration of response was 4.4 months.
Hematologic treatment-emergent toxicities occurring in 10% or more of patients included (in descending order of frequency) neutropenia, anemia, thrombocytopenia, leukopenia, and febrile neutropenia.
Nonhematologic treatment-emergent events occurring in at least 10% of patients included diarrhea, asthenia, peripheral edema, pyrexia, rash, decreased appetite, hypokalemia, fatigue, and similar events, the majority of which were grade 1 or 2 in severity.
“The durable responses and favorable overall survival I would say represent a remarkable outcome, and this combination of lenalidomide with tafasitamab results in a new chemo-free immunotherapy for patients with relapsed/refractory DLBCL,” Dr. Salles said.
The L-MIND study is funded by MorphoSys Ag. Dr. Salles reported receiving fees for advisory board/consulting activities and educational activities from MorphoSys and other companies.
SOURCE: Salles G et al. 15-ICML, Abstract 124.
LUGANO, Switzerland – A chemotherapy-free combination of lenalidomide (Revlimid) and the novel anti-CD19 antibody tafasitamab (MOR208) continues to show encouraging clinical activity against relapsed/refractory diffuse large B cell lymphoma, with durable responses and promising progression-free and overall survival, investigators in the phase 2 L-MIND study reported.
After a median follow-up of 17.3 months, the overall response rate (ORR) – the primary endpoint in the single arm trial – was 60%, consisting of 42.5% complete responses (CR) and 17.5% partial responses (PR), reported Giles Salles, MD, PhD, of Claude Bernard University in Lyon, France.
“We see consistently high activity in transplant-ineligible subgroups, patients who have limited treatment options and who have really poor prognosis,” he said at the International Conference on Malignant Lymphoma (15-ICML).
In a preclinical study, a combination of MOR208 and lenalidomide showed synergistic antileukemic and antilymphoma activity both in vivo and in vitro. In addition, both lenalidomide and MOR208 have shown significant activity against relapsed, refractory B-cell non-Hodgkin lymphomas.
At the previous ICML meeting in 2017, Dr. Salles reported early interim results from the study, which showed that among 34 patients evaluable for response, the ORR was 56%, including complete responses in 32% of patients.
The L-MIND investigators enrolled transplant-ineligible patients 18 years and older with relapsed/refractory DLBCL, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function who had disease progression after 1-3 prior lines of therapy.
Patients with primary refractory DLBCL, double-hit or triple-hit DLBCL (i.e., mutations in Myc, BCL2, and/or BCL6), other non-Hodgkin lymphoma histological subtypes, or central nervous system lymphoma involvement were excluded.
Patients received tafasitamab 12 mg/kg intravenously on days 1, 8, 15, and 22 for cycles 1-3 and on days 1 and 15 of cycles 4-12. Lenalidomide 25 mg orally was delivered on days 1-21 of each cycle. Patients with stable disease or better at the end of 12 cycles could be maintained on tafasitamab at the same dose on days 1 and 15.
As noted, the combination was associated with an ORR among 80 patients of 60%, consisting of 34 CR (42.5%) complete responses and 14 (17.5%) PR. An additional 11 patients (13.75%) had stable disease, 13 (16.25%) had disease progression, and eight (10%) were not evaluable because of missing post-baseline tumor assessments.
The median duration of response in the entire cohort was 21.7 months. For patients with a CR, the median duration of response had not been reached at the time of data cutoff. For patients with a PR, the median duration of response was 4.4 months.
Hematologic treatment-emergent toxicities occurring in 10% or more of patients included (in descending order of frequency) neutropenia, anemia, thrombocytopenia, leukopenia, and febrile neutropenia.
Nonhematologic treatment-emergent events occurring in at least 10% of patients included diarrhea, asthenia, peripheral edema, pyrexia, rash, decreased appetite, hypokalemia, fatigue, and similar events, the majority of which were grade 1 or 2 in severity.
“The durable responses and favorable overall survival I would say represent a remarkable outcome, and this combination of lenalidomide with tafasitamab results in a new chemo-free immunotherapy for patients with relapsed/refractory DLBCL,” Dr. Salles said.
The L-MIND study is funded by MorphoSys Ag. Dr. Salles reported receiving fees for advisory board/consulting activities and educational activities from MorphoSys and other companies.
SOURCE: Salles G et al. 15-ICML, Abstract 124.
LUGANO, Switzerland – A chemotherapy-free combination of lenalidomide (Revlimid) and the novel anti-CD19 antibody tafasitamab (MOR208) continues to show encouraging clinical activity against relapsed/refractory diffuse large B cell lymphoma, with durable responses and promising progression-free and overall survival, investigators in the phase 2 L-MIND study reported.
After a median follow-up of 17.3 months, the overall response rate (ORR) – the primary endpoint in the single arm trial – was 60%, consisting of 42.5% complete responses (CR) and 17.5% partial responses (PR), reported Giles Salles, MD, PhD, of Claude Bernard University in Lyon, France.
“We see consistently high activity in transplant-ineligible subgroups, patients who have limited treatment options and who have really poor prognosis,” he said at the International Conference on Malignant Lymphoma (15-ICML).
In a preclinical study, a combination of MOR208 and lenalidomide showed synergistic antileukemic and antilymphoma activity both in vivo and in vitro. In addition, both lenalidomide and MOR208 have shown significant activity against relapsed, refractory B-cell non-Hodgkin lymphomas.
At the previous ICML meeting in 2017, Dr. Salles reported early interim results from the study, which showed that among 34 patients evaluable for response, the ORR was 56%, including complete responses in 32% of patients.
The L-MIND investigators enrolled transplant-ineligible patients 18 years and older with relapsed/refractory DLBCL, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function who had disease progression after 1-3 prior lines of therapy.
Patients with primary refractory DLBCL, double-hit or triple-hit DLBCL (i.e., mutations in Myc, BCL2, and/or BCL6), other non-Hodgkin lymphoma histological subtypes, or central nervous system lymphoma involvement were excluded.
Patients received tafasitamab 12 mg/kg intravenously on days 1, 8, 15, and 22 for cycles 1-3 and on days 1 and 15 of cycles 4-12. Lenalidomide 25 mg orally was delivered on days 1-21 of each cycle. Patients with stable disease or better at the end of 12 cycles could be maintained on tafasitamab at the same dose on days 1 and 15.
As noted, the combination was associated with an ORR among 80 patients of 60%, consisting of 34 CR (42.5%) complete responses and 14 (17.5%) PR. An additional 11 patients (13.75%) had stable disease, 13 (16.25%) had disease progression, and eight (10%) were not evaluable because of missing post-baseline tumor assessments.
The median duration of response in the entire cohort was 21.7 months. For patients with a CR, the median duration of response had not been reached at the time of data cutoff. For patients with a PR, the median duration of response was 4.4 months.
Hematologic treatment-emergent toxicities occurring in 10% or more of patients included (in descending order of frequency) neutropenia, anemia, thrombocytopenia, leukopenia, and febrile neutropenia.
Nonhematologic treatment-emergent events occurring in at least 10% of patients included diarrhea, asthenia, peripheral edema, pyrexia, rash, decreased appetite, hypokalemia, fatigue, and similar events, the majority of which were grade 1 or 2 in severity.
“The durable responses and favorable overall survival I would say represent a remarkable outcome, and this combination of lenalidomide with tafasitamab results in a new chemo-free immunotherapy for patients with relapsed/refractory DLBCL,” Dr. Salles said.
The L-MIND study is funded by MorphoSys Ag. Dr. Salles reported receiving fees for advisory board/consulting activities and educational activities from MorphoSys and other companies.
SOURCE: Salles G et al. 15-ICML, Abstract 124.
REPORTING FROM 15-ICML
Ibrutinib-venetoclax found highly active in hard-to-treat CLL
The strategy of simultaneously inhibiting proliferation and reactivating apoptosis can eradicate chronic lymphocytic leukemia (CLL) in a large share of patients, suggest results from the phase 2 CLARITY trial.
“Both ibrutinib and venetoclax are active in CLL with improved survival; however, as monotherapies, both currently are given until disease progression,” wrote Peter Hillmen, MBChB, PhD, St. James’s University Hospital, Leeds, England, and his colleagues.
In the single-arm, open-label trial, the investigators treated 53 patients with relapsed or refractory CLL with combination ibrutinib (Imbruvica), a small-molecule inhibitor of Bruton’s tyrosine kinase, and venetoclax (Venclexta), a small molecule inhibitor of the anti-apoptotic protein Bcl-2. The primary endpoint was MRD negativity, defined as presence of fewer than one CLL cell in 10,000 leukocytes, after 12 months of combination therapy.
Results reported in the Journal of Clinical Oncology showed that the combination was highly active, with 53% of patients achieving MRD negativity in the blood and 36% achieving MRD negativity in the marrow.
Most patients, 89%, had a treatment response, and slightly more than half, 51%, achieved a complete remission. With a median 21.1-month follow-up, only a single patient experienced progression and all were still alive.
Adverse effects were generally manageable. Grade 3-4 adverse events of special interest included 34 cases of neutropenia and 1 case of biochemical tumor lysis syndrome that was managed by delaying venetoclax.
“We have demonstrated promising efficacy that indicates potent synergy between ibrutinib and venetoclax for inducing MRD-negative responses with manageable adverse effects,” the investigators wrote. “The observation that a significant proportion of patients experience MRD-negative remission indicates that this combination can be given for a limited period and then stopped after patients achieve a deep remission.”
Whether the combination leads to permanent disease eradication in certain patients is still unclear, the investigators added.
The trial was supported by Bloodwise under the Trials Acceleration Programme, by the National Institute for Health Research Leeds Clinical Research Facility, and by an unrestricted educational grant from Janssen-Cilag and AbbVie. Ibrutinib was provided free of charge by Janssen-Cilag, and venetoclax was provided free of charge by AbbVie. Dr. Hillman reported financial relationships with Janssen, AbbVie, Roche, Pharmacyclics, and Gilead Sciences.
SOURCE: Hillmen P et al. J Clin Oncol. 2019 Jul 11. doi: 10.1200/JCO.19.00894.
The strategy of simultaneously inhibiting proliferation and reactivating apoptosis can eradicate chronic lymphocytic leukemia (CLL) in a large share of patients, suggest results from the phase 2 CLARITY trial.
“Both ibrutinib and venetoclax are active in CLL with improved survival; however, as monotherapies, both currently are given until disease progression,” wrote Peter Hillmen, MBChB, PhD, St. James’s University Hospital, Leeds, England, and his colleagues.
In the single-arm, open-label trial, the investigators treated 53 patients with relapsed or refractory CLL with combination ibrutinib (Imbruvica), a small-molecule inhibitor of Bruton’s tyrosine kinase, and venetoclax (Venclexta), a small molecule inhibitor of the anti-apoptotic protein Bcl-2. The primary endpoint was MRD negativity, defined as presence of fewer than one CLL cell in 10,000 leukocytes, after 12 months of combination therapy.
Results reported in the Journal of Clinical Oncology showed that the combination was highly active, with 53% of patients achieving MRD negativity in the blood and 36% achieving MRD negativity in the marrow.
Most patients, 89%, had a treatment response, and slightly more than half, 51%, achieved a complete remission. With a median 21.1-month follow-up, only a single patient experienced progression and all were still alive.
Adverse effects were generally manageable. Grade 3-4 adverse events of special interest included 34 cases of neutropenia and 1 case of biochemical tumor lysis syndrome that was managed by delaying venetoclax.
“We have demonstrated promising efficacy that indicates potent synergy between ibrutinib and venetoclax for inducing MRD-negative responses with manageable adverse effects,” the investigators wrote. “The observation that a significant proportion of patients experience MRD-negative remission indicates that this combination can be given for a limited period and then stopped after patients achieve a deep remission.”
Whether the combination leads to permanent disease eradication in certain patients is still unclear, the investigators added.
The trial was supported by Bloodwise under the Trials Acceleration Programme, by the National Institute for Health Research Leeds Clinical Research Facility, and by an unrestricted educational grant from Janssen-Cilag and AbbVie. Ibrutinib was provided free of charge by Janssen-Cilag, and venetoclax was provided free of charge by AbbVie. Dr. Hillman reported financial relationships with Janssen, AbbVie, Roche, Pharmacyclics, and Gilead Sciences.
SOURCE: Hillmen P et al. J Clin Oncol. 2019 Jul 11. doi: 10.1200/JCO.19.00894.
The strategy of simultaneously inhibiting proliferation and reactivating apoptosis can eradicate chronic lymphocytic leukemia (CLL) in a large share of patients, suggest results from the phase 2 CLARITY trial.
“Both ibrutinib and venetoclax are active in CLL with improved survival; however, as monotherapies, both currently are given until disease progression,” wrote Peter Hillmen, MBChB, PhD, St. James’s University Hospital, Leeds, England, and his colleagues.
In the single-arm, open-label trial, the investigators treated 53 patients with relapsed or refractory CLL with combination ibrutinib (Imbruvica), a small-molecule inhibitor of Bruton’s tyrosine kinase, and venetoclax (Venclexta), a small molecule inhibitor of the anti-apoptotic protein Bcl-2. The primary endpoint was MRD negativity, defined as presence of fewer than one CLL cell in 10,000 leukocytes, after 12 months of combination therapy.
Results reported in the Journal of Clinical Oncology showed that the combination was highly active, with 53% of patients achieving MRD negativity in the blood and 36% achieving MRD negativity in the marrow.
Most patients, 89%, had a treatment response, and slightly more than half, 51%, achieved a complete remission. With a median 21.1-month follow-up, only a single patient experienced progression and all were still alive.
Adverse effects were generally manageable. Grade 3-4 adverse events of special interest included 34 cases of neutropenia and 1 case of biochemical tumor lysis syndrome that was managed by delaying venetoclax.
“We have demonstrated promising efficacy that indicates potent synergy between ibrutinib and venetoclax for inducing MRD-negative responses with manageable adverse effects,” the investigators wrote. “The observation that a significant proportion of patients experience MRD-negative remission indicates that this combination can be given for a limited period and then stopped after patients achieve a deep remission.”
Whether the combination leads to permanent disease eradication in certain patients is still unclear, the investigators added.
The trial was supported by Bloodwise under the Trials Acceleration Programme, by the National Institute for Health Research Leeds Clinical Research Facility, and by an unrestricted educational grant from Janssen-Cilag and AbbVie. Ibrutinib was provided free of charge by Janssen-Cilag, and venetoclax was provided free of charge by AbbVie. Dr. Hillman reported financial relationships with Janssen, AbbVie, Roche, Pharmacyclics, and Gilead Sciences.
SOURCE: Hillmen P et al. J Clin Oncol. 2019 Jul 11. doi: 10.1200/JCO.19.00894.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
CAR T-cell therapy less effective in transformed follicular lymphoma
All complete responders with FL were still in remission at a median follow-up of 24 months, but the median duration of response was 10.2 months for patients with tFL.
Alexandre V. Hirayama, MD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues reported these results in Blood.
The trial enrolled 21 adults with relapsed/refractory CD19+ B-cell malignancies, including 8 patients with FL and 13 with tFL. At baseline, the FL/tFL patients had a median age of 56 years (range, 51-62), and 67% were male. Most patients (n = 19) had stage III/IV disease, 17 had extranodal disease, 8 had bulky disease, and 6 had bone marrow involvement. The patients had received a median of 5 prior therapies (range, 2-8), and 13 had received a transplant.
In this study, patients received a lymphodepleting regimen of cyclophosphamide and fludarabine, followed by 2 x 106 CD19 CAR T cells/kg. Five patients (one with FL and four with tFL) also received bridging chemotherapy between leukapheresis and lymphodepletion.
Grade 1-2 cytokine release syndrome occurred in 50% of FL patients and 39% of tFL patients (P = .35). Grade 1-2 neurotoxicity occurred in 50% and 23%, respectively (P = .67). There were no cases of grade 3 or higher cytokine release syndrome or neurotoxicity.
Most FL patients (7 of 8; 88%) achieved a complete response (CR) to treatment, and all of these patients were still in CR at a median follow-up of 24 months (range, 5-37 months). One FL patient received a transplant while in CR.
Six of 13 tFL patients (46%) achieved a CR. At a median follow-up of 38 months (range, 3-39 months), the median duration of response was 10.2 months. The median progression-free survival was 11.2 months in patients who achieved a CR and 1.4 months in all tFL patients.
The researchers noted that peak CAR T-cell counts and the duration of CAR T-cell detection were similar between FL and tFL patients. However, tFL patients had higher serum interleukin-8 concentrations and higher lactate dehydrogenase levels before treatment.
Past research suggested that IL-8 mediates the recruitment of tumor-associated neutrophils, promotes diffuse large B-cell lymphoma progression, and can contribute to local immune suppression. Other studies have linked elevated lactate dehydrogenase to aggressive disease and a more immunosuppressive tumor microenvironment.
“Although these data raise the possibility that differences in the tumor microenvironment may, in part, contribute to differences in outcomes after CAR T-cell immunotherapy in FL and tFL patients, additional studies are required,” the researchers wrote.
This research was supported by the National Institutes of Health, the Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinician Investigator Program, the Fred Hutchinson Cancer Research Center’s Immunotherapy Integrated Research Center, and Juno Therapeutics/Celgene.
The researchers disclosed relationships with Celgene, Juno Therapeutics, Lyell Immunopharma, Adaptive Biotechnologies, Nohla, Kite Pharma, Gilead, Genentech, Novartis, Eureka Therapeutics, Nektar Therapeutics, Caribou Biosciences, Precision Biosciences, Aptevo, Humanigen, and Allogene.
SOURCE: Hirayama AV et al. Blood. 2019 Jun 26. doi: 10.1182/blood.2019000905
All complete responders with FL were still in remission at a median follow-up of 24 months, but the median duration of response was 10.2 months for patients with tFL.
Alexandre V. Hirayama, MD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues reported these results in Blood.
The trial enrolled 21 adults with relapsed/refractory CD19+ B-cell malignancies, including 8 patients with FL and 13 with tFL. At baseline, the FL/tFL patients had a median age of 56 years (range, 51-62), and 67% were male. Most patients (n = 19) had stage III/IV disease, 17 had extranodal disease, 8 had bulky disease, and 6 had bone marrow involvement. The patients had received a median of 5 prior therapies (range, 2-8), and 13 had received a transplant.
In this study, patients received a lymphodepleting regimen of cyclophosphamide and fludarabine, followed by 2 x 106 CD19 CAR T cells/kg. Five patients (one with FL and four with tFL) also received bridging chemotherapy between leukapheresis and lymphodepletion.
Grade 1-2 cytokine release syndrome occurred in 50% of FL patients and 39% of tFL patients (P = .35). Grade 1-2 neurotoxicity occurred in 50% and 23%, respectively (P = .67). There were no cases of grade 3 or higher cytokine release syndrome or neurotoxicity.
Most FL patients (7 of 8; 88%) achieved a complete response (CR) to treatment, and all of these patients were still in CR at a median follow-up of 24 months (range, 5-37 months). One FL patient received a transplant while in CR.
Six of 13 tFL patients (46%) achieved a CR. At a median follow-up of 38 months (range, 3-39 months), the median duration of response was 10.2 months. The median progression-free survival was 11.2 months in patients who achieved a CR and 1.4 months in all tFL patients.
The researchers noted that peak CAR T-cell counts and the duration of CAR T-cell detection were similar between FL and tFL patients. However, tFL patients had higher serum interleukin-8 concentrations and higher lactate dehydrogenase levels before treatment.
Past research suggested that IL-8 mediates the recruitment of tumor-associated neutrophils, promotes diffuse large B-cell lymphoma progression, and can contribute to local immune suppression. Other studies have linked elevated lactate dehydrogenase to aggressive disease and a more immunosuppressive tumor microenvironment.
“Although these data raise the possibility that differences in the tumor microenvironment may, in part, contribute to differences in outcomes after CAR T-cell immunotherapy in FL and tFL patients, additional studies are required,” the researchers wrote.
This research was supported by the National Institutes of Health, the Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinician Investigator Program, the Fred Hutchinson Cancer Research Center’s Immunotherapy Integrated Research Center, and Juno Therapeutics/Celgene.
The researchers disclosed relationships with Celgene, Juno Therapeutics, Lyell Immunopharma, Adaptive Biotechnologies, Nohla, Kite Pharma, Gilead, Genentech, Novartis, Eureka Therapeutics, Nektar Therapeutics, Caribou Biosciences, Precision Biosciences, Aptevo, Humanigen, and Allogene.
SOURCE: Hirayama AV et al. Blood. 2019 Jun 26. doi: 10.1182/blood.2019000905
All complete responders with FL were still in remission at a median follow-up of 24 months, but the median duration of response was 10.2 months for patients with tFL.
Alexandre V. Hirayama, MD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues reported these results in Blood.
The trial enrolled 21 adults with relapsed/refractory CD19+ B-cell malignancies, including 8 patients with FL and 13 with tFL. At baseline, the FL/tFL patients had a median age of 56 years (range, 51-62), and 67% were male. Most patients (n = 19) had stage III/IV disease, 17 had extranodal disease, 8 had bulky disease, and 6 had bone marrow involvement. The patients had received a median of 5 prior therapies (range, 2-8), and 13 had received a transplant.
In this study, patients received a lymphodepleting regimen of cyclophosphamide and fludarabine, followed by 2 x 106 CD19 CAR T cells/kg. Five patients (one with FL and four with tFL) also received bridging chemotherapy between leukapheresis and lymphodepletion.
Grade 1-2 cytokine release syndrome occurred in 50% of FL patients and 39% of tFL patients (P = .35). Grade 1-2 neurotoxicity occurred in 50% and 23%, respectively (P = .67). There were no cases of grade 3 or higher cytokine release syndrome or neurotoxicity.
Most FL patients (7 of 8; 88%) achieved a complete response (CR) to treatment, and all of these patients were still in CR at a median follow-up of 24 months (range, 5-37 months). One FL patient received a transplant while in CR.
Six of 13 tFL patients (46%) achieved a CR. At a median follow-up of 38 months (range, 3-39 months), the median duration of response was 10.2 months. The median progression-free survival was 11.2 months in patients who achieved a CR and 1.4 months in all tFL patients.
The researchers noted that peak CAR T-cell counts and the duration of CAR T-cell detection were similar between FL and tFL patients. However, tFL patients had higher serum interleukin-8 concentrations and higher lactate dehydrogenase levels before treatment.
Past research suggested that IL-8 mediates the recruitment of tumor-associated neutrophils, promotes diffuse large B-cell lymphoma progression, and can contribute to local immune suppression. Other studies have linked elevated lactate dehydrogenase to aggressive disease and a more immunosuppressive tumor microenvironment.
“Although these data raise the possibility that differences in the tumor microenvironment may, in part, contribute to differences in outcomes after CAR T-cell immunotherapy in FL and tFL patients, additional studies are required,” the researchers wrote.
This research was supported by the National Institutes of Health, the Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinician Investigator Program, the Fred Hutchinson Cancer Research Center’s Immunotherapy Integrated Research Center, and Juno Therapeutics/Celgene.
The researchers disclosed relationships with Celgene, Juno Therapeutics, Lyell Immunopharma, Adaptive Biotechnologies, Nohla, Kite Pharma, Gilead, Genentech, Novartis, Eureka Therapeutics, Nektar Therapeutics, Caribou Biosciences, Precision Biosciences, Aptevo, Humanigen, and Allogene.
SOURCE: Hirayama AV et al. Blood. 2019 Jun 26. doi: 10.1182/blood.2019000905
FROM BLOOD
Potential improvements in convenience, tolerability of hematologic treatment
In this edition of “How I will treat my next patient,” I highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
SC-Dara in myeloma
At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.
Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
What this means in practice
It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.
However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.
Acalabrutinib in CLL/SLL
Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).
Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.
Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.
What this means in practice
The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.
With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.
With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
SC-Dara in myeloma
At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.
Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
What this means in practice
It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.
However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.
Acalabrutinib in CLL/SLL
Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).
Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.
Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.
What this means in practice
The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.
With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.
With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
SC-Dara in myeloma
At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.
Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
What this means in practice
It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.
However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.
Acalabrutinib in CLL/SLL
Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).
Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.
Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.
What this means in practice
The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.
With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.
With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
Flavopiridol elicits poor response in mantle cell lymphoma, DLBCL
Flavopiridol – also known as alvocidib – showed minimal clinical response in patients with relapsed or refractory mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and other B-cell lymphomas, according to results from a single-center, phase 1/2 trial.
“Promising preclinical data in cell lines derived from MCL and activated DLBCL led to a series of clinical trials of flavopiridol in various hematological malignancies,” wrote Milos D. Miljković, MD, and colleagues in the lymphoid malignancies branch of the National Cancer Institute in Bethesda, Md. The findings were published in a letter to the editor in Leukemia & Lymphoma.
The study included 28 patients with relapsed/refractory MCL, DLBCL, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma who received a hybrid dosing regimen of the novel CDK inhibitor. Flavopiridol was administered as a 30-minute bolus, followed by a 4-hour infusion.
The researchers used an intrapatient dose escalation between the first and successive cycles, in addition to a three-plus-three interpatient escalation, to lessen the risk of tumor lysis syndrome (TLS).
The primary outcomes were the clinical response rate, maximum tolerated dose, dose-limiting toxicities, and toxicity profile of the hybrid dosing regimen.
Of 26 evaluable patients, one patient with DLBCL maintained a partial response for 84 days (overall response rate, 3.8%). One patient with MCL had a 50% decrease in the size of target lesions at 2 months, but this was not sustained at 4 months. In total, nine patients had stable disease for a disease control rate of 38.4%.
“[Flavopiridol] had minimal efficacy in patients with relapsed/refractory non-Hodgkin B-cell lymphoma, casting doubt on the utility of CDK inhibition in this disease,” the researchers wrote.
With respect to safety, there were eight dose-limiting toxicities reported in three patients. These included grade 3 TLS, elevated transaminase levels, hypoalbuminemia, hyperkalemia, non-neutropenic infection, and grade 4 metabolic acidosis and gastrointestinal perforation.
The most common treatment-related toxicities were hematologic, including neutropenia, anemia, thrombocytopenia, leukocytosis, and lymphopenia.
Dr. Miljković and colleagues noted that CDK inhibitor therapy may elicit better responses when used in combination with other agents.
“Ongoing trials of more specific CDK inhibitors in combination with other agents will help elucidate their role in lymphoma treatment,” they wrote.
The trial is sponsored by the National Cancer Institute and the study authors are employees of the National Cancer Institute.
SOURCE: Miljkovic MD et al. Leuk Lymphoma. 2019 Jun 17. doi: 10.1080/10428194.2019.1627540.
Flavopiridol – also known as alvocidib – showed minimal clinical response in patients with relapsed or refractory mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and other B-cell lymphomas, according to results from a single-center, phase 1/2 trial.
“Promising preclinical data in cell lines derived from MCL and activated DLBCL led to a series of clinical trials of flavopiridol in various hematological malignancies,” wrote Milos D. Miljković, MD, and colleagues in the lymphoid malignancies branch of the National Cancer Institute in Bethesda, Md. The findings were published in a letter to the editor in Leukemia & Lymphoma.
The study included 28 patients with relapsed/refractory MCL, DLBCL, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma who received a hybrid dosing regimen of the novel CDK inhibitor. Flavopiridol was administered as a 30-minute bolus, followed by a 4-hour infusion.
The researchers used an intrapatient dose escalation between the first and successive cycles, in addition to a three-plus-three interpatient escalation, to lessen the risk of tumor lysis syndrome (TLS).
The primary outcomes were the clinical response rate, maximum tolerated dose, dose-limiting toxicities, and toxicity profile of the hybrid dosing regimen.
Of 26 evaluable patients, one patient with DLBCL maintained a partial response for 84 days (overall response rate, 3.8%). One patient with MCL had a 50% decrease in the size of target lesions at 2 months, but this was not sustained at 4 months. In total, nine patients had stable disease for a disease control rate of 38.4%.
“[Flavopiridol] had minimal efficacy in patients with relapsed/refractory non-Hodgkin B-cell lymphoma, casting doubt on the utility of CDK inhibition in this disease,” the researchers wrote.
With respect to safety, there were eight dose-limiting toxicities reported in three patients. These included grade 3 TLS, elevated transaminase levels, hypoalbuminemia, hyperkalemia, non-neutropenic infection, and grade 4 metabolic acidosis and gastrointestinal perforation.
The most common treatment-related toxicities were hematologic, including neutropenia, anemia, thrombocytopenia, leukocytosis, and lymphopenia.
Dr. Miljković and colleagues noted that CDK inhibitor therapy may elicit better responses when used in combination with other agents.
“Ongoing trials of more specific CDK inhibitors in combination with other agents will help elucidate their role in lymphoma treatment,” they wrote.
The trial is sponsored by the National Cancer Institute and the study authors are employees of the National Cancer Institute.
SOURCE: Miljkovic MD et al. Leuk Lymphoma. 2019 Jun 17. doi: 10.1080/10428194.2019.1627540.
Flavopiridol – also known as alvocidib – showed minimal clinical response in patients with relapsed or refractory mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and other B-cell lymphomas, according to results from a single-center, phase 1/2 trial.
“Promising preclinical data in cell lines derived from MCL and activated DLBCL led to a series of clinical trials of flavopiridol in various hematological malignancies,” wrote Milos D. Miljković, MD, and colleagues in the lymphoid malignancies branch of the National Cancer Institute in Bethesda, Md. The findings were published in a letter to the editor in Leukemia & Lymphoma.
The study included 28 patients with relapsed/refractory MCL, DLBCL, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma who received a hybrid dosing regimen of the novel CDK inhibitor. Flavopiridol was administered as a 30-minute bolus, followed by a 4-hour infusion.
The researchers used an intrapatient dose escalation between the first and successive cycles, in addition to a three-plus-three interpatient escalation, to lessen the risk of tumor lysis syndrome (TLS).
The primary outcomes were the clinical response rate, maximum tolerated dose, dose-limiting toxicities, and toxicity profile of the hybrid dosing regimen.
Of 26 evaluable patients, one patient with DLBCL maintained a partial response for 84 days (overall response rate, 3.8%). One patient with MCL had a 50% decrease in the size of target lesions at 2 months, but this was not sustained at 4 months. In total, nine patients had stable disease for a disease control rate of 38.4%.
“[Flavopiridol] had minimal efficacy in patients with relapsed/refractory non-Hodgkin B-cell lymphoma, casting doubt on the utility of CDK inhibition in this disease,” the researchers wrote.
With respect to safety, there were eight dose-limiting toxicities reported in three patients. These included grade 3 TLS, elevated transaminase levels, hypoalbuminemia, hyperkalemia, non-neutropenic infection, and grade 4 metabolic acidosis and gastrointestinal perforation.
The most common treatment-related toxicities were hematologic, including neutropenia, anemia, thrombocytopenia, leukocytosis, and lymphopenia.
Dr. Miljković and colleagues noted that CDK inhibitor therapy may elicit better responses when used in combination with other agents.
“Ongoing trials of more specific CDK inhibitors in combination with other agents will help elucidate their role in lymphoma treatment,” they wrote.
The trial is sponsored by the National Cancer Institute and the study authors are employees of the National Cancer Institute.
SOURCE: Miljkovic MD et al. Leuk Lymphoma. 2019 Jun 17. doi: 10.1080/10428194.2019.1627540.
FROM LEUKEMIA & LYMPHOMA
Intravenous CNS chemo looks best for testicular DLBCL
For patients with testicular diffuse large B-cell lymphoma (T-DLBCL), intravenous central nervous system (CNS)–directed chemotherapy and prophylactic treatment of the contralateral testis offer the best survival outcomes, according to findings from a recent retrospective analysis.
In contrast, intrathecal chemotherapy offered no benefit, reported lead author Susanna Mannisto, MD, of Helsinki University Hospital in Finland, and her colleagues. Survival advantages gained by CNS-directed chemotherapy were generally due to control of systemic disease rather than prevention of CNS progression, they noted.
There have not been randomized trials conducted specifically in T-DLBCL and treatment guidelines are currently based on phase 2 trials. Treatment for T-DLBCL typically involves cyclophosphamide, doxorubicin, vincristine, prednisolone plus rituximab (R–CHOP), with the addition of CNS prophylaxis with either intravenous or intrathecal methotrexate or cytarabine (AraC) in eligible patients. “Thus far, however, no prospective randomised studies on the benefit of this approach have been published,” the investigators wrote. The study is in the European Journal of Cancer.
They drew data from the Danish Lymphoma Registry and three Southern Finland University Hospitals. Out of 235 patients diagnosed with T-DLBCL between 1987 and 2013, 192 (82%) were treated with curative anthracycline-based chemotherapy. As some cases dated back to 1987, about one-third (36%) were treated before rituximab was available. A slightly higher proportion received intravenous CNS-directed chemotherapy (40%). Due to data availability, 189 patients were included in the survival analysis.
Results of multivariate analyses showed that CNS-directed chemotherapy (intravenous methotrexate, high-dose AraC, or both), was associated with an approximately 58% decreased risk of death across the entire population (hazard ratio [HR] for overall survival, 0.419; 95% confidence interval, 0.256-0.686; P = .001), with elderly patients realizing the greatest benefit.
“[I]t is important to note that we did not observe reduction in the CNS recurrence rate, but rather a better control of the systemic disease, suggesting that R–CHOP alone may not be a sufficient therapy for the patients with testicular DLBCL involvement,” the investigators wrote.
Intrathecal CNS-targeted therapy did not correlate with improved survival in the study. Likewise, for the entire population, rituximab did not boost survival; however, for high risk patients (International Prognostic Index, 3-5), immunochemotherapy did provide a better rate of 5-year disease-specific survival than that of conventional chemotherapy (44% vs 14%; P = .019).
Treatment of the contralateral testis was worthwhile for the entire population, with a 46% decreased risk of death (HR for overall survival, 0.514, 95% CI, 0.338-0.782; P = .002).
Shortest overall survival times, regardless of treatment type, were reported among patients with poor performance status, elevated lactate dehydrogenase (LDH), primary T-DLBCL, more extranodal sites, higher International Prognostic Index, and patients older than 70 years.
“[O]ur results recommend aggressive chemotherapy with [intravenous high-dose methotrexate and/or high-dose AraC] for better control of systemic disease for eligible patients,” the investigators concluded. “In addition, treatment of the contralateral testis with either radiotherapy or orchiectomy should be included in the management strategy of patients with T-DLBCL.”
The study was funded by the Academy of Finland, the Finnish Cancer Foundation, the Sigrid Juselius Foundation, and others. The investigators reported additional relationships with Pfizer, Takeda, Roche, Sanofi, and others.
SOURCE: Mannisto S et al. Eur J Cancer. 2019 May 10. doi: 10.1016/j.ejca.2019.04.004.
For patients with testicular diffuse large B-cell lymphoma (T-DLBCL), intravenous central nervous system (CNS)–directed chemotherapy and prophylactic treatment of the contralateral testis offer the best survival outcomes, according to findings from a recent retrospective analysis.
In contrast, intrathecal chemotherapy offered no benefit, reported lead author Susanna Mannisto, MD, of Helsinki University Hospital in Finland, and her colleagues. Survival advantages gained by CNS-directed chemotherapy were generally due to control of systemic disease rather than prevention of CNS progression, they noted.
There have not been randomized trials conducted specifically in T-DLBCL and treatment guidelines are currently based on phase 2 trials. Treatment for T-DLBCL typically involves cyclophosphamide, doxorubicin, vincristine, prednisolone plus rituximab (R–CHOP), with the addition of CNS prophylaxis with either intravenous or intrathecal methotrexate or cytarabine (AraC) in eligible patients. “Thus far, however, no prospective randomised studies on the benefit of this approach have been published,” the investigators wrote. The study is in the European Journal of Cancer.
They drew data from the Danish Lymphoma Registry and three Southern Finland University Hospitals. Out of 235 patients diagnosed with T-DLBCL between 1987 and 2013, 192 (82%) were treated with curative anthracycline-based chemotherapy. As some cases dated back to 1987, about one-third (36%) were treated before rituximab was available. A slightly higher proportion received intravenous CNS-directed chemotherapy (40%). Due to data availability, 189 patients were included in the survival analysis.
Results of multivariate analyses showed that CNS-directed chemotherapy (intravenous methotrexate, high-dose AraC, or both), was associated with an approximately 58% decreased risk of death across the entire population (hazard ratio [HR] for overall survival, 0.419; 95% confidence interval, 0.256-0.686; P = .001), with elderly patients realizing the greatest benefit.
“[I]t is important to note that we did not observe reduction in the CNS recurrence rate, but rather a better control of the systemic disease, suggesting that R–CHOP alone may not be a sufficient therapy for the patients with testicular DLBCL involvement,” the investigators wrote.
Intrathecal CNS-targeted therapy did not correlate with improved survival in the study. Likewise, for the entire population, rituximab did not boost survival; however, for high risk patients (International Prognostic Index, 3-5), immunochemotherapy did provide a better rate of 5-year disease-specific survival than that of conventional chemotherapy (44% vs 14%; P = .019).
Treatment of the contralateral testis was worthwhile for the entire population, with a 46% decreased risk of death (HR for overall survival, 0.514, 95% CI, 0.338-0.782; P = .002).
Shortest overall survival times, regardless of treatment type, were reported among patients with poor performance status, elevated lactate dehydrogenase (LDH), primary T-DLBCL, more extranodal sites, higher International Prognostic Index, and patients older than 70 years.
“[O]ur results recommend aggressive chemotherapy with [intravenous high-dose methotrexate and/or high-dose AraC] for better control of systemic disease for eligible patients,” the investigators concluded. “In addition, treatment of the contralateral testis with either radiotherapy or orchiectomy should be included in the management strategy of patients with T-DLBCL.”
The study was funded by the Academy of Finland, the Finnish Cancer Foundation, the Sigrid Juselius Foundation, and others. The investigators reported additional relationships with Pfizer, Takeda, Roche, Sanofi, and others.
SOURCE: Mannisto S et al. Eur J Cancer. 2019 May 10. doi: 10.1016/j.ejca.2019.04.004.
For patients with testicular diffuse large B-cell lymphoma (T-DLBCL), intravenous central nervous system (CNS)–directed chemotherapy and prophylactic treatment of the contralateral testis offer the best survival outcomes, according to findings from a recent retrospective analysis.
In contrast, intrathecal chemotherapy offered no benefit, reported lead author Susanna Mannisto, MD, of Helsinki University Hospital in Finland, and her colleagues. Survival advantages gained by CNS-directed chemotherapy were generally due to control of systemic disease rather than prevention of CNS progression, they noted.
There have not been randomized trials conducted specifically in T-DLBCL and treatment guidelines are currently based on phase 2 trials. Treatment for T-DLBCL typically involves cyclophosphamide, doxorubicin, vincristine, prednisolone plus rituximab (R–CHOP), with the addition of CNS prophylaxis with either intravenous or intrathecal methotrexate or cytarabine (AraC) in eligible patients. “Thus far, however, no prospective randomised studies on the benefit of this approach have been published,” the investigators wrote. The study is in the European Journal of Cancer.
They drew data from the Danish Lymphoma Registry and three Southern Finland University Hospitals. Out of 235 patients diagnosed with T-DLBCL between 1987 and 2013, 192 (82%) were treated with curative anthracycline-based chemotherapy. As some cases dated back to 1987, about one-third (36%) were treated before rituximab was available. A slightly higher proportion received intravenous CNS-directed chemotherapy (40%). Due to data availability, 189 patients were included in the survival analysis.
Results of multivariate analyses showed that CNS-directed chemotherapy (intravenous methotrexate, high-dose AraC, or both), was associated with an approximately 58% decreased risk of death across the entire population (hazard ratio [HR] for overall survival, 0.419; 95% confidence interval, 0.256-0.686; P = .001), with elderly patients realizing the greatest benefit.
“[I]t is important to note that we did not observe reduction in the CNS recurrence rate, but rather a better control of the systemic disease, suggesting that R–CHOP alone may not be a sufficient therapy for the patients with testicular DLBCL involvement,” the investigators wrote.
Intrathecal CNS-targeted therapy did not correlate with improved survival in the study. Likewise, for the entire population, rituximab did not boost survival; however, for high risk patients (International Prognostic Index, 3-5), immunochemotherapy did provide a better rate of 5-year disease-specific survival than that of conventional chemotherapy (44% vs 14%; P = .019).
Treatment of the contralateral testis was worthwhile for the entire population, with a 46% decreased risk of death (HR for overall survival, 0.514, 95% CI, 0.338-0.782; P = .002).
Shortest overall survival times, regardless of treatment type, were reported among patients with poor performance status, elevated lactate dehydrogenase (LDH), primary T-DLBCL, more extranodal sites, higher International Prognostic Index, and patients older than 70 years.
“[O]ur results recommend aggressive chemotherapy with [intravenous high-dose methotrexate and/or high-dose AraC] for better control of systemic disease for eligible patients,” the investigators concluded. “In addition, treatment of the contralateral testis with either radiotherapy or orchiectomy should be included in the management strategy of patients with T-DLBCL.”
The study was funded by the Academy of Finland, the Finnish Cancer Foundation, the Sigrid Juselius Foundation, and others. The investigators reported additional relationships with Pfizer, Takeda, Roche, Sanofi, and others.
SOURCE: Mannisto S et al. Eur J Cancer. 2019 May 10. doi: 10.1016/j.ejca.2019.04.004.
FROM EUROPEAN JOURNAL OF CANCER
On second thought, lenalidomide does improve DLBCL outcomes
LUGANO, Switzerland – Hot on the heels of the phase 3 ROBUST study showing that adding lenalidomide to standard chemotherapy did not improve outcomes for patients with untreated diffuse large B-cell lymphoma come results of a different study showing a significant benefit with the therapy.
Although, as previously reported, adding lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone in ROBUST, results from the randomized phase 2 ECOG-ACRIN 1412 study showed that R2-CHOP was associated with a 34% reduction in the risk of disease progression or death, compared with R-CHOP alone.
“The efficacy endpoints are consistent, with trends toward higher PET complete response rate and improved overall survival with R-squared CHOP,” Grzegorz S. Nowakowski, MD, of the Mayo Clinic, Rochester, Minn., said at the International Conference on Malignant Lymphoma.
So what’s behind the conflicting findings?
The differences between the results of the two studies may be accounted for by the higher lenalidomide dose used in ECOG-ACRIN 1412, the patient populations – all comers in ECOG-ACRIN versus only patients with activated B-cell (ABC) type DLBCL in ROBUST – and by a 10-day shorter median time to treatment in ECOG-ACRIN 1412, said invited discussant Margaret A. Shipp, MD, of the Dana-Farber Cancer Institute in Boston.
The rationale for adding lenalidomide to R-CHOP came from in vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non-germinal center-like B (GCB) type DLBCL.
In a subanalysis of patients enrolled in MC078E, Dr. Nowakowski and colleagues found that using classification of patients by cell of origin with the NanoString Lymphoma Subtype assay, the addition of lenalidomide to R-CHOP “appears to mitigate the negative impact of an ABC molecular subtype on the outcome.”
ECOG-ACRIN 1412 details
Goals of the ECOG-ACRIN 1412 study were to evaluate the effect of lenalidomide both in all DLBCL subtypes and in the ABC subtype, maximize the synergy of the immunomodulator with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) while maintaining R-CHOP dose intensity, and facilitate the enrollment of patients with rapidly progressive disease.
To accomplish the last goal, the study was designed to allow enrollment based on local laboratory findings, scans, and diagnostic pathology, without required identification of the cell of origin. Built in to the design was the plan for final eligibility to be based on central pathology review. In other words, the trial design took into account the likelihood that some enrolled patients would not qualify for eligibility based on later pathology review.
The investigators enrolled 349 adults aged 18 years or older with pathologically confirmed DLBCL (regardless of the cell of origin), stage II bulky to stage IV disease, International Prognostic Index (IPI) scores of 2 or greater, and Eastern Cooperative Oncology Group performance status scores of 2 or less.
The patients were stratified by age (younger than 60 years vs. 60 years and older) and by IPI score (2/3 vs. 4/5), and then randomized to receive either six cycles of R-CHOP or R2-CHOP. Lenalidomide was given in a dose of 25 mg on days 1-10 of each cycle. In contrast, the dose used in ROBUST was 15 mg given on days 1-14 of each cycle.
In ECOG-ACRIN 1412, patients assigned to lenalidomide received mandatory neutropenia prophylaxis with granulocyte-colony stimulating factor.
The time from diagnosis to treatment was a median of 21 days, with only 61 of 280 evaluable patients starting treatment more than 31 days after diagnosis. In ROBUST, the median time to start therapy was 31 days.
Dr. Nowakowski and his colleagues had previously shown that time to treatment is an important prognostic factor in DLBCL.
The efficacy evaluation included 145 patients assigned to R2-CHOP, and 135 assigned to R-CHOP. Primary reasons for exclusion were ineligibity following central pathology review or lack of diagnostic material for review.
After a median follow-up of 2.5 years, R2-CHOP was associated with a 34% improvement in progression-free survival, the primary endpoint (hazard ratio [HR] 0.66, P = .03). The 1-year progression-free survival rates were 83% with R2-CHOP and 73% with R-CHOP. Respective 2-year progression-free survival rates were 76% and 70%.
There was no significant difference, however, in the secondary overall survival endpoints with 1-year and 2-year overall survival of 93% vs. 87% and 86% vs. 80%, respectively.
Similarly, there was no difference in rates of PET-ascertained complete response, at 72% with R2-CHOP and 67% with R-CHOP.
R2-CHOP showed greater benefit across most subgroups, including patients with lower IPI score, patients with bulky disease, patients younger than 60 years, women, and patients with shorter time to treatment. There were also nonsignificant trends hinting at better outcomes with R2-CHOP, regardless of cell of origin.
Toxicities were typical for R-CHOP, although patients on R2-CHOP had significantly higher rates of grade 3 or 4 diarrhea, febrile neutropenia, and thrombocytopenia.
In addition to the trial differences mentioned previously, the differences in outcomes might be explained by the possibility that lenalidomide activity is not restricted to ABC DLBCL, Dr. Shipp said.
“One of the things that’s important to remember about lenalidomide is that it’s an immunomodulating agent and it has also has effects on tumor-infiltrating T cells,” she said.
Differences in response to therapy may also be explained by recent findings showing genetic heterogeneity in transcription-defined ABC DLBCLs, she said.
ECOG-ACRIN 1412 was supported by the National Cancer Institute and by Celgene. Dr. Nowakowski reported consulting/advising for and research funding from Celgene and others. Dr. Shipp reported consulting/advising for Bristol-Myers Squibb, honoraria from BMS and AstraZeneca, and institutional research funding from BMS and Bayer.
SOURCE: Nowakowski GS et al. 15-ICML, Abstract 006.
LUGANO, Switzerland – Hot on the heels of the phase 3 ROBUST study showing that adding lenalidomide to standard chemotherapy did not improve outcomes for patients with untreated diffuse large B-cell lymphoma come results of a different study showing a significant benefit with the therapy.
Although, as previously reported, adding lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone in ROBUST, results from the randomized phase 2 ECOG-ACRIN 1412 study showed that R2-CHOP was associated with a 34% reduction in the risk of disease progression or death, compared with R-CHOP alone.
“The efficacy endpoints are consistent, with trends toward higher PET complete response rate and improved overall survival with R-squared CHOP,” Grzegorz S. Nowakowski, MD, of the Mayo Clinic, Rochester, Minn., said at the International Conference on Malignant Lymphoma.
So what’s behind the conflicting findings?
The differences between the results of the two studies may be accounted for by the higher lenalidomide dose used in ECOG-ACRIN 1412, the patient populations – all comers in ECOG-ACRIN versus only patients with activated B-cell (ABC) type DLBCL in ROBUST – and by a 10-day shorter median time to treatment in ECOG-ACRIN 1412, said invited discussant Margaret A. Shipp, MD, of the Dana-Farber Cancer Institute in Boston.
The rationale for adding lenalidomide to R-CHOP came from in vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non-germinal center-like B (GCB) type DLBCL.
In a subanalysis of patients enrolled in MC078E, Dr. Nowakowski and colleagues found that using classification of patients by cell of origin with the NanoString Lymphoma Subtype assay, the addition of lenalidomide to R-CHOP “appears to mitigate the negative impact of an ABC molecular subtype on the outcome.”
ECOG-ACRIN 1412 details
Goals of the ECOG-ACRIN 1412 study were to evaluate the effect of lenalidomide both in all DLBCL subtypes and in the ABC subtype, maximize the synergy of the immunomodulator with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) while maintaining R-CHOP dose intensity, and facilitate the enrollment of patients with rapidly progressive disease.
To accomplish the last goal, the study was designed to allow enrollment based on local laboratory findings, scans, and diagnostic pathology, without required identification of the cell of origin. Built in to the design was the plan for final eligibility to be based on central pathology review. In other words, the trial design took into account the likelihood that some enrolled patients would not qualify for eligibility based on later pathology review.
The investigators enrolled 349 adults aged 18 years or older with pathologically confirmed DLBCL (regardless of the cell of origin), stage II bulky to stage IV disease, International Prognostic Index (IPI) scores of 2 or greater, and Eastern Cooperative Oncology Group performance status scores of 2 or less.
The patients were stratified by age (younger than 60 years vs. 60 years and older) and by IPI score (2/3 vs. 4/5), and then randomized to receive either six cycles of R-CHOP or R2-CHOP. Lenalidomide was given in a dose of 25 mg on days 1-10 of each cycle. In contrast, the dose used in ROBUST was 15 mg given on days 1-14 of each cycle.
In ECOG-ACRIN 1412, patients assigned to lenalidomide received mandatory neutropenia prophylaxis with granulocyte-colony stimulating factor.
The time from diagnosis to treatment was a median of 21 days, with only 61 of 280 evaluable patients starting treatment more than 31 days after diagnosis. In ROBUST, the median time to start therapy was 31 days.
Dr. Nowakowski and his colleagues had previously shown that time to treatment is an important prognostic factor in DLBCL.
The efficacy evaluation included 145 patients assigned to R2-CHOP, and 135 assigned to R-CHOP. Primary reasons for exclusion were ineligibity following central pathology review or lack of diagnostic material for review.
After a median follow-up of 2.5 years, R2-CHOP was associated with a 34% improvement in progression-free survival, the primary endpoint (hazard ratio [HR] 0.66, P = .03). The 1-year progression-free survival rates were 83% with R2-CHOP and 73% with R-CHOP. Respective 2-year progression-free survival rates were 76% and 70%.
There was no significant difference, however, in the secondary overall survival endpoints with 1-year and 2-year overall survival of 93% vs. 87% and 86% vs. 80%, respectively.
Similarly, there was no difference in rates of PET-ascertained complete response, at 72% with R2-CHOP and 67% with R-CHOP.
R2-CHOP showed greater benefit across most subgroups, including patients with lower IPI score, patients with bulky disease, patients younger than 60 years, women, and patients with shorter time to treatment. There were also nonsignificant trends hinting at better outcomes with R2-CHOP, regardless of cell of origin.
Toxicities were typical for R-CHOP, although patients on R2-CHOP had significantly higher rates of grade 3 or 4 diarrhea, febrile neutropenia, and thrombocytopenia.
In addition to the trial differences mentioned previously, the differences in outcomes might be explained by the possibility that lenalidomide activity is not restricted to ABC DLBCL, Dr. Shipp said.
“One of the things that’s important to remember about lenalidomide is that it’s an immunomodulating agent and it has also has effects on tumor-infiltrating T cells,” she said.
Differences in response to therapy may also be explained by recent findings showing genetic heterogeneity in transcription-defined ABC DLBCLs, she said.
ECOG-ACRIN 1412 was supported by the National Cancer Institute and by Celgene. Dr. Nowakowski reported consulting/advising for and research funding from Celgene and others. Dr. Shipp reported consulting/advising for Bristol-Myers Squibb, honoraria from BMS and AstraZeneca, and institutional research funding from BMS and Bayer.
SOURCE: Nowakowski GS et al. 15-ICML, Abstract 006.
LUGANO, Switzerland – Hot on the heels of the phase 3 ROBUST study showing that adding lenalidomide to standard chemotherapy did not improve outcomes for patients with untreated diffuse large B-cell lymphoma come results of a different study showing a significant benefit with the therapy.
Although, as previously reported, adding lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone in ROBUST, results from the randomized phase 2 ECOG-ACRIN 1412 study showed that R2-CHOP was associated with a 34% reduction in the risk of disease progression or death, compared with R-CHOP alone.
“The efficacy endpoints are consistent, with trends toward higher PET complete response rate and improved overall survival with R-squared CHOP,” Grzegorz S. Nowakowski, MD, of the Mayo Clinic, Rochester, Minn., said at the International Conference on Malignant Lymphoma.
So what’s behind the conflicting findings?
The differences between the results of the two studies may be accounted for by the higher lenalidomide dose used in ECOG-ACRIN 1412, the patient populations – all comers in ECOG-ACRIN versus only patients with activated B-cell (ABC) type DLBCL in ROBUST – and by a 10-day shorter median time to treatment in ECOG-ACRIN 1412, said invited discussant Margaret A. Shipp, MD, of the Dana-Farber Cancer Institute in Boston.
The rationale for adding lenalidomide to R-CHOP came from in vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non-germinal center-like B (GCB) type DLBCL.
In a subanalysis of patients enrolled in MC078E, Dr. Nowakowski and colleagues found that using classification of patients by cell of origin with the NanoString Lymphoma Subtype assay, the addition of lenalidomide to R-CHOP “appears to mitigate the negative impact of an ABC molecular subtype on the outcome.”
ECOG-ACRIN 1412 details
Goals of the ECOG-ACRIN 1412 study were to evaluate the effect of lenalidomide both in all DLBCL subtypes and in the ABC subtype, maximize the synergy of the immunomodulator with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) while maintaining R-CHOP dose intensity, and facilitate the enrollment of patients with rapidly progressive disease.
To accomplish the last goal, the study was designed to allow enrollment based on local laboratory findings, scans, and diagnostic pathology, without required identification of the cell of origin. Built in to the design was the plan for final eligibility to be based on central pathology review. In other words, the trial design took into account the likelihood that some enrolled patients would not qualify for eligibility based on later pathology review.
The investigators enrolled 349 adults aged 18 years or older with pathologically confirmed DLBCL (regardless of the cell of origin), stage II bulky to stage IV disease, International Prognostic Index (IPI) scores of 2 or greater, and Eastern Cooperative Oncology Group performance status scores of 2 or less.
The patients were stratified by age (younger than 60 years vs. 60 years and older) and by IPI score (2/3 vs. 4/5), and then randomized to receive either six cycles of R-CHOP or R2-CHOP. Lenalidomide was given in a dose of 25 mg on days 1-10 of each cycle. In contrast, the dose used in ROBUST was 15 mg given on days 1-14 of each cycle.
In ECOG-ACRIN 1412, patients assigned to lenalidomide received mandatory neutropenia prophylaxis with granulocyte-colony stimulating factor.
The time from diagnosis to treatment was a median of 21 days, with only 61 of 280 evaluable patients starting treatment more than 31 days after diagnosis. In ROBUST, the median time to start therapy was 31 days.
Dr. Nowakowski and his colleagues had previously shown that time to treatment is an important prognostic factor in DLBCL.
The efficacy evaluation included 145 patients assigned to R2-CHOP, and 135 assigned to R-CHOP. Primary reasons for exclusion were ineligibity following central pathology review or lack of diagnostic material for review.
After a median follow-up of 2.5 years, R2-CHOP was associated with a 34% improvement in progression-free survival, the primary endpoint (hazard ratio [HR] 0.66, P = .03). The 1-year progression-free survival rates were 83% with R2-CHOP and 73% with R-CHOP. Respective 2-year progression-free survival rates were 76% and 70%.
There was no significant difference, however, in the secondary overall survival endpoints with 1-year and 2-year overall survival of 93% vs. 87% and 86% vs. 80%, respectively.
Similarly, there was no difference in rates of PET-ascertained complete response, at 72% with R2-CHOP and 67% with R-CHOP.
R2-CHOP showed greater benefit across most subgroups, including patients with lower IPI score, patients with bulky disease, patients younger than 60 years, women, and patients with shorter time to treatment. There were also nonsignificant trends hinting at better outcomes with R2-CHOP, regardless of cell of origin.
Toxicities were typical for R-CHOP, although patients on R2-CHOP had significantly higher rates of grade 3 or 4 diarrhea, febrile neutropenia, and thrombocytopenia.
In addition to the trial differences mentioned previously, the differences in outcomes might be explained by the possibility that lenalidomide activity is not restricted to ABC DLBCL, Dr. Shipp said.
“One of the things that’s important to remember about lenalidomide is that it’s an immunomodulating agent and it has also has effects on tumor-infiltrating T cells,” she said.
Differences in response to therapy may also be explained by recent findings showing genetic heterogeneity in transcription-defined ABC DLBCLs, she said.
ECOG-ACRIN 1412 was supported by the National Cancer Institute and by Celgene. Dr. Nowakowski reported consulting/advising for and research funding from Celgene and others. Dr. Shipp reported consulting/advising for Bristol-Myers Squibb, honoraria from BMS and AstraZeneca, and institutional research funding from BMS and Bayer.
SOURCE: Nowakowski GS et al. 15-ICML, Abstract 006.
REPORTING FROM 15-ICML
Obesity tied to relapse in young patients with multiple sclerosis
, results of a recent large, single-center study show. The rate of switching to second-line disease-modifying therapy was consequently about 50% higher among the obese children in the study, which included a total of 453 pediatric patients.
The link between obesity and treatment response suggests that the management of these younger patients with MS could be improved through weight loss or body mass index (BMI)-adjusted dosing, according to Peter Huppke, MD, of Georg August University in Göttingen, Germany, and co-investigators.
“The findings do not indicate that obesity promotes greater disease activity, but pharmacokinetic factors are more likely associated with treatment response,” Dr. Huppke and co-authors said in a report on their study, which was published online ahead of print July 15 in JAMA Neurology.
This is believed to be the first-ever study to find an association between BMI and treatment response in pediatric patients with MS, according to the authors, who said they also confirmed a link between obesity and MS.
Specifically, obesity increased MS susceptibility by two-fold as compared with healthy controls, a finding that they said adds to a small but growing body of evidence that high BMI is associated with increased risk of the disease in these younger individuals.
This retrospective study included 453 pediatric patients with MS treated at the Center for MS in Childhood and Adolescence in Göttingen, Germany between 1990 and 2016. About two-thirds were female and the mean age at MS diagnosis was about 14 years.
Of those patients, 126 (27.8%) were classified as obese based on a BMI greater than the 90th percentile, according to the report.
Dr. Huppke and co-investigators found that high BMI was linked to a significantly increased odds of pediatric MS, with odds ratios of 2.19 (95% CI, 1.5-3.1; P < 0.001) in girls and 2.14 (95% CI, 1.3-3.5; P = 0.003) in boys.
A total of 277 of these pediatric patients received a first-line disease-modifying therapy for 6 months or longer, including 249 treated with interferon beta and 51 treated with glatiramer.
Relapses were more common in obese patients, according to the report. with an annualized relapse rate of 1.29, compared to just 0.72 for those who were not overweight (P < 0.001).
Consequently, likelihood of receiving a second-line treatment was about 1.5 times higher in the obese or extremely obese patients, investigators said.
“A healthy weight may potentially optimize treatment outcomes and reduce disease-related burden and health care costs,” they concluded in the report, adding that BMI-adjusted dosing may “increase the value” of first-line disease-modifying therapies.
Dr. Huppke reported disclosures related to Bayer Health Care, Merck Serono, and Novartis not associated with the current study.
SOURCE: Huppke B, et al. JAMA Neurol. 2019 Jul 15. doi: 10.1001/jamaneurol.2019.1997
, results of a recent large, single-center study show. The rate of switching to second-line disease-modifying therapy was consequently about 50% higher among the obese children in the study, which included a total of 453 pediatric patients.
The link between obesity and treatment response suggests that the management of these younger patients with MS could be improved through weight loss or body mass index (BMI)-adjusted dosing, according to Peter Huppke, MD, of Georg August University in Göttingen, Germany, and co-investigators.
“The findings do not indicate that obesity promotes greater disease activity, but pharmacokinetic factors are more likely associated with treatment response,” Dr. Huppke and co-authors said in a report on their study, which was published online ahead of print July 15 in JAMA Neurology.
This is believed to be the first-ever study to find an association between BMI and treatment response in pediatric patients with MS, according to the authors, who said they also confirmed a link between obesity and MS.
Specifically, obesity increased MS susceptibility by two-fold as compared with healthy controls, a finding that they said adds to a small but growing body of evidence that high BMI is associated with increased risk of the disease in these younger individuals.
This retrospective study included 453 pediatric patients with MS treated at the Center for MS in Childhood and Adolescence in Göttingen, Germany between 1990 and 2016. About two-thirds were female and the mean age at MS diagnosis was about 14 years.
Of those patients, 126 (27.8%) were classified as obese based on a BMI greater than the 90th percentile, according to the report.
Dr. Huppke and co-investigators found that high BMI was linked to a significantly increased odds of pediatric MS, with odds ratios of 2.19 (95% CI, 1.5-3.1; P < 0.001) in girls and 2.14 (95% CI, 1.3-3.5; P = 0.003) in boys.
A total of 277 of these pediatric patients received a first-line disease-modifying therapy for 6 months or longer, including 249 treated with interferon beta and 51 treated with glatiramer.
Relapses were more common in obese patients, according to the report. with an annualized relapse rate of 1.29, compared to just 0.72 for those who were not overweight (P < 0.001).
Consequently, likelihood of receiving a second-line treatment was about 1.5 times higher in the obese or extremely obese patients, investigators said.
“A healthy weight may potentially optimize treatment outcomes and reduce disease-related burden and health care costs,” they concluded in the report, adding that BMI-adjusted dosing may “increase the value” of first-line disease-modifying therapies.
Dr. Huppke reported disclosures related to Bayer Health Care, Merck Serono, and Novartis not associated with the current study.
SOURCE: Huppke B, et al. JAMA Neurol. 2019 Jul 15. doi: 10.1001/jamaneurol.2019.1997
, results of a recent large, single-center study show. The rate of switching to second-line disease-modifying therapy was consequently about 50% higher among the obese children in the study, which included a total of 453 pediatric patients.
The link between obesity and treatment response suggests that the management of these younger patients with MS could be improved through weight loss or body mass index (BMI)-adjusted dosing, according to Peter Huppke, MD, of Georg August University in Göttingen, Germany, and co-investigators.
“The findings do not indicate that obesity promotes greater disease activity, but pharmacokinetic factors are more likely associated with treatment response,” Dr. Huppke and co-authors said in a report on their study, which was published online ahead of print July 15 in JAMA Neurology.
This is believed to be the first-ever study to find an association between BMI and treatment response in pediatric patients with MS, according to the authors, who said they also confirmed a link between obesity and MS.
Specifically, obesity increased MS susceptibility by two-fold as compared with healthy controls, a finding that they said adds to a small but growing body of evidence that high BMI is associated with increased risk of the disease in these younger individuals.
This retrospective study included 453 pediatric patients with MS treated at the Center for MS in Childhood and Adolescence in Göttingen, Germany between 1990 and 2016. About two-thirds were female and the mean age at MS diagnosis was about 14 years.
Of those patients, 126 (27.8%) were classified as obese based on a BMI greater than the 90th percentile, according to the report.
Dr. Huppke and co-investigators found that high BMI was linked to a significantly increased odds of pediatric MS, with odds ratios of 2.19 (95% CI, 1.5-3.1; P < 0.001) in girls and 2.14 (95% CI, 1.3-3.5; P = 0.003) in boys.
A total of 277 of these pediatric patients received a first-line disease-modifying therapy for 6 months or longer, including 249 treated with interferon beta and 51 treated with glatiramer.
Relapses were more common in obese patients, according to the report. with an annualized relapse rate of 1.29, compared to just 0.72 for those who were not overweight (P < 0.001).
Consequently, likelihood of receiving a second-line treatment was about 1.5 times higher in the obese or extremely obese patients, investigators said.
“A healthy weight may potentially optimize treatment outcomes and reduce disease-related burden and health care costs,” they concluded in the report, adding that BMI-adjusted dosing may “increase the value” of first-line disease-modifying therapies.
Dr. Huppke reported disclosures related to Bayer Health Care, Merck Serono, and Novartis not associated with the current study.
SOURCE: Huppke B, et al. JAMA Neurol. 2019 Jul 15. doi: 10.1001/jamaneurol.2019.1997
FROM JAMA NEUROLOGY
Key clinical point: Obese children and adolescents with MS had about twice as many relapses on first-line treatment as compared with their non-obese counterparts.
Major finding: The annualized relapse rate was 1.29 for obese pediatric patients, compared to 0.72 for those who were not overweight (P < 0.001).
Study details: Retrospective study including 453 patients with pediatric MS treated at a center in Göttingen, Germany between 1990 and 2016.
Disclosures: The senior author reported disclosures related to Bayer Health Care, Merck Serono, and Novartis unrelated to the this study.
Source: Huppke B, et al. JAMA Neurol. 2019 Jul 15.
Nerve transfer improves function after spinal cord injury
according to research published online July 4 ahead of print in the Lancet. Combining nerve transfer with tendon transfer may maximize the functional benefit of surgery.
The loss of upper extremity function after cervical spinal cord injury can reduce independence and social and vocational engagement. People with tetraplegia rank improvement in hand function as their most important goal. Tendon transfers have been the traditional method of restoring function, but interest in nerve transfers has been increasing with the publication of successful results. Nerve transfers can reanimate several muscles at once and require a smaller incision and shorter immobilization, compared with tendon transfers.
Injury had occurred less than 18 months previously
Natasha van Zyl, MBBS, a plastic and reconstructive surgeon at Austin Health in Melbourne, and colleagues conducted a prospective case series to examine the clinical and functional outcomes of nerve transfer surgery for the reanimation of upper limb function in patients with tetraplegia. The investigators also sought to compare these outcomes with published outcomes for tendon transfer surgery.
Between April 14, 2014, and Nov. 22, 2018, Dr. van Zyl and colleagues recruited consecutive patients of any age with early cervical spinal cord injury of motor level C5 and below. Injury was required to have occurred fewer than 18 months before enrollment. Eligible participants had been referred to a single center for upper extremity reanimation and were considered candidates for nerve transfer.
Every participant underwent single or multiple nerve transfers in one or both upper limbs, and some participants also underwent tendon transfers. The goal of surgery was the restoration of elbow extension, grasp, pinch, and hand opening. An independent assessor evaluated participants at baseline and at 12 months and 24 months after surgery. The primary outcome measures were the action research arm test (ARAT), the grasp release test (GRT), and the spinal cord independence measure (SCIM).
Grasp function improved significantly
Dr. van Zyl and colleagues recruited 16 participants with traumatic spinal cord injury who underwent 59 nerve transfers. Ten participants also underwent tendon transfers. The population’s mean age at time of injury was 27.3 years. Three patients were female. Motor vehicle accidents were the most common cause of injury (31%). Follow-up data at 24 months were unavailable for three patients.
Participants’ median ARAT total score significantly improved from 16.5 at baseline to 34.0 at 24 months. Median GRT total score significantly improved from 35.0 at baseline to 125.2 at 24 months. The population’s mean total SCIM score and mobility in the room and toilet SCIM score improved by more than the minimal detectable change and the minimal clinically important difference. The mean self-care SCIM score improved by more than the minimal detectable change between baseline and 24 months.
The researchers observed six adverse events related to the surgery, but none had sustained functional consequences. No patients had an increase in musculoskeletal or neuropathic pain. Four of the 50 nerve transfers with 24-month follow-up failed.
A novel technique
“This project is the first to comprehensively examine outcomes for early, multiple nerve transfer surgery in the upper limbs of people with tetraplegia following traumatic spinal cord injury and is the largest prospective series of nerve transfers reported in this population to date,” said Dr. van Zyl and colleagues. Study limitations included the small sample size, the high variability of spinal cord injury patterns, and the potential for the multiple procedures that each participant underwent to confound data analysis.
Future research could explore whether nerve transfers are beneficial at more than 24 months after spinal cord injury, wrote the authors. In addition, it is unclear whether function and strength continue to improve beyond 24 months after surgery.
The study was funded by the Institute for Safety, Compensation, and Recovery Research in Australia. The authors had no competing interests.
SOURCE: van Zyl N et al. Lancet. 2019 Jul 4. doi: 10.1016/S0140-6736(19)31143-2.
The data from van Zyl et al. suggest that nerve transfers restore more natural movement and finer motor control than tendon transfers do, said Elspeth J.R. Hill, MD, PhD, and Ida K. Fox, MD, plastic and reconstructive surgeons at Washington University in St. Louis, in an accompanying editorial. Patients can engage in light activity immediately after surgery, and cortical plasticity enables function to improve over time. Two disadvantages of nerve transfers, however, are that it takes months before new motion can be observed, and years before full strength can be regained.
The heterogeneity of cervical spinal cord injury requires an individualized approach to surgical assessment and management, they continued. Physicians and patients should make treatment decisions collaboratively. “We envisage a role for nerve transfers in settings where the intensive therapy and immobilization required to optimize complementary tendon transfers are unavailable,” wrote Dr. Hill and Dr. Fox.
Continuing research will be necessary to improve surgical technique and outcomes. “This research should include efforts to compare nerve transfer with tendon transfer, find the optimal timing of such surgeries, and determine which approach produces the greatest functional improvement,” they wrote. “Detailed study of the reasons for nerve transfer failure is also required, as is improving our understanding of the effects of biopsychosocial factors, including access to information and care, psychological readiness, and social support, on patient decision making and outcomes.”
Nerve transfers are a “huge advance” in the restoration of function after spinal cord injury, the authors added. “Surgeons who integrate nerve transfers into their spinal cord injury practice should take a careful and measured approach and rigorously study and disseminate their outcomes to advance this growing field,” they concluded.
The data from van Zyl et al. suggest that nerve transfers restore more natural movement and finer motor control than tendon transfers do, said Elspeth J.R. Hill, MD, PhD, and Ida K. Fox, MD, plastic and reconstructive surgeons at Washington University in St. Louis, in an accompanying editorial. Patients can engage in light activity immediately after surgery, and cortical plasticity enables function to improve over time. Two disadvantages of nerve transfers, however, are that it takes months before new motion can be observed, and years before full strength can be regained.
The heterogeneity of cervical spinal cord injury requires an individualized approach to surgical assessment and management, they continued. Physicians and patients should make treatment decisions collaboratively. “We envisage a role for nerve transfers in settings where the intensive therapy and immobilization required to optimize complementary tendon transfers are unavailable,” wrote Dr. Hill and Dr. Fox.
Continuing research will be necessary to improve surgical technique and outcomes. “This research should include efforts to compare nerve transfer with tendon transfer, find the optimal timing of such surgeries, and determine which approach produces the greatest functional improvement,” they wrote. “Detailed study of the reasons for nerve transfer failure is also required, as is improving our understanding of the effects of biopsychosocial factors, including access to information and care, psychological readiness, and social support, on patient decision making and outcomes.”
Nerve transfers are a “huge advance” in the restoration of function after spinal cord injury, the authors added. “Surgeons who integrate nerve transfers into their spinal cord injury practice should take a careful and measured approach and rigorously study and disseminate their outcomes to advance this growing field,” they concluded.
The data from van Zyl et al. suggest that nerve transfers restore more natural movement and finer motor control than tendon transfers do, said Elspeth J.R. Hill, MD, PhD, and Ida K. Fox, MD, plastic and reconstructive surgeons at Washington University in St. Louis, in an accompanying editorial. Patients can engage in light activity immediately after surgery, and cortical plasticity enables function to improve over time. Two disadvantages of nerve transfers, however, are that it takes months before new motion can be observed, and years before full strength can be regained.
The heterogeneity of cervical spinal cord injury requires an individualized approach to surgical assessment and management, they continued. Physicians and patients should make treatment decisions collaboratively. “We envisage a role for nerve transfers in settings where the intensive therapy and immobilization required to optimize complementary tendon transfers are unavailable,” wrote Dr. Hill and Dr. Fox.
Continuing research will be necessary to improve surgical technique and outcomes. “This research should include efforts to compare nerve transfer with tendon transfer, find the optimal timing of such surgeries, and determine which approach produces the greatest functional improvement,” they wrote. “Detailed study of the reasons for nerve transfer failure is also required, as is improving our understanding of the effects of biopsychosocial factors, including access to information and care, psychological readiness, and social support, on patient decision making and outcomes.”
Nerve transfers are a “huge advance” in the restoration of function after spinal cord injury, the authors added. “Surgeons who integrate nerve transfers into their spinal cord injury practice should take a careful and measured approach and rigorously study and disseminate their outcomes to advance this growing field,” they concluded.
according to research published online July 4 ahead of print in the Lancet. Combining nerve transfer with tendon transfer may maximize the functional benefit of surgery.
The loss of upper extremity function after cervical spinal cord injury can reduce independence and social and vocational engagement. People with tetraplegia rank improvement in hand function as their most important goal. Tendon transfers have been the traditional method of restoring function, but interest in nerve transfers has been increasing with the publication of successful results. Nerve transfers can reanimate several muscles at once and require a smaller incision and shorter immobilization, compared with tendon transfers.
Injury had occurred less than 18 months previously
Natasha van Zyl, MBBS, a plastic and reconstructive surgeon at Austin Health in Melbourne, and colleagues conducted a prospective case series to examine the clinical and functional outcomes of nerve transfer surgery for the reanimation of upper limb function in patients with tetraplegia. The investigators also sought to compare these outcomes with published outcomes for tendon transfer surgery.
Between April 14, 2014, and Nov. 22, 2018, Dr. van Zyl and colleagues recruited consecutive patients of any age with early cervical spinal cord injury of motor level C5 and below. Injury was required to have occurred fewer than 18 months before enrollment. Eligible participants had been referred to a single center for upper extremity reanimation and were considered candidates for nerve transfer.
Every participant underwent single or multiple nerve transfers in one or both upper limbs, and some participants also underwent tendon transfers. The goal of surgery was the restoration of elbow extension, grasp, pinch, and hand opening. An independent assessor evaluated participants at baseline and at 12 months and 24 months after surgery. The primary outcome measures were the action research arm test (ARAT), the grasp release test (GRT), and the spinal cord independence measure (SCIM).
Grasp function improved significantly
Dr. van Zyl and colleagues recruited 16 participants with traumatic spinal cord injury who underwent 59 nerve transfers. Ten participants also underwent tendon transfers. The population’s mean age at time of injury was 27.3 years. Three patients were female. Motor vehicle accidents were the most common cause of injury (31%). Follow-up data at 24 months were unavailable for three patients.
Participants’ median ARAT total score significantly improved from 16.5 at baseline to 34.0 at 24 months. Median GRT total score significantly improved from 35.0 at baseline to 125.2 at 24 months. The population’s mean total SCIM score and mobility in the room and toilet SCIM score improved by more than the minimal detectable change and the minimal clinically important difference. The mean self-care SCIM score improved by more than the minimal detectable change between baseline and 24 months.
The researchers observed six adverse events related to the surgery, but none had sustained functional consequences. No patients had an increase in musculoskeletal or neuropathic pain. Four of the 50 nerve transfers with 24-month follow-up failed.
A novel technique
“This project is the first to comprehensively examine outcomes for early, multiple nerve transfer surgery in the upper limbs of people with tetraplegia following traumatic spinal cord injury and is the largest prospective series of nerve transfers reported in this population to date,” said Dr. van Zyl and colleagues. Study limitations included the small sample size, the high variability of spinal cord injury patterns, and the potential for the multiple procedures that each participant underwent to confound data analysis.
Future research could explore whether nerve transfers are beneficial at more than 24 months after spinal cord injury, wrote the authors. In addition, it is unclear whether function and strength continue to improve beyond 24 months after surgery.
The study was funded by the Institute for Safety, Compensation, and Recovery Research in Australia. The authors had no competing interests.
SOURCE: van Zyl N et al. Lancet. 2019 Jul 4. doi: 10.1016/S0140-6736(19)31143-2.
according to research published online July 4 ahead of print in the Lancet. Combining nerve transfer with tendon transfer may maximize the functional benefit of surgery.
The loss of upper extremity function after cervical spinal cord injury can reduce independence and social and vocational engagement. People with tetraplegia rank improvement in hand function as their most important goal. Tendon transfers have been the traditional method of restoring function, but interest in nerve transfers has been increasing with the publication of successful results. Nerve transfers can reanimate several muscles at once and require a smaller incision and shorter immobilization, compared with tendon transfers.
Injury had occurred less than 18 months previously
Natasha van Zyl, MBBS, a plastic and reconstructive surgeon at Austin Health in Melbourne, and colleagues conducted a prospective case series to examine the clinical and functional outcomes of nerve transfer surgery for the reanimation of upper limb function in patients with tetraplegia. The investigators also sought to compare these outcomes with published outcomes for tendon transfer surgery.
Between April 14, 2014, and Nov. 22, 2018, Dr. van Zyl and colleagues recruited consecutive patients of any age with early cervical spinal cord injury of motor level C5 and below. Injury was required to have occurred fewer than 18 months before enrollment. Eligible participants had been referred to a single center for upper extremity reanimation and were considered candidates for nerve transfer.
Every participant underwent single or multiple nerve transfers in one or both upper limbs, and some participants also underwent tendon transfers. The goal of surgery was the restoration of elbow extension, grasp, pinch, and hand opening. An independent assessor evaluated participants at baseline and at 12 months and 24 months after surgery. The primary outcome measures were the action research arm test (ARAT), the grasp release test (GRT), and the spinal cord independence measure (SCIM).
Grasp function improved significantly
Dr. van Zyl and colleagues recruited 16 participants with traumatic spinal cord injury who underwent 59 nerve transfers. Ten participants also underwent tendon transfers. The population’s mean age at time of injury was 27.3 years. Three patients were female. Motor vehicle accidents were the most common cause of injury (31%). Follow-up data at 24 months were unavailable for three patients.
Participants’ median ARAT total score significantly improved from 16.5 at baseline to 34.0 at 24 months. Median GRT total score significantly improved from 35.0 at baseline to 125.2 at 24 months. The population’s mean total SCIM score and mobility in the room and toilet SCIM score improved by more than the minimal detectable change and the minimal clinically important difference. The mean self-care SCIM score improved by more than the minimal detectable change between baseline and 24 months.
The researchers observed six adverse events related to the surgery, but none had sustained functional consequences. No patients had an increase in musculoskeletal or neuropathic pain. Four of the 50 nerve transfers with 24-month follow-up failed.
A novel technique
“This project is the first to comprehensively examine outcomes for early, multiple nerve transfer surgery in the upper limbs of people with tetraplegia following traumatic spinal cord injury and is the largest prospective series of nerve transfers reported in this population to date,” said Dr. van Zyl and colleagues. Study limitations included the small sample size, the high variability of spinal cord injury patterns, and the potential for the multiple procedures that each participant underwent to confound data analysis.
Future research could explore whether nerve transfers are beneficial at more than 24 months after spinal cord injury, wrote the authors. In addition, it is unclear whether function and strength continue to improve beyond 24 months after surgery.
The study was funded by the Institute for Safety, Compensation, and Recovery Research in Australia. The authors had no competing interests.
SOURCE: van Zyl N et al. Lancet. 2019 Jul 4. doi: 10.1016/S0140-6736(19)31143-2.
FROM LANCET
Interview with Mary Alissa Willis, MD, on MS and Mental Health
Mary Alissa Willis, MD, is the Medical Director for the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. We spoke with Dr. Willis about mental health issues in persons with MS and what health care facilities can do to better care for these patients.
What is the prevalence of depression in patients with MS?
Depression and anxiety are common in persons with multiple sclerosis (PwMS). In a systematic review, Ruth Ann Marrie, MD, PhD, and colleagues estimated the prevalence of depression in PwMS to be 23.7%. Approximately half of all PwMS experience depression at some point after their diagnosis.1-3 This makes depression nearly twice as common in MS as in the general population.
What are some reasons patients with MS might begin to experience depression? What are some warning signs to look out for?
Many people assume that PwMS experience depression because of psychosocial stressors, unpredictability of disease progression, or poor coping strategies. Although these factors do contribute to depression, there is increasing evidence that immune dysregulation and structural changes in the brain caused by MS disease activity make some PwMS uniquely vulnerable to depression. Functional MRI studies have shown abnormalities in the prefrontal-subcortical network connectivity, which is involved in mood regulation. In addition, persistent somatic symptoms such as severe pain and fatigue limit daily activities and social participation—generally considered to be protective factors in depression.4 Warning signs for depression include loss of interest in activities, weight loss or weight gain, changes in sleep—too much or too little, an increase in fatigue, expressions of hopelessness or guilt, or increasing drug or alcohol use.
What are some special considerations for patients with MS battling suicidal ideation?
Anthony Feinstein, MBBCh, MPhil, PhD, and colleagues reported that more than 28% of PwMS had suicidal ideation at some point.5 This is a huge number of people struggling with thoughts of suicide. Depression is a risk factor for suicide but other risks specific to PwMS include perceived loss of control, loss of job/income/social roles, loss of driving privileges, and marked physical or cognitive difficulties. While we are doing a better job screening for depression with quick screening tools such as the PHQ9, we could do better in suicide risk assessment.
What can health care providers do better to address depression and risk for suicide? What safety/preventative measures can they take?
The first step in better addressing depression and risk for suicide is to directly ask patients. Pay attention to changes in appearance, behavior, requests for prescription refills, frequency of appointments, and who accompanies patients to appointments. Explore the reasons for these changes. It is important to respond proactively when comments or behavior suggest a patient at risk. Ask specific questions about plan, access to means, previous suicide attempts, and support network. Refer promptly for emergency or mental health services when appropriate. Familiarity with mental health colleagues, local crisis centers, and helplines can be helpful in engaging a team of people to provide assistance to a patient in need.
References
1. Marrie RA, Fisk JD, Tremlett H, et al. Differences in the burden of psychiatric comorbidity in MS vs the general population. Neurology. 2015;85(22):1972-1979.
2. Minden SL, Schiffer RB. Affective disorders in multiple sclerosis. Review and recommendations for clinical research. Arch Neurol. 1990;47(1):98-104.
3. Marrie RA, Walld R, Bolton JM, et al; CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Estimating annual prevalence of depression and anxiety disorder in multiple sclerosis using administrative data. BMC Res Notes. 2017;10(1):619.
4. Passamonti L. Cerasa A, Liguori M, et al. Neurobiological mechanisms underlying emotional processing in relapsing-remitting multiple sclerosis. Brain. 2009;132(pt 12):3380-3391.
5. Feinstein A. An examination of suicidal intent in patients with multiple sclerosis. Neurology. 2002;59(5):674-678.
Mary Alissa Willis, MD, is the Medical Director for the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. We spoke with Dr. Willis about mental health issues in persons with MS and what health care facilities can do to better care for these patients.
What is the prevalence of depression in patients with MS?
Depression and anxiety are common in persons with multiple sclerosis (PwMS). In a systematic review, Ruth Ann Marrie, MD, PhD, and colleagues estimated the prevalence of depression in PwMS to be 23.7%. Approximately half of all PwMS experience depression at some point after their diagnosis.1-3 This makes depression nearly twice as common in MS as in the general population.
What are some reasons patients with MS might begin to experience depression? What are some warning signs to look out for?
Many people assume that PwMS experience depression because of psychosocial stressors, unpredictability of disease progression, or poor coping strategies. Although these factors do contribute to depression, there is increasing evidence that immune dysregulation and structural changes in the brain caused by MS disease activity make some PwMS uniquely vulnerable to depression. Functional MRI studies have shown abnormalities in the prefrontal-subcortical network connectivity, which is involved in mood regulation. In addition, persistent somatic symptoms such as severe pain and fatigue limit daily activities and social participation—generally considered to be protective factors in depression.4 Warning signs for depression include loss of interest in activities, weight loss or weight gain, changes in sleep—too much or too little, an increase in fatigue, expressions of hopelessness or guilt, or increasing drug or alcohol use.
What are some special considerations for patients with MS battling suicidal ideation?
Anthony Feinstein, MBBCh, MPhil, PhD, and colleagues reported that more than 28% of PwMS had suicidal ideation at some point.5 This is a huge number of people struggling with thoughts of suicide. Depression is a risk factor for suicide but other risks specific to PwMS include perceived loss of control, loss of job/income/social roles, loss of driving privileges, and marked physical or cognitive difficulties. While we are doing a better job screening for depression with quick screening tools such as the PHQ9, we could do better in suicide risk assessment.
What can health care providers do better to address depression and risk for suicide? What safety/preventative measures can they take?
The first step in better addressing depression and risk for suicide is to directly ask patients. Pay attention to changes in appearance, behavior, requests for prescription refills, frequency of appointments, and who accompanies patients to appointments. Explore the reasons for these changes. It is important to respond proactively when comments or behavior suggest a patient at risk. Ask specific questions about plan, access to means, previous suicide attempts, and support network. Refer promptly for emergency or mental health services when appropriate. Familiarity with mental health colleagues, local crisis centers, and helplines can be helpful in engaging a team of people to provide assistance to a patient in need.
References
1. Marrie RA, Fisk JD, Tremlett H, et al. Differences in the burden of psychiatric comorbidity in MS vs the general population. Neurology. 2015;85(22):1972-1979.
2. Minden SL, Schiffer RB. Affective disorders in multiple sclerosis. Review and recommendations for clinical research. Arch Neurol. 1990;47(1):98-104.
3. Marrie RA, Walld R, Bolton JM, et al; CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Estimating annual prevalence of depression and anxiety disorder in multiple sclerosis using administrative data. BMC Res Notes. 2017;10(1):619.
4. Passamonti L. Cerasa A, Liguori M, et al. Neurobiological mechanisms underlying emotional processing in relapsing-remitting multiple sclerosis. Brain. 2009;132(pt 12):3380-3391.
5. Feinstein A. An examination of suicidal intent in patients with multiple sclerosis. Neurology. 2002;59(5):674-678.
Mary Alissa Willis, MD, is the Medical Director for the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. We spoke with Dr. Willis about mental health issues in persons with MS and what health care facilities can do to better care for these patients.
What is the prevalence of depression in patients with MS?
Depression and anxiety are common in persons with multiple sclerosis (PwMS). In a systematic review, Ruth Ann Marrie, MD, PhD, and colleagues estimated the prevalence of depression in PwMS to be 23.7%. Approximately half of all PwMS experience depression at some point after their diagnosis.1-3 This makes depression nearly twice as common in MS as in the general population.
What are some reasons patients with MS might begin to experience depression? What are some warning signs to look out for?
Many people assume that PwMS experience depression because of psychosocial stressors, unpredictability of disease progression, or poor coping strategies. Although these factors do contribute to depression, there is increasing evidence that immune dysregulation and structural changes in the brain caused by MS disease activity make some PwMS uniquely vulnerable to depression. Functional MRI studies have shown abnormalities in the prefrontal-subcortical network connectivity, which is involved in mood regulation. In addition, persistent somatic symptoms such as severe pain and fatigue limit daily activities and social participation—generally considered to be protective factors in depression.4 Warning signs for depression include loss of interest in activities, weight loss or weight gain, changes in sleep—too much or too little, an increase in fatigue, expressions of hopelessness or guilt, or increasing drug or alcohol use.
What are some special considerations for patients with MS battling suicidal ideation?
Anthony Feinstein, MBBCh, MPhil, PhD, and colleagues reported that more than 28% of PwMS had suicidal ideation at some point.5 This is a huge number of people struggling with thoughts of suicide. Depression is a risk factor for suicide but other risks specific to PwMS include perceived loss of control, loss of job/income/social roles, loss of driving privileges, and marked physical or cognitive difficulties. While we are doing a better job screening for depression with quick screening tools such as the PHQ9, we could do better in suicide risk assessment.
What can health care providers do better to address depression and risk for suicide? What safety/preventative measures can they take?
The first step in better addressing depression and risk for suicide is to directly ask patients. Pay attention to changes in appearance, behavior, requests for prescription refills, frequency of appointments, and who accompanies patients to appointments. Explore the reasons for these changes. It is important to respond proactively when comments or behavior suggest a patient at risk. Ask specific questions about plan, access to means, previous suicide attempts, and support network. Refer promptly for emergency or mental health services when appropriate. Familiarity with mental health colleagues, local crisis centers, and helplines can be helpful in engaging a team of people to provide assistance to a patient in need.
References
1. Marrie RA, Fisk JD, Tremlett H, et al. Differences in the burden of psychiatric comorbidity in MS vs the general population. Neurology. 2015;85(22):1972-1979.
2. Minden SL, Schiffer RB. Affective disorders in multiple sclerosis. Review and recommendations for clinical research. Arch Neurol. 1990;47(1):98-104.
3. Marrie RA, Walld R, Bolton JM, et al; CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Estimating annual prevalence of depression and anxiety disorder in multiple sclerosis using administrative data. BMC Res Notes. 2017;10(1):619.
4. Passamonti L. Cerasa A, Liguori M, et al. Neurobiological mechanisms underlying emotional processing in relapsing-remitting multiple sclerosis. Brain. 2009;132(pt 12):3380-3391.
5. Feinstein A. An examination of suicidal intent in patients with multiple sclerosis. Neurology. 2002;59(5):674-678.
