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Acalabrutinib shows less off-target activity in mantle cell lymphoma
A new Bruton tyrosine kinase inhibitor has shown a high response rate and favorable safety profile in the treatment of patients with mantle cell lymphoma.
Researchers reported the results of an open-label, phase 2 study of oral acalabrutinib (100 mg, twice daily) in 124 patients with relapsed or refractory mantle cell lymphoma in The Lancet. Acalabrutinib (Calquence) received accelerated approval from the Food and Drug Administration in October 2017 for treatment of adults with mantle cell lymphoma who have received at least one prior therapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica), which was approved in 2013 for the treatment of mantle cell lymphoma, has been associated with side effects including atrial fibrillation, infections and bleeding, likely due to its off-target activity against other kinases. But acalabrutinib (ACP-196) “is a highly selective, potent BTK inhibitor developed to minimise off-target activity,” wrote Michael Wang, MD, of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
After a median follow-up of 15.2 months, 81% of patients in the study achieved an investigator-assessed overall response based on Lugano classification, with 40% achieving a complete response. The results were similar according to an independent review committee evaluation of responses based on CT and PET scans, bone-marrow biopsy specimens, endoscopy results, and clinical data.
There was also a reduction in lymphadenopathy seen in 94% of patients. The patients who showed a complete response took a median of 3.4 months to get there, and the median time to best response was 1.9 months.
The researchers also looked at response rates across a number of prespecified subgroups. Patients with Ann Arbor stage IV disease, those with bone marrow involvement, and those with extranodal disease were less likely to achieve a complete response (29%, 14% and 28% respectively). Patients with lymph nodes 5 cm or larger in diameter showed a 78% response rate.
While the Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached, 87% of patients achieved 12-month overall survival and 67% of patients achieved progression-free survival at 12 months.
Most of the adverse events were grade 1 or 2, and included headache, diarrhea, fatigue, and myalgia.
There were no grade 4 or 5 adverse events, but 10% of patients experienced neutropenia, 9% experienced anemia and 5% experienced pneumonia. There was also one case of grade 3 or worse hemorrhage, but no cases of atrial fibrillation. Lymphocytosis was seen in 31% of patients.
Nearly half of patients (44%) discontinued treatment, mostly because of progressive disease (31%) but 6% discontinued the treatment because of adverse events.
“Overall, treatment with acalabrutinib demonstrated a favourable benefit-risk profile and represents a promising treatment option for patients with relapsed or refractory mantle cell lymphoma,” the researchers wrote. “Data from the ongoing ACE-CL-006 trial directly comparing acalabrutinib with ibrutinib in previously treated patients with high-risk chronic lymphocytic leukaemia will further differentiate the safety profiles of the two treatments.”
The researchers noted a decrease in plasma levels of tumor necrosis factor alpha, the cytokine CXCL13, and other cytokines known to be involved in inflammation and cell trafficking.
“These findings add to the growing body of evidence indicating that BTK inhibition disrupts the tumour microenvironment, limiting the supply of cytokines and chemokines necessary for complex interactions with stromal and accessory cells important for tumour growth and survival.”
The study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. Several study authors reported grants, personal fees and other support from the pharmaceutical industry, including Acerta Pharma, most outside the submitted work. Several authors were also employees of Acerta and some had acalabrutinib patents pending or issued.
hematologynews@frontlinemedcom.com
SOURCE: Wang M et al., Lancet. 2018;391:659-67.
A new Bruton tyrosine kinase inhibitor has shown a high response rate and favorable safety profile in the treatment of patients with mantle cell lymphoma.
Researchers reported the results of an open-label, phase 2 study of oral acalabrutinib (100 mg, twice daily) in 124 patients with relapsed or refractory mantle cell lymphoma in The Lancet. Acalabrutinib (Calquence) received accelerated approval from the Food and Drug Administration in October 2017 for treatment of adults with mantle cell lymphoma who have received at least one prior therapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica), which was approved in 2013 for the treatment of mantle cell lymphoma, has been associated with side effects including atrial fibrillation, infections and bleeding, likely due to its off-target activity against other kinases. But acalabrutinib (ACP-196) “is a highly selective, potent BTK inhibitor developed to minimise off-target activity,” wrote Michael Wang, MD, of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
After a median follow-up of 15.2 months, 81% of patients in the study achieved an investigator-assessed overall response based on Lugano classification, with 40% achieving a complete response. The results were similar according to an independent review committee evaluation of responses based on CT and PET scans, bone-marrow biopsy specimens, endoscopy results, and clinical data.
There was also a reduction in lymphadenopathy seen in 94% of patients. The patients who showed a complete response took a median of 3.4 months to get there, and the median time to best response was 1.9 months.
The researchers also looked at response rates across a number of prespecified subgroups. Patients with Ann Arbor stage IV disease, those with bone marrow involvement, and those with extranodal disease were less likely to achieve a complete response (29%, 14% and 28% respectively). Patients with lymph nodes 5 cm or larger in diameter showed a 78% response rate.
While the Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached, 87% of patients achieved 12-month overall survival and 67% of patients achieved progression-free survival at 12 months.
Most of the adverse events were grade 1 or 2, and included headache, diarrhea, fatigue, and myalgia.
There were no grade 4 or 5 adverse events, but 10% of patients experienced neutropenia, 9% experienced anemia and 5% experienced pneumonia. There was also one case of grade 3 or worse hemorrhage, but no cases of atrial fibrillation. Lymphocytosis was seen in 31% of patients.
Nearly half of patients (44%) discontinued treatment, mostly because of progressive disease (31%) but 6% discontinued the treatment because of adverse events.
“Overall, treatment with acalabrutinib demonstrated a favourable benefit-risk profile and represents a promising treatment option for patients with relapsed or refractory mantle cell lymphoma,” the researchers wrote. “Data from the ongoing ACE-CL-006 trial directly comparing acalabrutinib with ibrutinib in previously treated patients with high-risk chronic lymphocytic leukaemia will further differentiate the safety profiles of the two treatments.”
The researchers noted a decrease in plasma levels of tumor necrosis factor alpha, the cytokine CXCL13, and other cytokines known to be involved in inflammation and cell trafficking.
“These findings add to the growing body of evidence indicating that BTK inhibition disrupts the tumour microenvironment, limiting the supply of cytokines and chemokines necessary for complex interactions with stromal and accessory cells important for tumour growth and survival.”
The study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. Several study authors reported grants, personal fees and other support from the pharmaceutical industry, including Acerta Pharma, most outside the submitted work. Several authors were also employees of Acerta and some had acalabrutinib patents pending or issued.
hematologynews@frontlinemedcom.com
SOURCE: Wang M et al., Lancet. 2018;391:659-67.
A new Bruton tyrosine kinase inhibitor has shown a high response rate and favorable safety profile in the treatment of patients with mantle cell lymphoma.
Researchers reported the results of an open-label, phase 2 study of oral acalabrutinib (100 mg, twice daily) in 124 patients with relapsed or refractory mantle cell lymphoma in The Lancet. Acalabrutinib (Calquence) received accelerated approval from the Food and Drug Administration in October 2017 for treatment of adults with mantle cell lymphoma who have received at least one prior therapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica), which was approved in 2013 for the treatment of mantle cell lymphoma, has been associated with side effects including atrial fibrillation, infections and bleeding, likely due to its off-target activity against other kinases. But acalabrutinib (ACP-196) “is a highly selective, potent BTK inhibitor developed to minimise off-target activity,” wrote Michael Wang, MD, of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
After a median follow-up of 15.2 months, 81% of patients in the study achieved an investigator-assessed overall response based on Lugano classification, with 40% achieving a complete response. The results were similar according to an independent review committee evaluation of responses based on CT and PET scans, bone-marrow biopsy specimens, endoscopy results, and clinical data.
There was also a reduction in lymphadenopathy seen in 94% of patients. The patients who showed a complete response took a median of 3.4 months to get there, and the median time to best response was 1.9 months.
The researchers also looked at response rates across a number of prespecified subgroups. Patients with Ann Arbor stage IV disease, those with bone marrow involvement, and those with extranodal disease were less likely to achieve a complete response (29%, 14% and 28% respectively). Patients with lymph nodes 5 cm or larger in diameter showed a 78% response rate.
While the Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached, 87% of patients achieved 12-month overall survival and 67% of patients achieved progression-free survival at 12 months.
Most of the adverse events were grade 1 or 2, and included headache, diarrhea, fatigue, and myalgia.
There were no grade 4 or 5 adverse events, but 10% of patients experienced neutropenia, 9% experienced anemia and 5% experienced pneumonia. There was also one case of grade 3 or worse hemorrhage, but no cases of atrial fibrillation. Lymphocytosis was seen in 31% of patients.
Nearly half of patients (44%) discontinued treatment, mostly because of progressive disease (31%) but 6% discontinued the treatment because of adverse events.
“Overall, treatment with acalabrutinib demonstrated a favourable benefit-risk profile and represents a promising treatment option for patients with relapsed or refractory mantle cell lymphoma,” the researchers wrote. “Data from the ongoing ACE-CL-006 trial directly comparing acalabrutinib with ibrutinib in previously treated patients with high-risk chronic lymphocytic leukaemia will further differentiate the safety profiles of the two treatments.”
The researchers noted a decrease in plasma levels of tumor necrosis factor alpha, the cytokine CXCL13, and other cytokines known to be involved in inflammation and cell trafficking.
“These findings add to the growing body of evidence indicating that BTK inhibition disrupts the tumour microenvironment, limiting the supply of cytokines and chemokines necessary for complex interactions with stromal and accessory cells important for tumour growth and survival.”
The study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. Several study authors reported grants, personal fees and other support from the pharmaceutical industry, including Acerta Pharma, most outside the submitted work. Several authors were also employees of Acerta and some had acalabrutinib patents pending or issued.
hematologynews@frontlinemedcom.com
SOURCE: Wang M et al., Lancet. 2018;391:659-67.
FROM THE LANCET
Key clinical point:
Major finding: Eighty-one percent of patients with relapsed or refractory mantle cell lymphoma showed a partial or complete response to Bruton tyrosine kinase inhibitor acalabrutinib.
Study details: An open-label, phase 2 study in 124 patients with relapsed or refractory mantle cell lymphoma.
Disclosures: The study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. Several study authors reported grants, personal fees and other support from the pharmaceutical industry, including Acerta Pharma, most outside the submitted work. Several authors were also employees of Acerta and some had acalabrutinib patents pending or issued.
Source: Wang M et al. Lancet. 2018;391:659-67.
NF-kappaB pathway could help solve resistance problem in mantle cell lymphoma
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
FROM CELL DEATH & DISEASE
Triple therapy ups response in refractory mantle cell lymphoma
A combination of ibrutinib, lenalidomide, and rituximab produced an overall response rate of 76% at 17.8 months median follow-up among 50 adults with relapsed or refractory mantle cell lymphoma, according to an open-label, single-arm, phase 2 trial.
There were complete responses in 28 patients (56%) and partial responses in 10 (20%). Median progression-free survival was 16 months and median overall survival was 22 months. Similar proportions of patients, with and without TP53 mutations, had overall and complete responses, suggesting that triple therapy might be particularly useful in patients with high-risk genetic features.
“Our results provide preliminary evidence that the triplet combination of ibrutinib, lenalidomide, and rituximab is an active regimen in patients with relapsed or refractory mantle cell lymphoma, and should be evaluated in a prospective randomized controlled trial,” wrote Mats Jerkeman, MD, of Lund University, Sweden, and colleagues. The report was published in The Lancet Haematology.
“Addition of lenalidomide to ibrutinib and rituximab might increase the proportion of patients who have complete remission ... Previous studies reported complete responses in 44% of patients on ibrutinib and rituximab, in 36% of patients on rituximab and lenalidomide, and in 19% of patients on ibrutinib alone,” they wrote.
Treatment was divided into an induction phase of 12 cycles of 28 days with all three drugs and a maintenance phase with ibrutinib and rituximab only, given until disease progression or unacceptable toxicity. All the patients had previously been treated with at least one rituximab-containing regimen.
Janssen and Celgene funded the work. Dr. Jerkeman reported ties to Janssen and Celgene, as well as AbbVie and Gilead.
SOURCE: Jerkeman M et al. Lancet Haematol. 2018 Jan 29. doi: 10.1016/S2352-3026(18)30018-8.
A combination of ibrutinib, lenalidomide, and rituximab produced an overall response rate of 76% at 17.8 months median follow-up among 50 adults with relapsed or refractory mantle cell lymphoma, according to an open-label, single-arm, phase 2 trial.
There were complete responses in 28 patients (56%) and partial responses in 10 (20%). Median progression-free survival was 16 months and median overall survival was 22 months. Similar proportions of patients, with and without TP53 mutations, had overall and complete responses, suggesting that triple therapy might be particularly useful in patients with high-risk genetic features.
“Our results provide preliminary evidence that the triplet combination of ibrutinib, lenalidomide, and rituximab is an active regimen in patients with relapsed or refractory mantle cell lymphoma, and should be evaluated in a prospective randomized controlled trial,” wrote Mats Jerkeman, MD, of Lund University, Sweden, and colleagues. The report was published in The Lancet Haematology.
“Addition of lenalidomide to ibrutinib and rituximab might increase the proportion of patients who have complete remission ... Previous studies reported complete responses in 44% of patients on ibrutinib and rituximab, in 36% of patients on rituximab and lenalidomide, and in 19% of patients on ibrutinib alone,” they wrote.
Treatment was divided into an induction phase of 12 cycles of 28 days with all three drugs and a maintenance phase with ibrutinib and rituximab only, given until disease progression or unacceptable toxicity. All the patients had previously been treated with at least one rituximab-containing regimen.
Janssen and Celgene funded the work. Dr. Jerkeman reported ties to Janssen and Celgene, as well as AbbVie and Gilead.
SOURCE: Jerkeman M et al. Lancet Haematol. 2018 Jan 29. doi: 10.1016/S2352-3026(18)30018-8.
A combination of ibrutinib, lenalidomide, and rituximab produced an overall response rate of 76% at 17.8 months median follow-up among 50 adults with relapsed or refractory mantle cell lymphoma, according to an open-label, single-arm, phase 2 trial.
There were complete responses in 28 patients (56%) and partial responses in 10 (20%). Median progression-free survival was 16 months and median overall survival was 22 months. Similar proportions of patients, with and without TP53 mutations, had overall and complete responses, suggesting that triple therapy might be particularly useful in patients with high-risk genetic features.
“Our results provide preliminary evidence that the triplet combination of ibrutinib, lenalidomide, and rituximab is an active regimen in patients with relapsed or refractory mantle cell lymphoma, and should be evaluated in a prospective randomized controlled trial,” wrote Mats Jerkeman, MD, of Lund University, Sweden, and colleagues. The report was published in The Lancet Haematology.
“Addition of lenalidomide to ibrutinib and rituximab might increase the proportion of patients who have complete remission ... Previous studies reported complete responses in 44% of patients on ibrutinib and rituximab, in 36% of patients on rituximab and lenalidomide, and in 19% of patients on ibrutinib alone,” they wrote.
Treatment was divided into an induction phase of 12 cycles of 28 days with all three drugs and a maintenance phase with ibrutinib and rituximab only, given until disease progression or unacceptable toxicity. All the patients had previously been treated with at least one rituximab-containing regimen.
Janssen and Celgene funded the work. Dr. Jerkeman reported ties to Janssen and Celgene, as well as AbbVie and Gilead.
SOURCE: Jerkeman M et al. Lancet Haematol. 2018 Jan 29. doi: 10.1016/S2352-3026(18)30018-8.
FROM THE LANCET HAEMATOLOGY
Key clinical point:
Major finding: The overall response from for the combination of the three drugs was 76% at 17.8 months median follow-up.
Study details: An open-label, single-arm, phase 2 trial of 50 adults with relapsed/refractory MCL.
Disclosures: Janssen and Celgene funded the work. Dr. Jerkeman reported ties to Janssen and Celgene, as well as AbbVie and Gilead.
Source: Jerkeman M et al. Lancet Haematol. 2018 Jan 29. doi: 10.1016/S2352-3026(18)30018-8.
VcR-CVAD yields high responses, ‘excellent’ survival in MCL
Adding rituximab and bortezomib to a moderate-intensity chemotherapy regimen and following it up with maintenance rituximab produced high response rates and “excellent” survival outcomes for adults with previously untreated mantle cell lymphoma (MCL), investigators reported in long-term follow-up of a small study.
The objective response rate (ORR) among 30 patients with MCL treated with VcR-CVAD – bortezomib (Velcade), rituximab, and hyperCVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) followed by rituximab maintenance – was 90%, including a high proportion of complete responses (CR) or unconfirmed complete responses.
After a median follow-up of 7.8 years, the rates of 6-year progression-free and overall survival (PFS and OS) were 53% and 70%, respectively, with patients older and younger than 60 years having equally good outcomes, according to Julie E. Chang, MD, of the Wisconsin Institute of Medical Research in Madison, and her colleagues.
VcR-CVAD is a moderate-intensity regimen with a favorable toxicity profile that allowed tolerability even in an older population, the investigators noted. “An important lesson illustrated by VcR-CVAD is that long-term remissions are achievable in some patients without intensive inductions or consolidation,” they wrote in Clinical Lymphoma, Myeloma & Leukemia.
The investigators previously reported that after a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively, and that these outcomes were comparable to those reported with more intensive regimens (Br J Haematol. 2011 Oct;155[2]:190-7).
As noted, the ORR was 90%, including 77% CR/unconfirmed CR, 6-year PFS was 53%, and 6-year OS was 70%.
A univariate analysis showed a significant interaction between lactate dehydrogenase levels and age for PFS, and a trend, albeit not significant, toward an interaction with LDH levels and age for OS.
In multivariate analysis, worse Eastern Cooperative Oncology Group (ECOG) performance status at baseline showed a nonsignificant trend toward worse OS. In contrast, an increase of one in the number of extranodal disease sites was associated with better OS (relative risk 0.66, 95% confidence interval 0.01-0.66).
The investigators noted that the advent of new agents with activity against MCL and the use of prognostic information, such as minimal residual disease measurements, could help clinicians develop induction and maintenance strategies with better efficacy and lower toxicity than VcR-CVAD.
The study was supported by the National Institutes of Health, Millennium Pharmaceuticals, and the University of Wisconsin Forward Lymphoma Research Fund. Dr. Chang reported research funding from Genentech. One coauthor disclosed consulting work for Genentech and Millennium and research funding from Genentech.
hematologynews@frontlinemedcom.com
SOURCE: Chang J et al. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e61-e67. doi: 10.1016/j.clml.2017.10.006.
Adding rituximab and bortezomib to a moderate-intensity chemotherapy regimen and following it up with maintenance rituximab produced high response rates and “excellent” survival outcomes for adults with previously untreated mantle cell lymphoma (MCL), investigators reported in long-term follow-up of a small study.
The objective response rate (ORR) among 30 patients with MCL treated with VcR-CVAD – bortezomib (Velcade), rituximab, and hyperCVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) followed by rituximab maintenance – was 90%, including a high proportion of complete responses (CR) or unconfirmed complete responses.
After a median follow-up of 7.8 years, the rates of 6-year progression-free and overall survival (PFS and OS) were 53% and 70%, respectively, with patients older and younger than 60 years having equally good outcomes, according to Julie E. Chang, MD, of the Wisconsin Institute of Medical Research in Madison, and her colleagues.
VcR-CVAD is a moderate-intensity regimen with a favorable toxicity profile that allowed tolerability even in an older population, the investigators noted. “An important lesson illustrated by VcR-CVAD is that long-term remissions are achievable in some patients without intensive inductions or consolidation,” they wrote in Clinical Lymphoma, Myeloma & Leukemia.
The investigators previously reported that after a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively, and that these outcomes were comparable to those reported with more intensive regimens (Br J Haematol. 2011 Oct;155[2]:190-7).
As noted, the ORR was 90%, including 77% CR/unconfirmed CR, 6-year PFS was 53%, and 6-year OS was 70%.
A univariate analysis showed a significant interaction between lactate dehydrogenase levels and age for PFS, and a trend, albeit not significant, toward an interaction with LDH levels and age for OS.
In multivariate analysis, worse Eastern Cooperative Oncology Group (ECOG) performance status at baseline showed a nonsignificant trend toward worse OS. In contrast, an increase of one in the number of extranodal disease sites was associated with better OS (relative risk 0.66, 95% confidence interval 0.01-0.66).
The investigators noted that the advent of new agents with activity against MCL and the use of prognostic information, such as minimal residual disease measurements, could help clinicians develop induction and maintenance strategies with better efficacy and lower toxicity than VcR-CVAD.
The study was supported by the National Institutes of Health, Millennium Pharmaceuticals, and the University of Wisconsin Forward Lymphoma Research Fund. Dr. Chang reported research funding from Genentech. One coauthor disclosed consulting work for Genentech and Millennium and research funding from Genentech.
hematologynews@frontlinemedcom.com
SOURCE: Chang J et al. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e61-e67. doi: 10.1016/j.clml.2017.10.006.
Adding rituximab and bortezomib to a moderate-intensity chemotherapy regimen and following it up with maintenance rituximab produced high response rates and “excellent” survival outcomes for adults with previously untreated mantle cell lymphoma (MCL), investigators reported in long-term follow-up of a small study.
The objective response rate (ORR) among 30 patients with MCL treated with VcR-CVAD – bortezomib (Velcade), rituximab, and hyperCVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) followed by rituximab maintenance – was 90%, including a high proportion of complete responses (CR) or unconfirmed complete responses.
After a median follow-up of 7.8 years, the rates of 6-year progression-free and overall survival (PFS and OS) were 53% and 70%, respectively, with patients older and younger than 60 years having equally good outcomes, according to Julie E. Chang, MD, of the Wisconsin Institute of Medical Research in Madison, and her colleagues.
VcR-CVAD is a moderate-intensity regimen with a favorable toxicity profile that allowed tolerability even in an older population, the investigators noted. “An important lesson illustrated by VcR-CVAD is that long-term remissions are achievable in some patients without intensive inductions or consolidation,” they wrote in Clinical Lymphoma, Myeloma & Leukemia.
The investigators previously reported that after a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively, and that these outcomes were comparable to those reported with more intensive regimens (Br J Haematol. 2011 Oct;155[2]:190-7).
As noted, the ORR was 90%, including 77% CR/unconfirmed CR, 6-year PFS was 53%, and 6-year OS was 70%.
A univariate analysis showed a significant interaction between lactate dehydrogenase levels and age for PFS, and a trend, albeit not significant, toward an interaction with LDH levels and age for OS.
In multivariate analysis, worse Eastern Cooperative Oncology Group (ECOG) performance status at baseline showed a nonsignificant trend toward worse OS. In contrast, an increase of one in the number of extranodal disease sites was associated with better OS (relative risk 0.66, 95% confidence interval 0.01-0.66).
The investigators noted that the advent of new agents with activity against MCL and the use of prognostic information, such as minimal residual disease measurements, could help clinicians develop induction and maintenance strategies with better efficacy and lower toxicity than VcR-CVAD.
The study was supported by the National Institutes of Health, Millennium Pharmaceuticals, and the University of Wisconsin Forward Lymphoma Research Fund. Dr. Chang reported research funding from Genentech. One coauthor disclosed consulting work for Genentech and Millennium and research funding from Genentech.
hematologynews@frontlinemedcom.com
SOURCE: Chang J et al. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e61-e67. doi: 10.1016/j.clml.2017.10.006.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
Key clinical point:
Major finding: The objective response rate was 90%, including 77% complete or unconfirmed complete responses.
Study details: Open-label study of 30 patients with previously untreated MCL.
Disclosures: The study was supported by the National Institutes of Health, Millennium Pharmaceuticals, and the University of Wisconsin Forward Lymphoma Research Fund. Dr. Chang reported research funding from Genentech. A coauthor reported consulting work for Genentech and Millennium and research funding from Genentech.
Source: Chang J et al. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e61-e67. doi: 10.1016/j.clml.2017.10.006.
BTK inhibitor zanubrutinib active in non-Hodgkin lymphomas
ATLANTA – , according to data presented at the annual meeting of the American Society of Hematology.
Response rates ranged from 31% to 88% depending on the lymphoma subtype. Overall, approximately 10% of patients discontinued the drug because of adverse events, reported Constantine S. Tam, MBBS, MD, of Peter MacCallum Cancer Centre & St. Vincent’s Hospital, Melbourne.
“There was encouraging activity against all the spectrum of indolent and aggressive NHL subtypes … and durable responses were observed across a variety of histologies,” Dr. Tam said.
Zanubrutinib is a second-generation BTK inhibitor that, based on biochemical assays, has higher selectivity against BTK than ibrutinib, Dr. Tam said.
He presented results of an open-label, multicenter, phase 1b study of daily or twice-daily zanubrutinib in patients with B-cell malignancies, most of them relapsed or refractory to prior therapies. The lymphoma subtypes he presented included diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL).
For 34 patients with indolent lymphomas (FL and MZL), the most frequent adverse events were petechiae/purpura/contusion and upper respiratory tract infection. Eleven grade 3-5 adverse events were reported, including neutropenia, infection, nausea, urinary tract infection, and abdominal pain.
Atrial fibrillation was observed in two patients in the aggressive NHL cohort, for an overall AF rate of approximately 2%, Dr. Tam said.
For 65 patients with aggressive lymphomas (DLBCL and MCL), the most frequent adverse events were petechiae/purpura/contusion and diarrhea; 27 grade 3-5 adverse events were reported, including neutropenia, pneumonia, and anemia.
The highest overall response rate reported was for MCL, at 88% (28 of 32 patients) followed by MZL at 78% (7 of 9 patients), FL at 41% (7 of 17 patients), and DLBCL 31% (8 of 26 patients).
The recommended phase 2 dose for zanubrutinib is either 320 mg/day once daily or a split dose of 160 mg twice daily, Dr. Tam said.
Based on this experience, investigators started a registration trial of zanubrutinib in combination with obinutuzumab for FL, and additional trials are planned, according to Dr. Tam.
There are also registration trials in Waldenstrom macroglobulinemia and chronic lymphocytic leukemia based on other data suggesting activity of zanubrutinib in those disease types, he added.
Zanubrutinib is a product of BeiGene. Dr. Tam reported disclosures related to Roche, Janssen Cilag, Abbvie, Celgene, Pharmacyclics, Onyx, and Amgen.
SOURCE: Tam C et al, ASH 2017, Abstract 152
ATLANTA – , according to data presented at the annual meeting of the American Society of Hematology.
Response rates ranged from 31% to 88% depending on the lymphoma subtype. Overall, approximately 10% of patients discontinued the drug because of adverse events, reported Constantine S. Tam, MBBS, MD, of Peter MacCallum Cancer Centre & St. Vincent’s Hospital, Melbourne.
“There was encouraging activity against all the spectrum of indolent and aggressive NHL subtypes … and durable responses were observed across a variety of histologies,” Dr. Tam said.
Zanubrutinib is a second-generation BTK inhibitor that, based on biochemical assays, has higher selectivity against BTK than ibrutinib, Dr. Tam said.
He presented results of an open-label, multicenter, phase 1b study of daily or twice-daily zanubrutinib in patients with B-cell malignancies, most of them relapsed or refractory to prior therapies. The lymphoma subtypes he presented included diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL).
For 34 patients with indolent lymphomas (FL and MZL), the most frequent adverse events were petechiae/purpura/contusion and upper respiratory tract infection. Eleven grade 3-5 adverse events were reported, including neutropenia, infection, nausea, urinary tract infection, and abdominal pain.
Atrial fibrillation was observed in two patients in the aggressive NHL cohort, for an overall AF rate of approximately 2%, Dr. Tam said.
For 65 patients with aggressive lymphomas (DLBCL and MCL), the most frequent adverse events were petechiae/purpura/contusion and diarrhea; 27 grade 3-5 adverse events were reported, including neutropenia, pneumonia, and anemia.
The highest overall response rate reported was for MCL, at 88% (28 of 32 patients) followed by MZL at 78% (7 of 9 patients), FL at 41% (7 of 17 patients), and DLBCL 31% (8 of 26 patients).
The recommended phase 2 dose for zanubrutinib is either 320 mg/day once daily or a split dose of 160 mg twice daily, Dr. Tam said.
Based on this experience, investigators started a registration trial of zanubrutinib in combination with obinutuzumab for FL, and additional trials are planned, according to Dr. Tam.
There are also registration trials in Waldenstrom macroglobulinemia and chronic lymphocytic leukemia based on other data suggesting activity of zanubrutinib in those disease types, he added.
Zanubrutinib is a product of BeiGene. Dr. Tam reported disclosures related to Roche, Janssen Cilag, Abbvie, Celgene, Pharmacyclics, Onyx, and Amgen.
SOURCE: Tam C et al, ASH 2017, Abstract 152
ATLANTA – , according to data presented at the annual meeting of the American Society of Hematology.
Response rates ranged from 31% to 88% depending on the lymphoma subtype. Overall, approximately 10% of patients discontinued the drug because of adverse events, reported Constantine S. Tam, MBBS, MD, of Peter MacCallum Cancer Centre & St. Vincent’s Hospital, Melbourne.
“There was encouraging activity against all the spectrum of indolent and aggressive NHL subtypes … and durable responses were observed across a variety of histologies,” Dr. Tam said.
Zanubrutinib is a second-generation BTK inhibitor that, based on biochemical assays, has higher selectivity against BTK than ibrutinib, Dr. Tam said.
He presented results of an open-label, multicenter, phase 1b study of daily or twice-daily zanubrutinib in patients with B-cell malignancies, most of them relapsed or refractory to prior therapies. The lymphoma subtypes he presented included diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL).
For 34 patients with indolent lymphomas (FL and MZL), the most frequent adverse events were petechiae/purpura/contusion and upper respiratory tract infection. Eleven grade 3-5 adverse events were reported, including neutropenia, infection, nausea, urinary tract infection, and abdominal pain.
Atrial fibrillation was observed in two patients in the aggressive NHL cohort, for an overall AF rate of approximately 2%, Dr. Tam said.
For 65 patients with aggressive lymphomas (DLBCL and MCL), the most frequent adverse events were petechiae/purpura/contusion and diarrhea; 27 grade 3-5 adverse events were reported, including neutropenia, pneumonia, and anemia.
The highest overall response rate reported was for MCL, at 88% (28 of 32 patients) followed by MZL at 78% (7 of 9 patients), FL at 41% (7 of 17 patients), and DLBCL 31% (8 of 26 patients).
The recommended phase 2 dose for zanubrutinib is either 320 mg/day once daily or a split dose of 160 mg twice daily, Dr. Tam said.
Based on this experience, investigators started a registration trial of zanubrutinib in combination with obinutuzumab for FL, and additional trials are planned, according to Dr. Tam.
There are also registration trials in Waldenstrom macroglobulinemia and chronic lymphocytic leukemia based on other data suggesting activity of zanubrutinib in those disease types, he added.
Zanubrutinib is a product of BeiGene. Dr. Tam reported disclosures related to Roche, Janssen Cilag, Abbvie, Celgene, Pharmacyclics, Onyx, and Amgen.
SOURCE: Tam C et al, ASH 2017, Abstract 152
REPORTING FROM ASH 2017
Key clinical point: Monotherapy with the BTK inhibitor zanubrutinib (BGB-3111) was active and well tolerated in patients with a variety of non-Hodgkin lymphoma (NHL) subtypes.
Major finding: Response rates ranged from 31% to 88% depending on the lymphoma subtype.
Data source: Preliminary results of an open-label, multicenter, phase 1b study including 99 patients with relapsed or refractory diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, or marginal zone lymphoma.
Disclosures: Zanubrutinib is a product of BeiGene. Constantine S. Tam, MBBS, MD, reported disclosures related to Roche, Janssen Cilag, Abbvie, Celgene, Pharmacyclics, Onyx, and Amgen.
Source: Tam C et al. ASH 2017, Abstract 152.
VIDEO - New lymphoma drug approvals: Clinical use, future directions
ATLANTA – 2017 was a banner year for the approval of new drugs to treat hematologic disorders.
At a special interest session at the annual meeting of American Society of Hematology, representatives from the Food and Drug Administration joined forces with clinicians to discuss the use of the newly approved treatments in the real-world setting.
In this video interview,
“This is extremely exciting,” she said regarding the pace of new approvals for hematologic malignancies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Axicabtagene ciloleucel, a CAR T-cell product approved in October for the treatment of relapsed/refractory large B-cell lymphoma in adults, is particularly interesting, she said.
“The data shows that if you look at a population of diffuse large B-cell lymphoma patients, that historically have a very poor outcome, there is definitely an impressive response rate and improved survival, compared to the natural history cohort,” said Dr. Heslop of Baylor College of Medicine, Houston.
However, while the findings are encouraging, only 30%-40% are having a durable response, she added.
“So I think there’ll be lots of efforts to try and improve the response rate by combination with other agents such as checkpoint inhibitors or other immunomodulators,” she said.
With respect to the second-generation Bruton’s tyrosine kinase inhibitor acalabrutinib, which was approved in October for adults with mantle cell lymphoma who have been treated with at least one prior therapy, she discussed the potential for improved outcomes and the importance of looking further into its use in patients who have failed ibrutinib therapy, as well as its use in combination with other agents, such as bendamustine and rituximab early in the course of disease.
Copanlisib, a PI3 kinase inhibitor approved in September, is an addition to the armamentarium for adult patients with relapsed follicular lymphoma after two lines of previous therapy.
“It still does have some side effects, as do other drugs in this class, so I think it’s place will still need to be defined,” Dr. Heslop said.
She reported having no relevant financial disclosures.
ATLANTA – 2017 was a banner year for the approval of new drugs to treat hematologic disorders.
At a special interest session at the annual meeting of American Society of Hematology, representatives from the Food and Drug Administration joined forces with clinicians to discuss the use of the newly approved treatments in the real-world setting.
In this video interview,
“This is extremely exciting,” she said regarding the pace of new approvals for hematologic malignancies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Axicabtagene ciloleucel, a CAR T-cell product approved in October for the treatment of relapsed/refractory large B-cell lymphoma in adults, is particularly interesting, she said.
“The data shows that if you look at a population of diffuse large B-cell lymphoma patients, that historically have a very poor outcome, there is definitely an impressive response rate and improved survival, compared to the natural history cohort,” said Dr. Heslop of Baylor College of Medicine, Houston.
However, while the findings are encouraging, only 30%-40% are having a durable response, she added.
“So I think there’ll be lots of efforts to try and improve the response rate by combination with other agents such as checkpoint inhibitors or other immunomodulators,” she said.
With respect to the second-generation Bruton’s tyrosine kinase inhibitor acalabrutinib, which was approved in October for adults with mantle cell lymphoma who have been treated with at least one prior therapy, she discussed the potential for improved outcomes and the importance of looking further into its use in patients who have failed ibrutinib therapy, as well as its use in combination with other agents, such as bendamustine and rituximab early in the course of disease.
Copanlisib, a PI3 kinase inhibitor approved in September, is an addition to the armamentarium for adult patients with relapsed follicular lymphoma after two lines of previous therapy.
“It still does have some side effects, as do other drugs in this class, so I think it’s place will still need to be defined,” Dr. Heslop said.
She reported having no relevant financial disclosures.
ATLANTA – 2017 was a banner year for the approval of new drugs to treat hematologic disorders.
At a special interest session at the annual meeting of American Society of Hematology, representatives from the Food and Drug Administration joined forces with clinicians to discuss the use of the newly approved treatments in the real-world setting.
In this video interview,
“This is extremely exciting,” she said regarding the pace of new approvals for hematologic malignancies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Axicabtagene ciloleucel, a CAR T-cell product approved in October for the treatment of relapsed/refractory large B-cell lymphoma in adults, is particularly interesting, she said.
“The data shows that if you look at a population of diffuse large B-cell lymphoma patients, that historically have a very poor outcome, there is definitely an impressive response rate and improved survival, compared to the natural history cohort,” said Dr. Heslop of Baylor College of Medicine, Houston.
However, while the findings are encouraging, only 30%-40% are having a durable response, she added.
“So I think there’ll be lots of efforts to try and improve the response rate by combination with other agents such as checkpoint inhibitors or other immunomodulators,” she said.
With respect to the second-generation Bruton’s tyrosine kinase inhibitor acalabrutinib, which was approved in October for adults with mantle cell lymphoma who have been treated with at least one prior therapy, she discussed the potential for improved outcomes and the importance of looking further into its use in patients who have failed ibrutinib therapy, as well as its use in combination with other agents, such as bendamustine and rituximab early in the course of disease.
Copanlisib, a PI3 kinase inhibitor approved in September, is an addition to the armamentarium for adult patients with relapsed follicular lymphoma after two lines of previous therapy.
“It still does have some side effects, as do other drugs in this class, so I think it’s place will still need to be defined,” Dr. Heslop said.
She reported having no relevant financial disclosures.
REPORTING FROM ASH 2017
VIDEO: Ibrutinib PFS is nearly 3 years in MCL patients who had one prior therapy
ATLANTA – Ibrutinib yielded a median progression-free survival (PFS) of nearly 3 years for patients with relapsed or refractory mantle cell lymphoma (MCL) treated with the agent after just one prior line of therapy, according to pooled long-term follow-up data presented at the annual meeting of the American Society of Hematology.
With a 3.5-year median follow-up, a median PFS of 33.6 months was reported for MCL patients with one prior line of therapy, compared to 8.4 months for patients who had two or more prior lines of therapy, reported lead study author Simon Rule, MD, of Plymouth (England) University Medical School.
“I think the take-home message from the ibrutinib data is the earlier you use the drug in the relapse setting, the better the outcomes you’re going to get,” Dr. Rule said in an interview. “It is quite dramatic, the difference between one prior line of therapy and subsequent lines of therapy.”
Response rates were also higher in MCL patients who had only one prior line of therapy, Dr. Rule said.
The overall and complete response rates for that group were 77.8% and 36.4%, respectively, according to data Dr. Rule presented in an oral presentation. For patients receiving more than one line of therapy prior to ibrutinib, overall and complete response rates were 66.8% and 22.9%.
The pooled analysis presented by Dr. Rule included 370 patients enrolled in ibrutinib trials between 2011 and 2013. Patients in those trials received oral ibrutinib 560 mg daily until progressive disease or unacceptable toxicity.
Patients achieving a CR had an “extraordinary” PFS of nearly 4 years and a median duration of response of 55 months, Dr. Rule said.
Atrial fibrillation (AF) rates were reported to be 5.7% (21/370 patients). A total of 53 patients in the analysis had ongoing controlled AF/arrhythmia or had a history of it. Over the course of follow-up, 70% of them (37 patients) had no recurrences, according to Dr. Rule and his colleagues.
No patients discontinued ibrutinib because of grade 3-4 AF, they reported. Moreover, less than 2% of the 370 patients discontinued or reduced dose of ibrutinib because of grade 3-4 bleeding or AF.
New onset grade 3-4 adverse events were more common in the first year of treatment and generally were less frequent over time, Dr. Rule said.
Patients with only one prior line of therapy were less likely to have grade 3-4 adverse events, suggesting again that “the earlier you use [ibrutinib], the fewer side effects you get, particularly with hematologic toxicity,” Dr. Rule said.
Sponsorship for the research came from Janssen, and funding for writing assistance came from Janssen Global Services. Dr. Rule reported financial relationships with Janssen and several other companies.
SOURCE: Rule S et al. ASH 2017 Abstract 151.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ATLANTA – Ibrutinib yielded a median progression-free survival (PFS) of nearly 3 years for patients with relapsed or refractory mantle cell lymphoma (MCL) treated with the agent after just one prior line of therapy, according to pooled long-term follow-up data presented at the annual meeting of the American Society of Hematology.
With a 3.5-year median follow-up, a median PFS of 33.6 months was reported for MCL patients with one prior line of therapy, compared to 8.4 months for patients who had two or more prior lines of therapy, reported lead study author Simon Rule, MD, of Plymouth (England) University Medical School.
“I think the take-home message from the ibrutinib data is the earlier you use the drug in the relapse setting, the better the outcomes you’re going to get,” Dr. Rule said in an interview. “It is quite dramatic, the difference between one prior line of therapy and subsequent lines of therapy.”
Response rates were also higher in MCL patients who had only one prior line of therapy, Dr. Rule said.
The overall and complete response rates for that group were 77.8% and 36.4%, respectively, according to data Dr. Rule presented in an oral presentation. For patients receiving more than one line of therapy prior to ibrutinib, overall and complete response rates were 66.8% and 22.9%.
The pooled analysis presented by Dr. Rule included 370 patients enrolled in ibrutinib trials between 2011 and 2013. Patients in those trials received oral ibrutinib 560 mg daily until progressive disease or unacceptable toxicity.
Patients achieving a CR had an “extraordinary” PFS of nearly 4 years and a median duration of response of 55 months, Dr. Rule said.
Atrial fibrillation (AF) rates were reported to be 5.7% (21/370 patients). A total of 53 patients in the analysis had ongoing controlled AF/arrhythmia or had a history of it. Over the course of follow-up, 70% of them (37 patients) had no recurrences, according to Dr. Rule and his colleagues.
No patients discontinued ibrutinib because of grade 3-4 AF, they reported. Moreover, less than 2% of the 370 patients discontinued or reduced dose of ibrutinib because of grade 3-4 bleeding or AF.
New onset grade 3-4 adverse events were more common in the first year of treatment and generally were less frequent over time, Dr. Rule said.
Patients with only one prior line of therapy were less likely to have grade 3-4 adverse events, suggesting again that “the earlier you use [ibrutinib], the fewer side effects you get, particularly with hematologic toxicity,” Dr. Rule said.
Sponsorship for the research came from Janssen, and funding for writing assistance came from Janssen Global Services. Dr. Rule reported financial relationships with Janssen and several other companies.
SOURCE: Rule S et al. ASH 2017 Abstract 151.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ATLANTA – Ibrutinib yielded a median progression-free survival (PFS) of nearly 3 years for patients with relapsed or refractory mantle cell lymphoma (MCL) treated with the agent after just one prior line of therapy, according to pooled long-term follow-up data presented at the annual meeting of the American Society of Hematology.
With a 3.5-year median follow-up, a median PFS of 33.6 months was reported for MCL patients with one prior line of therapy, compared to 8.4 months for patients who had two or more prior lines of therapy, reported lead study author Simon Rule, MD, of Plymouth (England) University Medical School.
“I think the take-home message from the ibrutinib data is the earlier you use the drug in the relapse setting, the better the outcomes you’re going to get,” Dr. Rule said in an interview. “It is quite dramatic, the difference between one prior line of therapy and subsequent lines of therapy.”
Response rates were also higher in MCL patients who had only one prior line of therapy, Dr. Rule said.
The overall and complete response rates for that group were 77.8% and 36.4%, respectively, according to data Dr. Rule presented in an oral presentation. For patients receiving more than one line of therapy prior to ibrutinib, overall and complete response rates were 66.8% and 22.9%.
The pooled analysis presented by Dr. Rule included 370 patients enrolled in ibrutinib trials between 2011 and 2013. Patients in those trials received oral ibrutinib 560 mg daily until progressive disease or unacceptable toxicity.
Patients achieving a CR had an “extraordinary” PFS of nearly 4 years and a median duration of response of 55 months, Dr. Rule said.
Atrial fibrillation (AF) rates were reported to be 5.7% (21/370 patients). A total of 53 patients in the analysis had ongoing controlled AF/arrhythmia or had a history of it. Over the course of follow-up, 70% of them (37 patients) had no recurrences, according to Dr. Rule and his colleagues.
No patients discontinued ibrutinib because of grade 3-4 AF, they reported. Moreover, less than 2% of the 370 patients discontinued or reduced dose of ibrutinib because of grade 3-4 bleeding or AF.
New onset grade 3-4 adverse events were more common in the first year of treatment and generally were less frequent over time, Dr. Rule said.
Patients with only one prior line of therapy were less likely to have grade 3-4 adverse events, suggesting again that “the earlier you use [ibrutinib], the fewer side effects you get, particularly with hematologic toxicity,” Dr. Rule said.
Sponsorship for the research came from Janssen, and funding for writing assistance came from Janssen Global Services. Dr. Rule reported financial relationships with Janssen and several other companies.
SOURCE: Rule S et al. ASH 2017 Abstract 151.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
REPORTING FROM ASH 2017
Key clinical point:
Major finding: Median PFS was 33.6 months for MCL patients with one prior line of therapy, versus 8.4 months for patients who had two or more prior lines of therapy.
Study details: A pooled analysis of 370 patients enrolled in ibrutinib clinical trials with a median 3.5-year follow-up.
Disclosures: Janssen sponsored the research and Janssen Global Services funded writing assistance. Lead author Simon Rule, MD, reported financial relationships with Janssen and several other companies.
Source: Rule S et al. ASH 2017 Abstract 151.
Avapritinib yields high response rate in patients with systemic mastocytosis
ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.
that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.
Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.
The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.
This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.
The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.
Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.
The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”
More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.
A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.
Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.
SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.
ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.
that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.
Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.
The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.
This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.
The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.
Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.
The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”
More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.
A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.
Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.
SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.
ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.
that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.
Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.
The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.
This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.
The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.
Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.
The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”
More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.
A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.
Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.
SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.
REPORTING FROM ASH 2017
Key clinical point: Avapritinib produced complete or partial responses in the majority of patients with advanced systemic mastocytosis.
Major finding: The overall response rate was 72%, including a 56% rate of complete or partial response.
Data source: Phase 1 dose-escalation study of 18 patients with advanced systemic mastocytosis.
Disclosures: The study was supported by Blueprint Medicines. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.
Source: DeAngelo D et al. ASH 2017 Abstract 2
Rituximab key to survival after transplant for mantle cell lymphoma
The study, which outlines the experience across a variety of different treatment patterns at City of Hope National Medical Center, Duarte, Calif., between January 1997 and November 2013, suggests a “large benefit” of adding rituximab, wrote Matthew G. Mei, MD, of the center’s department of hematology and hematopoietic cell transplantation, and his colleagues. Further, maintenance rituximab was associated with improved survival outcomes in patients with positron emission tomography (PET)-negative status at first complete remission.
The benefit of rituximab “stands out, and adds to the increasing body of evidence supporting this practice for all MCL patients after ASCT, regardless of age and frontline induction regimens,” wrote Dr. Mei and his colleagues (Biol Blood Marrow Transplant 2017 November. doi: 10.1016/j.bbmt.2017.07.006). This was the case even with improvements in early diagnosis and supportive care, and the incorporation of novel agents such as bortezomib, lenalidomide, and ibrutinib, they wrote, noting significantly better outcomes for patients who underwent ASCT after 2007.
In multivariate analysis, maintenance rituximab therapy after ASCT was the single most important factor associated with improvement in progression-free survival (relative risk [RR], .25; 95% confidence interval, .14-.44) and overall survival (RR, .17; 95% CI, .07-.38).
Positron emission tomography scans were done prior to ASCT for 133 patients; after ASCT, 105 (79%) were found to be in a PET-negative complete remission. All but one of the patients with PET-negative disease received rituximab before ASCT. For that PET-negative subset, maintenance rituximab was significantly associated with improvements in progression-free survival (RR, .20; 95% CI, .09-.43) and overall survival (RR, .17; 95% CI, .05-.59).
This study represents one of the largest single-center reports to date on MCL patients who have undergone ASCT, according to the authors. “This study also sets the stage for prospective investigation aiming at optimization of maintenance therapy following ASCT.”
Dr. Mei reported no disclosures, and senior author Lihua E. Budde, MD, PhD, reported being a member of the Lymphoma Research Foundation MCL consortium. The study was supported by research funding from the National Cancer Institute.
This study confirms the value of maintenance rituximab for a large cohort of patients with mantle cell lymphoma who have undergone high-dose chemotherapy and autologous stem cell transplantation outside of clinical trials.
The findings also affirm results of a recent phase 3 randomized trial (LyMa) suggesting that in previously untreated MCL patients who have undergone ASCT, rituximab maintenance is superior to observation in improving overall survival and progression-free survival.
However, the most interesting aspect of this study is the positron emission tomography data. Namely, the benefit of rituximab maintenance was apparent in patients regardless of whether they were in a PET-positive or PET-negative first complete remission at ASCT. “This important finding implies that the benefit of rituximab maintenance after ASCT is present for low- and high-risk MCL patients.”
Despite these confirmatory findings, the treatment landscape for MCL has changed significantly in recent years, particularly with the introduction of treatments such as ibrutinib.
In a clinical trial currently underway, the European Mantle Cell Lymphoma Network is evaluating ibrutinib as an upfront treatment for young and fit patients. Specifically, the study compares first-line ASCT and rituximab maintenance, ASCT with ibrutinib maintenance, or a transplant-free approach with ibrutinib and chemotherapy.
Unless and until the data from this study “redefine the value of ASCT in the ibrutinib era, ASCT and rituximab maintenance should be recommended as the standard treatment after ASCT for transplant-eligible patients with MCL.”
Tobias Roider, MD, and Sascha Dietrich, MD, are with the Department of Medicine V, University of Heidelberg, Germany. Their comments are in an editorial (Biol Blood Marrow Transplant 2017 November. doi: 10.1016/j.bbmt.2017.09.008). The authors reported no financial disclosures or conflicts of interest.
This study confirms the value of maintenance rituximab for a large cohort of patients with mantle cell lymphoma who have undergone high-dose chemotherapy and autologous stem cell transplantation outside of clinical trials.
The findings also affirm results of a recent phase 3 randomized trial (LyMa) suggesting that in previously untreated MCL patients who have undergone ASCT, rituximab maintenance is superior to observation in improving overall survival and progression-free survival.
However, the most interesting aspect of this study is the positron emission tomography data. Namely, the benefit of rituximab maintenance was apparent in patients regardless of whether they were in a PET-positive or PET-negative first complete remission at ASCT. “This important finding implies that the benefit of rituximab maintenance after ASCT is present for low- and high-risk MCL patients.”
Despite these confirmatory findings, the treatment landscape for MCL has changed significantly in recent years, particularly with the introduction of treatments such as ibrutinib.
In a clinical trial currently underway, the European Mantle Cell Lymphoma Network is evaluating ibrutinib as an upfront treatment for young and fit patients. Specifically, the study compares first-line ASCT and rituximab maintenance, ASCT with ibrutinib maintenance, or a transplant-free approach with ibrutinib and chemotherapy.
Unless and until the data from this study “redefine the value of ASCT in the ibrutinib era, ASCT and rituximab maintenance should be recommended as the standard treatment after ASCT for transplant-eligible patients with MCL.”
Tobias Roider, MD, and Sascha Dietrich, MD, are with the Department of Medicine V, University of Heidelberg, Germany. Their comments are in an editorial (Biol Blood Marrow Transplant 2017 November. doi: 10.1016/j.bbmt.2017.09.008). The authors reported no financial disclosures or conflicts of interest.
This study confirms the value of maintenance rituximab for a large cohort of patients with mantle cell lymphoma who have undergone high-dose chemotherapy and autologous stem cell transplantation outside of clinical trials.
The findings also affirm results of a recent phase 3 randomized trial (LyMa) suggesting that in previously untreated MCL patients who have undergone ASCT, rituximab maintenance is superior to observation in improving overall survival and progression-free survival.
However, the most interesting aspect of this study is the positron emission tomography data. Namely, the benefit of rituximab maintenance was apparent in patients regardless of whether they were in a PET-positive or PET-negative first complete remission at ASCT. “This important finding implies that the benefit of rituximab maintenance after ASCT is present for low- and high-risk MCL patients.”
Despite these confirmatory findings, the treatment landscape for MCL has changed significantly in recent years, particularly with the introduction of treatments such as ibrutinib.
In a clinical trial currently underway, the European Mantle Cell Lymphoma Network is evaluating ibrutinib as an upfront treatment for young and fit patients. Specifically, the study compares first-line ASCT and rituximab maintenance, ASCT with ibrutinib maintenance, or a transplant-free approach with ibrutinib and chemotherapy.
Unless and until the data from this study “redefine the value of ASCT in the ibrutinib era, ASCT and rituximab maintenance should be recommended as the standard treatment after ASCT for transplant-eligible patients with MCL.”
Tobias Roider, MD, and Sascha Dietrich, MD, are with the Department of Medicine V, University of Heidelberg, Germany. Their comments are in an editorial (Biol Blood Marrow Transplant 2017 November. doi: 10.1016/j.bbmt.2017.09.008). The authors reported no financial disclosures or conflicts of interest.
The study, which outlines the experience across a variety of different treatment patterns at City of Hope National Medical Center, Duarte, Calif., between January 1997 and November 2013, suggests a “large benefit” of adding rituximab, wrote Matthew G. Mei, MD, of the center’s department of hematology and hematopoietic cell transplantation, and his colleagues. Further, maintenance rituximab was associated with improved survival outcomes in patients with positron emission tomography (PET)-negative status at first complete remission.
The benefit of rituximab “stands out, and adds to the increasing body of evidence supporting this practice for all MCL patients after ASCT, regardless of age and frontline induction regimens,” wrote Dr. Mei and his colleagues (Biol Blood Marrow Transplant 2017 November. doi: 10.1016/j.bbmt.2017.07.006). This was the case even with improvements in early diagnosis and supportive care, and the incorporation of novel agents such as bortezomib, lenalidomide, and ibrutinib, they wrote, noting significantly better outcomes for patients who underwent ASCT after 2007.
In multivariate analysis, maintenance rituximab therapy after ASCT was the single most important factor associated with improvement in progression-free survival (relative risk [RR], .25; 95% confidence interval, .14-.44) and overall survival (RR, .17; 95% CI, .07-.38).
Positron emission tomography scans were done prior to ASCT for 133 patients; after ASCT, 105 (79%) were found to be in a PET-negative complete remission. All but one of the patients with PET-negative disease received rituximab before ASCT. For that PET-negative subset, maintenance rituximab was significantly associated with improvements in progression-free survival (RR, .20; 95% CI, .09-.43) and overall survival (RR, .17; 95% CI, .05-.59).
This study represents one of the largest single-center reports to date on MCL patients who have undergone ASCT, according to the authors. “This study also sets the stage for prospective investigation aiming at optimization of maintenance therapy following ASCT.”
Dr. Mei reported no disclosures, and senior author Lihua E. Budde, MD, PhD, reported being a member of the Lymphoma Research Foundation MCL consortium. The study was supported by research funding from the National Cancer Institute.
The study, which outlines the experience across a variety of different treatment patterns at City of Hope National Medical Center, Duarte, Calif., between January 1997 and November 2013, suggests a “large benefit” of adding rituximab, wrote Matthew G. Mei, MD, of the center’s department of hematology and hematopoietic cell transplantation, and his colleagues. Further, maintenance rituximab was associated with improved survival outcomes in patients with positron emission tomography (PET)-negative status at first complete remission.
The benefit of rituximab “stands out, and adds to the increasing body of evidence supporting this practice for all MCL patients after ASCT, regardless of age and frontline induction regimens,” wrote Dr. Mei and his colleagues (Biol Blood Marrow Transplant 2017 November. doi: 10.1016/j.bbmt.2017.07.006). This was the case even with improvements in early diagnosis and supportive care, and the incorporation of novel agents such as bortezomib, lenalidomide, and ibrutinib, they wrote, noting significantly better outcomes for patients who underwent ASCT after 2007.
In multivariate analysis, maintenance rituximab therapy after ASCT was the single most important factor associated with improvement in progression-free survival (relative risk [RR], .25; 95% confidence interval, .14-.44) and overall survival (RR, .17; 95% CI, .07-.38).
Positron emission tomography scans were done prior to ASCT for 133 patients; after ASCT, 105 (79%) were found to be in a PET-negative complete remission. All but one of the patients with PET-negative disease received rituximab before ASCT. For that PET-negative subset, maintenance rituximab was significantly associated with improvements in progression-free survival (RR, .20; 95% CI, .09-.43) and overall survival (RR, .17; 95% CI, .05-.59).
This study represents one of the largest single-center reports to date on MCL patients who have undergone ASCT, according to the authors. “This study also sets the stage for prospective investigation aiming at optimization of maintenance therapy following ASCT.”
Dr. Mei reported no disclosures, and senior author Lihua E. Budde, MD, PhD, reported being a member of the Lymphoma Research Foundation MCL consortium. The study was supported by research funding from the National Cancer Institute.
FROM BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
Key clinical point: Over time and in many different patterns, rituximab maintenance therapy stood out as the prominent factor influencing survival in patients with mantle cell lymphoma who undergo autologous stem cell transplant.
Major finding: Maintenance rituximab was significantly associated with superior progression-free survival (relative risk, .25; 95% confidence interval, .14-.44) and overall survival (RR, .17; 95% CI, .07-.38).
Data source: Retrospective analysis of data for 191 patients with MCL who underwent ASCT at a medical center in California between January 1997 and November 2013.
Disclosures: The study was supported by research funding from the National Cancer Institute. Senior author Lihua E. Budde, MD, PhD, reported being a member of the Lymphoma Research Foundation MCL consortium.
TP53 mutations could help stratify MCL patients
TP53 mutations identified a phenotypically distinct and aggressive form of mantle cell lymphoma (MCL) that did not respond to standard-of-care treatments, according to results from 183 patients younger than 66 years from the Nordic MCL2 and MCL3 trials.
, and that patients with the mutations should be considered for experimental trials of novel agents, wrote Christian W. Eskelund of the department of hematology at Rigshospitalet, Copenhagen, and colleagues.
The researchers collected DNA from the Nordic MCL2 and MCL3 trials and 183 samples were of sufficient quality for genetic analyses. They examined the prognostic value of eight recurrently mutated and two recurrently deleted genes. Only TP53 mutations showed an independent prognostic effect for overall survival (hazard ratio 6.2; P less than .0001) in multivariate Cox regression analyses.
“Our data show that TP53 mutations identify a unique MCL subtype associated with high-risk baseline characteristics, dismal response to standard treatment, and poor clinical outcome,” the researchers wrote.
Read the full study in Blood (2017 Oct 26;130[17]:1903-10).
mschneider@frontlinemedcom.com
On Twitter @maryellenny
TP53 mutations identified a phenotypically distinct and aggressive form of mantle cell lymphoma (MCL) that did not respond to standard-of-care treatments, according to results from 183 patients younger than 66 years from the Nordic MCL2 and MCL3 trials.
, and that patients with the mutations should be considered for experimental trials of novel agents, wrote Christian W. Eskelund of the department of hematology at Rigshospitalet, Copenhagen, and colleagues.
The researchers collected DNA from the Nordic MCL2 and MCL3 trials and 183 samples were of sufficient quality for genetic analyses. They examined the prognostic value of eight recurrently mutated and two recurrently deleted genes. Only TP53 mutations showed an independent prognostic effect for overall survival (hazard ratio 6.2; P less than .0001) in multivariate Cox regression analyses.
“Our data show that TP53 mutations identify a unique MCL subtype associated with high-risk baseline characteristics, dismal response to standard treatment, and poor clinical outcome,” the researchers wrote.
Read the full study in Blood (2017 Oct 26;130[17]:1903-10).
mschneider@frontlinemedcom.com
On Twitter @maryellenny
TP53 mutations identified a phenotypically distinct and aggressive form of mantle cell lymphoma (MCL) that did not respond to standard-of-care treatments, according to results from 183 patients younger than 66 years from the Nordic MCL2 and MCL3 trials.
, and that patients with the mutations should be considered for experimental trials of novel agents, wrote Christian W. Eskelund of the department of hematology at Rigshospitalet, Copenhagen, and colleagues.
The researchers collected DNA from the Nordic MCL2 and MCL3 trials and 183 samples were of sufficient quality for genetic analyses. They examined the prognostic value of eight recurrently mutated and two recurrently deleted genes. Only TP53 mutations showed an independent prognostic effect for overall survival (hazard ratio 6.2; P less than .0001) in multivariate Cox regression analyses.
“Our data show that TP53 mutations identify a unique MCL subtype associated with high-risk baseline characteristics, dismal response to standard treatment, and poor clinical outcome,” the researchers wrote.
Read the full study in Blood (2017 Oct 26;130[17]:1903-10).
mschneider@frontlinemedcom.com
On Twitter @maryellenny
FROM BLOOD