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Relapsed MCL: Options for treatment
CHICAGO – according to Kristie A. Blum, MD.
Venetoclax and lenalidomide can also be considered in the relapsed mantle cell lymphoma (MCL) setting, Dr. Blum, a professor in the department of hematology and medical oncology at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
“I tend to favor BTK inhibitors as my first line of therapy,” she said, later qualifying that this applies when clinical trial enrollment is unavailable.
Ibrutinib
The BTK inhibitor ibrutinib is well established as a treatment for MCL and for use in the relapsed setting, she said, noting that pooled data from the phase 2 CYC-1104 trial, the phase 2 MCL 2001 (SPARK) trial, and the phase 3 MCL3001 (RAY) trial showed an overall response (OR) rate of 66% in 370 patients and a complete response (CR) rate of 20%.
The median duration of response (DOR) was 18.6 months, median progression-free survival (PFS) was 12.8 months, and median overall survival (OS) was 25 months (Br J Haematol. 2017 Nov;179[3]:430-8).
Adding rituximab to ibrutinib (R-ibrutinib) improved outcomes, at least in one single center phase 2 trial of 50 relapsed patients with a median of three prior therapies, she said. The OR rate in that study was 88%, and the CR rate was 58% (Br J Haematol. 2018 May;182[3]:404-11).
“What was really impressive to me was that the median duration of response was about 46 months. PFS was 43 months, and patients were on [treatment] as long as 56 cycles,” she said.
Acalabrutinib
The newer BTK inhibitor acalabrutinib also shows benefit in the relapsed MCL setting, Dr. Blum said.
In a recent multicenter, open-label, phase 2 study of 124 patients with a median age of 68 years and a median of two prior therapies, acalabrutinib at a dose of 100 mg twice daily was associated with an OR rate of 81% and a CR rate of 40% (Lancet. 2018 Feb 17;391:659-67).
“Seems a little better than what you’d expect with single agent ibrutinib,” she said, noting that median DOR and PFS have not been reached in that study.
The main toxicities have been “headache and some diarrhea,” but follow-up is currently only about 15 months, she added.
Venetoclax
Another option in this setting is the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax, which was shown in a recent phase 1 study of patients with various lymphoma subtypes to have activity in relapsed MCL, Dr. Blum said.
The OR rate in 28 relapsed MCL patients in that study was 75%, and the median PFS was 14 months (J Clin Oncol. 2017 Mar;35:826-33).
Additionally, an “intriguing combination study of venetoclax and ibrutinib” was recently published in the New England Journal of Medicine, she noted.
That study included only 23 patients with relapsed MCL, but they were a “pretty high-risk” group with a median age of 68 years, about half having a TP53 abnormality, and 30% having a prior transplant.
The OR and CR rates at 16 weeks by positron emission tomography were 71% and 62%, respectively (N Engl J Med. 2018 Mar 29;378:1211-23).
“Actually, about 40% achieved [minimal residual disease] negativity, but this was only checked in about half the patients,” she said. “So this is an intriguing combination and hopefully something we’ll see more of in the upcoming years.”
Lenalidomide
In the randomized phase 2 SPRINT study, patients received either single-agent lenolidamine or the investigator’s choice of single-agent rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine.
The expected OR rate in 170 patients treated with lenalidomide was 40% versus 11% in 84 patients treated with investigator’s choice of treatment, and the respective CR rates were 5% and 0% (Lancet Oncol. 2016 Mar 1;17(3):319-31).
Median DOR was 16 months versus 10.4 months, PFS was 8.7 versus 5.2 months, and median OS was 27.9 versus 21.1 months in the groups, respectively.
Other options
Combination regimens, such as R-CHOP and R-bendamustine, are also options for the treatment of relapsed MCL patients who haven’t received combination therapy in the past, Dr. Blum said. Transplant is another option in some patients.
“I will consider transplants for younger patients if they come to me and they actually hadn’t had one in [their] first CR,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
CHICAGO – according to Kristie A. Blum, MD.
Venetoclax and lenalidomide can also be considered in the relapsed mantle cell lymphoma (MCL) setting, Dr. Blum, a professor in the department of hematology and medical oncology at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
“I tend to favor BTK inhibitors as my first line of therapy,” she said, later qualifying that this applies when clinical trial enrollment is unavailable.
Ibrutinib
The BTK inhibitor ibrutinib is well established as a treatment for MCL and for use in the relapsed setting, she said, noting that pooled data from the phase 2 CYC-1104 trial, the phase 2 MCL 2001 (SPARK) trial, and the phase 3 MCL3001 (RAY) trial showed an overall response (OR) rate of 66% in 370 patients and a complete response (CR) rate of 20%.
The median duration of response (DOR) was 18.6 months, median progression-free survival (PFS) was 12.8 months, and median overall survival (OS) was 25 months (Br J Haematol. 2017 Nov;179[3]:430-8).
Adding rituximab to ibrutinib (R-ibrutinib) improved outcomes, at least in one single center phase 2 trial of 50 relapsed patients with a median of three prior therapies, she said. The OR rate in that study was 88%, and the CR rate was 58% (Br J Haematol. 2018 May;182[3]:404-11).
“What was really impressive to me was that the median duration of response was about 46 months. PFS was 43 months, and patients were on [treatment] as long as 56 cycles,” she said.
Acalabrutinib
The newer BTK inhibitor acalabrutinib also shows benefit in the relapsed MCL setting, Dr. Blum said.
In a recent multicenter, open-label, phase 2 study of 124 patients with a median age of 68 years and a median of two prior therapies, acalabrutinib at a dose of 100 mg twice daily was associated with an OR rate of 81% and a CR rate of 40% (Lancet. 2018 Feb 17;391:659-67).
“Seems a little better than what you’d expect with single agent ibrutinib,” she said, noting that median DOR and PFS have not been reached in that study.
The main toxicities have been “headache and some diarrhea,” but follow-up is currently only about 15 months, she added.
Venetoclax
Another option in this setting is the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax, which was shown in a recent phase 1 study of patients with various lymphoma subtypes to have activity in relapsed MCL, Dr. Blum said.
The OR rate in 28 relapsed MCL patients in that study was 75%, and the median PFS was 14 months (J Clin Oncol. 2017 Mar;35:826-33).
Additionally, an “intriguing combination study of venetoclax and ibrutinib” was recently published in the New England Journal of Medicine, she noted.
That study included only 23 patients with relapsed MCL, but they were a “pretty high-risk” group with a median age of 68 years, about half having a TP53 abnormality, and 30% having a prior transplant.
The OR and CR rates at 16 weeks by positron emission tomography were 71% and 62%, respectively (N Engl J Med. 2018 Mar 29;378:1211-23).
“Actually, about 40% achieved [minimal residual disease] negativity, but this was only checked in about half the patients,” she said. “So this is an intriguing combination and hopefully something we’ll see more of in the upcoming years.”
Lenalidomide
In the randomized phase 2 SPRINT study, patients received either single-agent lenolidamine or the investigator’s choice of single-agent rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine.
The expected OR rate in 170 patients treated with lenalidomide was 40% versus 11% in 84 patients treated with investigator’s choice of treatment, and the respective CR rates were 5% and 0% (Lancet Oncol. 2016 Mar 1;17(3):319-31).
Median DOR was 16 months versus 10.4 months, PFS was 8.7 versus 5.2 months, and median OS was 27.9 versus 21.1 months in the groups, respectively.
Other options
Combination regimens, such as R-CHOP and R-bendamustine, are also options for the treatment of relapsed MCL patients who haven’t received combination therapy in the past, Dr. Blum said. Transplant is another option in some patients.
“I will consider transplants for younger patients if they come to me and they actually hadn’t had one in [their] first CR,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
CHICAGO – according to Kristie A. Blum, MD.
Venetoclax and lenalidomide can also be considered in the relapsed mantle cell lymphoma (MCL) setting, Dr. Blum, a professor in the department of hematology and medical oncology at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
“I tend to favor BTK inhibitors as my first line of therapy,” she said, later qualifying that this applies when clinical trial enrollment is unavailable.
Ibrutinib
The BTK inhibitor ibrutinib is well established as a treatment for MCL and for use in the relapsed setting, she said, noting that pooled data from the phase 2 CYC-1104 trial, the phase 2 MCL 2001 (SPARK) trial, and the phase 3 MCL3001 (RAY) trial showed an overall response (OR) rate of 66% in 370 patients and a complete response (CR) rate of 20%.
The median duration of response (DOR) was 18.6 months, median progression-free survival (PFS) was 12.8 months, and median overall survival (OS) was 25 months (Br J Haematol. 2017 Nov;179[3]:430-8).
Adding rituximab to ibrutinib (R-ibrutinib) improved outcomes, at least in one single center phase 2 trial of 50 relapsed patients with a median of three prior therapies, she said. The OR rate in that study was 88%, and the CR rate was 58% (Br J Haematol. 2018 May;182[3]:404-11).
“What was really impressive to me was that the median duration of response was about 46 months. PFS was 43 months, and patients were on [treatment] as long as 56 cycles,” she said.
Acalabrutinib
The newer BTK inhibitor acalabrutinib also shows benefit in the relapsed MCL setting, Dr. Blum said.
In a recent multicenter, open-label, phase 2 study of 124 patients with a median age of 68 years and a median of two prior therapies, acalabrutinib at a dose of 100 mg twice daily was associated with an OR rate of 81% and a CR rate of 40% (Lancet. 2018 Feb 17;391:659-67).
“Seems a little better than what you’d expect with single agent ibrutinib,” she said, noting that median DOR and PFS have not been reached in that study.
The main toxicities have been “headache and some diarrhea,” but follow-up is currently only about 15 months, she added.
Venetoclax
Another option in this setting is the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax, which was shown in a recent phase 1 study of patients with various lymphoma subtypes to have activity in relapsed MCL, Dr. Blum said.
The OR rate in 28 relapsed MCL patients in that study was 75%, and the median PFS was 14 months (J Clin Oncol. 2017 Mar;35:826-33).
Additionally, an “intriguing combination study of venetoclax and ibrutinib” was recently published in the New England Journal of Medicine, she noted.
That study included only 23 patients with relapsed MCL, but they were a “pretty high-risk” group with a median age of 68 years, about half having a TP53 abnormality, and 30% having a prior transplant.
The OR and CR rates at 16 weeks by positron emission tomography were 71% and 62%, respectively (N Engl J Med. 2018 Mar 29;378:1211-23).
“Actually, about 40% achieved [minimal residual disease] negativity, but this was only checked in about half the patients,” she said. “So this is an intriguing combination and hopefully something we’ll see more of in the upcoming years.”
Lenalidomide
In the randomized phase 2 SPRINT study, patients received either single-agent lenolidamine or the investigator’s choice of single-agent rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine.
The expected OR rate in 170 patients treated with lenalidomide was 40% versus 11% in 84 patients treated with investigator’s choice of treatment, and the respective CR rates were 5% and 0% (Lancet Oncol. 2016 Mar 1;17(3):319-31).
Median DOR was 16 months versus 10.4 months, PFS was 8.7 versus 5.2 months, and median OS was 27.9 versus 21.1 months in the groups, respectively.
Other options
Combination regimens, such as R-CHOP and R-bendamustine, are also options for the treatment of relapsed MCL patients who haven’t received combination therapy in the past, Dr. Blum said. Transplant is another option in some patients.
“I will consider transplants for younger patients if they come to me and they actually hadn’t had one in [their] first CR,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
EXPERT ANALYSIS FROM MHM 2018
FDA puts selinexor on fast track for DLBCL
The Food and Drug Administration has granted fast track designation to selinexor for the treatment of diffuse large B-cell lymphoma (DLBCL).
The designation is for selinexor to treat DLBCL patients who have received at least two prior therapies and who are not eligible for high-dose chemotherapy with stem cell rescue or chimeric antigen receptor (CAR) T-cell therapy.
Selinexor is being studied in the phase 2b SADAL trial (NCT02227251), which is enrolling patients with relapsed or refractory DLBCL who have received two to five prior therapies and are not eligible for stem cell transplant.
Top-line results from this trial are scheduled to be presented at the 2018 ASH Annual Meeting (Abstract 1677).
Selinexor is an oral selective inhibitor of nuclear export compound being developed by Karyopharm Therapeutics.
The company previously received fast track designation for selinexor to treat patients with penta-refractory multiple myeloma who have received at least three prior lines of therapy.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products that are intended to treat serious conditions and have the potential to address unmet medical needs. Fast track designation provides developers with greater access to the FDA as well as eligibility for accelerated approval, priority review, and rolling review.
“Pending positive results from the phase 2b SADAL study, we plan to submit a second NDA [new drug application] to the FDA in the first half of 2019, with a request for accelerated approval, for oral selinexor as a potential new treatment for patients with relapsed or refractory DLBCL,” Sharon Shacham, PhD, founder, president, and chief scientific officer of Karyopharm, said in a statement.
In October, the FDA accepted an NDA for selinexor as a treatment for penta-refractory multiple myeloma. The agency granted the application priority review and set an action date of April 6, 2019.
The Food and Drug Administration has granted fast track designation to selinexor for the treatment of diffuse large B-cell lymphoma (DLBCL).
The designation is for selinexor to treat DLBCL patients who have received at least two prior therapies and who are not eligible for high-dose chemotherapy with stem cell rescue or chimeric antigen receptor (CAR) T-cell therapy.
Selinexor is being studied in the phase 2b SADAL trial (NCT02227251), which is enrolling patients with relapsed or refractory DLBCL who have received two to five prior therapies and are not eligible for stem cell transplant.
Top-line results from this trial are scheduled to be presented at the 2018 ASH Annual Meeting (Abstract 1677).
Selinexor is an oral selective inhibitor of nuclear export compound being developed by Karyopharm Therapeutics.
The company previously received fast track designation for selinexor to treat patients with penta-refractory multiple myeloma who have received at least three prior lines of therapy.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products that are intended to treat serious conditions and have the potential to address unmet medical needs. Fast track designation provides developers with greater access to the FDA as well as eligibility for accelerated approval, priority review, and rolling review.
“Pending positive results from the phase 2b SADAL study, we plan to submit a second NDA [new drug application] to the FDA in the first half of 2019, with a request for accelerated approval, for oral selinexor as a potential new treatment for patients with relapsed or refractory DLBCL,” Sharon Shacham, PhD, founder, president, and chief scientific officer of Karyopharm, said in a statement.
In October, the FDA accepted an NDA for selinexor as a treatment for penta-refractory multiple myeloma. The agency granted the application priority review and set an action date of April 6, 2019.
The Food and Drug Administration has granted fast track designation to selinexor for the treatment of diffuse large B-cell lymphoma (DLBCL).
The designation is for selinexor to treat DLBCL patients who have received at least two prior therapies and who are not eligible for high-dose chemotherapy with stem cell rescue or chimeric antigen receptor (CAR) T-cell therapy.
Selinexor is being studied in the phase 2b SADAL trial (NCT02227251), which is enrolling patients with relapsed or refractory DLBCL who have received two to five prior therapies and are not eligible for stem cell transplant.
Top-line results from this trial are scheduled to be presented at the 2018 ASH Annual Meeting (Abstract 1677).
Selinexor is an oral selective inhibitor of nuclear export compound being developed by Karyopharm Therapeutics.
The company previously received fast track designation for selinexor to treat patients with penta-refractory multiple myeloma who have received at least three prior lines of therapy.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products that are intended to treat serious conditions and have the potential to address unmet medical needs. Fast track designation provides developers with greater access to the FDA as well as eligibility for accelerated approval, priority review, and rolling review.
“Pending positive results from the phase 2b SADAL study, we plan to submit a second NDA [new drug application] to the FDA in the first half of 2019, with a request for accelerated approval, for oral selinexor as a potential new treatment for patients with relapsed or refractory DLBCL,” Sharon Shacham, PhD, founder, president, and chief scientific officer of Karyopharm, said in a statement.
In October, the FDA accepted an NDA for selinexor as a treatment for penta-refractory multiple myeloma. The agency granted the application priority review and set an action date of April 6, 2019.
Selinexor on fast track for DLBCL
The U.S. Food and Drug Administration (FDA) has granted fast track designation to selinexor for the treatment of diffuse large B-cell lymphoma (DLBCL).
The designation is for selinexor to treat DLBCL patients who have received at least two prior therapies and are not eligible for high-dose chemotherapy with stem cell rescue or chimeric antigen receptor T-cell therapy.
Selinexor is being studied in the phase 2b SADAL trial (NCT02227251), which is enrolling patients with relapsed or refractory DLBCL who have received two to five prior therapies and are not eligible for stem cell transplant.
Top-line results from this trial are scheduled to be presented at the 2018 ASH Annual Meeting (abstract 1677).
Selinexor is an oral selective inhibitor of nuclear export (SINE) compound being developed by Karyopharm Therapeutics Inc.
The company previously received fast track designation for selinexor to treat patients with penta-refractory multiple myeloma who have received at least three prior lines of therapy.
The FDA says its fast track program is designed to facilitate the development and expedite the review of products that are intended to treat serious conditions and have the potential to address unmet medical needs.
Fast track designation provides developers with greater access to the FDA as well as eligibility for accelerated approval, priority review, and rolling review.
“The receipt of fast track designation from the FDA for selinexor in relapsed DLBCL underscores the great unmet medical need for this aggressive form of lymphoma,” said Sharon Shacham, PhD, founder, president, and chief scientific officer of Karyopharm.
“Pending positive results from the phase 2b SADAL study, we plan to submit a second NDA [new drug application] to the FDA in the first half of 2019, with a request for accelerated approval, for oral selinexor as a potential new treatment for patients with relapsed or refractory DLBCL.”
Last month, the FDA accepted a new drug application for selinexor as a treatment for penta-refractory multiple myeloma. The agency granted the application priority review and set an action date of April 6, 2019.
The U.S. Food and Drug Administration (FDA) has granted fast track designation to selinexor for the treatment of diffuse large B-cell lymphoma (DLBCL).
The designation is for selinexor to treat DLBCL patients who have received at least two prior therapies and are not eligible for high-dose chemotherapy with stem cell rescue or chimeric antigen receptor T-cell therapy.
Selinexor is being studied in the phase 2b SADAL trial (NCT02227251), which is enrolling patients with relapsed or refractory DLBCL who have received two to five prior therapies and are not eligible for stem cell transplant.
Top-line results from this trial are scheduled to be presented at the 2018 ASH Annual Meeting (abstract 1677).
Selinexor is an oral selective inhibitor of nuclear export (SINE) compound being developed by Karyopharm Therapeutics Inc.
The company previously received fast track designation for selinexor to treat patients with penta-refractory multiple myeloma who have received at least three prior lines of therapy.
The FDA says its fast track program is designed to facilitate the development and expedite the review of products that are intended to treat serious conditions and have the potential to address unmet medical needs.
Fast track designation provides developers with greater access to the FDA as well as eligibility for accelerated approval, priority review, and rolling review.
“The receipt of fast track designation from the FDA for selinexor in relapsed DLBCL underscores the great unmet medical need for this aggressive form of lymphoma,” said Sharon Shacham, PhD, founder, president, and chief scientific officer of Karyopharm.
“Pending positive results from the phase 2b SADAL study, we plan to submit a second NDA [new drug application] to the FDA in the first half of 2019, with a request for accelerated approval, for oral selinexor as a potential new treatment for patients with relapsed or refractory DLBCL.”
Last month, the FDA accepted a new drug application for selinexor as a treatment for penta-refractory multiple myeloma. The agency granted the application priority review and set an action date of April 6, 2019.
The U.S. Food and Drug Administration (FDA) has granted fast track designation to selinexor for the treatment of diffuse large B-cell lymphoma (DLBCL).
The designation is for selinexor to treat DLBCL patients who have received at least two prior therapies and are not eligible for high-dose chemotherapy with stem cell rescue or chimeric antigen receptor T-cell therapy.
Selinexor is being studied in the phase 2b SADAL trial (NCT02227251), which is enrolling patients with relapsed or refractory DLBCL who have received two to five prior therapies and are not eligible for stem cell transplant.
Top-line results from this trial are scheduled to be presented at the 2018 ASH Annual Meeting (abstract 1677).
Selinexor is an oral selective inhibitor of nuclear export (SINE) compound being developed by Karyopharm Therapeutics Inc.
The company previously received fast track designation for selinexor to treat patients with penta-refractory multiple myeloma who have received at least three prior lines of therapy.
The FDA says its fast track program is designed to facilitate the development and expedite the review of products that are intended to treat serious conditions and have the potential to address unmet medical needs.
Fast track designation provides developers with greater access to the FDA as well as eligibility for accelerated approval, priority review, and rolling review.
“The receipt of fast track designation from the FDA for selinexor in relapsed DLBCL underscores the great unmet medical need for this aggressive form of lymphoma,” said Sharon Shacham, PhD, founder, president, and chief scientific officer of Karyopharm.
“Pending positive results from the phase 2b SADAL study, we plan to submit a second NDA [new drug application] to the FDA in the first half of 2019, with a request for accelerated approval, for oral selinexor as a potential new treatment for patients with relapsed or refractory DLBCL.”
Last month, the FDA accepted a new drug application for selinexor as a treatment for penta-refractory multiple myeloma. The agency granted the application priority review and set an action date of April 6, 2019.
Combo appears safe, active in rel/ref NHL
The combination of Hu5F9-G4 (5F9) and rituximab was considered safe and produced durable complete responses (CRs) in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) in a phase 1b trial.
Mainly low-grade adverse events (AEs) were observed with rituximab and 5F9, a macrophage-activating immune checkpoint inhibitor blocking CD47.
In addition, the combination produced an objective response rate (ORR) of 50% and a CR rate of 36%.
Most of the responses were ongoing at the time of data cutoff.
“It was very gratifying to see how the treatment was well-tolerated and showed a clinically meaningful response,” said Ranjana Advani, MD, of Stanford University in California.
She and her colleagues reported these results in The New England Journal of Medicine.
The study included 22 patients with relapsed or refractory NHL. Fifteen had diffuse large B-cell lymphoma (DLBCL), and seven had follicular lymphoma (FL).
The patients had received a median of four prior therapies (range, 2-10). Twenty-one patients had disease that was refractory to rituximab (all FL and 14 DLBCL patients).
All patients received 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10 to 30 mg/kg in three dose-escalation cohorts. The treatment was given until disease progression or lack of clinical benefit.
Patients received rituximab at 375 mg/m2 weekly starting on the second week of the first cycle and then monthly for cycles two through six.
Results
The most common treatment-related AEs were chills (41%), headache (41%), anemia (41%), and infusion-related reactions (36%).
Serious AEs included infections (18%), anemia (4.5%), dyspnea (4.5%), pyrexia (4.5%), lactic acidosis (4.5%), retroperitoneal mass (4.5%), pulmonary embolism (4.5%), and infusion-related reaction (4.5%).
For the entire cohort, the ORR was 50% (n=11), and the CR rate was 36% (n=8).
Among DLBCL patients, the ORR was 40% (n=6), and the CR rate was 33% (n=5). In FL patients, the ORR was 71% (n=5), and the CR rate was 43% (n=3).
The median duration of response was not reached in either disease cohort. The median follow-up was 6.2 months for DLBCL and 8.1 months for FL.
Ten of 11 responders (91%) were still in response at the time of data cutoff.
The researchers said a phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell NHL is ongoing.
The phase 1b study was supported by Forty Seven, Inc., and the Leukemia and Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Inc., Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.
The combination of Hu5F9-G4 (5F9) and rituximab was considered safe and produced durable complete responses (CRs) in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) in a phase 1b trial.
Mainly low-grade adverse events (AEs) were observed with rituximab and 5F9, a macrophage-activating immune checkpoint inhibitor blocking CD47.
In addition, the combination produced an objective response rate (ORR) of 50% and a CR rate of 36%.
Most of the responses were ongoing at the time of data cutoff.
“It was very gratifying to see how the treatment was well-tolerated and showed a clinically meaningful response,” said Ranjana Advani, MD, of Stanford University in California.
She and her colleagues reported these results in The New England Journal of Medicine.
The study included 22 patients with relapsed or refractory NHL. Fifteen had diffuse large B-cell lymphoma (DLBCL), and seven had follicular lymphoma (FL).
The patients had received a median of four prior therapies (range, 2-10). Twenty-one patients had disease that was refractory to rituximab (all FL and 14 DLBCL patients).
All patients received 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10 to 30 mg/kg in three dose-escalation cohorts. The treatment was given until disease progression or lack of clinical benefit.
Patients received rituximab at 375 mg/m2 weekly starting on the second week of the first cycle and then monthly for cycles two through six.
Results
The most common treatment-related AEs were chills (41%), headache (41%), anemia (41%), and infusion-related reactions (36%).
Serious AEs included infections (18%), anemia (4.5%), dyspnea (4.5%), pyrexia (4.5%), lactic acidosis (4.5%), retroperitoneal mass (4.5%), pulmonary embolism (4.5%), and infusion-related reaction (4.5%).
For the entire cohort, the ORR was 50% (n=11), and the CR rate was 36% (n=8).
Among DLBCL patients, the ORR was 40% (n=6), and the CR rate was 33% (n=5). In FL patients, the ORR was 71% (n=5), and the CR rate was 43% (n=3).
The median duration of response was not reached in either disease cohort. The median follow-up was 6.2 months for DLBCL and 8.1 months for FL.
Ten of 11 responders (91%) were still in response at the time of data cutoff.
The researchers said a phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell NHL is ongoing.
The phase 1b study was supported by Forty Seven, Inc., and the Leukemia and Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Inc., Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.
The combination of Hu5F9-G4 (5F9) and rituximab was considered safe and produced durable complete responses (CRs) in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) in a phase 1b trial.
Mainly low-grade adverse events (AEs) were observed with rituximab and 5F9, a macrophage-activating immune checkpoint inhibitor blocking CD47.
In addition, the combination produced an objective response rate (ORR) of 50% and a CR rate of 36%.
Most of the responses were ongoing at the time of data cutoff.
“It was very gratifying to see how the treatment was well-tolerated and showed a clinically meaningful response,” said Ranjana Advani, MD, of Stanford University in California.
She and her colleagues reported these results in The New England Journal of Medicine.
The study included 22 patients with relapsed or refractory NHL. Fifteen had diffuse large B-cell lymphoma (DLBCL), and seven had follicular lymphoma (FL).
The patients had received a median of four prior therapies (range, 2-10). Twenty-one patients had disease that was refractory to rituximab (all FL and 14 DLBCL patients).
All patients received 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10 to 30 mg/kg in three dose-escalation cohorts. The treatment was given until disease progression or lack of clinical benefit.
Patients received rituximab at 375 mg/m2 weekly starting on the second week of the first cycle and then monthly for cycles two through six.
Results
The most common treatment-related AEs were chills (41%), headache (41%), anemia (41%), and infusion-related reactions (36%).
Serious AEs included infections (18%), anemia (4.5%), dyspnea (4.5%), pyrexia (4.5%), lactic acidosis (4.5%), retroperitoneal mass (4.5%), pulmonary embolism (4.5%), and infusion-related reaction (4.5%).
For the entire cohort, the ORR was 50% (n=11), and the CR rate was 36% (n=8).
Among DLBCL patients, the ORR was 40% (n=6), and the CR rate was 33% (n=5). In FL patients, the ORR was 71% (n=5), and the CR rate was 43% (n=3).
The median duration of response was not reached in either disease cohort. The median follow-up was 6.2 months for DLBCL and 8.1 months for FL.
Ten of 11 responders (91%) were still in response at the time of data cutoff.
The researchers said a phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell NHL is ongoing.
The phase 1b study was supported by Forty Seven, Inc., and the Leukemia and Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Inc., Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.
Sandoz won’t seek U.S. approval for rituximab biosimilar
Sandoz has decided not to pursue U.S. approval for its rituximab product (GP2013), a proposed biosimiliar of Rituxan/Mabthera.
GP2013 (Rixathon, Riximyo) is already approved outside the U.S.
Sandoz was seeking U.S. approval of GP2013 for all the same indications as the reference product—B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris.
The U.S. Food and Drug Administration (FDA) had accepted the biologics license application (BLA) for GP2013 in September 2017.
In May of this year, the FDA issued a complete response letter saying it could not approve GP2013. The agency also requested additional information to complement the BLA submission for GP2013.
At the time of the complete response letter, Sandoz said it was still committed to bringing GP2013 to the U.S. market. Now, the company’s position has changed.
“We appreciate the important conversations with the FDA, which have provided specific requirements for our potential U.S. biosimilar rituximab, but believe the patient and marketplace needs in the U.S. will be satisfied before we can generate the data required,” said Stefan Hendriks, global head of biopharmaceuticals at Sandoz.
“We are disappointed to have to make this decision and stand behind the safety, efficacy, and quality of our medicine, which met the stringent criteria for approval in the European Union, Switzerland, Japan, New Zealand, and Australia.”
The BLA for GP2013 was supported, in part, by the ASSIST-FL trial (NCT01419665), in which researchers compared GP2013 to the reference product. Results from this trial were published in The Lancet Haematology in July 2017.
The phase 3 trial included adults with previously untreated, advanced stage follicular lymphoma. Patients received 8 cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.
At a median follow-up of 11.6 months, the overall response rate was 87% (271/311) in the GP2013 arm and 88% in the rituximab arm (274/313). Complete response rates were 15% (n=46) and 13% (n=42), respectively.
Rates of adverse events (AEs) were 93% in the GP2013 arm and 91% in the rituximab arm. Rates of serious AEs were 23% and 20%, respectively. The rate of discontinuation due to AEs was 7% in both arms.
The most common AE was neutropenia, which occurred in 26% of patients in the GP2013 arm and 30% of those in the rituximab arm in the combination phase. Rates of neutropenia in the maintenance phase were 10% and 6%, respectively.
Sandoz has decided not to pursue U.S. approval for its rituximab product (GP2013), a proposed biosimiliar of Rituxan/Mabthera.
GP2013 (Rixathon, Riximyo) is already approved outside the U.S.
Sandoz was seeking U.S. approval of GP2013 for all the same indications as the reference product—B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris.
The U.S. Food and Drug Administration (FDA) had accepted the biologics license application (BLA) for GP2013 in September 2017.
In May of this year, the FDA issued a complete response letter saying it could not approve GP2013. The agency also requested additional information to complement the BLA submission for GP2013.
At the time of the complete response letter, Sandoz said it was still committed to bringing GP2013 to the U.S. market. Now, the company’s position has changed.
“We appreciate the important conversations with the FDA, which have provided specific requirements for our potential U.S. biosimilar rituximab, but believe the patient and marketplace needs in the U.S. will be satisfied before we can generate the data required,” said Stefan Hendriks, global head of biopharmaceuticals at Sandoz.
“We are disappointed to have to make this decision and stand behind the safety, efficacy, and quality of our medicine, which met the stringent criteria for approval in the European Union, Switzerland, Japan, New Zealand, and Australia.”
The BLA for GP2013 was supported, in part, by the ASSIST-FL trial (NCT01419665), in which researchers compared GP2013 to the reference product. Results from this trial were published in The Lancet Haematology in July 2017.
The phase 3 trial included adults with previously untreated, advanced stage follicular lymphoma. Patients received 8 cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.
At a median follow-up of 11.6 months, the overall response rate was 87% (271/311) in the GP2013 arm and 88% in the rituximab arm (274/313). Complete response rates were 15% (n=46) and 13% (n=42), respectively.
Rates of adverse events (AEs) were 93% in the GP2013 arm and 91% in the rituximab arm. Rates of serious AEs were 23% and 20%, respectively. The rate of discontinuation due to AEs was 7% in both arms.
The most common AE was neutropenia, which occurred in 26% of patients in the GP2013 arm and 30% of those in the rituximab arm in the combination phase. Rates of neutropenia in the maintenance phase were 10% and 6%, respectively.
Sandoz has decided not to pursue U.S. approval for its rituximab product (GP2013), a proposed biosimiliar of Rituxan/Mabthera.
GP2013 (Rixathon, Riximyo) is already approved outside the U.S.
Sandoz was seeking U.S. approval of GP2013 for all the same indications as the reference product—B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris.
The U.S. Food and Drug Administration (FDA) had accepted the biologics license application (BLA) for GP2013 in September 2017.
In May of this year, the FDA issued a complete response letter saying it could not approve GP2013. The agency also requested additional information to complement the BLA submission for GP2013.
At the time of the complete response letter, Sandoz said it was still committed to bringing GP2013 to the U.S. market. Now, the company’s position has changed.
“We appreciate the important conversations with the FDA, which have provided specific requirements for our potential U.S. biosimilar rituximab, but believe the patient and marketplace needs in the U.S. will be satisfied before we can generate the data required,” said Stefan Hendriks, global head of biopharmaceuticals at Sandoz.
“We are disappointed to have to make this decision and stand behind the safety, efficacy, and quality of our medicine, which met the stringent criteria for approval in the European Union, Switzerland, Japan, New Zealand, and Australia.”
The BLA for GP2013 was supported, in part, by the ASSIST-FL trial (NCT01419665), in which researchers compared GP2013 to the reference product. Results from this trial were published in The Lancet Haematology in July 2017.
The phase 3 trial included adults with previously untreated, advanced stage follicular lymphoma. Patients received 8 cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.
At a median follow-up of 11.6 months, the overall response rate was 87% (271/311) in the GP2013 arm and 88% in the rituximab arm (274/313). Complete response rates were 15% (n=46) and 13% (n=42), respectively.
Rates of adverse events (AEs) were 93% in the GP2013 arm and 91% in the rituximab arm. Rates of serious AEs were 23% and 20%, respectively. The rate of discontinuation due to AEs was 7% in both arms.
The most common AE was neutropenia, which occurred in 26% of patients in the GP2013 arm and 30% of those in the rituximab arm in the combination phase. Rates of neutropenia in the maintenance phase were 10% and 6%, respectively.
Novel risk factors for febrile neutropenia in NHL, solid tumors
A retrospective study has revealed new potential risk factors for chemotherapy-induced febrile neutropenia in patients with solid tumors and non-Hodgkin lymphoma (NHL).
Researchers found the timing and duration of corticosteroid use were both associated with febrile neutropenia. The team also observed “marginal” associations between febrile neutropenia and certain dermatologic and mucosal conditions, as well as the use of intravenous antibiotics before chemotherapy.
However, there was no association found between oral antibiotic use and febrile neutropenia or between radiation therapy and febrile neutropenia.
Chun Rebecca Chao, PhD, of the Kaiser Permanente Southern California in Pasadena, and her colleagues reported these findings in the Journal of the National Comprehensive Cancer Network.
“Febrile neutropenia is life threatening and often requires hospitalization,” Dr. Chao said in a statement. “Furthermore, [febrile neutropenia] can lead to chemotherapy dose delay and dose reduction, which, in turn, negatively impacts antitumor efficacy. However, it can be prevented if high-risk individuals are identified and treated prophylactically.”
With this in mind, Dr. Chao and her colleagues set out to identify novel risk factors for febrile neutropenia by analyzing 15,971 patients who were treated with myelosuppressive chemotherapy at Kaiser Permanente Southern California between 2000 and 2009.
Patients had been diagnosed with NHL (n = 1,617) or breast (n = 6,323), lung (n = 3,584), colorectal (n = 3,062), ovarian (n = 924), or gastric (n = 461) cancers. In all, 4.3% of patients developed febrile neutropenia during their first cycle of chemotherapy.
The researchers found that corticosteroid use was associated with an increased risk of febrile neutropenia in a propensity score–adjusted (PSA) model. The hazard ratio was 1.53 (95% confidence interval, 1.17-1.98; P less than .01) for patients who received corticosteroids.
A longer duration of corticosteroid use was associated with a greater risk of febrile neutropenia. The adjusted HR, compared with no corticosteroid use, was 1.78 for corticosteroid treatment lasting less than 15 days and rose to 2.86 for treatment lasting 45-90 days.
“One way to reduce the incidence rate for [febrile neutropenia] could be to schedule prior corticosteroid use and subsequent chemotherapy with at least 2 weeks between them, given the magnitude of the risk increase and prevalence of this risk factor,” Dr. Chao said.
The researchers found a “marginally” increased risk of febrile neutropenia in patients with certain dermatologic conditions (dermatitis, psoriasis, pruritus) and mucosal conditions (gastritis, stomatitis, mucositis). In the PSA model, the HR was 1.40 (95% CI, 0.98-1.93; P = 0.05) for patients with these conditions.
Intravenous antibiotic use was also found to be marginally associated with an increased risk of febrile neutropenia in a restricted analysis covering patients treated in 2008 and 2009. In the PSA model, the HR was 1.35 (95% CI, 0.97-1.87; P = .08).
There was no association found between febrile neutropenia and oral antibiotic use in the restricted analysis. In the PSA model, the HR was 1.07 (95% CI, 0.77-1.48; P = .70) for patients who received oral antibiotics.
Dr. Chao and her colleagues wrote that these results suggest intravenous antibiotics may have a more profound impact than oral antibiotics on the balance of bacterial flora and other immune functions. Another possible explanation is that patients who received intravenous antibiotics were generally sicker and more prone to severe infection than patients who received oral antibiotics.
The researchers also found no association between febrile neutropenia and prior surgery, prior radiation therapy, and concurrent radiation therapy in the PSA model.
The study was funded by Amgen. Three of the authors reported being employees and stockholders of Amgen.
[email protected]
SOURCE: Chao CR et al. J Natl Compr Canc Netw. 2018;16(10):1201-8.
A retrospective study has revealed new potential risk factors for chemotherapy-induced febrile neutropenia in patients with solid tumors and non-Hodgkin lymphoma (NHL).
Researchers found the timing and duration of corticosteroid use were both associated with febrile neutropenia. The team also observed “marginal” associations between febrile neutropenia and certain dermatologic and mucosal conditions, as well as the use of intravenous antibiotics before chemotherapy.
However, there was no association found between oral antibiotic use and febrile neutropenia or between radiation therapy and febrile neutropenia.
Chun Rebecca Chao, PhD, of the Kaiser Permanente Southern California in Pasadena, and her colleagues reported these findings in the Journal of the National Comprehensive Cancer Network.
“Febrile neutropenia is life threatening and often requires hospitalization,” Dr. Chao said in a statement. “Furthermore, [febrile neutropenia] can lead to chemotherapy dose delay and dose reduction, which, in turn, negatively impacts antitumor efficacy. However, it can be prevented if high-risk individuals are identified and treated prophylactically.”
With this in mind, Dr. Chao and her colleagues set out to identify novel risk factors for febrile neutropenia by analyzing 15,971 patients who were treated with myelosuppressive chemotherapy at Kaiser Permanente Southern California between 2000 and 2009.
Patients had been diagnosed with NHL (n = 1,617) or breast (n = 6,323), lung (n = 3,584), colorectal (n = 3,062), ovarian (n = 924), or gastric (n = 461) cancers. In all, 4.3% of patients developed febrile neutropenia during their first cycle of chemotherapy.
The researchers found that corticosteroid use was associated with an increased risk of febrile neutropenia in a propensity score–adjusted (PSA) model. The hazard ratio was 1.53 (95% confidence interval, 1.17-1.98; P less than .01) for patients who received corticosteroids.
A longer duration of corticosteroid use was associated with a greater risk of febrile neutropenia. The adjusted HR, compared with no corticosteroid use, was 1.78 for corticosteroid treatment lasting less than 15 days and rose to 2.86 for treatment lasting 45-90 days.
“One way to reduce the incidence rate for [febrile neutropenia] could be to schedule prior corticosteroid use and subsequent chemotherapy with at least 2 weeks between them, given the magnitude of the risk increase and prevalence of this risk factor,” Dr. Chao said.
The researchers found a “marginally” increased risk of febrile neutropenia in patients with certain dermatologic conditions (dermatitis, psoriasis, pruritus) and mucosal conditions (gastritis, stomatitis, mucositis). In the PSA model, the HR was 1.40 (95% CI, 0.98-1.93; P = 0.05) for patients with these conditions.
Intravenous antibiotic use was also found to be marginally associated with an increased risk of febrile neutropenia in a restricted analysis covering patients treated in 2008 and 2009. In the PSA model, the HR was 1.35 (95% CI, 0.97-1.87; P = .08).
There was no association found between febrile neutropenia and oral antibiotic use in the restricted analysis. In the PSA model, the HR was 1.07 (95% CI, 0.77-1.48; P = .70) for patients who received oral antibiotics.
Dr. Chao and her colleagues wrote that these results suggest intravenous antibiotics may have a more profound impact than oral antibiotics on the balance of bacterial flora and other immune functions. Another possible explanation is that patients who received intravenous antibiotics were generally sicker and more prone to severe infection than patients who received oral antibiotics.
The researchers also found no association between febrile neutropenia and prior surgery, prior radiation therapy, and concurrent radiation therapy in the PSA model.
The study was funded by Amgen. Three of the authors reported being employees and stockholders of Amgen.
[email protected]
SOURCE: Chao CR et al. J Natl Compr Canc Netw. 2018;16(10):1201-8.
A retrospective study has revealed new potential risk factors for chemotherapy-induced febrile neutropenia in patients with solid tumors and non-Hodgkin lymphoma (NHL).
Researchers found the timing and duration of corticosteroid use were both associated with febrile neutropenia. The team also observed “marginal” associations between febrile neutropenia and certain dermatologic and mucosal conditions, as well as the use of intravenous antibiotics before chemotherapy.
However, there was no association found between oral antibiotic use and febrile neutropenia or between radiation therapy and febrile neutropenia.
Chun Rebecca Chao, PhD, of the Kaiser Permanente Southern California in Pasadena, and her colleagues reported these findings in the Journal of the National Comprehensive Cancer Network.
“Febrile neutropenia is life threatening and often requires hospitalization,” Dr. Chao said in a statement. “Furthermore, [febrile neutropenia] can lead to chemotherapy dose delay and dose reduction, which, in turn, negatively impacts antitumor efficacy. However, it can be prevented if high-risk individuals are identified and treated prophylactically.”
With this in mind, Dr. Chao and her colleagues set out to identify novel risk factors for febrile neutropenia by analyzing 15,971 patients who were treated with myelosuppressive chemotherapy at Kaiser Permanente Southern California between 2000 and 2009.
Patients had been diagnosed with NHL (n = 1,617) or breast (n = 6,323), lung (n = 3,584), colorectal (n = 3,062), ovarian (n = 924), or gastric (n = 461) cancers. In all, 4.3% of patients developed febrile neutropenia during their first cycle of chemotherapy.
The researchers found that corticosteroid use was associated with an increased risk of febrile neutropenia in a propensity score–adjusted (PSA) model. The hazard ratio was 1.53 (95% confidence interval, 1.17-1.98; P less than .01) for patients who received corticosteroids.
A longer duration of corticosteroid use was associated with a greater risk of febrile neutropenia. The adjusted HR, compared with no corticosteroid use, was 1.78 for corticosteroid treatment lasting less than 15 days and rose to 2.86 for treatment lasting 45-90 days.
“One way to reduce the incidence rate for [febrile neutropenia] could be to schedule prior corticosteroid use and subsequent chemotherapy with at least 2 weeks between them, given the magnitude of the risk increase and prevalence of this risk factor,” Dr. Chao said.
The researchers found a “marginally” increased risk of febrile neutropenia in patients with certain dermatologic conditions (dermatitis, psoriasis, pruritus) and mucosal conditions (gastritis, stomatitis, mucositis). In the PSA model, the HR was 1.40 (95% CI, 0.98-1.93; P = 0.05) for patients with these conditions.
Intravenous antibiotic use was also found to be marginally associated with an increased risk of febrile neutropenia in a restricted analysis covering patients treated in 2008 and 2009. In the PSA model, the HR was 1.35 (95% CI, 0.97-1.87; P = .08).
There was no association found between febrile neutropenia and oral antibiotic use in the restricted analysis. In the PSA model, the HR was 1.07 (95% CI, 0.77-1.48; P = .70) for patients who received oral antibiotics.
Dr. Chao and her colleagues wrote that these results suggest intravenous antibiotics may have a more profound impact than oral antibiotics on the balance of bacterial flora and other immune functions. Another possible explanation is that patients who received intravenous antibiotics were generally sicker and more prone to severe infection than patients who received oral antibiotics.
The researchers also found no association between febrile neutropenia and prior surgery, prior radiation therapy, and concurrent radiation therapy in the PSA model.
The study was funded by Amgen. Three of the authors reported being employees and stockholders of Amgen.
[email protected]
SOURCE: Chao CR et al. J Natl Compr Canc Netw. 2018;16(10):1201-8.
FROM THE JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK
Key clinical point:
Major finding: Corticosteroid use was associated with an increased risk of febrile neutropenia, compared with no corticosteroid use (hazard ratio, 1.53; P less than .01).
Study details: This retrospective study included 15,971 patients with non-Hodgkin lymphoma or five solid tumors.
Disclosures: The study was funded by Amgen. Three of the authors reported being employers and stockholders of Amgen.
Source: Chao CR et al. J Natl Compr Canc Netw. 2018;16(10):1201-8.
EC approves venetoclax in combo with rituximab
The European Commission (EC) has approved a new indication for venetoclax (Venclyxto®).
The drug is now approved for use in combination with rituximab to treat patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.
The approval is valid in all member states of the European Union as well as Iceland, Liechtenstein, and Norway.
The EC’s approval is based on results from the phase 3 MURANO trial, which were published in The New England Journal of Medicine in March.
The trial included 389 CLL patients who were randomized to receive venetoclax plus rituximab (VEN+R) or bendamustine plus rituximab (B+R). The median follow-up was 23.8 months.
According to an independent review committee, the overall response rate was 92.3% in the VEN+R arm and 72.3% in the B+R arm. The investigator-assessed overall response rates were 93.3% and 67.7%, respectively.
According to investigators, the median progression-free survival (PFS) was not reached in the VEN+R arm and was 17.0 months in the B+R arm (hazard ratio [HR]=0.17; P<0.0001).
According to the independent review committee, the median PFS was not reached in the VEN+R arm and was 18.1 months in the B+R arm (HR=0.20; P<0.0001).
Investigators said the 2-year PFS rate was 84.9% in the VEN+R arm and 36.3% in the B+R arm.
They said the 2-year overall survival rates were 91.9% and 86.6%, respectively (HR=0.48; P<0.0001). The median overall survival was not reached in either arm.
Grade 3/4 adverse events (AEs) with at least a 2% difference in incidence between the treatment arms (in the VEN+R and B+R arms, respectively) included:
- Neutropenia (57.7% and 38.8%)
- Infections and infestations (17.5% and 21.8%)
- Anemia (10.8% and 13.8%)
- Thrombocytopenia (5.7% and 10.1%)
- Febrile neutropenia (3.6% and 9.6%)
- Pneumonia (5.2% and 8.0%)
- Infusion-related reactions (1.5% and 5.3%)
- Tumor lysis syndrome (3.1% and 1.1%)
- Hypotension (0% and 2.7%)
- Hyperglycemia (2.1% and 0%)
- Hypogammaglobulinemia (2.1% and 0%).
Serious AEs with at least a 2% difference in incidence between the arms (in the VEN+R and B+R arms, respectively) were:
- Pneumonia (8.2% and 8.0%)
- Febrile neutropenia (3.6% and 8.5%)
- Pyrexia (2.6% and 6.9%)
- Anemia (1.5% and 2.7%)
- Infusion-related reactions (0.5% and 3.2%)
- Sepsis (0.5% and 2.1%)
- Tumor lysis syndrome (2.1% and 0.5%)
- Hypotension (0% and 2.7%).
Fatal AEs occurred in 5.2% of patients in the VEN+R arm and 5.9% in the B+R arm.
Fatal AEs in the VEN+R arm included pneumonia (n=3), sepsis (n=1), thrombocytopenia (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1). Two cases of pneumonia occurred in the setting of progression/Richter’s transformation.
The European Commission (EC) has approved a new indication for venetoclax (Venclyxto®).
The drug is now approved for use in combination with rituximab to treat patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.
The approval is valid in all member states of the European Union as well as Iceland, Liechtenstein, and Norway.
The EC’s approval is based on results from the phase 3 MURANO trial, which were published in The New England Journal of Medicine in March.
The trial included 389 CLL patients who were randomized to receive venetoclax plus rituximab (VEN+R) or bendamustine plus rituximab (B+R). The median follow-up was 23.8 months.
According to an independent review committee, the overall response rate was 92.3% in the VEN+R arm and 72.3% in the B+R arm. The investigator-assessed overall response rates were 93.3% and 67.7%, respectively.
According to investigators, the median progression-free survival (PFS) was not reached in the VEN+R arm and was 17.0 months in the B+R arm (hazard ratio [HR]=0.17; P<0.0001).
According to the independent review committee, the median PFS was not reached in the VEN+R arm and was 18.1 months in the B+R arm (HR=0.20; P<0.0001).
Investigators said the 2-year PFS rate was 84.9% in the VEN+R arm and 36.3% in the B+R arm.
They said the 2-year overall survival rates were 91.9% and 86.6%, respectively (HR=0.48; P<0.0001). The median overall survival was not reached in either arm.
Grade 3/4 adverse events (AEs) with at least a 2% difference in incidence between the treatment arms (in the VEN+R and B+R arms, respectively) included:
- Neutropenia (57.7% and 38.8%)
- Infections and infestations (17.5% and 21.8%)
- Anemia (10.8% and 13.8%)
- Thrombocytopenia (5.7% and 10.1%)
- Febrile neutropenia (3.6% and 9.6%)
- Pneumonia (5.2% and 8.0%)
- Infusion-related reactions (1.5% and 5.3%)
- Tumor lysis syndrome (3.1% and 1.1%)
- Hypotension (0% and 2.7%)
- Hyperglycemia (2.1% and 0%)
- Hypogammaglobulinemia (2.1% and 0%).
Serious AEs with at least a 2% difference in incidence between the arms (in the VEN+R and B+R arms, respectively) were:
- Pneumonia (8.2% and 8.0%)
- Febrile neutropenia (3.6% and 8.5%)
- Pyrexia (2.6% and 6.9%)
- Anemia (1.5% and 2.7%)
- Infusion-related reactions (0.5% and 3.2%)
- Sepsis (0.5% and 2.1%)
- Tumor lysis syndrome (2.1% and 0.5%)
- Hypotension (0% and 2.7%).
Fatal AEs occurred in 5.2% of patients in the VEN+R arm and 5.9% in the B+R arm.
Fatal AEs in the VEN+R arm included pneumonia (n=3), sepsis (n=1), thrombocytopenia (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1). Two cases of pneumonia occurred in the setting of progression/Richter’s transformation.
The European Commission (EC) has approved a new indication for venetoclax (Venclyxto®).
The drug is now approved for use in combination with rituximab to treat patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.
The approval is valid in all member states of the European Union as well as Iceland, Liechtenstein, and Norway.
The EC’s approval is based on results from the phase 3 MURANO trial, which were published in The New England Journal of Medicine in March.
The trial included 389 CLL patients who were randomized to receive venetoclax plus rituximab (VEN+R) or bendamustine plus rituximab (B+R). The median follow-up was 23.8 months.
According to an independent review committee, the overall response rate was 92.3% in the VEN+R arm and 72.3% in the B+R arm. The investigator-assessed overall response rates were 93.3% and 67.7%, respectively.
According to investigators, the median progression-free survival (PFS) was not reached in the VEN+R arm and was 17.0 months in the B+R arm (hazard ratio [HR]=0.17; P<0.0001).
According to the independent review committee, the median PFS was not reached in the VEN+R arm and was 18.1 months in the B+R arm (HR=0.20; P<0.0001).
Investigators said the 2-year PFS rate was 84.9% in the VEN+R arm and 36.3% in the B+R arm.
They said the 2-year overall survival rates were 91.9% and 86.6%, respectively (HR=0.48; P<0.0001). The median overall survival was not reached in either arm.
Grade 3/4 adverse events (AEs) with at least a 2% difference in incidence between the treatment arms (in the VEN+R and B+R arms, respectively) included:
- Neutropenia (57.7% and 38.8%)
- Infections and infestations (17.5% and 21.8%)
- Anemia (10.8% and 13.8%)
- Thrombocytopenia (5.7% and 10.1%)
- Febrile neutropenia (3.6% and 9.6%)
- Pneumonia (5.2% and 8.0%)
- Infusion-related reactions (1.5% and 5.3%)
- Tumor lysis syndrome (3.1% and 1.1%)
- Hypotension (0% and 2.7%)
- Hyperglycemia (2.1% and 0%)
- Hypogammaglobulinemia (2.1% and 0%).
Serious AEs with at least a 2% difference in incidence between the arms (in the VEN+R and B+R arms, respectively) were:
- Pneumonia (8.2% and 8.0%)
- Febrile neutropenia (3.6% and 8.5%)
- Pyrexia (2.6% and 6.9%)
- Anemia (1.5% and 2.7%)
- Infusion-related reactions (0.5% and 3.2%)
- Sepsis (0.5% and 2.1%)
- Tumor lysis syndrome (2.1% and 0.5%)
- Hypotension (0% and 2.7%).
Fatal AEs occurred in 5.2% of patients in the VEN+R arm and 5.9% in the B+R arm.
Fatal AEs in the VEN+R arm included pneumonia (n=3), sepsis (n=1), thrombocytopenia (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1). Two cases of pneumonia occurred in the setting of progression/Richter’s transformation.
Novel risk factors for febrile neutropenia in NHL, other cancers
A retrospective study has revealed new potential risk factors for chemotherapy-induced febrile neutropenia (FN) in patients with solid tumors and non-Hodgkin lymphoma (NHL).
Researchers found the timing and duration of corticosteroid use were both associated with FN.
The team also observed “marginal” associations between FN and certain dermatologic and mucosal conditions as well as the use of intravenous (IV) antibiotics before chemotherapy.
On the other hand, there was no association between oral antibiotic use and FN or between radiation therapy (RT) and FN.
Chun Rebecca Chao, PhD, of Kaiser Permanente Southern California in Pasadena, and her colleagues reported these findings in JNCCN.
“Febrile neutropenia is life-threatening and often requires hospitalization,” Dr. Chao noted. “Furthermore, FN can lead to chemotherapy dose delay and dose reduction, which, in turn, negatively impacts antitumor efficacy. However, it can be prevented if high-risk individuals are identified and treated prophylactically.”
With this in mind, Dr. Chao and her colleagues set out to identify novel risk factors for FN by analyzing 15,971 patients who were treated with myelosuppressive chemotherapy at Kaiser Permanente Southern California between 2000 and 2009.
Patients had been diagnosed with NHL (n=1,617) or breast (n=6,323), lung (n=3,584), colorectal (n=3,062), ovarian (n=924), or gastric (n=461) cancers.
In all, 4.3% of patients developed FN during their first cycle of chemotherapy.
Corticosteroid use
The researchers found corticosteroid use was associated with an increased risk of FN in a propensity score-adjusted (PSA) model (adjusted for age, sex, socioeconomic factors, comorbidities, etc.). The hazard ratio (HR) was 1.53 (95% CI, 1.17-1.98; P<0.01) for patients who received corticosteroids.
A longer duration of corticosteroid use was associated with a greater risk of FN. The adjusted HR (compared to no corticosteroid use) was:
- 1.78 for corticosteroid treatment lasting less than 15 days (P<0.01)
- 1.84 for treatment lasting 15 to 29 days (P<0.01)
- 2.27 for treatment lasting 30 to 44 days (P<0.01)
- 2.86 for treatment lasting 45 to 90 days (P<0.01).
More recent corticosteroid use was associated with a greater risk of FN as well. The adjusted HR was:
- 1.88 for corticosteroid treatment less than 15 days before chemotherapy (P<0.01)
- 1.13 for treatment 15 to 29 days before chemotherapy (P=0.72)
- 1.22 for treatment 30 to 44 days before chemotherapy (P=0.66)
- 1.41 for treatment 45 to 90 days before chemotherapy (P=0.32).
“One way to reduce the incidence rate for FN could be to schedule prior corticosteroid use and subsequent chemotherapy with at least 2 weeks between them, given the magnitude of the risk increase and prevalence of this risk factor,” Dr. Chao said.
Other potential risk factors
The researchers found a “marginally” increased risk of FN in patients with certain dermatologic conditions (dermatitis, psoriasis, pruritus, etc.) and mucosal conditions (gastritis, stomatitis, mucositis, etc.).
In the PSA model, the HR was 1.40 (95% CI, 0.98-1.93; P=0.05) for patients with these conditions.
IV antibiotic use was also found to be marginally associated with an increased risk of FN in a restricted analysis covering patients treated in 2008 and 2009. In the PSA model, the HR was 1.35 (95% CI, 0.97-1.87; P=0.08).
On the other hand, there was no association between FN and oral antibiotic use in the restricted analysis. In the PSA model, the HR was 1.07 (95% CI, 0.77-1.48; P=0.70) for patients who received oral antibiotics.
Dr. Chao and her colleagues said these results suggest IV antibiotics may have a more profound impact than oral antibiotics on the balance of bacterial flora and other immune functions. Another possible explanation is that patients who received IV antibiotics were generally sicker and more prone to severe infection than patients who received oral antibiotics.
As with oral antibiotics, the researchers found no association between FN and the following factors (with the PSA model):
- Prior surgery (HR=0.89; 95% CI, 0.72-1.11; P=0.30)
- Prior RT (HR=0.91; 95% CI, 0.64-1.27; P=0.61)
- Concurrent RT (HR=1.32; 95% CI, 0.69-2.37; P=0.37).
The researchers noted that they did not account for radiation field or dose in this study, so additional evaluation of RT as a risk factor is needed.
In closing, Dr. Chao and her colleagues said these results suggest corticosteroid use, IV antibiotics, and certain dermatologic and mucosal conditions should be taken into consideration when monitoring patients receiving myelosuppressive chemotherapy and when evaluating the need for prophylactic granulocyte colony-stimulating factor or chemotherapy dose reduction.
Dr. Chao and her colleagues received funding from Amgen, Inc., to perform this study.
A retrospective study has revealed new potential risk factors for chemotherapy-induced febrile neutropenia (FN) in patients with solid tumors and non-Hodgkin lymphoma (NHL).
Researchers found the timing and duration of corticosteroid use were both associated with FN.
The team also observed “marginal” associations between FN and certain dermatologic and mucosal conditions as well as the use of intravenous (IV) antibiotics before chemotherapy.
On the other hand, there was no association between oral antibiotic use and FN or between radiation therapy (RT) and FN.
Chun Rebecca Chao, PhD, of Kaiser Permanente Southern California in Pasadena, and her colleagues reported these findings in JNCCN.
“Febrile neutropenia is life-threatening and often requires hospitalization,” Dr. Chao noted. “Furthermore, FN can lead to chemotherapy dose delay and dose reduction, which, in turn, negatively impacts antitumor efficacy. However, it can be prevented if high-risk individuals are identified and treated prophylactically.”
With this in mind, Dr. Chao and her colleagues set out to identify novel risk factors for FN by analyzing 15,971 patients who were treated with myelosuppressive chemotherapy at Kaiser Permanente Southern California between 2000 and 2009.
Patients had been diagnosed with NHL (n=1,617) or breast (n=6,323), lung (n=3,584), colorectal (n=3,062), ovarian (n=924), or gastric (n=461) cancers.
In all, 4.3% of patients developed FN during their first cycle of chemotherapy.
Corticosteroid use
The researchers found corticosteroid use was associated with an increased risk of FN in a propensity score-adjusted (PSA) model (adjusted for age, sex, socioeconomic factors, comorbidities, etc.). The hazard ratio (HR) was 1.53 (95% CI, 1.17-1.98; P<0.01) for patients who received corticosteroids.
A longer duration of corticosteroid use was associated with a greater risk of FN. The adjusted HR (compared to no corticosteroid use) was:
- 1.78 for corticosteroid treatment lasting less than 15 days (P<0.01)
- 1.84 for treatment lasting 15 to 29 days (P<0.01)
- 2.27 for treatment lasting 30 to 44 days (P<0.01)
- 2.86 for treatment lasting 45 to 90 days (P<0.01).
More recent corticosteroid use was associated with a greater risk of FN as well. The adjusted HR was:
- 1.88 for corticosteroid treatment less than 15 days before chemotherapy (P<0.01)
- 1.13 for treatment 15 to 29 days before chemotherapy (P=0.72)
- 1.22 for treatment 30 to 44 days before chemotherapy (P=0.66)
- 1.41 for treatment 45 to 90 days before chemotherapy (P=0.32).
“One way to reduce the incidence rate for FN could be to schedule prior corticosteroid use and subsequent chemotherapy with at least 2 weeks between them, given the magnitude of the risk increase and prevalence of this risk factor,” Dr. Chao said.
Other potential risk factors
The researchers found a “marginally” increased risk of FN in patients with certain dermatologic conditions (dermatitis, psoriasis, pruritus, etc.) and mucosal conditions (gastritis, stomatitis, mucositis, etc.).
In the PSA model, the HR was 1.40 (95% CI, 0.98-1.93; P=0.05) for patients with these conditions.
IV antibiotic use was also found to be marginally associated with an increased risk of FN in a restricted analysis covering patients treated in 2008 and 2009. In the PSA model, the HR was 1.35 (95% CI, 0.97-1.87; P=0.08).
On the other hand, there was no association between FN and oral antibiotic use in the restricted analysis. In the PSA model, the HR was 1.07 (95% CI, 0.77-1.48; P=0.70) for patients who received oral antibiotics.
Dr. Chao and her colleagues said these results suggest IV antibiotics may have a more profound impact than oral antibiotics on the balance of bacterial flora and other immune functions. Another possible explanation is that patients who received IV antibiotics were generally sicker and more prone to severe infection than patients who received oral antibiotics.
As with oral antibiotics, the researchers found no association between FN and the following factors (with the PSA model):
- Prior surgery (HR=0.89; 95% CI, 0.72-1.11; P=0.30)
- Prior RT (HR=0.91; 95% CI, 0.64-1.27; P=0.61)
- Concurrent RT (HR=1.32; 95% CI, 0.69-2.37; P=0.37).
The researchers noted that they did not account for radiation field or dose in this study, so additional evaluation of RT as a risk factor is needed.
In closing, Dr. Chao and her colleagues said these results suggest corticosteroid use, IV antibiotics, and certain dermatologic and mucosal conditions should be taken into consideration when monitoring patients receiving myelosuppressive chemotherapy and when evaluating the need for prophylactic granulocyte colony-stimulating factor or chemotherapy dose reduction.
Dr. Chao and her colleagues received funding from Amgen, Inc., to perform this study.
A retrospective study has revealed new potential risk factors for chemotherapy-induced febrile neutropenia (FN) in patients with solid tumors and non-Hodgkin lymphoma (NHL).
Researchers found the timing and duration of corticosteroid use were both associated with FN.
The team also observed “marginal” associations between FN and certain dermatologic and mucosal conditions as well as the use of intravenous (IV) antibiotics before chemotherapy.
On the other hand, there was no association between oral antibiotic use and FN or between radiation therapy (RT) and FN.
Chun Rebecca Chao, PhD, of Kaiser Permanente Southern California in Pasadena, and her colleagues reported these findings in JNCCN.
“Febrile neutropenia is life-threatening and often requires hospitalization,” Dr. Chao noted. “Furthermore, FN can lead to chemotherapy dose delay and dose reduction, which, in turn, negatively impacts antitumor efficacy. However, it can be prevented if high-risk individuals are identified and treated prophylactically.”
With this in mind, Dr. Chao and her colleagues set out to identify novel risk factors for FN by analyzing 15,971 patients who were treated with myelosuppressive chemotherapy at Kaiser Permanente Southern California between 2000 and 2009.
Patients had been diagnosed with NHL (n=1,617) or breast (n=6,323), lung (n=3,584), colorectal (n=3,062), ovarian (n=924), or gastric (n=461) cancers.
In all, 4.3% of patients developed FN during their first cycle of chemotherapy.
Corticosteroid use
The researchers found corticosteroid use was associated with an increased risk of FN in a propensity score-adjusted (PSA) model (adjusted for age, sex, socioeconomic factors, comorbidities, etc.). The hazard ratio (HR) was 1.53 (95% CI, 1.17-1.98; P<0.01) for patients who received corticosteroids.
A longer duration of corticosteroid use was associated with a greater risk of FN. The adjusted HR (compared to no corticosteroid use) was:
- 1.78 for corticosteroid treatment lasting less than 15 days (P<0.01)
- 1.84 for treatment lasting 15 to 29 days (P<0.01)
- 2.27 for treatment lasting 30 to 44 days (P<0.01)
- 2.86 for treatment lasting 45 to 90 days (P<0.01).
More recent corticosteroid use was associated with a greater risk of FN as well. The adjusted HR was:
- 1.88 for corticosteroid treatment less than 15 days before chemotherapy (P<0.01)
- 1.13 for treatment 15 to 29 days before chemotherapy (P=0.72)
- 1.22 for treatment 30 to 44 days before chemotherapy (P=0.66)
- 1.41 for treatment 45 to 90 days before chemotherapy (P=0.32).
“One way to reduce the incidence rate for FN could be to schedule prior corticosteroid use and subsequent chemotherapy with at least 2 weeks between them, given the magnitude of the risk increase and prevalence of this risk factor,” Dr. Chao said.
Other potential risk factors
The researchers found a “marginally” increased risk of FN in patients with certain dermatologic conditions (dermatitis, psoriasis, pruritus, etc.) and mucosal conditions (gastritis, stomatitis, mucositis, etc.).
In the PSA model, the HR was 1.40 (95% CI, 0.98-1.93; P=0.05) for patients with these conditions.
IV antibiotic use was also found to be marginally associated with an increased risk of FN in a restricted analysis covering patients treated in 2008 and 2009. In the PSA model, the HR was 1.35 (95% CI, 0.97-1.87; P=0.08).
On the other hand, there was no association between FN and oral antibiotic use in the restricted analysis. In the PSA model, the HR was 1.07 (95% CI, 0.77-1.48; P=0.70) for patients who received oral antibiotics.
Dr. Chao and her colleagues said these results suggest IV antibiotics may have a more profound impact than oral antibiotics on the balance of bacterial flora and other immune functions. Another possible explanation is that patients who received IV antibiotics were generally sicker and more prone to severe infection than patients who received oral antibiotics.
As with oral antibiotics, the researchers found no association between FN and the following factors (with the PSA model):
- Prior surgery (HR=0.89; 95% CI, 0.72-1.11; P=0.30)
- Prior RT (HR=0.91; 95% CI, 0.64-1.27; P=0.61)
- Concurrent RT (HR=1.32; 95% CI, 0.69-2.37; P=0.37).
The researchers noted that they did not account for radiation field or dose in this study, so additional evaluation of RT as a risk factor is needed.
In closing, Dr. Chao and her colleagues said these results suggest corticosteroid use, IV antibiotics, and certain dermatologic and mucosal conditions should be taken into consideration when monitoring patients receiving myelosuppressive chemotherapy and when evaluating the need for prophylactic granulocyte colony-stimulating factor or chemotherapy dose reduction.
Dr. Chao and her colleagues received funding from Amgen, Inc., to perform this study.
Checkpoint inhibitor plus rituximab is active in non-Hodgkin lymphoma
A macrophage-activating immune checkpoint inhibitor, combined with rituximab therapy, was safe and produced durable complete responses in patients with relapsed or refractory non-Hodgkin lymphoma, according to results of a phase 1b study.
Mainly low-grade toxic effects were seen on treatment with Hu5F9-G4 (5F9) and rituximab, which induced responses in more than half of patients, of which more than one-third were complete responses, the study investigators reported.
Most of the responses were ongoing at the time of data cutoff, suggesting durable responses with the combination of rituximab and 5F9 – a humanized monoclonal antibody that blocks CD47, an antiphagocytic or “do not eat me” signal overexpressed by most cancers, Ranjana Advani, MD, of Stanford (Calif.) University, and her coauthors wrote.
“The macrophage-mediated activity of 5F9 plus rituximab may serve as an effective new immunotherapy for stimulating the innate immune system,” Dr. Advani and her colleagues reported in the New England Journal of Medicine.
The study included 22 patients, including 15 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma, who had received a median of four prior therapies. Almost all of the non-Hodgkin lymphomas (21, or 95%) were refractory to rituximab.
All patients received intravenous 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10-30 mg/kg in three dose-escalation cohorts, given until disease progression or lack of clinical benefit. Intravenous rituximab at 375 mg/m2 weekly was started on the second week of the first cycle, and then monthly for cycles 2 through 6.
“Substantial antitumor activity” was seen with this chemotherapy-free regimen in a group of heavily pretreated, largely rituximab-refractory patients, Dr. Advani and her coauthors wrote in their report.
The objective response rate was 50%, including a 36% complete response rate in the intent-to-treat analysis. For DLBCL, the rates of objective and complete responses were 40% and 33%, while for follicular lymphoma, they were 71% and 43%.
The median duration of response was not reached in either disease cohort with a median follow-up of 6.2 months for DLBCL and 8.1 months for follicular lymphoma. Of the 11 patients who responded, 10 (91%) were still in response at the time of data cutoff. “Longer follow-up is needed,” the investigators wrote.
Most adverse events were seen within the first few weeks of treatment and mainly included anemia and infusion-related reactions. The anemia was an expected, on-target effect of 5F9 because of selective clearance of older red cells, which was predictable, transient, and mitigated by the maintenance dosing strategy employed in this phase 1b trial.
“As red cells age, they lose CD47 expression and gain expression of prophagocytic signals, leading to homeostatic clearance,” they wrote.
The activity of 5F9 and rituximab is “synergistic” based on the results of previous, preclinical investigations in models of lymphoma, Dr. Advani and her coauthors added.
A phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell non-Hodgkin lymphoma is ongoing, according to their report.
The study was supported by Forty Seven and the Leukemia & Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.
SOURCE: Advani R et al. N Engl J Med. 2018;379:1711-21.
A macrophage-activating immune checkpoint inhibitor, combined with rituximab therapy, was safe and produced durable complete responses in patients with relapsed or refractory non-Hodgkin lymphoma, according to results of a phase 1b study.
Mainly low-grade toxic effects were seen on treatment with Hu5F9-G4 (5F9) and rituximab, which induced responses in more than half of patients, of which more than one-third were complete responses, the study investigators reported.
Most of the responses were ongoing at the time of data cutoff, suggesting durable responses with the combination of rituximab and 5F9 – a humanized monoclonal antibody that blocks CD47, an antiphagocytic or “do not eat me” signal overexpressed by most cancers, Ranjana Advani, MD, of Stanford (Calif.) University, and her coauthors wrote.
“The macrophage-mediated activity of 5F9 plus rituximab may serve as an effective new immunotherapy for stimulating the innate immune system,” Dr. Advani and her colleagues reported in the New England Journal of Medicine.
The study included 22 patients, including 15 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma, who had received a median of four prior therapies. Almost all of the non-Hodgkin lymphomas (21, or 95%) were refractory to rituximab.
All patients received intravenous 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10-30 mg/kg in three dose-escalation cohorts, given until disease progression or lack of clinical benefit. Intravenous rituximab at 375 mg/m2 weekly was started on the second week of the first cycle, and then monthly for cycles 2 through 6.
“Substantial antitumor activity” was seen with this chemotherapy-free regimen in a group of heavily pretreated, largely rituximab-refractory patients, Dr. Advani and her coauthors wrote in their report.
The objective response rate was 50%, including a 36% complete response rate in the intent-to-treat analysis. For DLBCL, the rates of objective and complete responses were 40% and 33%, while for follicular lymphoma, they were 71% and 43%.
The median duration of response was not reached in either disease cohort with a median follow-up of 6.2 months for DLBCL and 8.1 months for follicular lymphoma. Of the 11 patients who responded, 10 (91%) were still in response at the time of data cutoff. “Longer follow-up is needed,” the investigators wrote.
Most adverse events were seen within the first few weeks of treatment and mainly included anemia and infusion-related reactions. The anemia was an expected, on-target effect of 5F9 because of selective clearance of older red cells, which was predictable, transient, and mitigated by the maintenance dosing strategy employed in this phase 1b trial.
“As red cells age, they lose CD47 expression and gain expression of prophagocytic signals, leading to homeostatic clearance,” they wrote.
The activity of 5F9 and rituximab is “synergistic” based on the results of previous, preclinical investigations in models of lymphoma, Dr. Advani and her coauthors added.
A phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell non-Hodgkin lymphoma is ongoing, according to their report.
The study was supported by Forty Seven and the Leukemia & Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.
SOURCE: Advani R et al. N Engl J Med. 2018;379:1711-21.
A macrophage-activating immune checkpoint inhibitor, combined with rituximab therapy, was safe and produced durable complete responses in patients with relapsed or refractory non-Hodgkin lymphoma, according to results of a phase 1b study.
Mainly low-grade toxic effects were seen on treatment with Hu5F9-G4 (5F9) and rituximab, which induced responses in more than half of patients, of which more than one-third were complete responses, the study investigators reported.
Most of the responses were ongoing at the time of data cutoff, suggesting durable responses with the combination of rituximab and 5F9 – a humanized monoclonal antibody that blocks CD47, an antiphagocytic or “do not eat me” signal overexpressed by most cancers, Ranjana Advani, MD, of Stanford (Calif.) University, and her coauthors wrote.
“The macrophage-mediated activity of 5F9 plus rituximab may serve as an effective new immunotherapy for stimulating the innate immune system,” Dr. Advani and her colleagues reported in the New England Journal of Medicine.
The study included 22 patients, including 15 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma, who had received a median of four prior therapies. Almost all of the non-Hodgkin lymphomas (21, or 95%) were refractory to rituximab.
All patients received intravenous 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10-30 mg/kg in three dose-escalation cohorts, given until disease progression or lack of clinical benefit. Intravenous rituximab at 375 mg/m2 weekly was started on the second week of the first cycle, and then monthly for cycles 2 through 6.
“Substantial antitumor activity” was seen with this chemotherapy-free regimen in a group of heavily pretreated, largely rituximab-refractory patients, Dr. Advani and her coauthors wrote in their report.
The objective response rate was 50%, including a 36% complete response rate in the intent-to-treat analysis. For DLBCL, the rates of objective and complete responses were 40% and 33%, while for follicular lymphoma, they were 71% and 43%.
The median duration of response was not reached in either disease cohort with a median follow-up of 6.2 months for DLBCL and 8.1 months for follicular lymphoma. Of the 11 patients who responded, 10 (91%) were still in response at the time of data cutoff. “Longer follow-up is needed,” the investigators wrote.
Most adverse events were seen within the first few weeks of treatment and mainly included anemia and infusion-related reactions. The anemia was an expected, on-target effect of 5F9 because of selective clearance of older red cells, which was predictable, transient, and mitigated by the maintenance dosing strategy employed in this phase 1b trial.
“As red cells age, they lose CD47 expression and gain expression of prophagocytic signals, leading to homeostatic clearance,” they wrote.
The activity of 5F9 and rituximab is “synergistic” based on the results of previous, preclinical investigations in models of lymphoma, Dr. Advani and her coauthors added.
A phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell non-Hodgkin lymphoma is ongoing, according to their report.
The study was supported by Forty Seven and the Leukemia & Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.
SOURCE: Advani R et al. N Engl J Med. 2018;379:1711-21.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Rates of overall and complete responses were 50% and 36%, respectively, with most responses ongoing at the time of data cutoff.
Study details: A phase 1b study of 22 patients, including 15 with diffuse large B-cell lymphoma and 7 with follicular lymphoma.
Disclosures: The study was supported by Forty Seven and the Leukemia & Lymphoma Society. Study authors reported disclosures related to Forty Seven, Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.
Source: Advani R et al. N Engl J Med. 2018;379:1711-21.
Line complications plague dose-adjusted EPOCH-R in non-Hodgkin lymphoma
Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R), which is used to treat several types of aggressive non-Hodgkin lymphomas, is associated with high rates of line-associated complications, a new study suggests. 
These findings, published in Clinical Lymphoma, Myeloma & Leukemia, confirm other recent findings that DA-EPOCH-R has a significantly greater rate of complications, compared with that of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy.
The authors note that the use of DA-EPOCH-R is based on data from early phase trials, as well as retrospective data, that support its use as induction chemotherapy in high-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 translocations. But currently, there are no data published from randomized trials that support the use of upfront DA-EPOCH-R therapy.
DA-EPOCH-R is an infusion-based therapy that requires a central venous catheter.
In their study, Rachel J. David, MD, of Wilmot Cancer Institute, Rochester, N.Y., and her colleagues conducted a retrospective study that included all patients treated with DA-EPOCH-R at their institution between March 2011 and July 2016, and also included a concurrent cohort of patients with diffuse large B-cell lymphoma (DLBCL) who were treated with R-CHOP. The goal was to identify the rates and predictors of line-associated complications linked with the use of DA-EPOCH-R therapy in this population.
The patient cohort comprised 43 patients who received DA-EPOCH-R and 44 patients who received RCHOP.
Patients in the DA-EPOCH-R cohort experienced a significantly higher rate of complications (P =.03), compared with the R-CHOP group.
In the DA-EPOCH-R cohort, 17 patients (39.5%) reported at least one LAC, which included venous thromboembolism, chemotherapy extravasation, and line-associated infection, during the study period. Grade 3 toxicity was observed in 41% of these patients.
In contrast, eight patients (18.2%) in the R-CHOP arm experienced at least one complication, with five of the eight patients experiencing grade 3-4 toxicity.
In a univariate analysis, body mass index of 35 kg/m2 and the use of a peripherally inserted central catheter line were both significantly associated with a higher risk of venous thromboembolism (P = .04 and P = .02, respectively).
“For patients undergoing treatment with DA-EPOCH-R in whom the use of [central venous catheters] cannot be avoided, the morbidity of [line-associated complications] should be factored in by the clinician when determining upfront treatment,” the researchers wrote.
They reported having no conflicts of interest.
SOURCE: David RJ et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 29. doi: 10.1016/j.clml.2018.08.014.
Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R), which is used to treat several types of aggressive non-Hodgkin lymphomas, is associated with high rates of line-associated complications, a new study suggests.
These findings, published in Clinical Lymphoma, Myeloma & Leukemia, confirm other recent findings that DA-EPOCH-R has a significantly greater rate of complications, compared with that of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy.
The authors note that the use of DA-EPOCH-R is based on data from early phase trials, as well as retrospective data, that support its use as induction chemotherapy in high-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 translocations. But currently, there are no data published from randomized trials that support the use of upfront DA-EPOCH-R therapy.
DA-EPOCH-R is an infusion-based therapy that requires a central venous catheter.
In their study, Rachel J. David, MD, of Wilmot Cancer Institute, Rochester, N.Y., and her colleagues conducted a retrospective study that included all patients treated with DA-EPOCH-R at their institution between March 2011 and July 2016, and also included a concurrent cohort of patients with diffuse large B-cell lymphoma (DLBCL) who were treated with R-CHOP. The goal was to identify the rates and predictors of line-associated complications linked with the use of DA-EPOCH-R therapy in this population.
The patient cohort comprised 43 patients who received DA-EPOCH-R and 44 patients who received RCHOP.
Patients in the DA-EPOCH-R cohort experienced a significantly higher rate of complications (P =.03), compared with the R-CHOP group.
In the DA-EPOCH-R cohort, 17 patients (39.5%) reported at least one LAC, which included venous thromboembolism, chemotherapy extravasation, and line-associated infection, during the study period. Grade 3 toxicity was observed in 41% of these patients.
In contrast, eight patients (18.2%) in the R-CHOP arm experienced at least one complication, with five of the eight patients experiencing grade 3-4 toxicity.
In a univariate analysis, body mass index of 35 kg/m2 and the use of a peripherally inserted central catheter line were both significantly associated with a higher risk of venous thromboembolism (P = .04 and P = .02, respectively).
“For patients undergoing treatment with DA-EPOCH-R in whom the use of [central venous catheters] cannot be avoided, the morbidity of [line-associated complications] should be factored in by the clinician when determining upfront treatment,” the researchers wrote.
They reported having no conflicts of interest.
SOURCE: David RJ et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 29. doi: 10.1016/j.clml.2018.08.014.
Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R), which is used to treat several types of aggressive non-Hodgkin lymphomas, is associated with high rates of line-associated complications, a new study suggests.
These findings, published in Clinical Lymphoma, Myeloma & Leukemia, confirm other recent findings that DA-EPOCH-R has a significantly greater rate of complications, compared with that of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy.
The authors note that the use of DA-EPOCH-R is based on data from early phase trials, as well as retrospective data, that support its use as induction chemotherapy in high-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 translocations. But currently, there are no data published from randomized trials that support the use of upfront DA-EPOCH-R therapy.
DA-EPOCH-R is an infusion-based therapy that requires a central venous catheter.
In their study, Rachel J. David, MD, of Wilmot Cancer Institute, Rochester, N.Y., and her colleagues conducted a retrospective study that included all patients treated with DA-EPOCH-R at their institution between March 2011 and July 2016, and also included a concurrent cohort of patients with diffuse large B-cell lymphoma (DLBCL) who were treated with R-CHOP. The goal was to identify the rates and predictors of line-associated complications linked with the use of DA-EPOCH-R therapy in this population.
The patient cohort comprised 43 patients who received DA-EPOCH-R and 44 patients who received RCHOP.
Patients in the DA-EPOCH-R cohort experienced a significantly higher rate of complications (P =.03), compared with the R-CHOP group.
In the DA-EPOCH-R cohort, 17 patients (39.5%) reported at least one LAC, which included venous thromboembolism, chemotherapy extravasation, and line-associated infection, during the study period. Grade 3 toxicity was observed in 41% of these patients.
In contrast, eight patients (18.2%) in the R-CHOP arm experienced at least one complication, with five of the eight patients experiencing grade 3-4 toxicity.
In a univariate analysis, body mass index of 35 kg/m2 and the use of a peripherally inserted central catheter line were both significantly associated with a higher risk of venous thromboembolism (P = .04 and P = .02, respectively).
“For patients undergoing treatment with DA-EPOCH-R in whom the use of [central venous catheters] cannot be avoided, the morbidity of [line-associated complications] should be factored in by the clinician when determining upfront treatment,” the researchers wrote.
They reported having no conflicts of interest.
SOURCE: David RJ et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 29. doi: 10.1016/j.clml.2018.08.014.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
Key clinical point:
Major finding: In all, 17 dose-adjusted R-EPOCH patients (39.5%) experienced at least one line-associated complication, versus 8 patients (18.2%) in the R-CHOP group.
Study details: A retrospective single-institution study with 87 patients.
Disclosures: The researchers reported having no conflicts of interest.
Source: David RJ et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 29. doi: 10.1016/j.clml.2018.08.014.