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CAR T-cell products shine in real-world setting, reveal new insights
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
FROM CART21
Chronic GVHD therapies offer hope for treating refractory disease
Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.
“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.
Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.
Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.
Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).
There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
Treatment goals
Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:
- Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
- Preventing further tissue and organ damage
- Minimizing toxicity
- Maintaining graft-versus-tumor effect
- Achieving graft tolerance and stopping immunosuppression
- Decreasing nonrelapse mortality and improving survival
Active trials
Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.
Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.
“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
BTK inhibitors
The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.
The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.
Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
JAK1/2 inhibition
The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.
The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
Selective T-cell expansion
Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.
Monocyte/macrophage depletion
Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.
It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
Hedgehog pathway inhibition
There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.
This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.
The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
ROCK2 inhibition
Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.
This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.
At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
Hard-to-manage patients
“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.
“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
‘Exciting time’
“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.
“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.
She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.
“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.
Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.
Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.
“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.
Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.
Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.
Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).
There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
Treatment goals
Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:
- Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
- Preventing further tissue and organ damage
- Minimizing toxicity
- Maintaining graft-versus-tumor effect
- Achieving graft tolerance and stopping immunosuppression
- Decreasing nonrelapse mortality and improving survival
Active trials
Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.
Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.
“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
BTK inhibitors
The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.
The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.
Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
JAK1/2 inhibition
The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.
The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
Selective T-cell expansion
Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.
Monocyte/macrophage depletion
Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.
It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
Hedgehog pathway inhibition
There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.
This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.
The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
ROCK2 inhibition
Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.
This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.
At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
Hard-to-manage patients
“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.
“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
‘Exciting time’
“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.
“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.
She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.
“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.
Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.
Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.
“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.
Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.
Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.
Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).
There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
Treatment goals
Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:
- Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
- Preventing further tissue and organ damage
- Minimizing toxicity
- Maintaining graft-versus-tumor effect
- Achieving graft tolerance and stopping immunosuppression
- Decreasing nonrelapse mortality and improving survival
Active trials
Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.
Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.
“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
BTK inhibitors
The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.
The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.
Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
JAK1/2 inhibition
The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.
The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
Selective T-cell expansion
Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.
Monocyte/macrophage depletion
Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.
It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
Hedgehog pathway inhibition
There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.
This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.
The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
ROCK2 inhibition
Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.
This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.
At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
Hard-to-manage patients
“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.
“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
‘Exciting time’
“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.
“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.
She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.
“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.
Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.
FROM TCT 2021
Prognostic gene signature identifies high- vs. low-risk DLBCL patients
according to the results of a database analysis.
A total of 33 genes formed the signature that could be transformed into a risk score, according to a study by Santosh Khanal, a senior bioinformatics scientist at Children’s Mercy Kansas City (Mo.), and colleagues published in Cancer Genetics.
Their study used gene expression and clinical parameters from the Lymphoma/Leukemia Molecular Profiling Project from 233 patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy to identify genes whose expression was associated with overall survival (OS). They refined the information to develop prognostic gene signature that could be used to calculate risk scores for each individual and predict OS.
Significant separation
The researchers initially found 61 genes individually associated with OS that had a nonadjusted P ≤ .001 using the univariate Cox regression model. The 61 genes were then assessed using multivariate Cox analysis to identify a minimal set of genes that could predict OS, resulting in a minimal set of 33 genes that were used to develop a survival risk score for each individual.
The OS of the high-risk group was significantly reduced, compared with the low-risk group (hazard ratio, 0.046; P < .0001). Upon stratification of individuals by risk score into quartiles, patients in the lowest quartile risk score had a 100% probability of survival, while individuals in the highest quartile had a 9.2% OS by year 5.
In order to validate their results, the researchers calculated risk scores using their prognostic gene set in three additional published DLBCL studies. For all three studies, individuals with low risk score had significantly better OS, “indicating the robustness of the gene signature for multiple external datasets,” according to the researchers.
The top biological pathways and processes that were significantly overrepresented in the 33-gene set were the thioester biosynthetic process (P = .00005), cellular response to hormone stimulus (P = .002), G protein–coupled receptor ligand binding (P = .003), and myeloid cell activation involved in immune responses (P = 0.006).
“As new therapies for lymphoma become available, including new immunotherapies and personalized medicine approaches such as [chimeric antigen receptor] T cells, it will be important to identify candidate individuals that are at high risk and may benefit from experimental therapeutic approaches compared with individuals who will have lower risk of death with current therapies,” the researchers concluded.
The authors reported that they had no competing interests.
according to the results of a database analysis.
A total of 33 genes formed the signature that could be transformed into a risk score, according to a study by Santosh Khanal, a senior bioinformatics scientist at Children’s Mercy Kansas City (Mo.), and colleagues published in Cancer Genetics.
Their study used gene expression and clinical parameters from the Lymphoma/Leukemia Molecular Profiling Project from 233 patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy to identify genes whose expression was associated with overall survival (OS). They refined the information to develop prognostic gene signature that could be used to calculate risk scores for each individual and predict OS.
Significant separation
The researchers initially found 61 genes individually associated with OS that had a nonadjusted P ≤ .001 using the univariate Cox regression model. The 61 genes were then assessed using multivariate Cox analysis to identify a minimal set of genes that could predict OS, resulting in a minimal set of 33 genes that were used to develop a survival risk score for each individual.
The OS of the high-risk group was significantly reduced, compared with the low-risk group (hazard ratio, 0.046; P < .0001). Upon stratification of individuals by risk score into quartiles, patients in the lowest quartile risk score had a 100% probability of survival, while individuals in the highest quartile had a 9.2% OS by year 5.
In order to validate their results, the researchers calculated risk scores using their prognostic gene set in three additional published DLBCL studies. For all three studies, individuals with low risk score had significantly better OS, “indicating the robustness of the gene signature for multiple external datasets,” according to the researchers.
The top biological pathways and processes that were significantly overrepresented in the 33-gene set were the thioester biosynthetic process (P = .00005), cellular response to hormone stimulus (P = .002), G protein–coupled receptor ligand binding (P = .003), and myeloid cell activation involved in immune responses (P = 0.006).
“As new therapies for lymphoma become available, including new immunotherapies and personalized medicine approaches such as [chimeric antigen receptor] T cells, it will be important to identify candidate individuals that are at high risk and may benefit from experimental therapeutic approaches compared with individuals who will have lower risk of death with current therapies,” the researchers concluded.
The authors reported that they had no competing interests.
according to the results of a database analysis.
A total of 33 genes formed the signature that could be transformed into a risk score, according to a study by Santosh Khanal, a senior bioinformatics scientist at Children’s Mercy Kansas City (Mo.), and colleagues published in Cancer Genetics.
Their study used gene expression and clinical parameters from the Lymphoma/Leukemia Molecular Profiling Project from 233 patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy to identify genes whose expression was associated with overall survival (OS). They refined the information to develop prognostic gene signature that could be used to calculate risk scores for each individual and predict OS.
Significant separation
The researchers initially found 61 genes individually associated with OS that had a nonadjusted P ≤ .001 using the univariate Cox regression model. The 61 genes were then assessed using multivariate Cox analysis to identify a minimal set of genes that could predict OS, resulting in a minimal set of 33 genes that were used to develop a survival risk score for each individual.
The OS of the high-risk group was significantly reduced, compared with the low-risk group (hazard ratio, 0.046; P < .0001). Upon stratification of individuals by risk score into quartiles, patients in the lowest quartile risk score had a 100% probability of survival, while individuals in the highest quartile had a 9.2% OS by year 5.
In order to validate their results, the researchers calculated risk scores using their prognostic gene set in three additional published DLBCL studies. For all three studies, individuals with low risk score had significantly better OS, “indicating the robustness of the gene signature for multiple external datasets,” according to the researchers.
The top biological pathways and processes that were significantly overrepresented in the 33-gene set were the thioester biosynthetic process (P = .00005), cellular response to hormone stimulus (P = .002), G protein–coupled receptor ligand binding (P = .003), and myeloid cell activation involved in immune responses (P = 0.006).
“As new therapies for lymphoma become available, including new immunotherapies and personalized medicine approaches such as [chimeric antigen receptor] T cells, it will be important to identify candidate individuals that are at high risk and may benefit from experimental therapeutic approaches compared with individuals who will have lower risk of death with current therapies,” the researchers concluded.
The authors reported that they had no competing interests.
FROM CANCER GENETICS
FDA okays new CAR T-cell treatment for large B-cell lymphomas
The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.
The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).
The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.
The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.
The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%.
“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”
Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.
The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.
Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.
Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.
A postmarketing study to further evaluate the long-term safety will also be required.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.
The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).
The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.
The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.
The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%.
“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”
Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.
The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.
Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.
Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.
A postmarketing study to further evaluate the long-term safety will also be required.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.
The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).
The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.
The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.
The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%.
“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”
Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.
The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.
Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.
Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.
A postmarketing study to further evaluate the long-term safety will also be required.
A version of this article first appeared on Medscape.com.
Concern over response to COVID-19 in patients with blood cancers
Patients with cancer, particularly those with solid tumors, mounted an immune response to COVID-19 similar to that seen in people without cancer, but among patients with hematologic cancers, immune responses were less pronounced and were highly variable, typically taking longer to clear the virus.
The findings come from a small U.K. study published online Jan. 4 in Cancer Cell as a fast-track preprint article.
The findings may have implications for vaccinating against COVID-19, said the researchers, led by Sheeba Irshad, MD, PhD, a Cancer Research UK clinician scientist based at King’s College London.
“Our study provides some confidence and reassurance to care providers that many of our patients with solid cancers will mount a good immune response against the virus, develop antibodies that last, and hopefully resume their cancer treatment as soon as possible,” Dr. Irshad said in a statement.
“These conclusions imply that many patients, despite being on immunosuppressive therapies, will respond satisfactorily to COVID-19 vaccines,” she added.
Although “the data would suggest that solid cancer patients are likely to mount an efficient immune response to the vaccine ... the same cannot be said for hematological cancers, especially those with B-cell malignancies,” Dr. Irshad said in an interview.
“They may be susceptible to persistent infection despite developing antibodies, so the next stage of our study will focus on monitoring their response to the vaccines.
“At present, the best way to protect them alongside vaccinating them may be to vaccinate all their health care providers and carers to achieve herd immunity and continue to respect the public health measures put in place,” such as wearing a mask, practicing social distancing, and testing asymptomatic persons, she commented.
Study details
This study, known as the SARS-CoV-2 for Cancer Patients study, involved 76 patients with cancer; 41 of these patients had COVID-19, and 35 served as non-COVID cancer control patients.
Peripheral blood was collected from all patients; multiple samples were taken every 2-4 days where possible.
The COVID-19 and control groups were matched for age, body mass index, and tumor type, and both groups included patients with solid and hematologic cancers.
The groups were also comparable in terms of the proportion of patients with stage IV disease, those who received palliative as opposed to radical treatment, and patients who were treated within 4 weeks of recruitment to the study.
The results showed that 24.4% of cancer patients who were exposed to COVID-19 remained asymptomatic, 21.9% had mild disease, 31.7% had moderate disease, and 21.9% had severe disease.
Patients with hematologic cancers were more likely to experience dyspnea than those with solid tumors, and 39% received corticosteroid/antiviral therapies that specifically targeted COVID-19 infection.
The median duration of virus shedding was 39 days across the whole cohort. It was notably longer among patients with hematologic cancers, at a median of 55 days versus 29 days for patients with solid tumors.
Of 46 patients who survived beyond 30 days and for whom complete data were available, the team found that those with moderate or severe COVID-19 were more likely to be diagnosed with progressive cancer at their next assessment in comparison with those who were asymptomatic with COVID-19 or with control patients.
Solid-cancer patients with moderate to severe COVID-19 had sustained lymphopenia and increased neutrophil-to-lymphocyte ratios up to days 40-49 of the infection, whereas among those with mild infection, clinical blood parameters were typically in the normal range.
Although overall blood profiles of patients with hematologic cancers were similar to those of patients with solid cancers, the trajectories between mild and moderate/severe COVID-19 overlapped, and there was a large degree of heterogeneity between patients.
The team also reports that among patients with solid tumors, all parameters returned to values that were close to baseline 4-6 weeks after the patients tested negative for COVID-19 on nasopharyngeal swabbing; by contrast, many of the patients with hematologic cancers experienced ongoing immune dysregulation.
Further analysis revealed differences in immune signatures between patients with solid cancers who had active SARS-CoV-2 infection and noninfected control patients. The former showed, for example, interleukin-8, IL-6, and IL-10, IP-10 enrichment.
In contrast, there were few differences between infected and noninfected hematologic cancer patients.
Across both cohorts, approximately 75% of patients had detectable antibodies against COVID-19. Antibodies were sustained for up to 78 days after exposure to the virus.
However, patients with solid tumors showed earlier seroconversion than those with hematologic cancers. The latter had more varied responses to infection, displaying three distinct phenotypes: failure to mount an antibody response, with prolonged viral shedding, even beyond day 50 after the first positive swab; an antibody response but failure to clear the virus; and an antibody response and successful clearing of the virus.
The team noted that overall patients with hematologic cancers showed a mild response to COVID-19 in the active/early phases of the disease and that the response grew stronger over time, similar to the immune changes typically seen with chronic infections.
This was particularly the case for patients with cancers that affect B cells.
The team acknowledged that there are several limitations to the study, including its small sample size and lack of statistical power to detect differences between, for example, different treatment modalities.
“An important question which remains unanswered is if a ‘reinforced’ immune system following immunotherapy results in an under-/overactivation of the immune response” to COVID-19, the investigators commented. They note that one such patient had a good response.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas’ Foundation NHS Trust. It is funded from grants from the KCL Charity funds, MRC, Cancer Research UK, program grants from Breast Cancer Now at King’s College London and by grants to the Breast Cancer Now Toby Robin’s Research Center at the Institute of Cancer Research, London, and the Wellcome Trust Investigator Award, and is supported by the Cancer Research UK Cancer Immunotherapy Accelerator and the UK COVID-Immunology-Consortium. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients with cancer, particularly those with solid tumors, mounted an immune response to COVID-19 similar to that seen in people without cancer, but among patients with hematologic cancers, immune responses were less pronounced and were highly variable, typically taking longer to clear the virus.
The findings come from a small U.K. study published online Jan. 4 in Cancer Cell as a fast-track preprint article.
The findings may have implications for vaccinating against COVID-19, said the researchers, led by Sheeba Irshad, MD, PhD, a Cancer Research UK clinician scientist based at King’s College London.
“Our study provides some confidence and reassurance to care providers that many of our patients with solid cancers will mount a good immune response against the virus, develop antibodies that last, and hopefully resume their cancer treatment as soon as possible,” Dr. Irshad said in a statement.
“These conclusions imply that many patients, despite being on immunosuppressive therapies, will respond satisfactorily to COVID-19 vaccines,” she added.
Although “the data would suggest that solid cancer patients are likely to mount an efficient immune response to the vaccine ... the same cannot be said for hematological cancers, especially those with B-cell malignancies,” Dr. Irshad said in an interview.
“They may be susceptible to persistent infection despite developing antibodies, so the next stage of our study will focus on monitoring their response to the vaccines.
“At present, the best way to protect them alongside vaccinating them may be to vaccinate all their health care providers and carers to achieve herd immunity and continue to respect the public health measures put in place,” such as wearing a mask, practicing social distancing, and testing asymptomatic persons, she commented.
Study details
This study, known as the SARS-CoV-2 for Cancer Patients study, involved 76 patients with cancer; 41 of these patients had COVID-19, and 35 served as non-COVID cancer control patients.
Peripheral blood was collected from all patients; multiple samples were taken every 2-4 days where possible.
The COVID-19 and control groups were matched for age, body mass index, and tumor type, and both groups included patients with solid and hematologic cancers.
The groups were also comparable in terms of the proportion of patients with stage IV disease, those who received palliative as opposed to radical treatment, and patients who were treated within 4 weeks of recruitment to the study.
The results showed that 24.4% of cancer patients who were exposed to COVID-19 remained asymptomatic, 21.9% had mild disease, 31.7% had moderate disease, and 21.9% had severe disease.
Patients with hematologic cancers were more likely to experience dyspnea than those with solid tumors, and 39% received corticosteroid/antiviral therapies that specifically targeted COVID-19 infection.
The median duration of virus shedding was 39 days across the whole cohort. It was notably longer among patients with hematologic cancers, at a median of 55 days versus 29 days for patients with solid tumors.
Of 46 patients who survived beyond 30 days and for whom complete data were available, the team found that those with moderate or severe COVID-19 were more likely to be diagnosed with progressive cancer at their next assessment in comparison with those who were asymptomatic with COVID-19 or with control patients.
Solid-cancer patients with moderate to severe COVID-19 had sustained lymphopenia and increased neutrophil-to-lymphocyte ratios up to days 40-49 of the infection, whereas among those with mild infection, clinical blood parameters were typically in the normal range.
Although overall blood profiles of patients with hematologic cancers were similar to those of patients with solid cancers, the trajectories between mild and moderate/severe COVID-19 overlapped, and there was a large degree of heterogeneity between patients.
The team also reports that among patients with solid tumors, all parameters returned to values that were close to baseline 4-6 weeks after the patients tested negative for COVID-19 on nasopharyngeal swabbing; by contrast, many of the patients with hematologic cancers experienced ongoing immune dysregulation.
Further analysis revealed differences in immune signatures between patients with solid cancers who had active SARS-CoV-2 infection and noninfected control patients. The former showed, for example, interleukin-8, IL-6, and IL-10, IP-10 enrichment.
In contrast, there were few differences between infected and noninfected hematologic cancer patients.
Across both cohorts, approximately 75% of patients had detectable antibodies against COVID-19. Antibodies were sustained for up to 78 days after exposure to the virus.
However, patients with solid tumors showed earlier seroconversion than those with hematologic cancers. The latter had more varied responses to infection, displaying three distinct phenotypes: failure to mount an antibody response, with prolonged viral shedding, even beyond day 50 after the first positive swab; an antibody response but failure to clear the virus; and an antibody response and successful clearing of the virus.
The team noted that overall patients with hematologic cancers showed a mild response to COVID-19 in the active/early phases of the disease and that the response grew stronger over time, similar to the immune changes typically seen with chronic infections.
This was particularly the case for patients with cancers that affect B cells.
The team acknowledged that there are several limitations to the study, including its small sample size and lack of statistical power to detect differences between, for example, different treatment modalities.
“An important question which remains unanswered is if a ‘reinforced’ immune system following immunotherapy results in an under-/overactivation of the immune response” to COVID-19, the investigators commented. They note that one such patient had a good response.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas’ Foundation NHS Trust. It is funded from grants from the KCL Charity funds, MRC, Cancer Research UK, program grants from Breast Cancer Now at King’s College London and by grants to the Breast Cancer Now Toby Robin’s Research Center at the Institute of Cancer Research, London, and the Wellcome Trust Investigator Award, and is supported by the Cancer Research UK Cancer Immunotherapy Accelerator and the UK COVID-Immunology-Consortium. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients with cancer, particularly those with solid tumors, mounted an immune response to COVID-19 similar to that seen in people without cancer, but among patients with hematologic cancers, immune responses were less pronounced and were highly variable, typically taking longer to clear the virus.
The findings come from a small U.K. study published online Jan. 4 in Cancer Cell as a fast-track preprint article.
The findings may have implications for vaccinating against COVID-19, said the researchers, led by Sheeba Irshad, MD, PhD, a Cancer Research UK clinician scientist based at King’s College London.
“Our study provides some confidence and reassurance to care providers that many of our patients with solid cancers will mount a good immune response against the virus, develop antibodies that last, and hopefully resume their cancer treatment as soon as possible,” Dr. Irshad said in a statement.
“These conclusions imply that many patients, despite being on immunosuppressive therapies, will respond satisfactorily to COVID-19 vaccines,” she added.
Although “the data would suggest that solid cancer patients are likely to mount an efficient immune response to the vaccine ... the same cannot be said for hematological cancers, especially those with B-cell malignancies,” Dr. Irshad said in an interview.
“They may be susceptible to persistent infection despite developing antibodies, so the next stage of our study will focus on monitoring their response to the vaccines.
“At present, the best way to protect them alongside vaccinating them may be to vaccinate all their health care providers and carers to achieve herd immunity and continue to respect the public health measures put in place,” such as wearing a mask, practicing social distancing, and testing asymptomatic persons, she commented.
Study details
This study, known as the SARS-CoV-2 for Cancer Patients study, involved 76 patients with cancer; 41 of these patients had COVID-19, and 35 served as non-COVID cancer control patients.
Peripheral blood was collected from all patients; multiple samples were taken every 2-4 days where possible.
The COVID-19 and control groups were matched for age, body mass index, and tumor type, and both groups included patients with solid and hematologic cancers.
The groups were also comparable in terms of the proportion of patients with stage IV disease, those who received palliative as opposed to radical treatment, and patients who were treated within 4 weeks of recruitment to the study.
The results showed that 24.4% of cancer patients who were exposed to COVID-19 remained asymptomatic, 21.9% had mild disease, 31.7% had moderate disease, and 21.9% had severe disease.
Patients with hematologic cancers were more likely to experience dyspnea than those with solid tumors, and 39% received corticosteroid/antiviral therapies that specifically targeted COVID-19 infection.
The median duration of virus shedding was 39 days across the whole cohort. It was notably longer among patients with hematologic cancers, at a median of 55 days versus 29 days for patients with solid tumors.
Of 46 patients who survived beyond 30 days and for whom complete data were available, the team found that those with moderate or severe COVID-19 were more likely to be diagnosed with progressive cancer at their next assessment in comparison with those who were asymptomatic with COVID-19 or with control patients.
Solid-cancer patients with moderate to severe COVID-19 had sustained lymphopenia and increased neutrophil-to-lymphocyte ratios up to days 40-49 of the infection, whereas among those with mild infection, clinical blood parameters were typically in the normal range.
Although overall blood profiles of patients with hematologic cancers were similar to those of patients with solid cancers, the trajectories between mild and moderate/severe COVID-19 overlapped, and there was a large degree of heterogeneity between patients.
The team also reports that among patients with solid tumors, all parameters returned to values that were close to baseline 4-6 weeks after the patients tested negative for COVID-19 on nasopharyngeal swabbing; by contrast, many of the patients with hematologic cancers experienced ongoing immune dysregulation.
Further analysis revealed differences in immune signatures between patients with solid cancers who had active SARS-CoV-2 infection and noninfected control patients. The former showed, for example, interleukin-8, IL-6, and IL-10, IP-10 enrichment.
In contrast, there were few differences between infected and noninfected hematologic cancer patients.
Across both cohorts, approximately 75% of patients had detectable antibodies against COVID-19. Antibodies were sustained for up to 78 days after exposure to the virus.
However, patients with solid tumors showed earlier seroconversion than those with hematologic cancers. The latter had more varied responses to infection, displaying three distinct phenotypes: failure to mount an antibody response, with prolonged viral shedding, even beyond day 50 after the first positive swab; an antibody response but failure to clear the virus; and an antibody response and successful clearing of the virus.
The team noted that overall patients with hematologic cancers showed a mild response to COVID-19 in the active/early phases of the disease and that the response grew stronger over time, similar to the immune changes typically seen with chronic infections.
This was particularly the case for patients with cancers that affect B cells.
The team acknowledged that there are several limitations to the study, including its small sample size and lack of statistical power to detect differences between, for example, different treatment modalities.
“An important question which remains unanswered is if a ‘reinforced’ immune system following immunotherapy results in an under-/overactivation of the immune response” to COVID-19, the investigators commented. They note that one such patient had a good response.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas’ Foundation NHS Trust. It is funded from grants from the KCL Charity funds, MRC, Cancer Research UK, program grants from Breast Cancer Now at King’s College London and by grants to the Breast Cancer Now Toby Robin’s Research Center at the Institute of Cancer Research, London, and the Wellcome Trust Investigator Award, and is supported by the Cancer Research UK Cancer Immunotherapy Accelerator and the UK COVID-Immunology-Consortium. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Four-item prognostic index predicts survival in adult Burkitt lymphoma
A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.
In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.
“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
Inconsistent criteria
There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.
“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.
A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.
To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.
They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.
For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.
The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).
Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.
In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.
Rituximab was administered to 91% of U.S. and 95% of international patients.
Higher survival rates outside US
Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.
In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.
Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.
In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).
“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.
Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.
“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).
Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).
Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).
There were no significant differences in either PFS or OS when either LDH or stage was added into the model.
The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.
As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
Why the CNS discrepancy?
In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.
“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.
Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”
Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”
He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”
No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.
SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.
A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.
In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.
“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
Inconsistent criteria
There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.
“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.
A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.
To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.
They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.
For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.
The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).
Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.
In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.
Rituximab was administered to 91% of U.S. and 95% of international patients.
Higher survival rates outside US
Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.
In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.
Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.
In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).
“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.
Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.
“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).
Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).
Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).
There were no significant differences in either PFS or OS when either LDH or stage was added into the model.
The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.
As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
Why the CNS discrepancy?
In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.
“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.
Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”
Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”
He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”
No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.
SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.
A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.
In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.
“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
Inconsistent criteria
There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.
“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.
A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.
To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.
They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.
For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.
The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).
Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.
In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.
Rituximab was administered to 91% of U.S. and 95% of international patients.
Higher survival rates outside US
Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.
In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.
Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.
In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).
“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.
Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.
“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).
Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).
Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).
There were no significant differences in either PFS or OS when either LDH or stage was added into the model.
The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.
As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
Why the CNS discrepancy?
In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.
“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.
Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”
Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”
He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”
No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.
SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.
FROM ASH 2020
Synthetic lethality: Triple combination is a viable strategy for B-cell malignancies
For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
Richter’s transformation, a rare event
Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.
Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.
The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.
Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.
DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
Manageable adverse events
Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
Favorable responses
In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.
“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”
The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.
“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”
To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”
A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.
Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.
SOURCE: Mato AR et al. ASH 2020, Abstract 126.
For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
Richter’s transformation, a rare event
Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.
Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.
The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.
Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.
DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
Manageable adverse events
Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
Favorable responses
In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.
“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”
The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.
“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”
To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”
A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.
Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.
SOURCE: Mato AR et al. ASH 2020, Abstract 126.
For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
Richter’s transformation, a rare event
Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.
Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.
The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.
Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.
DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
Manageable adverse events
Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
Favorable responses
In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.
“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”
The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.
“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”
To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”
A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.
Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.
SOURCE: Mato AR et al. ASH 2020, Abstract 126.
FROM ASH 2020
ZUMA-12 study shows frontline axi-cel has substantial activity in high-risk large B-cell lymphoma
Axicabtagene ciloleucel (axi-cel) can be safely administered and has substantial clinical benefit as part of first-line therapy in patients with high-risk large B-cell lymphoma, according to an investigator in a phase 2 study.
The chimeric antigen receptor (CAR) T-cell therapy had a “very high” overall response rate (ORR) of 85% and a complete response (CR) rate of 74% in the ZUMA-12 study, said investigator Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston.
Nearly three-quarters of responses were ongoing with a median of follow-up of about 9 months, Dr. Neelapu said in interim analysis of ZUMA-12 presented at the annual meeting of the American Society of Hematology, which was held virtually.
While axi-cel is approved for treatment of certain relapsed/refractory large B-cell lymphomas (LBCLs), Dr. Neelapu said this is the first-ever study evaluating a CAR T-cell therapy as a first-line treatment for patients with LBCL that is high risk as defined by histology or International Prognostic Index (IPI) scoring.
Treatment with axi-cel was guided by dynamic risk assessment, Dr. Neelapu explained, meaning that patients received the CAR T-cell treatment if they had a positive interim positron emission tomography (PET) scan after two cycles of an anti-CD20 monoclonal antibody and anthracycline-containing regimen.
Longer follow-up needed
The interim efficacy analysis is based on 27 evaluable patients out of 40 patients planned to be enrolled, meaning that the final analysis is needed, and longer follow-up is needed to ensure that durability is maintained, Dr. Neelapu said in a question-and-answer session following his presentation.
Nevertheless, the 74% complete response rate in the frontline setting is “quite encouraging” compared to historical data in high-risk LBCL, where CR rates have generally been less than 50%, Dr. Neelapu added.
“Assuming that long-term data in the final analysis confirms this encouraging activity, I think we likely would need a randomized phase 3 trial to compare (axi-cel) head-to-head with frontline therapy,” he said.
Without mature data available, it’s hard to say in this single-arm study how much axi-cel is improving outcomes at the cost of significant toxicity, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.
Adverse events as reported by Dr. Neelapu included grade 3 cytokine release syndrome (CRS) in 9% of patients, and 25% grade 3 or greater neurologic events in 25%.
“It appears as though it may be salvaging some patients, as the response rate is higher than that expected for chemotherapy alone in this setting,” Dr. Diefenbach said in an interview, “but toxicity is not trivial, so the long-term data will provide better clarity as to the degree of benefit.”
Ongoing responses at 9 months
The phase 2 ZUMA-12 study includes patients classified as high risk based on MYC and BCL2 and/or BCL6 translocations, or by an International Prognostic Indicator score of 3 or greater.
Patients initially received two cycles of anti-CD20 monoclonal antibody therapy plus an anthracycline containing regimen. Those with a positive interim PET (score of 4 or 5 on the 5-point Deauville scale) received fludarabine/cyclophosphamide conditioning plus axi-cel as a single intravenous infusion of 2 x 106 CAR T cells per kg of body weight.
As of the report at the ASH meeting, 32 patient had received axi-cel, of whom 32 were evaluable for safety and 27 were evaluable for efficacy.
The ORR was 85% (23 of 27 patients), and the CR rate was 74% (20 of 27 patients), Dr. Neelapu reported, noting that with a median follow-up of 9.3 months, 70% of responders (19 of 27) were in ongoing response.
Median duration of response, progression-free survival, and overall survival have not been reached, he added.
Encephalopathy was the most common grade 3 or greater adverse event related to axi-cel, occurring in 16% of patients, while increased alanine aminotransferase and decreased neutrophil count were each seen in 9% of patients, Dr. Neelapu said.
All 32 patients experienced CRS, including grade 3 CRS in 3 patients (9%), according to the reported data. Neurologic events were seen in 22 patients (69%) including grade 3 or greater in 8 (25%). There were 2 grade 4 neurologic events – both encephalopathies that resolved, according to Dr. Neelapu – and no grade 5 neurologic events.
ZUMA-12 is sponsored by Kite, a Gilead Company. Dr. Neelapu reported disclosures related to Acerta, Adicet Bio, Bristol-Myers Squibb, Kite, and various other pharmaceutical and biotechnology companies.
SOURCE: Neelapu SS et al. ASH 2020, Abstract 405.
Axicabtagene ciloleucel (axi-cel) can be safely administered and has substantial clinical benefit as part of first-line therapy in patients with high-risk large B-cell lymphoma, according to an investigator in a phase 2 study.
The chimeric antigen receptor (CAR) T-cell therapy had a “very high” overall response rate (ORR) of 85% and a complete response (CR) rate of 74% in the ZUMA-12 study, said investigator Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston.
Nearly three-quarters of responses were ongoing with a median of follow-up of about 9 months, Dr. Neelapu said in interim analysis of ZUMA-12 presented at the annual meeting of the American Society of Hematology, which was held virtually.
While axi-cel is approved for treatment of certain relapsed/refractory large B-cell lymphomas (LBCLs), Dr. Neelapu said this is the first-ever study evaluating a CAR T-cell therapy as a first-line treatment for patients with LBCL that is high risk as defined by histology or International Prognostic Index (IPI) scoring.
Treatment with axi-cel was guided by dynamic risk assessment, Dr. Neelapu explained, meaning that patients received the CAR T-cell treatment if they had a positive interim positron emission tomography (PET) scan after two cycles of an anti-CD20 monoclonal antibody and anthracycline-containing regimen.
Longer follow-up needed
The interim efficacy analysis is based on 27 evaluable patients out of 40 patients planned to be enrolled, meaning that the final analysis is needed, and longer follow-up is needed to ensure that durability is maintained, Dr. Neelapu said in a question-and-answer session following his presentation.
Nevertheless, the 74% complete response rate in the frontline setting is “quite encouraging” compared to historical data in high-risk LBCL, where CR rates have generally been less than 50%, Dr. Neelapu added.
“Assuming that long-term data in the final analysis confirms this encouraging activity, I think we likely would need a randomized phase 3 trial to compare (axi-cel) head-to-head with frontline therapy,” he said.
Without mature data available, it’s hard to say in this single-arm study how much axi-cel is improving outcomes at the cost of significant toxicity, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.
Adverse events as reported by Dr. Neelapu included grade 3 cytokine release syndrome (CRS) in 9% of patients, and 25% grade 3 or greater neurologic events in 25%.
“It appears as though it may be salvaging some patients, as the response rate is higher than that expected for chemotherapy alone in this setting,” Dr. Diefenbach said in an interview, “but toxicity is not trivial, so the long-term data will provide better clarity as to the degree of benefit.”
Ongoing responses at 9 months
The phase 2 ZUMA-12 study includes patients classified as high risk based on MYC and BCL2 and/or BCL6 translocations, or by an International Prognostic Indicator score of 3 or greater.
Patients initially received two cycles of anti-CD20 monoclonal antibody therapy plus an anthracycline containing regimen. Those with a positive interim PET (score of 4 or 5 on the 5-point Deauville scale) received fludarabine/cyclophosphamide conditioning plus axi-cel as a single intravenous infusion of 2 x 106 CAR T cells per kg of body weight.
As of the report at the ASH meeting, 32 patient had received axi-cel, of whom 32 were evaluable for safety and 27 were evaluable for efficacy.
The ORR was 85% (23 of 27 patients), and the CR rate was 74% (20 of 27 patients), Dr. Neelapu reported, noting that with a median follow-up of 9.3 months, 70% of responders (19 of 27) were in ongoing response.
Median duration of response, progression-free survival, and overall survival have not been reached, he added.
Encephalopathy was the most common grade 3 or greater adverse event related to axi-cel, occurring in 16% of patients, while increased alanine aminotransferase and decreased neutrophil count were each seen in 9% of patients, Dr. Neelapu said.
All 32 patients experienced CRS, including grade 3 CRS in 3 patients (9%), according to the reported data. Neurologic events were seen in 22 patients (69%) including grade 3 or greater in 8 (25%). There were 2 grade 4 neurologic events – both encephalopathies that resolved, according to Dr. Neelapu – and no grade 5 neurologic events.
ZUMA-12 is sponsored by Kite, a Gilead Company. Dr. Neelapu reported disclosures related to Acerta, Adicet Bio, Bristol-Myers Squibb, Kite, and various other pharmaceutical and biotechnology companies.
SOURCE: Neelapu SS et al. ASH 2020, Abstract 405.
Axicabtagene ciloleucel (axi-cel) can be safely administered and has substantial clinical benefit as part of first-line therapy in patients with high-risk large B-cell lymphoma, according to an investigator in a phase 2 study.
The chimeric antigen receptor (CAR) T-cell therapy had a “very high” overall response rate (ORR) of 85% and a complete response (CR) rate of 74% in the ZUMA-12 study, said investigator Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston.
Nearly three-quarters of responses were ongoing with a median of follow-up of about 9 months, Dr. Neelapu said in interim analysis of ZUMA-12 presented at the annual meeting of the American Society of Hematology, which was held virtually.
While axi-cel is approved for treatment of certain relapsed/refractory large B-cell lymphomas (LBCLs), Dr. Neelapu said this is the first-ever study evaluating a CAR T-cell therapy as a first-line treatment for patients with LBCL that is high risk as defined by histology or International Prognostic Index (IPI) scoring.
Treatment with axi-cel was guided by dynamic risk assessment, Dr. Neelapu explained, meaning that patients received the CAR T-cell treatment if they had a positive interim positron emission tomography (PET) scan after two cycles of an anti-CD20 monoclonal antibody and anthracycline-containing regimen.
Longer follow-up needed
The interim efficacy analysis is based on 27 evaluable patients out of 40 patients planned to be enrolled, meaning that the final analysis is needed, and longer follow-up is needed to ensure that durability is maintained, Dr. Neelapu said in a question-and-answer session following his presentation.
Nevertheless, the 74% complete response rate in the frontline setting is “quite encouraging” compared to historical data in high-risk LBCL, where CR rates have generally been less than 50%, Dr. Neelapu added.
“Assuming that long-term data in the final analysis confirms this encouraging activity, I think we likely would need a randomized phase 3 trial to compare (axi-cel) head-to-head with frontline therapy,” he said.
Without mature data available, it’s hard to say in this single-arm study how much axi-cel is improving outcomes at the cost of significant toxicity, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.
Adverse events as reported by Dr. Neelapu included grade 3 cytokine release syndrome (CRS) in 9% of patients, and 25% grade 3 or greater neurologic events in 25%.
“It appears as though it may be salvaging some patients, as the response rate is higher than that expected for chemotherapy alone in this setting,” Dr. Diefenbach said in an interview, “but toxicity is not trivial, so the long-term data will provide better clarity as to the degree of benefit.”
Ongoing responses at 9 months
The phase 2 ZUMA-12 study includes patients classified as high risk based on MYC and BCL2 and/or BCL6 translocations, or by an International Prognostic Indicator score of 3 or greater.
Patients initially received two cycles of anti-CD20 monoclonal antibody therapy plus an anthracycline containing regimen. Those with a positive interim PET (score of 4 or 5 on the 5-point Deauville scale) received fludarabine/cyclophosphamide conditioning plus axi-cel as a single intravenous infusion of 2 x 106 CAR T cells per kg of body weight.
As of the report at the ASH meeting, 32 patient had received axi-cel, of whom 32 were evaluable for safety and 27 were evaluable for efficacy.
The ORR was 85% (23 of 27 patients), and the CR rate was 74% (20 of 27 patients), Dr. Neelapu reported, noting that with a median follow-up of 9.3 months, 70% of responders (19 of 27) were in ongoing response.
Median duration of response, progression-free survival, and overall survival have not been reached, he added.
Encephalopathy was the most common grade 3 or greater adverse event related to axi-cel, occurring in 16% of patients, while increased alanine aminotransferase and decreased neutrophil count were each seen in 9% of patients, Dr. Neelapu said.
All 32 patients experienced CRS, including grade 3 CRS in 3 patients (9%), according to the reported data. Neurologic events were seen in 22 patients (69%) including grade 3 or greater in 8 (25%). There were 2 grade 4 neurologic events – both encephalopathies that resolved, according to Dr. Neelapu – and no grade 5 neurologic events.
ZUMA-12 is sponsored by Kite, a Gilead Company. Dr. Neelapu reported disclosures related to Acerta, Adicet Bio, Bristol-Myers Squibb, Kite, and various other pharmaceutical and biotechnology companies.
SOURCE: Neelapu SS et al. ASH 2020, Abstract 405.
FROM ASH 2020
Pediatric regimens better for adolescents/young adults with aggressive B-cell NHL
Adolescents and young adults with aggressive mature B-cell non-Hodgkin lymphomas appear to have better outcomes when they’re treated under pediatric protocols rather than adult regimens, Canadian investigators say.
Results of a study of patients from the ages of 15 to 21 years with either diffuse large B-cell lymphoma (DLBCL) or Burkitt’s lymphoma treated at regional or community cancer centers in the province of Ontario indicated that adolescents and young adult (AYA) patients treated at adult centers had a more than fourfold risk for disease relapse or progression, compared with their counterparts who were treated at pediatric centers, reported Sumit Gupta, MD, PhD, from the Hospital for Sick Children in Toronto and colleagues.
“Our data suggest that pediatric approaches are associated with improved event-free survival and overall survival, primarily due to a decrease in the risk of relapse or progression, while still using lower cumulative doses of chemotherapy,” he said in an oral abstract presented at the American Society of Hematology annual meeting, held virtually.
The findings echo those seen in the treatment of patients with acute lymphoblastic leukemia (ALL). As previously reported, a study from Nordic and Baltic countries showed that young adults with ALL who were treated with a pediatric regimen had a 4-year event-free survival rate of 73%, compared with 42% for historical controls.
Similarly, a prospective U.S. study reported in 2014 showed that AYA with ALL treated with a pediatric regimen had better overall and event-free survival rates, compared with historical controls.
As with ALL, pediatric and adult regimens for treatment of patients with aggressive mature B-cell NHL differ substantially, with pediatric patients receiving more intensive short-term therapy with lower cumulative doses.
In addition, while pediatric regimens for DLBCL and Burkitt’s lymphoma are identical, adult regimens differ substantially between the two histologies, Dr. Gupta pointed out.
Adult regimens for DLBCL most often incorporate CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP plus rituximab (R-CHOP), whereas Burkitt’s lymphoma in adults is generally treated with more aggressive multidrug regimens, in combination with rituximab.
Rituximab was incorporated into adults’ regimens far earlier than in pediatric regimens, with Food and Drug Administration approval of rituximab in frontline therapy of adults with DLBCL in 2006, “whereas the first pediatric large-scale randomized controlled trial of rituximab in pediatric mature B-cell lymphoma was only published earlier this year,” he noted.
Population-based study
To see how treatment patterns for AYA patients with aggressive mature B-cell non-Hodgkin lymphomas differ between pediatric and adult centers, Dr. Gupta and colleagues conducted a population-based study of all AYA in Ontario diagnosed with Burkitt’s or DLBCL from the ages of 15 to 21 years from 1992 through 2012.
AYA from the ages of 15 to 18 years who were treated at pediatric centers were identified through the Provincial Pediatric Oncology Registry, which includes data on demographics, disease treatment, and outcomes from each of Ontario’s five childhood cancer treatments centers.
Adolescents and young adults from 15 to 21 years who were treated at adult centers with adult regimens were identified through the Ontario Cancer Registry using chart abstraction by trained personnel at all treatment centers, with all data validated by clinician reviewers.
A total of 176 patients were identified, 129 with DLBCL and 47 with Burkitt’s lymphoma. In all, 62 of the 176 patients (35.2%) were treated in pediatric centers. Not surprisingly, multivariable analysis showed that AYA treated in adult centers were older, and more likely to have been treated earlier in the study period.
Comparing treatment patterns by locus of care, the investigators found that patients with DLBCL in pediatric centers received half of the cumulative anthracycline doses as those in adult centers (150 mg/m2 vs. 300 mg/m2; P < .001) and about 75% of cumulative alkylating agent doses (3,300 mg/m2 vs. 4,465 mg/m2; P = .009).
Patients with Burkitt’s lymphoma had identical exposures to anthracyclines in pediatric vs. adult centers (120 mg/m2), but those treated in pediatric centers had half the exposure to alkylators as those treated in adult centers (3,300 mg/m2 vs. 6,600 mg/m2; P = .03).
Among patients with DLBCL, none of those treated at pediatric centers received rituximab, compared with 32.3% of those treated at adult centers (P < .001), whereas only a handful of patients with Burkitt’s lymphoma received rituximab in both pediatric and adult centers (nonsignificant).
Among all patients. 5-year event-free survival was 82.3% for those treated in pediatric centers, compared with 66.7% for those treated in adult centers (P = .02). Respective 5-year overall survival rates were 85.5% and 71.1% (P = .03).
Looking at survival by histology, the investigators saw that 5-year event-free survival for patients with DLBCL was 83.3% when they were treated like children vs. 66.7% when they were treated like adults (P = .04). Respective 5-year overall survival rates were 88.9% and 72% (P = .04).
Both event-free survival (80.8% vs. 66.7%) and overall survival (80.8% vs. 66.7%) were numerically but not statistically higher among patients with Burkitt’s treated at pediatric vs. adult centers.
An analysis adjusting for disease histology, stage, and time period of diagnosis showed that treatment at an adult center was associated with higher risk for death, with a hazard ratio of 2.4 (P = .03).
Additionally, an analysis adjusted for age, disease stage, and histology showed that patients treated in adult centers had a significantly increased risk of relapse or progression, compared with a HR of 4.4 (95% confidence interval; P = .008).
There were no significant differences in the risk of treatment-related mortality between the center types, however.
“It is important to note, however, that pediatric approaches to mature B-cell NHL [non-Hodgkin lymphoma] are associated with increased inpatient needs as compared to adult approaches, and with greater supportive care requirements. Thus the safety of such approaches in adults centers need to be established,” Dr. Gupta said.
Lower doses, better outcomes
In the question and answer session following the presentation, Jennifer Teichman, MD, MSc, a fellow in hematology at the University of Toronto who was not involved in the study asked why patients treated at adult centers would have higher relapse rates despite receiving higher doses of chemotherapy, noting that the poorer outcomes in those patients were not attributable to treatment-related mortality.
“I think one of the distinctions is that higher cumulative doses versus higher intensity of treatment over a shorter period of time are two different things, perhaps, and so giving lower cumulative doses but over a short period of time, and so giving higher intensity within that short period of time, may be what explains the higher success rate in pediatric trials,” Dr. Gupta said.
R. Michael Crump, MD, from the Princess Margaret Cancer Center, also in Toronto, asked whether the study results could have been influenced by differences between the pediatric center and adult center datasets in regard to pathology review, staging information, and International Prognostic Index.
Dr. Gupta acknowledged that, while the pediatric data were captured prospectively at each center by pediatric cancer registry staff and adult data were extracted retrospectively by trained chart reviewers, “the information that we were collecting was relatively basic – basic stage, basic histology, and that is a limitation.”
He also noted that clinicians reviewed the submitted retrospective data for completeness and had the ability to request chart extractors to return to a particular record for additional information or to correct potential errors.
The study was supported by the Canadian Institutes of Health Research, the C17 Council on Children’s Cancer & Blood Disorders, and the Pediatric Oncology Group of Ontario. Dr. Gupta, Dr. Teichman, and Dr. Crump all reported no relevant conflicts of interest.
SOURCE: Gupta S et al. ASH 2020, Abstract 708.
Adolescents and young adults with aggressive mature B-cell non-Hodgkin lymphomas appear to have better outcomes when they’re treated under pediatric protocols rather than adult regimens, Canadian investigators say.
Results of a study of patients from the ages of 15 to 21 years with either diffuse large B-cell lymphoma (DLBCL) or Burkitt’s lymphoma treated at regional or community cancer centers in the province of Ontario indicated that adolescents and young adult (AYA) patients treated at adult centers had a more than fourfold risk for disease relapse or progression, compared with their counterparts who were treated at pediatric centers, reported Sumit Gupta, MD, PhD, from the Hospital for Sick Children in Toronto and colleagues.
“Our data suggest that pediatric approaches are associated with improved event-free survival and overall survival, primarily due to a decrease in the risk of relapse or progression, while still using lower cumulative doses of chemotherapy,” he said in an oral abstract presented at the American Society of Hematology annual meeting, held virtually.
The findings echo those seen in the treatment of patients with acute lymphoblastic leukemia (ALL). As previously reported, a study from Nordic and Baltic countries showed that young adults with ALL who were treated with a pediatric regimen had a 4-year event-free survival rate of 73%, compared with 42% for historical controls.
Similarly, a prospective U.S. study reported in 2014 showed that AYA with ALL treated with a pediatric regimen had better overall and event-free survival rates, compared with historical controls.
As with ALL, pediatric and adult regimens for treatment of patients with aggressive mature B-cell NHL differ substantially, with pediatric patients receiving more intensive short-term therapy with lower cumulative doses.
In addition, while pediatric regimens for DLBCL and Burkitt’s lymphoma are identical, adult regimens differ substantially between the two histologies, Dr. Gupta pointed out.
Adult regimens for DLBCL most often incorporate CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP plus rituximab (R-CHOP), whereas Burkitt’s lymphoma in adults is generally treated with more aggressive multidrug regimens, in combination with rituximab.
Rituximab was incorporated into adults’ regimens far earlier than in pediatric regimens, with Food and Drug Administration approval of rituximab in frontline therapy of adults with DLBCL in 2006, “whereas the first pediatric large-scale randomized controlled trial of rituximab in pediatric mature B-cell lymphoma was only published earlier this year,” he noted.
Population-based study
To see how treatment patterns for AYA patients with aggressive mature B-cell non-Hodgkin lymphomas differ between pediatric and adult centers, Dr. Gupta and colleagues conducted a population-based study of all AYA in Ontario diagnosed with Burkitt’s or DLBCL from the ages of 15 to 21 years from 1992 through 2012.
AYA from the ages of 15 to 18 years who were treated at pediatric centers were identified through the Provincial Pediatric Oncology Registry, which includes data on demographics, disease treatment, and outcomes from each of Ontario’s five childhood cancer treatments centers.
Adolescents and young adults from 15 to 21 years who were treated at adult centers with adult regimens were identified through the Ontario Cancer Registry using chart abstraction by trained personnel at all treatment centers, with all data validated by clinician reviewers.
A total of 176 patients were identified, 129 with DLBCL and 47 with Burkitt’s lymphoma. In all, 62 of the 176 patients (35.2%) were treated in pediatric centers. Not surprisingly, multivariable analysis showed that AYA treated in adult centers were older, and more likely to have been treated earlier in the study period.
Comparing treatment patterns by locus of care, the investigators found that patients with DLBCL in pediatric centers received half of the cumulative anthracycline doses as those in adult centers (150 mg/m2 vs. 300 mg/m2; P < .001) and about 75% of cumulative alkylating agent doses (3,300 mg/m2 vs. 4,465 mg/m2; P = .009).
Patients with Burkitt’s lymphoma had identical exposures to anthracyclines in pediatric vs. adult centers (120 mg/m2), but those treated in pediatric centers had half the exposure to alkylators as those treated in adult centers (3,300 mg/m2 vs. 6,600 mg/m2; P = .03).
Among patients with DLBCL, none of those treated at pediatric centers received rituximab, compared with 32.3% of those treated at adult centers (P < .001), whereas only a handful of patients with Burkitt’s lymphoma received rituximab in both pediatric and adult centers (nonsignificant).
Among all patients. 5-year event-free survival was 82.3% for those treated in pediatric centers, compared with 66.7% for those treated in adult centers (P = .02). Respective 5-year overall survival rates were 85.5% and 71.1% (P = .03).
Looking at survival by histology, the investigators saw that 5-year event-free survival for patients with DLBCL was 83.3% when they were treated like children vs. 66.7% when they were treated like adults (P = .04). Respective 5-year overall survival rates were 88.9% and 72% (P = .04).
Both event-free survival (80.8% vs. 66.7%) and overall survival (80.8% vs. 66.7%) were numerically but not statistically higher among patients with Burkitt’s treated at pediatric vs. adult centers.
An analysis adjusting for disease histology, stage, and time period of diagnosis showed that treatment at an adult center was associated with higher risk for death, with a hazard ratio of 2.4 (P = .03).
Additionally, an analysis adjusted for age, disease stage, and histology showed that patients treated in adult centers had a significantly increased risk of relapse or progression, compared with a HR of 4.4 (95% confidence interval; P = .008).
There were no significant differences in the risk of treatment-related mortality between the center types, however.
“It is important to note, however, that pediatric approaches to mature B-cell NHL [non-Hodgkin lymphoma] are associated with increased inpatient needs as compared to adult approaches, and with greater supportive care requirements. Thus the safety of such approaches in adults centers need to be established,” Dr. Gupta said.
Lower doses, better outcomes
In the question and answer session following the presentation, Jennifer Teichman, MD, MSc, a fellow in hematology at the University of Toronto who was not involved in the study asked why patients treated at adult centers would have higher relapse rates despite receiving higher doses of chemotherapy, noting that the poorer outcomes in those patients were not attributable to treatment-related mortality.
“I think one of the distinctions is that higher cumulative doses versus higher intensity of treatment over a shorter period of time are two different things, perhaps, and so giving lower cumulative doses but over a short period of time, and so giving higher intensity within that short period of time, may be what explains the higher success rate in pediatric trials,” Dr. Gupta said.
R. Michael Crump, MD, from the Princess Margaret Cancer Center, also in Toronto, asked whether the study results could have been influenced by differences between the pediatric center and adult center datasets in regard to pathology review, staging information, and International Prognostic Index.
Dr. Gupta acknowledged that, while the pediatric data were captured prospectively at each center by pediatric cancer registry staff and adult data were extracted retrospectively by trained chart reviewers, “the information that we were collecting was relatively basic – basic stage, basic histology, and that is a limitation.”
He also noted that clinicians reviewed the submitted retrospective data for completeness and had the ability to request chart extractors to return to a particular record for additional information or to correct potential errors.
The study was supported by the Canadian Institutes of Health Research, the C17 Council on Children’s Cancer & Blood Disorders, and the Pediatric Oncology Group of Ontario. Dr. Gupta, Dr. Teichman, and Dr. Crump all reported no relevant conflicts of interest.
SOURCE: Gupta S et al. ASH 2020, Abstract 708.
Adolescents and young adults with aggressive mature B-cell non-Hodgkin lymphomas appear to have better outcomes when they’re treated under pediatric protocols rather than adult regimens, Canadian investigators say.
Results of a study of patients from the ages of 15 to 21 years with either diffuse large B-cell lymphoma (DLBCL) or Burkitt’s lymphoma treated at regional or community cancer centers in the province of Ontario indicated that adolescents and young adult (AYA) patients treated at adult centers had a more than fourfold risk for disease relapse or progression, compared with their counterparts who were treated at pediatric centers, reported Sumit Gupta, MD, PhD, from the Hospital for Sick Children in Toronto and colleagues.
“Our data suggest that pediatric approaches are associated with improved event-free survival and overall survival, primarily due to a decrease in the risk of relapse or progression, while still using lower cumulative doses of chemotherapy,” he said in an oral abstract presented at the American Society of Hematology annual meeting, held virtually.
The findings echo those seen in the treatment of patients with acute lymphoblastic leukemia (ALL). As previously reported, a study from Nordic and Baltic countries showed that young adults with ALL who were treated with a pediatric regimen had a 4-year event-free survival rate of 73%, compared with 42% for historical controls.
Similarly, a prospective U.S. study reported in 2014 showed that AYA with ALL treated with a pediatric regimen had better overall and event-free survival rates, compared with historical controls.
As with ALL, pediatric and adult regimens for treatment of patients with aggressive mature B-cell NHL differ substantially, with pediatric patients receiving more intensive short-term therapy with lower cumulative doses.
In addition, while pediatric regimens for DLBCL and Burkitt’s lymphoma are identical, adult regimens differ substantially between the two histologies, Dr. Gupta pointed out.
Adult regimens for DLBCL most often incorporate CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP plus rituximab (R-CHOP), whereas Burkitt’s lymphoma in adults is generally treated with more aggressive multidrug regimens, in combination with rituximab.
Rituximab was incorporated into adults’ regimens far earlier than in pediatric regimens, with Food and Drug Administration approval of rituximab in frontline therapy of adults with DLBCL in 2006, “whereas the first pediatric large-scale randomized controlled trial of rituximab in pediatric mature B-cell lymphoma was only published earlier this year,” he noted.
Population-based study
To see how treatment patterns for AYA patients with aggressive mature B-cell non-Hodgkin lymphomas differ between pediatric and adult centers, Dr. Gupta and colleagues conducted a population-based study of all AYA in Ontario diagnosed with Burkitt’s or DLBCL from the ages of 15 to 21 years from 1992 through 2012.
AYA from the ages of 15 to 18 years who were treated at pediatric centers were identified through the Provincial Pediatric Oncology Registry, which includes data on demographics, disease treatment, and outcomes from each of Ontario’s five childhood cancer treatments centers.
Adolescents and young adults from 15 to 21 years who were treated at adult centers with adult regimens were identified through the Ontario Cancer Registry using chart abstraction by trained personnel at all treatment centers, with all data validated by clinician reviewers.
A total of 176 patients were identified, 129 with DLBCL and 47 with Burkitt’s lymphoma. In all, 62 of the 176 patients (35.2%) were treated in pediatric centers. Not surprisingly, multivariable analysis showed that AYA treated in adult centers were older, and more likely to have been treated earlier in the study period.
Comparing treatment patterns by locus of care, the investigators found that patients with DLBCL in pediatric centers received half of the cumulative anthracycline doses as those in adult centers (150 mg/m2 vs. 300 mg/m2; P < .001) and about 75% of cumulative alkylating agent doses (3,300 mg/m2 vs. 4,465 mg/m2; P = .009).
Patients with Burkitt’s lymphoma had identical exposures to anthracyclines in pediatric vs. adult centers (120 mg/m2), but those treated in pediatric centers had half the exposure to alkylators as those treated in adult centers (3,300 mg/m2 vs. 6,600 mg/m2; P = .03).
Among patients with DLBCL, none of those treated at pediatric centers received rituximab, compared with 32.3% of those treated at adult centers (P < .001), whereas only a handful of patients with Burkitt’s lymphoma received rituximab in both pediatric and adult centers (nonsignificant).
Among all patients. 5-year event-free survival was 82.3% for those treated in pediatric centers, compared with 66.7% for those treated in adult centers (P = .02). Respective 5-year overall survival rates were 85.5% and 71.1% (P = .03).
Looking at survival by histology, the investigators saw that 5-year event-free survival for patients with DLBCL was 83.3% when they were treated like children vs. 66.7% when they were treated like adults (P = .04). Respective 5-year overall survival rates were 88.9% and 72% (P = .04).
Both event-free survival (80.8% vs. 66.7%) and overall survival (80.8% vs. 66.7%) were numerically but not statistically higher among patients with Burkitt’s treated at pediatric vs. adult centers.
An analysis adjusting for disease histology, stage, and time period of diagnosis showed that treatment at an adult center was associated with higher risk for death, with a hazard ratio of 2.4 (P = .03).
Additionally, an analysis adjusted for age, disease stage, and histology showed that patients treated in adult centers had a significantly increased risk of relapse or progression, compared with a HR of 4.4 (95% confidence interval; P = .008).
There were no significant differences in the risk of treatment-related mortality between the center types, however.
“It is important to note, however, that pediatric approaches to mature B-cell NHL [non-Hodgkin lymphoma] are associated with increased inpatient needs as compared to adult approaches, and with greater supportive care requirements. Thus the safety of such approaches in adults centers need to be established,” Dr. Gupta said.
Lower doses, better outcomes
In the question and answer session following the presentation, Jennifer Teichman, MD, MSc, a fellow in hematology at the University of Toronto who was not involved in the study asked why patients treated at adult centers would have higher relapse rates despite receiving higher doses of chemotherapy, noting that the poorer outcomes in those patients were not attributable to treatment-related mortality.
“I think one of the distinctions is that higher cumulative doses versus higher intensity of treatment over a shorter period of time are two different things, perhaps, and so giving lower cumulative doses but over a short period of time, and so giving higher intensity within that short period of time, may be what explains the higher success rate in pediatric trials,” Dr. Gupta said.
R. Michael Crump, MD, from the Princess Margaret Cancer Center, also in Toronto, asked whether the study results could have been influenced by differences between the pediatric center and adult center datasets in regard to pathology review, staging information, and International Prognostic Index.
Dr. Gupta acknowledged that, while the pediatric data were captured prospectively at each center by pediatric cancer registry staff and adult data were extracted retrospectively by trained chart reviewers, “the information that we were collecting was relatively basic – basic stage, basic histology, and that is a limitation.”
He also noted that clinicians reviewed the submitted retrospective data for completeness and had the ability to request chart extractors to return to a particular record for additional information or to correct potential errors.
The study was supported by the Canadian Institutes of Health Research, the C17 Council on Children’s Cancer & Blood Disorders, and the Pediatric Oncology Group of Ontario. Dr. Gupta, Dr. Teichman, and Dr. Crump all reported no relevant conflicts of interest.
SOURCE: Gupta S et al. ASH 2020, Abstract 708.
FROM ASH 2020
Key clinical point: Pediatric cancer regimens may offer better outcomes for adolescents/young adults with aggressive mature B-cell lymphomas.
Major finding: The hazard ratio for relapse or progression for patients treated in adults centers was 4.4 (P = .008)
Study details: Retrospective study of 176 adolescents/young adults with diffuse large B-cell lymphoma or Burkitt’s lymphoma.
Disclosures: The study was supported the Canadian Institutes of Health Research, the C17 Council on Children’s Cancer & Blood Disorders, and the Pediatric Oncology Group of Ontario. Dr. Gupta, Dr. Teichman, and Dr. Crump all reported no relevant conflicts of interest.
Source: Gupta S. et al. ASH 2020, Abstract 708.
Bispecific antibody odronextamab demonstrates durable complete responses in refractory NHL
The novel bispecific antibody odronextamab (REGN1979) is demonstrating encouraging activity, durable responses, and acceptable safety in a phase 1 study of patients with highly refractory B-cell non-Hodgkin lymphoma, according to an investigator.
Durable complete responses (CRs) to odronextamab are being observed in more than 80% of heavily pretreated patients with follicular lymphoma (FL) in the ongoing study, said Rajat Bannerji, MD, PhD, of Rutgers Cancer Institute of New Jersey, New Brunswick.
Likewise, durable CRs were seen in greater than 80% of patients diffuse large B-cell lymphoma (DLBCL) not previously exposed to chimeric antigen receptor (CAR) T-cell therapy, and also in about 20% of patients who were treated with CAR T cells, Dr. Bannerji reported at the annual meeting of the American Society of Hematology, held virtually this year.
For these patients with FL or DLBCL in the phase 1 study, cytokine release syndrome (CRS) and neurotoxicity events did not exceed grade 3 in severity, and no cases of tumor lysis syndrome (TLS) were observed, Dr. Bannerji added in his presentation.
Those findings suggest odronextamab, which binds to CD3 on T cells and CD20 on malignant B cells, may offer an “off-the-shelf, primarily outpatient treatment option” for patients with relapsed or refractory B-cell NHL, he said in concluding remarks on the study.
This first-in-human study took a conservative approach, according to Dr. Bannerji, by mandating hospital admission during an initial step-up dosing schedule used along with dexamethasone to mitigate risk of CRS.
“With our step-up dosing and steroid premedication, we really have not seen too many cytokine release issues, and I do think that in the future it would be safe even to do step-up in the majority of patients as an outpatient,” he said in a discussion following his presentation.
Durability with further follow-up
Phase 1 data for odronextamab reported by Dr. Bannerji at the 2019 ASH meeting showed encouraging safety, tolerability, and preliminary efficacy in patients with relapsed or refractory B-cell NHL at doses up to 320 mg weekly.
In the presentation at this year’s ASH meeting, Dr. Bannerji provided updated safety and efficacy results, including longer follow-up for duration of response.
In patients with relapsed/refractory FL, the overall response rate (ORR) was 90% (27 of 30 patients), including a CR rate of 70% (21 of 30 patients), it was reported at ASH 2020. The median duration of complete response (DoCR) was not reached, with 81% of CRs durable and ongoing for up to 41 months, according to Dr. Bannerji.
In patients with relapsed/refractory DLBCL who had not received prior CAR T-cell therapy, the ORR was 55% (6 of 11 patients), all of which were complete responses, data show. The median DoCR was again not reached, with 83% of CRs durable and ongoing for up to 21 months as of this report.
In a larger group of patients with relapsed/refractory DLBCL who had received CAR T-cell therapy, the ORR was 33% (8 of 24 patients) including a 21% CR rate (5 of 24 patients). Median DoCR was not reached, the study data show, with 100% of these CRs ongoing for up to 20 months.
Odronextamab was given up to 320 mg weekly with no dose-limiting toxicities and the maximum tolerated dose not reached, according to Dr. Bannerji, who noted that no patients had discontinued treatment because of CRS or neurotoxicity.
Cytokine release syndrome was seen in about 35% of patients with DLBCL, FL, or other B-cell NHLs (48 of 136 patients), and most cases were grade 1 or 2 in severity. No FL or DLBCL patients experienced CRS higher than grade 3, according to the investigator, who reported one case of grade 3 CRS occurring out of 38 FL patients (about 3%) and four cases of grade 3 CRS out of 78 total DLBCL patients (about 5%).
No patients with FL experienced immune effector cell-associated neurotoxicity syndrome (ICANS)-like events of grade 3 or greater, the investigator said. Three cases of grade 3 ICANS-like events were reported among DLBCL patients: two cases that occurred during the step-up dosing phase and one that occurred at full dose.
No TLS events of grade 3 or greater were observed in any FL or DLBCL patients, he added.
More research needed
Although efficacy and safety results from this phase 1 study of odronextamab are encouraging, the durability, combinability, and potential for sequencing of bispecific antibodies deserves further investigation, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.
“Bispecifics in lymphoma as a class are extremely promising,” Dr. Diefenbach said in an interview. “They’re highly active and they activate an immune response against the tumor without inducing, for the most part, the same degree of neurotoxicity and CRS most CAR T cells do.
“I think the challenge is going to be to figure out how to give them in combination with other therapies to maximize durability, and how to sequence bispecifics and CAR T cells,” she added.
A global phase 2 trial of odronextamab in patients with relapsed or refractory B-cell NHL is currently recruiting. According to Dr. Bannerji, further studies are planned to evaluate odronextamab with chemotherapy and in chemotherapy-free combinations in earlier lines of treatment.
The study is sponsored by Regeneron Pharmaceuticals. Dr. Bannerji reported research funding from Regeneron, AbbVie, F. Hoffmann La Roche Ltd/Genentech Inc., and Pharmacyclics LLC, an AbbVie company. Dr. Bannerji’s spouse is an employee of Sanofi Pasteur.
SOURCE: Bannerji R et al. ASH 2020, Abstract 400.
The novel bispecific antibody odronextamab (REGN1979) is demonstrating encouraging activity, durable responses, and acceptable safety in a phase 1 study of patients with highly refractory B-cell non-Hodgkin lymphoma, according to an investigator.
Durable complete responses (CRs) to odronextamab are being observed in more than 80% of heavily pretreated patients with follicular lymphoma (FL) in the ongoing study, said Rajat Bannerji, MD, PhD, of Rutgers Cancer Institute of New Jersey, New Brunswick.
Likewise, durable CRs were seen in greater than 80% of patients diffuse large B-cell lymphoma (DLBCL) not previously exposed to chimeric antigen receptor (CAR) T-cell therapy, and also in about 20% of patients who were treated with CAR T cells, Dr. Bannerji reported at the annual meeting of the American Society of Hematology, held virtually this year.
For these patients with FL or DLBCL in the phase 1 study, cytokine release syndrome (CRS) and neurotoxicity events did not exceed grade 3 in severity, and no cases of tumor lysis syndrome (TLS) were observed, Dr. Bannerji added in his presentation.
Those findings suggest odronextamab, which binds to CD3 on T cells and CD20 on malignant B cells, may offer an “off-the-shelf, primarily outpatient treatment option” for patients with relapsed or refractory B-cell NHL, he said in concluding remarks on the study.
This first-in-human study took a conservative approach, according to Dr. Bannerji, by mandating hospital admission during an initial step-up dosing schedule used along with dexamethasone to mitigate risk of CRS.
“With our step-up dosing and steroid premedication, we really have not seen too many cytokine release issues, and I do think that in the future it would be safe even to do step-up in the majority of patients as an outpatient,” he said in a discussion following his presentation.
Durability with further follow-up
Phase 1 data for odronextamab reported by Dr. Bannerji at the 2019 ASH meeting showed encouraging safety, tolerability, and preliminary efficacy in patients with relapsed or refractory B-cell NHL at doses up to 320 mg weekly.
In the presentation at this year’s ASH meeting, Dr. Bannerji provided updated safety and efficacy results, including longer follow-up for duration of response.
In patients with relapsed/refractory FL, the overall response rate (ORR) was 90% (27 of 30 patients), including a CR rate of 70% (21 of 30 patients), it was reported at ASH 2020. The median duration of complete response (DoCR) was not reached, with 81% of CRs durable and ongoing for up to 41 months, according to Dr. Bannerji.
In patients with relapsed/refractory DLBCL who had not received prior CAR T-cell therapy, the ORR was 55% (6 of 11 patients), all of which were complete responses, data show. The median DoCR was again not reached, with 83% of CRs durable and ongoing for up to 21 months as of this report.
In a larger group of patients with relapsed/refractory DLBCL who had received CAR T-cell therapy, the ORR was 33% (8 of 24 patients) including a 21% CR rate (5 of 24 patients). Median DoCR was not reached, the study data show, with 100% of these CRs ongoing for up to 20 months.
Odronextamab was given up to 320 mg weekly with no dose-limiting toxicities and the maximum tolerated dose not reached, according to Dr. Bannerji, who noted that no patients had discontinued treatment because of CRS or neurotoxicity.
Cytokine release syndrome was seen in about 35% of patients with DLBCL, FL, or other B-cell NHLs (48 of 136 patients), and most cases were grade 1 or 2 in severity. No FL or DLBCL patients experienced CRS higher than grade 3, according to the investigator, who reported one case of grade 3 CRS occurring out of 38 FL patients (about 3%) and four cases of grade 3 CRS out of 78 total DLBCL patients (about 5%).
No patients with FL experienced immune effector cell-associated neurotoxicity syndrome (ICANS)-like events of grade 3 or greater, the investigator said. Three cases of grade 3 ICANS-like events were reported among DLBCL patients: two cases that occurred during the step-up dosing phase and one that occurred at full dose.
No TLS events of grade 3 or greater were observed in any FL or DLBCL patients, he added.
More research needed
Although efficacy and safety results from this phase 1 study of odronextamab are encouraging, the durability, combinability, and potential for sequencing of bispecific antibodies deserves further investigation, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.
“Bispecifics in lymphoma as a class are extremely promising,” Dr. Diefenbach said in an interview. “They’re highly active and they activate an immune response against the tumor without inducing, for the most part, the same degree of neurotoxicity and CRS most CAR T cells do.
“I think the challenge is going to be to figure out how to give them in combination with other therapies to maximize durability, and how to sequence bispecifics and CAR T cells,” she added.
A global phase 2 trial of odronextamab in patients with relapsed or refractory B-cell NHL is currently recruiting. According to Dr. Bannerji, further studies are planned to evaluate odronextamab with chemotherapy and in chemotherapy-free combinations in earlier lines of treatment.
The study is sponsored by Regeneron Pharmaceuticals. Dr. Bannerji reported research funding from Regeneron, AbbVie, F. Hoffmann La Roche Ltd/Genentech Inc., and Pharmacyclics LLC, an AbbVie company. Dr. Bannerji’s spouse is an employee of Sanofi Pasteur.
SOURCE: Bannerji R et al. ASH 2020, Abstract 400.
The novel bispecific antibody odronextamab (REGN1979) is demonstrating encouraging activity, durable responses, and acceptable safety in a phase 1 study of patients with highly refractory B-cell non-Hodgkin lymphoma, according to an investigator.
Durable complete responses (CRs) to odronextamab are being observed in more than 80% of heavily pretreated patients with follicular lymphoma (FL) in the ongoing study, said Rajat Bannerji, MD, PhD, of Rutgers Cancer Institute of New Jersey, New Brunswick.
Likewise, durable CRs were seen in greater than 80% of patients diffuse large B-cell lymphoma (DLBCL) not previously exposed to chimeric antigen receptor (CAR) T-cell therapy, and also in about 20% of patients who were treated with CAR T cells, Dr. Bannerji reported at the annual meeting of the American Society of Hematology, held virtually this year.
For these patients with FL or DLBCL in the phase 1 study, cytokine release syndrome (CRS) and neurotoxicity events did not exceed grade 3 in severity, and no cases of tumor lysis syndrome (TLS) were observed, Dr. Bannerji added in his presentation.
Those findings suggest odronextamab, which binds to CD3 on T cells and CD20 on malignant B cells, may offer an “off-the-shelf, primarily outpatient treatment option” for patients with relapsed or refractory B-cell NHL, he said in concluding remarks on the study.
This first-in-human study took a conservative approach, according to Dr. Bannerji, by mandating hospital admission during an initial step-up dosing schedule used along with dexamethasone to mitigate risk of CRS.
“With our step-up dosing and steroid premedication, we really have not seen too many cytokine release issues, and I do think that in the future it would be safe even to do step-up in the majority of patients as an outpatient,” he said in a discussion following his presentation.
Durability with further follow-up
Phase 1 data for odronextamab reported by Dr. Bannerji at the 2019 ASH meeting showed encouraging safety, tolerability, and preliminary efficacy in patients with relapsed or refractory B-cell NHL at doses up to 320 mg weekly.
In the presentation at this year’s ASH meeting, Dr. Bannerji provided updated safety and efficacy results, including longer follow-up for duration of response.
In patients with relapsed/refractory FL, the overall response rate (ORR) was 90% (27 of 30 patients), including a CR rate of 70% (21 of 30 patients), it was reported at ASH 2020. The median duration of complete response (DoCR) was not reached, with 81% of CRs durable and ongoing for up to 41 months, according to Dr. Bannerji.
In patients with relapsed/refractory DLBCL who had not received prior CAR T-cell therapy, the ORR was 55% (6 of 11 patients), all of which were complete responses, data show. The median DoCR was again not reached, with 83% of CRs durable and ongoing for up to 21 months as of this report.
In a larger group of patients with relapsed/refractory DLBCL who had received CAR T-cell therapy, the ORR was 33% (8 of 24 patients) including a 21% CR rate (5 of 24 patients). Median DoCR was not reached, the study data show, with 100% of these CRs ongoing for up to 20 months.
Odronextamab was given up to 320 mg weekly with no dose-limiting toxicities and the maximum tolerated dose not reached, according to Dr. Bannerji, who noted that no patients had discontinued treatment because of CRS or neurotoxicity.
Cytokine release syndrome was seen in about 35% of patients with DLBCL, FL, or other B-cell NHLs (48 of 136 patients), and most cases were grade 1 or 2 in severity. No FL or DLBCL patients experienced CRS higher than grade 3, according to the investigator, who reported one case of grade 3 CRS occurring out of 38 FL patients (about 3%) and four cases of grade 3 CRS out of 78 total DLBCL patients (about 5%).
No patients with FL experienced immune effector cell-associated neurotoxicity syndrome (ICANS)-like events of grade 3 or greater, the investigator said. Three cases of grade 3 ICANS-like events were reported among DLBCL patients: two cases that occurred during the step-up dosing phase and one that occurred at full dose.
No TLS events of grade 3 or greater were observed in any FL or DLBCL patients, he added.
More research needed
Although efficacy and safety results from this phase 1 study of odronextamab are encouraging, the durability, combinability, and potential for sequencing of bispecific antibodies deserves further investigation, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.
“Bispecifics in lymphoma as a class are extremely promising,” Dr. Diefenbach said in an interview. “They’re highly active and they activate an immune response against the tumor without inducing, for the most part, the same degree of neurotoxicity and CRS most CAR T cells do.
“I think the challenge is going to be to figure out how to give them in combination with other therapies to maximize durability, and how to sequence bispecifics and CAR T cells,” she added.
A global phase 2 trial of odronextamab in patients with relapsed or refractory B-cell NHL is currently recruiting. According to Dr. Bannerji, further studies are planned to evaluate odronextamab with chemotherapy and in chemotherapy-free combinations in earlier lines of treatment.
The study is sponsored by Regeneron Pharmaceuticals. Dr. Bannerji reported research funding from Regeneron, AbbVie, F. Hoffmann La Roche Ltd/Genentech Inc., and Pharmacyclics LLC, an AbbVie company. Dr. Bannerji’s spouse is an employee of Sanofi Pasteur.
SOURCE: Bannerji R et al. ASH 2020, Abstract 400.
FROM ASH 2020