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Sickle Cell: Good Outcomes for Haploidentical Transplants
Of 42 patients aged 15-45 who were fully treated, 95% survived to 2 years post transplant (overall survival, (95% CI, 81.5%-98.7%), and 88% reached the primary endpoint of event-free survival at 2 years (95% CI, 73.5%-94.8%), according to the findings, which were released at the annual meeting of the American Society of Hematology.
At an ASH news briefing, study lead author Adetola A. Kassim, MBBS, MS, of Vanderbilt University Medical Center, in Nashville, Tennessee, said the results support haploidentical stem cell transplants “as a suitable and tolerable curative therapy for adults with sickle cell disease and severe end-organ toxicity such as stroke or pulmonary hypertension, a population typically excluded from participating in gene therapy.”
Dr. Kassim added that the findings are especially promising since there are so many potential donors in stem-cell transplants: “Your siblings can be donors, your parents can be donors, your cousins can be donors. First-, second-, and third-degree relatives can be donors. So there’s really endless donors within the family.”
In an interview, Mayo Clinic SCD specialist Asmaa Ferdjallah, MD, MPH, of Mayo Clinic in Rochester, Minnesota, who was not involved with the study but is familiar with its findings, said stem cell transplant is the only option to cure SCD.
“This is advantageous because SCD is otherwise a chronic disease that is marked by chronic pain, risk of stroke, frequent interruptions of school/work due to sick days, and decreased life span,” she said. “Most patients, assuming they can tolerate the conditioning chemotherapy that is given before transplant, are eligible.”
Matched sibling donors are preferable, but they can be hard to find, she said. It hasn’t been clear whether half-matched donors are feasible options in SCD, she said. “This means that, if you are a patient with sickle cell disease, and you don’t have a suitable matched donor, haploidentical transplant is not a recommendation we can make outside of enrollment in a clinical trial.”
For the study, researchers enlisted 54 patients with SCD and prior stroke, recurrent acute chest syndrome or pain, chronic transfusion regimen, or tricuspid valve regurgitant jet velocity ≥2.7 m/sec. Participants had to have an HLA-haploidentical first-degree relative donor who would donate bone marrow.
“The median age was 22.8 years at enrollment; 47/54 (87%) of enrolled participants had hemoglobin SS disease, 40/54 (74.1%) had a Lansky/Karnofsky score of 90-100 at baseline, and 41/54 (75.9%) had an HLA match score of 4/8,” the researchers reported. “Recurrent vaso-occlusive pain episodes (38.9%), acute chest syndrome (16.8%), and overt stroke (16.7%) were the most common indications for transplant.”
“We knew going into this that we were going to get very high-risk patients,” Dr. Kassim said.
Forty-two patients went through with transplants. As for adverse events, 2 patients died, all within the first year, of organ failure and acute respiratory distress syndrome; 4.8% of participants had primary graft failure, and 2.4% had secondary graft failure before day 100. “The cumulative incidence of grades II-IV acute GVHD [graft-versus-host disease] at day 100 was 26.2% (95% CI, 14.0%-40.2%), and grades III-IV acute GVHD at day 100 was 4.8% (95% CI, 0.9%-14.4%).”
The outcomes are similar to those in transplants with matched sibling donors, Dr. Kassim said.
Dr. Ferdjallah said the new study is “robust” and impressive, although it’s small.
“As a clinician, these are the kind of outcomes I have been hoping for,” Dr. Ferdjallah said. “I have been very reluctant to suggest haploidentical transplant for my sickle cell disease patients. However, reviewing the results of this study with my motivated patients and families can help us both to use shared medical decision-making and come together with what is best for that specific patient.”
As for adverse events, she said they “confirm a fear of using haploidentical transplant, which is graft failure. Fortunately, out of 42 who proceeded to transplant, only 2 had primary graft failure and 1 had secondary graft failure. This is not overtly a large number. Of course, we would hope for more durable engraftment. The other side effects including GVHD and infection are all to be expected.”
As for cost, Dr. Kassim said the transplants run from $200,000 to $400,000 vs over $2 million for gene therapy, and Dr. Ferdjallah said insurance is likely to cover the treatment.
Moving ahead, Dr. Ferdjallah said she looks forward to getting study data about pediatric patients specifically. For now, “we should consider HLA-haploidentical seriously in patients with sickle cell disease and no available HLA-matched donors.”
Grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and National Cancer Institute funded the study. Dr. Kassim had no disclosures. Some other authors disclosed various and multiple relationships with industry. Dr. Ferdjallah has no disclosures.
Of 42 patients aged 15-45 who were fully treated, 95% survived to 2 years post transplant (overall survival, (95% CI, 81.5%-98.7%), and 88% reached the primary endpoint of event-free survival at 2 years (95% CI, 73.5%-94.8%), according to the findings, which were released at the annual meeting of the American Society of Hematology.
At an ASH news briefing, study lead author Adetola A. Kassim, MBBS, MS, of Vanderbilt University Medical Center, in Nashville, Tennessee, said the results support haploidentical stem cell transplants “as a suitable and tolerable curative therapy for adults with sickle cell disease and severe end-organ toxicity such as stroke or pulmonary hypertension, a population typically excluded from participating in gene therapy.”
Dr. Kassim added that the findings are especially promising since there are so many potential donors in stem-cell transplants: “Your siblings can be donors, your parents can be donors, your cousins can be donors. First-, second-, and third-degree relatives can be donors. So there’s really endless donors within the family.”
In an interview, Mayo Clinic SCD specialist Asmaa Ferdjallah, MD, MPH, of Mayo Clinic in Rochester, Minnesota, who was not involved with the study but is familiar with its findings, said stem cell transplant is the only option to cure SCD.
“This is advantageous because SCD is otherwise a chronic disease that is marked by chronic pain, risk of stroke, frequent interruptions of school/work due to sick days, and decreased life span,” she said. “Most patients, assuming they can tolerate the conditioning chemotherapy that is given before transplant, are eligible.”
Matched sibling donors are preferable, but they can be hard to find, she said. It hasn’t been clear whether half-matched donors are feasible options in SCD, she said. “This means that, if you are a patient with sickle cell disease, and you don’t have a suitable matched donor, haploidentical transplant is not a recommendation we can make outside of enrollment in a clinical trial.”
For the study, researchers enlisted 54 patients with SCD and prior stroke, recurrent acute chest syndrome or pain, chronic transfusion regimen, or tricuspid valve regurgitant jet velocity ≥2.7 m/sec. Participants had to have an HLA-haploidentical first-degree relative donor who would donate bone marrow.
“The median age was 22.8 years at enrollment; 47/54 (87%) of enrolled participants had hemoglobin SS disease, 40/54 (74.1%) had a Lansky/Karnofsky score of 90-100 at baseline, and 41/54 (75.9%) had an HLA match score of 4/8,” the researchers reported. “Recurrent vaso-occlusive pain episodes (38.9%), acute chest syndrome (16.8%), and overt stroke (16.7%) were the most common indications for transplant.”
“We knew going into this that we were going to get very high-risk patients,” Dr. Kassim said.
Forty-two patients went through with transplants. As for adverse events, 2 patients died, all within the first year, of organ failure and acute respiratory distress syndrome; 4.8% of participants had primary graft failure, and 2.4% had secondary graft failure before day 100. “The cumulative incidence of grades II-IV acute GVHD [graft-versus-host disease] at day 100 was 26.2% (95% CI, 14.0%-40.2%), and grades III-IV acute GVHD at day 100 was 4.8% (95% CI, 0.9%-14.4%).”
The outcomes are similar to those in transplants with matched sibling donors, Dr. Kassim said.
Dr. Ferdjallah said the new study is “robust” and impressive, although it’s small.
“As a clinician, these are the kind of outcomes I have been hoping for,” Dr. Ferdjallah said. “I have been very reluctant to suggest haploidentical transplant for my sickle cell disease patients. However, reviewing the results of this study with my motivated patients and families can help us both to use shared medical decision-making and come together with what is best for that specific patient.”
As for adverse events, she said they “confirm a fear of using haploidentical transplant, which is graft failure. Fortunately, out of 42 who proceeded to transplant, only 2 had primary graft failure and 1 had secondary graft failure. This is not overtly a large number. Of course, we would hope for more durable engraftment. The other side effects including GVHD and infection are all to be expected.”
As for cost, Dr. Kassim said the transplants run from $200,000 to $400,000 vs over $2 million for gene therapy, and Dr. Ferdjallah said insurance is likely to cover the treatment.
Moving ahead, Dr. Ferdjallah said she looks forward to getting study data about pediatric patients specifically. For now, “we should consider HLA-haploidentical seriously in patients with sickle cell disease and no available HLA-matched donors.”
Grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and National Cancer Institute funded the study. Dr. Kassim had no disclosures. Some other authors disclosed various and multiple relationships with industry. Dr. Ferdjallah has no disclosures.
Of 42 patients aged 15-45 who were fully treated, 95% survived to 2 years post transplant (overall survival, (95% CI, 81.5%-98.7%), and 88% reached the primary endpoint of event-free survival at 2 years (95% CI, 73.5%-94.8%), according to the findings, which were released at the annual meeting of the American Society of Hematology.
At an ASH news briefing, study lead author Adetola A. Kassim, MBBS, MS, of Vanderbilt University Medical Center, in Nashville, Tennessee, said the results support haploidentical stem cell transplants “as a suitable and tolerable curative therapy for adults with sickle cell disease and severe end-organ toxicity such as stroke or pulmonary hypertension, a population typically excluded from participating in gene therapy.”
Dr. Kassim added that the findings are especially promising since there are so many potential donors in stem-cell transplants: “Your siblings can be donors, your parents can be donors, your cousins can be donors. First-, second-, and third-degree relatives can be donors. So there’s really endless donors within the family.”
In an interview, Mayo Clinic SCD specialist Asmaa Ferdjallah, MD, MPH, of Mayo Clinic in Rochester, Minnesota, who was not involved with the study but is familiar with its findings, said stem cell transplant is the only option to cure SCD.
“This is advantageous because SCD is otherwise a chronic disease that is marked by chronic pain, risk of stroke, frequent interruptions of school/work due to sick days, and decreased life span,” she said. “Most patients, assuming they can tolerate the conditioning chemotherapy that is given before transplant, are eligible.”
Matched sibling donors are preferable, but they can be hard to find, she said. It hasn’t been clear whether half-matched donors are feasible options in SCD, she said. “This means that, if you are a patient with sickle cell disease, and you don’t have a suitable matched donor, haploidentical transplant is not a recommendation we can make outside of enrollment in a clinical trial.”
For the study, researchers enlisted 54 patients with SCD and prior stroke, recurrent acute chest syndrome or pain, chronic transfusion regimen, or tricuspid valve regurgitant jet velocity ≥2.7 m/sec. Participants had to have an HLA-haploidentical first-degree relative donor who would donate bone marrow.
“The median age was 22.8 years at enrollment; 47/54 (87%) of enrolled participants had hemoglobin SS disease, 40/54 (74.1%) had a Lansky/Karnofsky score of 90-100 at baseline, and 41/54 (75.9%) had an HLA match score of 4/8,” the researchers reported. “Recurrent vaso-occlusive pain episodes (38.9%), acute chest syndrome (16.8%), and overt stroke (16.7%) were the most common indications for transplant.”
“We knew going into this that we were going to get very high-risk patients,” Dr. Kassim said.
Forty-two patients went through with transplants. As for adverse events, 2 patients died, all within the first year, of organ failure and acute respiratory distress syndrome; 4.8% of participants had primary graft failure, and 2.4% had secondary graft failure before day 100. “The cumulative incidence of grades II-IV acute GVHD [graft-versus-host disease] at day 100 was 26.2% (95% CI, 14.0%-40.2%), and grades III-IV acute GVHD at day 100 was 4.8% (95% CI, 0.9%-14.4%).”
The outcomes are similar to those in transplants with matched sibling donors, Dr. Kassim said.
Dr. Ferdjallah said the new study is “robust” and impressive, although it’s small.
“As a clinician, these are the kind of outcomes I have been hoping for,” Dr. Ferdjallah said. “I have been very reluctant to suggest haploidentical transplant for my sickle cell disease patients. However, reviewing the results of this study with my motivated patients and families can help us both to use shared medical decision-making and come together with what is best for that specific patient.”
As for adverse events, she said they “confirm a fear of using haploidentical transplant, which is graft failure. Fortunately, out of 42 who proceeded to transplant, only 2 had primary graft failure and 1 had secondary graft failure. This is not overtly a large number. Of course, we would hope for more durable engraftment. The other side effects including GVHD and infection are all to be expected.”
As for cost, Dr. Kassim said the transplants run from $200,000 to $400,000 vs over $2 million for gene therapy, and Dr. Ferdjallah said insurance is likely to cover the treatment.
Moving ahead, Dr. Ferdjallah said she looks forward to getting study data about pediatric patients specifically. For now, “we should consider HLA-haploidentical seriously in patients with sickle cell disease and no available HLA-matched donors.”
Grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and National Cancer Institute funded the study. Dr. Kassim had no disclosures. Some other authors disclosed various and multiple relationships with industry. Dr. Ferdjallah has no disclosures.
FROM ASH 2023
Measurable residual disease–guided therapy promising for CLL
The targeted therapy combination was also associated with better progression-free survival among patients with CLL with worse prognostic features, including immunoglobulin heavy chain variable (IGHV) unmutated disease and cytogenetic abnormalities, such as the 11q deletion, trisomy 12, and 13q deletion.
Personalizing treatment duration of ibrutinib-venetoclax, as determined by measurable residual disease (MRD), allowed more than half of patients assigned to the combination therapy to stop therapy by 3 years because they had achieved MRD negativity, reported Peter Hillmen, MBChB, PhD, from the Leeds Institute of Medical Research at St James’s University Hospital in Leeds, United Kingdom.
The shorter course of therapy could help to ameliorate toxicities and lower the risk for the development of drug-resistant disease, he said.
“This is the first trial to show that an MRD-guided approach with treatment beyond [MRD] negativity has a significant advantage over chemoimmunotherapy, both in terms of [progression-free] and overall survival. Over 90% of patients achieve an MRD-negative in this combination in the peripheral blood,” said Dr. Hillmen in a media briefing prior to his presentation of the data in an oral abstract session here at the American Society of Hematology annual meeting.
The study results were also published online in The New England Journal of Medicine to coincide with the presentation.
Adaptive Trial
The FLAIR study is a phase 3 open-label platform trial that initially compared ibrutinib-rituximab with fludarabine-cyclophosphamide-rituximab (FCR) in patients with untreated CLL. However, in 2017 the trial was adapted to include both an ibrutinib monotherapy and an ibrutinib-venetoclax arm with therapy duration determined by MRD.
At ASH 2023, Dr. Hillmen presented data from an interim analysis of 523 patients comparing ibrutinib-venetoclax with FCR.
In the ibrutinib-venetoclax group, patients received oral ibrutinib 420 mg daily, with venetoclax added after 2 months, beginning with a 20-mg dose ramped up to 400 mg in a weekly dose-escalation schedule. The combination could be given for 2-6 years, depending on MRD responses. FCR was delivered in up to six cycles of 28 days each. Two thirds of patients assigned to FCR completed all six cycles.
After a median follow-up of 43.7 months, 12 patients (4.6%) randomly assigned to ibrutinib-venetoclax had disease progression or died compared with 75 patients (28.5%) assigned to FCR. The estimated 3-year progression-free survival with ibrutinib-venetoclax was 97.2%, compared with 76.8% with FCR, translating into a hazard ratio (HR) for progression or death with the targeted therapy combination of 0.13 (P <.001).
Among patients with unmutated IGHV, the combination led to improved progression-free survival compared with FCR (hazard ratio [HR] for progression or death, 0.07); for patients with mutated IGHV, however, the combination did not improve progression-free survival (HR, 0.54; 95% CI, 0.21-1.38).
In all, eight patients (3.5%) assigned to ibrutinib-venetoclax and 23 assigned to FCR (9.5%) died.
The 3-year overall survival rates were 98% in the targeted therapy group vs 93% in the FCR group (HR for progression or death, 0.31).
At 2 years, 52.4% of patients assigned to ibrutinib-venetoclax had undetectable MRD in bone marrow compared with 49.8% with FCR. At 5 years, the respective percentages for MRD in bone marrow were 65.9% vs 49.8% and 92.7% vs 67.9% for MRD in peripheral blood.
The safety analysis showed higher rates of blood and lymphatic system disorders with FCR, whereas cardiac, metabolic/nutrition disorders, and eye disorders occurred more frequent with ibrutinib-venetoclax.
A total of 24 secondary cancers were diagnosed in 17 patients randomly assigned to ibrutinib-venetoclax and 45 secondary cancers among 34 patients randomly assigned to FCR. One patient assigned to ibrutinib-venetoclax developed myelodysplastic syndrome/acute myeloid leukemia (AML), as did eight patients assigned to FCR. One patient in the ibrutinib-venetoclax arm and four patients in the FCR arm had Richter’s transformation.
The incidence rate for other cancers was 2.6 per 100 person-years with ibrutinib-venetoclax compared with 5.4 per 100 person-years with FCR.
The most frequently occurring cancers in each arm were basal cell or squamous cell carcinomas. The incidence of myelodysplastic syndromes, AML lymphoma, and prostate/urologic cancers was higher among patients on FCR.
This research “unequivocally shows the superiority of targeted therapy over traditional cytotoxic chemotherapy,” commented briefing moderator Mikkael A. Sekeres, MD, from the University of Miami Miller School of Medicine.
The ibrutinib-venetoclax combination has the potential to reduce the incidence of myelodysplastic syndromes secondary to CLL therapy, Dr. Sekeres suggested.
“As someone who specializes in leukemia and myelodysplastic syndromes, I have the feeling I won’t be seeing these CLL patients in my clinic — years after being treated for CLL — much longer,” he said.
In an interview with this news organization, Lee Greenberger, PhD, said that “I think that duration-adapted therapy is a great story. Using MRD negativity is a perfectly justified way, I think, to go about a new combination that’s going to be really potent for CLL patients and probably give them many years of treatment and then to get off the drug, because ultimately the goal is to get cures.”
This combination, though highly efficacious, is unlikely to be curative; however, because even when MRD is undetectable, “it will come back,” said Dr. Greenberger, chief scientific officer for the Leukemia & Lymphoma Society.
Dr. Greenberger added that MRD testing of bone marrow, which provides a more detailed picture of MRD status than testing of peripheral blood, is feasible in academic medical centers but may be a barrier to MRD-adapted therapy in community oncology practices.
The FLAIR study is supported by grants from Cancer Research UK, Janssen, Pharmacyclics, and AbbVie. Dr. Hillmen disclosed employment and equity participation with Apellis Pharmaceuticals. Dr. Sekeres disclosed board activities for Geron, Novartis, and Bristol-Myers Squibb and owner of stock options Kurome. Dr. Greenberger reported no relevant financial disclosures.
A version of this article appeared on Medscape.com.
The targeted therapy combination was also associated with better progression-free survival among patients with CLL with worse prognostic features, including immunoglobulin heavy chain variable (IGHV) unmutated disease and cytogenetic abnormalities, such as the 11q deletion, trisomy 12, and 13q deletion.
Personalizing treatment duration of ibrutinib-venetoclax, as determined by measurable residual disease (MRD), allowed more than half of patients assigned to the combination therapy to stop therapy by 3 years because they had achieved MRD negativity, reported Peter Hillmen, MBChB, PhD, from the Leeds Institute of Medical Research at St James’s University Hospital in Leeds, United Kingdom.
The shorter course of therapy could help to ameliorate toxicities and lower the risk for the development of drug-resistant disease, he said.
“This is the first trial to show that an MRD-guided approach with treatment beyond [MRD] negativity has a significant advantage over chemoimmunotherapy, both in terms of [progression-free] and overall survival. Over 90% of patients achieve an MRD-negative in this combination in the peripheral blood,” said Dr. Hillmen in a media briefing prior to his presentation of the data in an oral abstract session here at the American Society of Hematology annual meeting.
The study results were also published online in The New England Journal of Medicine to coincide with the presentation.
Adaptive Trial
The FLAIR study is a phase 3 open-label platform trial that initially compared ibrutinib-rituximab with fludarabine-cyclophosphamide-rituximab (FCR) in patients with untreated CLL. However, in 2017 the trial was adapted to include both an ibrutinib monotherapy and an ibrutinib-venetoclax arm with therapy duration determined by MRD.
At ASH 2023, Dr. Hillmen presented data from an interim analysis of 523 patients comparing ibrutinib-venetoclax with FCR.
In the ibrutinib-venetoclax group, patients received oral ibrutinib 420 mg daily, with venetoclax added after 2 months, beginning with a 20-mg dose ramped up to 400 mg in a weekly dose-escalation schedule. The combination could be given for 2-6 years, depending on MRD responses. FCR was delivered in up to six cycles of 28 days each. Two thirds of patients assigned to FCR completed all six cycles.
After a median follow-up of 43.7 months, 12 patients (4.6%) randomly assigned to ibrutinib-venetoclax had disease progression or died compared with 75 patients (28.5%) assigned to FCR. The estimated 3-year progression-free survival with ibrutinib-venetoclax was 97.2%, compared with 76.8% with FCR, translating into a hazard ratio (HR) for progression or death with the targeted therapy combination of 0.13 (P <.001).
Among patients with unmutated IGHV, the combination led to improved progression-free survival compared with FCR (hazard ratio [HR] for progression or death, 0.07); for patients with mutated IGHV, however, the combination did not improve progression-free survival (HR, 0.54; 95% CI, 0.21-1.38).
In all, eight patients (3.5%) assigned to ibrutinib-venetoclax and 23 assigned to FCR (9.5%) died.
The 3-year overall survival rates were 98% in the targeted therapy group vs 93% in the FCR group (HR for progression or death, 0.31).
At 2 years, 52.4% of patients assigned to ibrutinib-venetoclax had undetectable MRD in bone marrow compared with 49.8% with FCR. At 5 years, the respective percentages for MRD in bone marrow were 65.9% vs 49.8% and 92.7% vs 67.9% for MRD in peripheral blood.
The safety analysis showed higher rates of blood and lymphatic system disorders with FCR, whereas cardiac, metabolic/nutrition disorders, and eye disorders occurred more frequent with ibrutinib-venetoclax.
A total of 24 secondary cancers were diagnosed in 17 patients randomly assigned to ibrutinib-venetoclax and 45 secondary cancers among 34 patients randomly assigned to FCR. One patient assigned to ibrutinib-venetoclax developed myelodysplastic syndrome/acute myeloid leukemia (AML), as did eight patients assigned to FCR. One patient in the ibrutinib-venetoclax arm and four patients in the FCR arm had Richter’s transformation.
The incidence rate for other cancers was 2.6 per 100 person-years with ibrutinib-venetoclax compared with 5.4 per 100 person-years with FCR.
The most frequently occurring cancers in each arm were basal cell or squamous cell carcinomas. The incidence of myelodysplastic syndromes, AML lymphoma, and prostate/urologic cancers was higher among patients on FCR.
This research “unequivocally shows the superiority of targeted therapy over traditional cytotoxic chemotherapy,” commented briefing moderator Mikkael A. Sekeres, MD, from the University of Miami Miller School of Medicine.
The ibrutinib-venetoclax combination has the potential to reduce the incidence of myelodysplastic syndromes secondary to CLL therapy, Dr. Sekeres suggested.
“As someone who specializes in leukemia and myelodysplastic syndromes, I have the feeling I won’t be seeing these CLL patients in my clinic — years after being treated for CLL — much longer,” he said.
In an interview with this news organization, Lee Greenberger, PhD, said that “I think that duration-adapted therapy is a great story. Using MRD negativity is a perfectly justified way, I think, to go about a new combination that’s going to be really potent for CLL patients and probably give them many years of treatment and then to get off the drug, because ultimately the goal is to get cures.”
This combination, though highly efficacious, is unlikely to be curative; however, because even when MRD is undetectable, “it will come back,” said Dr. Greenberger, chief scientific officer for the Leukemia & Lymphoma Society.
Dr. Greenberger added that MRD testing of bone marrow, which provides a more detailed picture of MRD status than testing of peripheral blood, is feasible in academic medical centers but may be a barrier to MRD-adapted therapy in community oncology practices.
The FLAIR study is supported by grants from Cancer Research UK, Janssen, Pharmacyclics, and AbbVie. Dr. Hillmen disclosed employment and equity participation with Apellis Pharmaceuticals. Dr. Sekeres disclosed board activities for Geron, Novartis, and Bristol-Myers Squibb and owner of stock options Kurome. Dr. Greenberger reported no relevant financial disclosures.
A version of this article appeared on Medscape.com.
The targeted therapy combination was also associated with better progression-free survival among patients with CLL with worse prognostic features, including immunoglobulin heavy chain variable (IGHV) unmutated disease and cytogenetic abnormalities, such as the 11q deletion, trisomy 12, and 13q deletion.
Personalizing treatment duration of ibrutinib-venetoclax, as determined by measurable residual disease (MRD), allowed more than half of patients assigned to the combination therapy to stop therapy by 3 years because they had achieved MRD negativity, reported Peter Hillmen, MBChB, PhD, from the Leeds Institute of Medical Research at St James’s University Hospital in Leeds, United Kingdom.
The shorter course of therapy could help to ameliorate toxicities and lower the risk for the development of drug-resistant disease, he said.
“This is the first trial to show that an MRD-guided approach with treatment beyond [MRD] negativity has a significant advantage over chemoimmunotherapy, both in terms of [progression-free] and overall survival. Over 90% of patients achieve an MRD-negative in this combination in the peripheral blood,” said Dr. Hillmen in a media briefing prior to his presentation of the data in an oral abstract session here at the American Society of Hematology annual meeting.
The study results were also published online in The New England Journal of Medicine to coincide with the presentation.
Adaptive Trial
The FLAIR study is a phase 3 open-label platform trial that initially compared ibrutinib-rituximab with fludarabine-cyclophosphamide-rituximab (FCR) in patients with untreated CLL. However, in 2017 the trial was adapted to include both an ibrutinib monotherapy and an ibrutinib-venetoclax arm with therapy duration determined by MRD.
At ASH 2023, Dr. Hillmen presented data from an interim analysis of 523 patients comparing ibrutinib-venetoclax with FCR.
In the ibrutinib-venetoclax group, patients received oral ibrutinib 420 mg daily, with venetoclax added after 2 months, beginning with a 20-mg dose ramped up to 400 mg in a weekly dose-escalation schedule. The combination could be given for 2-6 years, depending on MRD responses. FCR was delivered in up to six cycles of 28 days each. Two thirds of patients assigned to FCR completed all six cycles.
After a median follow-up of 43.7 months, 12 patients (4.6%) randomly assigned to ibrutinib-venetoclax had disease progression or died compared with 75 patients (28.5%) assigned to FCR. The estimated 3-year progression-free survival with ibrutinib-venetoclax was 97.2%, compared with 76.8% with FCR, translating into a hazard ratio (HR) for progression or death with the targeted therapy combination of 0.13 (P <.001).
Among patients with unmutated IGHV, the combination led to improved progression-free survival compared with FCR (hazard ratio [HR] for progression or death, 0.07); for patients with mutated IGHV, however, the combination did not improve progression-free survival (HR, 0.54; 95% CI, 0.21-1.38).
In all, eight patients (3.5%) assigned to ibrutinib-venetoclax and 23 assigned to FCR (9.5%) died.
The 3-year overall survival rates were 98% in the targeted therapy group vs 93% in the FCR group (HR for progression or death, 0.31).
At 2 years, 52.4% of patients assigned to ibrutinib-venetoclax had undetectable MRD in bone marrow compared with 49.8% with FCR. At 5 years, the respective percentages for MRD in bone marrow were 65.9% vs 49.8% and 92.7% vs 67.9% for MRD in peripheral blood.
The safety analysis showed higher rates of blood and lymphatic system disorders with FCR, whereas cardiac, metabolic/nutrition disorders, and eye disorders occurred more frequent with ibrutinib-venetoclax.
A total of 24 secondary cancers were diagnosed in 17 patients randomly assigned to ibrutinib-venetoclax and 45 secondary cancers among 34 patients randomly assigned to FCR. One patient assigned to ibrutinib-venetoclax developed myelodysplastic syndrome/acute myeloid leukemia (AML), as did eight patients assigned to FCR. One patient in the ibrutinib-venetoclax arm and four patients in the FCR arm had Richter’s transformation.
The incidence rate for other cancers was 2.6 per 100 person-years with ibrutinib-venetoclax compared with 5.4 per 100 person-years with FCR.
The most frequently occurring cancers in each arm were basal cell or squamous cell carcinomas. The incidence of myelodysplastic syndromes, AML lymphoma, and prostate/urologic cancers was higher among patients on FCR.
This research “unequivocally shows the superiority of targeted therapy over traditional cytotoxic chemotherapy,” commented briefing moderator Mikkael A. Sekeres, MD, from the University of Miami Miller School of Medicine.
The ibrutinib-venetoclax combination has the potential to reduce the incidence of myelodysplastic syndromes secondary to CLL therapy, Dr. Sekeres suggested.
“As someone who specializes in leukemia and myelodysplastic syndromes, I have the feeling I won’t be seeing these CLL patients in my clinic — years after being treated for CLL — much longer,” he said.
In an interview with this news organization, Lee Greenberger, PhD, said that “I think that duration-adapted therapy is a great story. Using MRD negativity is a perfectly justified way, I think, to go about a new combination that’s going to be really potent for CLL patients and probably give them many years of treatment and then to get off the drug, because ultimately the goal is to get cures.”
This combination, though highly efficacious, is unlikely to be curative; however, because even when MRD is undetectable, “it will come back,” said Dr. Greenberger, chief scientific officer for the Leukemia & Lymphoma Society.
Dr. Greenberger added that MRD testing of bone marrow, which provides a more detailed picture of MRD status than testing of peripheral blood, is feasible in academic medical centers but may be a barrier to MRD-adapted therapy in community oncology practices.
The FLAIR study is supported by grants from Cancer Research UK, Janssen, Pharmacyclics, and AbbVie. Dr. Hillmen disclosed employment and equity participation with Apellis Pharmaceuticals. Dr. Sekeres disclosed board activities for Geron, Novartis, and Bristol-Myers Squibb and owner of stock options Kurome. Dr. Greenberger reported no relevant financial disclosures.
A version of this article appeared on Medscape.com.
FROM ASH 2023
Mantle Cell Lymphoma: Drug Combo Improves PFS
Still, “in the countries where ibrutinib is indicated, this combination should be a new standard therapy for relapsed/refractory mantle cell lymphoma,” Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in a media briefing at the annual meeting of the American Society of Hematology.
Its use would be off label, according to the authors of the industry-funded trial, because no nation has approved the combination therapy for MCL, a rare, aggressive form of non-Hodgkin lymphoma.
As Dr. Wang noted, ibrutinib (a Bruton tyrosine kinase inhibitor) is approved by the Food and Drug Administration to treat MCL, while venetoclax (a BCL-2 inhibitor) is approved for chronic lymphocytic leukemia and previously untreated acute myeloid leukemia. “The combination of these two agents leverages complementary modes of action and has demonstrated synergistic anti-tumor activity in preclinical models of mantle cell lymphoma,” he said. And “in patients with relapsed/refractory mantle cell lymphoma, promising clinical activity has also been observed in early-phase studies.”
For the multinational, randomized, phase 3, double-blind SYMPATICO study, researchers assigned 267 adults with relapsed/refractory MCL after 1-5 prior therapies 1:1 to receive oral ibrutinib 560 mg daily with oral venetoclax (standard 5-wk ramp-up to a target dose of 400 mg once daily) or placebo for 2 years. Then they continued with ibrutinib alone until progressive disease or unacceptable toxicity.
The study began in 2017. The median age of patients was 68, and the numbers of patients in each group were 134 (both drugs) and 133 (ibrutinib plus placebo).
At a median of 51.2 months, median PFS — the primary endpoint — was higher in the combination group vs. ibrutinib alone (31.9 vs. 22.1 months, hazard ratio [HR]=0.65, 95% CI, 0.47–0.88, P = .0052). While overall survival was higher in the combination group vs. ibrutinib alone, an interim analysis found that the difference was not statistically significant (44.9 months vs. 38.6 months, 95% CI, HR = 0.85, 0.62-1.19, P = .3465).
When questioned about this finding at the ASH news briefing, Dr. Wang said that 170 events are needed for a full overall survival analysis, and there are just 144 now. The study may reach that point in early 2025, he said.
Over a median treatment duration of 22.0 months for the combination treatment and 17.7 months for ibrutinib alone, grade ≥ 3 adverse events occurred in 84% and 76% of patients, respectively. At 60%, the level of serious adverse events was the same in both groups.
In an interview, Brian T. Hill, MD, PhD, of Cleveland Clinic, noted that in general, MCL “has a pretty relentless pattern of relapses and disease progression without an easy cure in the vast majority of patients.”
Ibrutinib has revolutionized treatment over the past decade with generally manageable side effects, and clinicians are now turning to other Bruton tyrosine kinase inhibitors, he said. Still, “there is a need for improving the durability and the response rates second-line treatment or beyond,” Dr. Hill said.
The new study is important since it’s the first randomized trial “that demonstrates that additional venetoclax significantly improves not only response rates, but also progression-free survival with a trend toward overall survival,” he said. “The toxicity profile doesn’t really seem to be significantly more worse than what we might expect with each agent given individually.”
However, Dr. Hill noted that “it’s a relatively small study and relatively short follow-up.”
It may be difficult to get an ibrutinib-venetoclax combination approved today since ibrutinib is no longer the preferred Bruton tyrosine kinase inhibitor for clinicians, he said.
Pharmacyclics, maker of ibrutinib, is the study sponsor and Janssen is a collaborator.
Dr. Wang reports research funding Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, and VelosBio. Other authors report multiple and various relationships with industry. Dr. Hill discloses research funding and consulting relationships with Pharmacyclics, AbbVie, BeiGene, and AstraZeneca.
Still, “in the countries where ibrutinib is indicated, this combination should be a new standard therapy for relapsed/refractory mantle cell lymphoma,” Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in a media briefing at the annual meeting of the American Society of Hematology.
Its use would be off label, according to the authors of the industry-funded trial, because no nation has approved the combination therapy for MCL, a rare, aggressive form of non-Hodgkin lymphoma.
As Dr. Wang noted, ibrutinib (a Bruton tyrosine kinase inhibitor) is approved by the Food and Drug Administration to treat MCL, while venetoclax (a BCL-2 inhibitor) is approved for chronic lymphocytic leukemia and previously untreated acute myeloid leukemia. “The combination of these two agents leverages complementary modes of action and has demonstrated synergistic anti-tumor activity in preclinical models of mantle cell lymphoma,” he said. And “in patients with relapsed/refractory mantle cell lymphoma, promising clinical activity has also been observed in early-phase studies.”
For the multinational, randomized, phase 3, double-blind SYMPATICO study, researchers assigned 267 adults with relapsed/refractory MCL after 1-5 prior therapies 1:1 to receive oral ibrutinib 560 mg daily with oral venetoclax (standard 5-wk ramp-up to a target dose of 400 mg once daily) or placebo for 2 years. Then they continued with ibrutinib alone until progressive disease or unacceptable toxicity.
The study began in 2017. The median age of patients was 68, and the numbers of patients in each group were 134 (both drugs) and 133 (ibrutinib plus placebo).
At a median of 51.2 months, median PFS — the primary endpoint — was higher in the combination group vs. ibrutinib alone (31.9 vs. 22.1 months, hazard ratio [HR]=0.65, 95% CI, 0.47–0.88, P = .0052). While overall survival was higher in the combination group vs. ibrutinib alone, an interim analysis found that the difference was not statistically significant (44.9 months vs. 38.6 months, 95% CI, HR = 0.85, 0.62-1.19, P = .3465).
When questioned about this finding at the ASH news briefing, Dr. Wang said that 170 events are needed for a full overall survival analysis, and there are just 144 now. The study may reach that point in early 2025, he said.
Over a median treatment duration of 22.0 months for the combination treatment and 17.7 months for ibrutinib alone, grade ≥ 3 adverse events occurred in 84% and 76% of patients, respectively. At 60%, the level of serious adverse events was the same in both groups.
In an interview, Brian T. Hill, MD, PhD, of Cleveland Clinic, noted that in general, MCL “has a pretty relentless pattern of relapses and disease progression without an easy cure in the vast majority of patients.”
Ibrutinib has revolutionized treatment over the past decade with generally manageable side effects, and clinicians are now turning to other Bruton tyrosine kinase inhibitors, he said. Still, “there is a need for improving the durability and the response rates second-line treatment or beyond,” Dr. Hill said.
The new study is important since it’s the first randomized trial “that demonstrates that additional venetoclax significantly improves not only response rates, but also progression-free survival with a trend toward overall survival,” he said. “The toxicity profile doesn’t really seem to be significantly more worse than what we might expect with each agent given individually.”
However, Dr. Hill noted that “it’s a relatively small study and relatively short follow-up.”
It may be difficult to get an ibrutinib-venetoclax combination approved today since ibrutinib is no longer the preferred Bruton tyrosine kinase inhibitor for clinicians, he said.
Pharmacyclics, maker of ibrutinib, is the study sponsor and Janssen is a collaborator.
Dr. Wang reports research funding Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, and VelosBio. Other authors report multiple and various relationships with industry. Dr. Hill discloses research funding and consulting relationships with Pharmacyclics, AbbVie, BeiGene, and AstraZeneca.
Still, “in the countries where ibrutinib is indicated, this combination should be a new standard therapy for relapsed/refractory mantle cell lymphoma,” Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in a media briefing at the annual meeting of the American Society of Hematology.
Its use would be off label, according to the authors of the industry-funded trial, because no nation has approved the combination therapy for MCL, a rare, aggressive form of non-Hodgkin lymphoma.
As Dr. Wang noted, ibrutinib (a Bruton tyrosine kinase inhibitor) is approved by the Food and Drug Administration to treat MCL, while venetoclax (a BCL-2 inhibitor) is approved for chronic lymphocytic leukemia and previously untreated acute myeloid leukemia. “The combination of these two agents leverages complementary modes of action and has demonstrated synergistic anti-tumor activity in preclinical models of mantle cell lymphoma,” he said. And “in patients with relapsed/refractory mantle cell lymphoma, promising clinical activity has also been observed in early-phase studies.”
For the multinational, randomized, phase 3, double-blind SYMPATICO study, researchers assigned 267 adults with relapsed/refractory MCL after 1-5 prior therapies 1:1 to receive oral ibrutinib 560 mg daily with oral venetoclax (standard 5-wk ramp-up to a target dose of 400 mg once daily) or placebo for 2 years. Then they continued with ibrutinib alone until progressive disease or unacceptable toxicity.
The study began in 2017. The median age of patients was 68, and the numbers of patients in each group were 134 (both drugs) and 133 (ibrutinib plus placebo).
At a median of 51.2 months, median PFS — the primary endpoint — was higher in the combination group vs. ibrutinib alone (31.9 vs. 22.1 months, hazard ratio [HR]=0.65, 95% CI, 0.47–0.88, P = .0052). While overall survival was higher in the combination group vs. ibrutinib alone, an interim analysis found that the difference was not statistically significant (44.9 months vs. 38.6 months, 95% CI, HR = 0.85, 0.62-1.19, P = .3465).
When questioned about this finding at the ASH news briefing, Dr. Wang said that 170 events are needed for a full overall survival analysis, and there are just 144 now. The study may reach that point in early 2025, he said.
Over a median treatment duration of 22.0 months for the combination treatment and 17.7 months for ibrutinib alone, grade ≥ 3 adverse events occurred in 84% and 76% of patients, respectively. At 60%, the level of serious adverse events was the same in both groups.
In an interview, Brian T. Hill, MD, PhD, of Cleveland Clinic, noted that in general, MCL “has a pretty relentless pattern of relapses and disease progression without an easy cure in the vast majority of patients.”
Ibrutinib has revolutionized treatment over the past decade with generally manageable side effects, and clinicians are now turning to other Bruton tyrosine kinase inhibitors, he said. Still, “there is a need for improving the durability and the response rates second-line treatment or beyond,” Dr. Hill said.
The new study is important since it’s the first randomized trial “that demonstrates that additional venetoclax significantly improves not only response rates, but also progression-free survival with a trend toward overall survival,” he said. “The toxicity profile doesn’t really seem to be significantly more worse than what we might expect with each agent given individually.”
However, Dr. Hill noted that “it’s a relatively small study and relatively short follow-up.”
It may be difficult to get an ibrutinib-venetoclax combination approved today since ibrutinib is no longer the preferred Bruton tyrosine kinase inhibitor for clinicians, he said.
Pharmacyclics, maker of ibrutinib, is the study sponsor and Janssen is a collaborator.
Dr. Wang reports research funding Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, and VelosBio. Other authors report multiple and various relationships with industry. Dr. Hill discloses research funding and consulting relationships with Pharmacyclics, AbbVie, BeiGene, and AstraZeneca.
FROM ASH 2023
Distinct toxicity profiles for anti-BCMA myeloma therapies
Among 1803 patients with multiple myeloma treated with either chimeric antigen receptor (CAR) T-cell constructs or a bispecific antibody, CAR T-cell therapy was associated with a “prominent” risk for both cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, while the antibody was associated with a high risk for infection-related mortality, reported Zimu Gong, MD, PhD, from the Cancer Center at Houston Methodist Hospital.“When we are selecting or sequencing these agents, because they are approved for almost identical indications, we need to carefully consider their unique toxicity profile,” he said in an oral abstract session at the annual meeting of the American Society of Hematology (ASH) here.
Going to the FAERS
Dr. Gong and colleagues drew on the FDA Adverse Event Reporting System (FAERS) database for data on toxicities associated with three BCMA-directed therapies: CAR T-cell treatments idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti), and the bispecific antibody teclistamab (Tecvayli).
They identified a total of 1803 cases with a total of 4423 reported adverse events.
The authors calculated a reporting odds ratio (ROR) by dividing the odds of a specific event occurring with an agent by the odds of the same event occurring with all other BCMA-directed agents in the FAERS database.
They found that the highest ROR for cytokine release syndrome was with ide-cel, at 1.8, compared with 0.74 with cilta-cel, and 0.63 with teclistamab. Ide-cel was also most strongly associated with risk for both immune effector cell-associated neurotoxicity syndrome, with an ROR of 1.38, compared with 1.04 with cilta-cel and 0.69 with teclistamab, and with non-immune effector cell-associated neurotoxicity, with an ROR of 2.19 vs 0.83 and 0.4, respectively.
There were 14 reported cases of Bell’s palsy, 13 of which were associated with cilta-cel and 1 with teclistamab, and 11 cases of Parkinsonism, including 7 occurring with cilta-cel, 4 with ide-cel, and none with teclistamab.
In contrast, risk for infection was highest with teclistamab, with an ROR of 4.38 compared with 1.3 with cilta-cel and 0.12 with ide-cel. The infections most commonly reported with teclistamab included pneumonia, sepsis, COVID-19 pneumonia, pneumocystis jirovecii pneumonia, cytomegalovirus reactive and cytomegalovirus pneumonia.
The antibody was also associated with the highest risk for nonrelapse mortality, with an ROR of 1.73 compared with 1.28 with cilta-cel and 0.13 with ide-cel.
There were 309 reported deaths. The investigators calculated nonrelapse mortality by excluding disease progress from cases with death as the final reported outcome. Ide-cell had the lowest odds ratio for non-relapse mortality, at 0.53, compared with 0.99 for cilta-cel, and 1.72 for teclistamab. The most common cause of nonrelapse deaths was toxicities associated with CAR T-cell therapy, and infections, Dr. Gong said.
Dr. Gong acknowledged that one of the major limitations of the study is the nature of the FAERS database itself, which includes both mandatory reports on adverse events, medication errors, and product quality complaints submitted as required by law by manufacturers, but also voluntarily reported by healthcare professionals and consumers.
In an interview with this news organization, David Miklos, MD, PhD, chief of the blood and marrow transplantation and cellular therapy division at Stanford University, who attended the session but was not involved in the study, commented that although the study showed differences among various anti-BCMA products in terms of adverse events, the analysis is only one of several that show different values.
“The concern I have about the FAERS database is simply the lack of validation, and maybe, with no disrespect to the institution, this is kind of like review scores on Amazon.com: not validated, nobody knows who put them out there, and we don’t even know if it’s true,” he said.
He noted that whatever the system, data collection and reporting is both time- and resource-consuming, and given the potential of cellular therapies to significantly improve survival may burden clinicians with requirements for decades of follow-up and reporting.
“Self-reporting isn’t the answer either,” said Dr. Miklos. Perhaps, he suggested, there is a role for apps with “patients self-reporting” and medical practitioners validating the reports.
Dr. Gong and colleagues did not report a study funding source. Dr. Gong had no conflict of interest disclosures. Dr. Miklos has disclosed serving as a director, officer, partner, employee, advisor, consultant, or trustee for: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen; received research funding from: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclic; patents, royalties, or other intellectual property from Pharmacyclics, and travel support from Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen.
A version of this article first appeared on Medscape.com.
Among 1803 patients with multiple myeloma treated with either chimeric antigen receptor (CAR) T-cell constructs or a bispecific antibody, CAR T-cell therapy was associated with a “prominent” risk for both cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, while the antibody was associated with a high risk for infection-related mortality, reported Zimu Gong, MD, PhD, from the Cancer Center at Houston Methodist Hospital.“When we are selecting or sequencing these agents, because they are approved for almost identical indications, we need to carefully consider their unique toxicity profile,” he said in an oral abstract session at the annual meeting of the American Society of Hematology (ASH) here.
Going to the FAERS
Dr. Gong and colleagues drew on the FDA Adverse Event Reporting System (FAERS) database for data on toxicities associated with three BCMA-directed therapies: CAR T-cell treatments idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti), and the bispecific antibody teclistamab (Tecvayli).
They identified a total of 1803 cases with a total of 4423 reported adverse events.
The authors calculated a reporting odds ratio (ROR) by dividing the odds of a specific event occurring with an agent by the odds of the same event occurring with all other BCMA-directed agents in the FAERS database.
They found that the highest ROR for cytokine release syndrome was with ide-cel, at 1.8, compared with 0.74 with cilta-cel, and 0.63 with teclistamab. Ide-cel was also most strongly associated with risk for both immune effector cell-associated neurotoxicity syndrome, with an ROR of 1.38, compared with 1.04 with cilta-cel and 0.69 with teclistamab, and with non-immune effector cell-associated neurotoxicity, with an ROR of 2.19 vs 0.83 and 0.4, respectively.
There were 14 reported cases of Bell’s palsy, 13 of which were associated with cilta-cel and 1 with teclistamab, and 11 cases of Parkinsonism, including 7 occurring with cilta-cel, 4 with ide-cel, and none with teclistamab.
In contrast, risk for infection was highest with teclistamab, with an ROR of 4.38 compared with 1.3 with cilta-cel and 0.12 with ide-cel. The infections most commonly reported with teclistamab included pneumonia, sepsis, COVID-19 pneumonia, pneumocystis jirovecii pneumonia, cytomegalovirus reactive and cytomegalovirus pneumonia.
The antibody was also associated with the highest risk for nonrelapse mortality, with an ROR of 1.73 compared with 1.28 with cilta-cel and 0.13 with ide-cel.
There were 309 reported deaths. The investigators calculated nonrelapse mortality by excluding disease progress from cases with death as the final reported outcome. Ide-cell had the lowest odds ratio for non-relapse mortality, at 0.53, compared with 0.99 for cilta-cel, and 1.72 for teclistamab. The most common cause of nonrelapse deaths was toxicities associated with CAR T-cell therapy, and infections, Dr. Gong said.
Dr. Gong acknowledged that one of the major limitations of the study is the nature of the FAERS database itself, which includes both mandatory reports on adverse events, medication errors, and product quality complaints submitted as required by law by manufacturers, but also voluntarily reported by healthcare professionals and consumers.
In an interview with this news organization, David Miklos, MD, PhD, chief of the blood and marrow transplantation and cellular therapy division at Stanford University, who attended the session but was not involved in the study, commented that although the study showed differences among various anti-BCMA products in terms of adverse events, the analysis is only one of several that show different values.
“The concern I have about the FAERS database is simply the lack of validation, and maybe, with no disrespect to the institution, this is kind of like review scores on Amazon.com: not validated, nobody knows who put them out there, and we don’t even know if it’s true,” he said.
He noted that whatever the system, data collection and reporting is both time- and resource-consuming, and given the potential of cellular therapies to significantly improve survival may burden clinicians with requirements for decades of follow-up and reporting.
“Self-reporting isn’t the answer either,” said Dr. Miklos. Perhaps, he suggested, there is a role for apps with “patients self-reporting” and medical practitioners validating the reports.
Dr. Gong and colleagues did not report a study funding source. Dr. Gong had no conflict of interest disclosures. Dr. Miklos has disclosed serving as a director, officer, partner, employee, advisor, consultant, or trustee for: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen; received research funding from: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclic; patents, royalties, or other intellectual property from Pharmacyclics, and travel support from Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen.
A version of this article first appeared on Medscape.com.
Among 1803 patients with multiple myeloma treated with either chimeric antigen receptor (CAR) T-cell constructs or a bispecific antibody, CAR T-cell therapy was associated with a “prominent” risk for both cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, while the antibody was associated with a high risk for infection-related mortality, reported Zimu Gong, MD, PhD, from the Cancer Center at Houston Methodist Hospital.“When we are selecting or sequencing these agents, because they are approved for almost identical indications, we need to carefully consider their unique toxicity profile,” he said in an oral abstract session at the annual meeting of the American Society of Hematology (ASH) here.
Going to the FAERS
Dr. Gong and colleagues drew on the FDA Adverse Event Reporting System (FAERS) database for data on toxicities associated with three BCMA-directed therapies: CAR T-cell treatments idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti), and the bispecific antibody teclistamab (Tecvayli).
They identified a total of 1803 cases with a total of 4423 reported adverse events.
The authors calculated a reporting odds ratio (ROR) by dividing the odds of a specific event occurring with an agent by the odds of the same event occurring with all other BCMA-directed agents in the FAERS database.
They found that the highest ROR for cytokine release syndrome was with ide-cel, at 1.8, compared with 0.74 with cilta-cel, and 0.63 with teclistamab. Ide-cel was also most strongly associated with risk for both immune effector cell-associated neurotoxicity syndrome, with an ROR of 1.38, compared with 1.04 with cilta-cel and 0.69 with teclistamab, and with non-immune effector cell-associated neurotoxicity, with an ROR of 2.19 vs 0.83 and 0.4, respectively.
There were 14 reported cases of Bell’s palsy, 13 of which were associated with cilta-cel and 1 with teclistamab, and 11 cases of Parkinsonism, including 7 occurring with cilta-cel, 4 with ide-cel, and none with teclistamab.
In contrast, risk for infection was highest with teclistamab, with an ROR of 4.38 compared with 1.3 with cilta-cel and 0.12 with ide-cel. The infections most commonly reported with teclistamab included pneumonia, sepsis, COVID-19 pneumonia, pneumocystis jirovecii pneumonia, cytomegalovirus reactive and cytomegalovirus pneumonia.
The antibody was also associated with the highest risk for nonrelapse mortality, with an ROR of 1.73 compared with 1.28 with cilta-cel and 0.13 with ide-cel.
There were 309 reported deaths. The investigators calculated nonrelapse mortality by excluding disease progress from cases with death as the final reported outcome. Ide-cell had the lowest odds ratio for non-relapse mortality, at 0.53, compared with 0.99 for cilta-cel, and 1.72 for teclistamab. The most common cause of nonrelapse deaths was toxicities associated with CAR T-cell therapy, and infections, Dr. Gong said.
Dr. Gong acknowledged that one of the major limitations of the study is the nature of the FAERS database itself, which includes both mandatory reports on adverse events, medication errors, and product quality complaints submitted as required by law by manufacturers, but also voluntarily reported by healthcare professionals and consumers.
In an interview with this news organization, David Miklos, MD, PhD, chief of the blood and marrow transplantation and cellular therapy division at Stanford University, who attended the session but was not involved in the study, commented that although the study showed differences among various anti-BCMA products in terms of adverse events, the analysis is only one of several that show different values.
“The concern I have about the FAERS database is simply the lack of validation, and maybe, with no disrespect to the institution, this is kind of like review scores on Amazon.com: not validated, nobody knows who put them out there, and we don’t even know if it’s true,” he said.
He noted that whatever the system, data collection and reporting is both time- and resource-consuming, and given the potential of cellular therapies to significantly improve survival may burden clinicians with requirements for decades of follow-up and reporting.
“Self-reporting isn’t the answer either,” said Dr. Miklos. Perhaps, he suggested, there is a role for apps with “patients self-reporting” and medical practitioners validating the reports.
Dr. Gong and colleagues did not report a study funding source. Dr. Gong had no conflict of interest disclosures. Dr. Miklos has disclosed serving as a director, officer, partner, employee, advisor, consultant, or trustee for: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen; received research funding from: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclic; patents, royalties, or other intellectual property from Pharmacyclics, and travel support from Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen.
A version of this article first appeared on Medscape.com.
FROM ASH 2023
Myeloma: Isatuximab Four-Drug Regimen Boosts MRD Negativity
“This [research] builds on our experience that four-drug combinations with a monoclonal antibody, proteasome inhibitor, immunomodulatory drug and steroids are superior to three-drug combinations,” Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, said in an interview on the study.
“It also demonstrates the value of CD38 antibodies, and specifically isatuximab, in the frontline setting,” said Dr. Mikhael, professor at the Translational Genomics Research Institute (TGen), City of Hope Cancer Center in Goodyear, Ariz.
The findings were presented at the annual meeting of the American Society of Hematology.
The current standard of care for transplant-eligible, newly diagnosed MM consists of the quadruple combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid, followed by high-dose melphalan and autologous stem-cell transplantation (ASCT).
Isatuximab already has approval in combination with the regimen of carfilzomib and dexamethasone (KRd) in the treatment of relapsed or refractory MM patients who have received prior lines of therapy.
To investigate the efficacy and safety of addition of isatuximab in the setting of transplant-eligible, newly diagnosed MM patients, first author Francesca Gay, MD, PhD, of the Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy, and colleagues conducted the multisite, phase-3 Iskia trial, enrolling 302 transplant-eligible newly diagnosed MM patients.
The patients were randomized to groups of 151 each to treatment either with IsaKRd or KRd alone. The treatment regimen for KRd included four cycles in induction including weekly carfilzomib at 56 mg on day 1, 8 and 15, lenalidomide 25 mg at day 1-21, and dexamethasone at 40 mg weekly, and the IsaKRd group included four 28-day cycles of isatuximab 10 mg/kg IV days 1, 8, 15, and 22 in cycle 1, followed by 10 mg/kg days 1, 15 in cycles 2-4.
The induction was followed by stem cell mobilization and collection and high dose chemotherapy, followed by four cycles of full-dose consolidation at the same doses and schedule as induction, followed by a light consolidation phase of 12 28-day cycles of reduced dose KRd.
Patients had a median age of 61 and 60 in the isatuximab versus KRd group, respectively, and characteristics were similar between the two arms.
With the current follow-up of a mean of 21 months, the primary endpoint was met, with the intention-to-treat analysis showing a rate of post-consolidation MRD negativity, as assessed with a next-generation sequencing (NGS) cut-off of 10-5, of 77% with isatuximab versus 67% with KRd alone (OR 1.67; P = .049).
With an NGS cut-off of 10-6, the respective rates were 67% vs. 48% (OR 2.29; P < .001).
“This difference in MRD negativity in the depth of response was seen despite the responses analyzed according to the conventional criteria being comparable in the two arms, with more than 90% of patients achieving at least a very good partial response and more than 70% achieving at least a complete response,” Dr. Gay noted.
For the key secondary endpoint of MRD negativity over time, the rates were also significantly higher with IsaKRd vs. KRd at post-induction (10-5 cut-off, 45% vs. 26%, OR 2.34; P < .001; 10-6 cut-off, 27% vs. 14%, OR 2.36, P = .004).
IsaKRd also had greater MRD negativity post-ASCT (10-5 cutoff 64% vs. 49%; P = .006; 10-6 cutoff, 52% vs. 27%, P < .001) and post-consolidation (10-5 cutoff, 77% vs. 67%; P = .049 and 10-6 cutoff, 67% vs. 48%, P < .001).
The increase in the MRD negativity in the IsaKRd group was observed in all subgroups of patients analyzed at the 10-5 and 10-6 cut-offs.
The improved post-consolidation rate of MRD negativity with IsaKRd was also observed among patients based on all levels of cytogenetic risk, which was not the case in the KRd alone arm, which showed a reduction in MRD negativity among very high-risk patients, Dr. Gay observed.
The study’s other key secondary endpoint of progression-free survival will be presented in the future, when longer-term outcomes are available.
As of the current follow-up, 17% of patients in the IsaKRd group had discontinued the study treatment versus 10% with KRd, with the leading cause of adverse events for 6% and 5%, respectively.
At least one hematologic adverse event occurred in 55% of patients treated with IsaKRd and 44% in the KRd alone group, with the most prominent grade 3-4 adverse events occurring more commonly with IsaKRd being neutropenia (36% vs. 22%) and thrombocytopenia (15% vs. 17%).
Non-hematologic grade 3-4 adverse events occurred in 41% of patients in the IsaKRd group versus 37% in KRd only, which included infections (15% vs. 11%), and gastrointestinal (7% vs. 5%), vascular (5% vs. 10%) and cardiac events (<1% vs. 3%).
Discontinuation for toxicity occurred in similar rates in both groups (6% in IsaKRd vs. 5% in KRd); with four treatment-related deaths occurring with IsaKRd (two COVID, one pneumonia, one pulmonary embolism) and one with KRd (septic shock).
“Treatment was tolerable with a toxicity profile that was similar to that in previous reports,” Dr. Gay said.
“In the context of these highly effective regimens that produce a high rate of response, the 10-6 MRD cutoff might be more informative than other result categories,” she added.
Longer follow-up will provide more insights in survival endpoints, and “the trial can potentially offer the opportunity to explore correlations between depth of MRD negativity and survival endpoints,” Dr. Gay noted.
Further commenting on the study, Irene Ghobrial, MD, of Medical Oncology, with the Dana-Farber Cancer Institute, Boston, said the results are encouraging.
“We’re seeing two phase three trials now showing us that indeed a CD38 antibody in addition to our triplet standards of care are making a huge difference in MRD response,” she said in an interview.
“So, I think the main message here is that the four-drug regimen is the way to go from now on in multiple myeloma.”
The study received funding from Sanofi and Amgen. Dr. Gay disclosed relationships with AbbVie; Bristol Myers Squibb/Celgene; Sanofi; Roche; GlaxoSmithKline; Pfizer; Oncopeptides; Takeda; Janssen; and Amgen. Dr. Mikhael reported ties with Amgen, BMS, Janssen, Sanofi and Takeda.
“This [research] builds on our experience that four-drug combinations with a monoclonal antibody, proteasome inhibitor, immunomodulatory drug and steroids are superior to three-drug combinations,” Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, said in an interview on the study.
“It also demonstrates the value of CD38 antibodies, and specifically isatuximab, in the frontline setting,” said Dr. Mikhael, professor at the Translational Genomics Research Institute (TGen), City of Hope Cancer Center in Goodyear, Ariz.
The findings were presented at the annual meeting of the American Society of Hematology.
The current standard of care for transplant-eligible, newly diagnosed MM consists of the quadruple combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid, followed by high-dose melphalan and autologous stem-cell transplantation (ASCT).
Isatuximab already has approval in combination with the regimen of carfilzomib and dexamethasone (KRd) in the treatment of relapsed or refractory MM patients who have received prior lines of therapy.
To investigate the efficacy and safety of addition of isatuximab in the setting of transplant-eligible, newly diagnosed MM patients, first author Francesca Gay, MD, PhD, of the Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy, and colleagues conducted the multisite, phase-3 Iskia trial, enrolling 302 transplant-eligible newly diagnosed MM patients.
The patients were randomized to groups of 151 each to treatment either with IsaKRd or KRd alone. The treatment regimen for KRd included four cycles in induction including weekly carfilzomib at 56 mg on day 1, 8 and 15, lenalidomide 25 mg at day 1-21, and dexamethasone at 40 mg weekly, and the IsaKRd group included four 28-day cycles of isatuximab 10 mg/kg IV days 1, 8, 15, and 22 in cycle 1, followed by 10 mg/kg days 1, 15 in cycles 2-4.
The induction was followed by stem cell mobilization and collection and high dose chemotherapy, followed by four cycles of full-dose consolidation at the same doses and schedule as induction, followed by a light consolidation phase of 12 28-day cycles of reduced dose KRd.
Patients had a median age of 61 and 60 in the isatuximab versus KRd group, respectively, and characteristics were similar between the two arms.
With the current follow-up of a mean of 21 months, the primary endpoint was met, with the intention-to-treat analysis showing a rate of post-consolidation MRD negativity, as assessed with a next-generation sequencing (NGS) cut-off of 10-5, of 77% with isatuximab versus 67% with KRd alone (OR 1.67; P = .049).
With an NGS cut-off of 10-6, the respective rates were 67% vs. 48% (OR 2.29; P < .001).
“This difference in MRD negativity in the depth of response was seen despite the responses analyzed according to the conventional criteria being comparable in the two arms, with more than 90% of patients achieving at least a very good partial response and more than 70% achieving at least a complete response,” Dr. Gay noted.
For the key secondary endpoint of MRD negativity over time, the rates were also significantly higher with IsaKRd vs. KRd at post-induction (10-5 cut-off, 45% vs. 26%, OR 2.34; P < .001; 10-6 cut-off, 27% vs. 14%, OR 2.36, P = .004).
IsaKRd also had greater MRD negativity post-ASCT (10-5 cutoff 64% vs. 49%; P = .006; 10-6 cutoff, 52% vs. 27%, P < .001) and post-consolidation (10-5 cutoff, 77% vs. 67%; P = .049 and 10-6 cutoff, 67% vs. 48%, P < .001).
The increase in the MRD negativity in the IsaKRd group was observed in all subgroups of patients analyzed at the 10-5 and 10-6 cut-offs.
The improved post-consolidation rate of MRD negativity with IsaKRd was also observed among patients based on all levels of cytogenetic risk, which was not the case in the KRd alone arm, which showed a reduction in MRD negativity among very high-risk patients, Dr. Gay observed.
The study’s other key secondary endpoint of progression-free survival will be presented in the future, when longer-term outcomes are available.
As of the current follow-up, 17% of patients in the IsaKRd group had discontinued the study treatment versus 10% with KRd, with the leading cause of adverse events for 6% and 5%, respectively.
At least one hematologic adverse event occurred in 55% of patients treated with IsaKRd and 44% in the KRd alone group, with the most prominent grade 3-4 adverse events occurring more commonly with IsaKRd being neutropenia (36% vs. 22%) and thrombocytopenia (15% vs. 17%).
Non-hematologic grade 3-4 adverse events occurred in 41% of patients in the IsaKRd group versus 37% in KRd only, which included infections (15% vs. 11%), and gastrointestinal (7% vs. 5%), vascular (5% vs. 10%) and cardiac events (<1% vs. 3%).
Discontinuation for toxicity occurred in similar rates in both groups (6% in IsaKRd vs. 5% in KRd); with four treatment-related deaths occurring with IsaKRd (two COVID, one pneumonia, one pulmonary embolism) and one with KRd (septic shock).
“Treatment was tolerable with a toxicity profile that was similar to that in previous reports,” Dr. Gay said.
“In the context of these highly effective regimens that produce a high rate of response, the 10-6 MRD cutoff might be more informative than other result categories,” she added.
Longer follow-up will provide more insights in survival endpoints, and “the trial can potentially offer the opportunity to explore correlations between depth of MRD negativity and survival endpoints,” Dr. Gay noted.
Further commenting on the study, Irene Ghobrial, MD, of Medical Oncology, with the Dana-Farber Cancer Institute, Boston, said the results are encouraging.
“We’re seeing two phase three trials now showing us that indeed a CD38 antibody in addition to our triplet standards of care are making a huge difference in MRD response,” she said in an interview.
“So, I think the main message here is that the four-drug regimen is the way to go from now on in multiple myeloma.”
The study received funding from Sanofi and Amgen. Dr. Gay disclosed relationships with AbbVie; Bristol Myers Squibb/Celgene; Sanofi; Roche; GlaxoSmithKline; Pfizer; Oncopeptides; Takeda; Janssen; and Amgen. Dr. Mikhael reported ties with Amgen, BMS, Janssen, Sanofi and Takeda.
“This [research] builds on our experience that four-drug combinations with a monoclonal antibody, proteasome inhibitor, immunomodulatory drug and steroids are superior to three-drug combinations,” Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, said in an interview on the study.
“It also demonstrates the value of CD38 antibodies, and specifically isatuximab, in the frontline setting,” said Dr. Mikhael, professor at the Translational Genomics Research Institute (TGen), City of Hope Cancer Center in Goodyear, Ariz.
The findings were presented at the annual meeting of the American Society of Hematology.
The current standard of care for transplant-eligible, newly diagnosed MM consists of the quadruple combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid, followed by high-dose melphalan and autologous stem-cell transplantation (ASCT).
Isatuximab already has approval in combination with the regimen of carfilzomib and dexamethasone (KRd) in the treatment of relapsed or refractory MM patients who have received prior lines of therapy.
To investigate the efficacy and safety of addition of isatuximab in the setting of transplant-eligible, newly diagnosed MM patients, first author Francesca Gay, MD, PhD, of the Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy, and colleagues conducted the multisite, phase-3 Iskia trial, enrolling 302 transplant-eligible newly diagnosed MM patients.
The patients were randomized to groups of 151 each to treatment either with IsaKRd or KRd alone. The treatment regimen for KRd included four cycles in induction including weekly carfilzomib at 56 mg on day 1, 8 and 15, lenalidomide 25 mg at day 1-21, and dexamethasone at 40 mg weekly, and the IsaKRd group included four 28-day cycles of isatuximab 10 mg/kg IV days 1, 8, 15, and 22 in cycle 1, followed by 10 mg/kg days 1, 15 in cycles 2-4.
The induction was followed by stem cell mobilization and collection and high dose chemotherapy, followed by four cycles of full-dose consolidation at the same doses and schedule as induction, followed by a light consolidation phase of 12 28-day cycles of reduced dose KRd.
Patients had a median age of 61 and 60 in the isatuximab versus KRd group, respectively, and characteristics were similar between the two arms.
With the current follow-up of a mean of 21 months, the primary endpoint was met, with the intention-to-treat analysis showing a rate of post-consolidation MRD negativity, as assessed with a next-generation sequencing (NGS) cut-off of 10-5, of 77% with isatuximab versus 67% with KRd alone (OR 1.67; P = .049).
With an NGS cut-off of 10-6, the respective rates were 67% vs. 48% (OR 2.29; P < .001).
“This difference in MRD negativity in the depth of response was seen despite the responses analyzed according to the conventional criteria being comparable in the two arms, with more than 90% of patients achieving at least a very good partial response and more than 70% achieving at least a complete response,” Dr. Gay noted.
For the key secondary endpoint of MRD negativity over time, the rates were also significantly higher with IsaKRd vs. KRd at post-induction (10-5 cut-off, 45% vs. 26%, OR 2.34; P < .001; 10-6 cut-off, 27% vs. 14%, OR 2.36, P = .004).
IsaKRd also had greater MRD negativity post-ASCT (10-5 cutoff 64% vs. 49%; P = .006; 10-6 cutoff, 52% vs. 27%, P < .001) and post-consolidation (10-5 cutoff, 77% vs. 67%; P = .049 and 10-6 cutoff, 67% vs. 48%, P < .001).
The increase in the MRD negativity in the IsaKRd group was observed in all subgroups of patients analyzed at the 10-5 and 10-6 cut-offs.
The improved post-consolidation rate of MRD negativity with IsaKRd was also observed among patients based on all levels of cytogenetic risk, which was not the case in the KRd alone arm, which showed a reduction in MRD negativity among very high-risk patients, Dr. Gay observed.
The study’s other key secondary endpoint of progression-free survival will be presented in the future, when longer-term outcomes are available.
As of the current follow-up, 17% of patients in the IsaKRd group had discontinued the study treatment versus 10% with KRd, with the leading cause of adverse events for 6% and 5%, respectively.
At least one hematologic adverse event occurred in 55% of patients treated with IsaKRd and 44% in the KRd alone group, with the most prominent grade 3-4 adverse events occurring more commonly with IsaKRd being neutropenia (36% vs. 22%) and thrombocytopenia (15% vs. 17%).
Non-hematologic grade 3-4 adverse events occurred in 41% of patients in the IsaKRd group versus 37% in KRd only, which included infections (15% vs. 11%), and gastrointestinal (7% vs. 5%), vascular (5% vs. 10%) and cardiac events (<1% vs. 3%).
Discontinuation for toxicity occurred in similar rates in both groups (6% in IsaKRd vs. 5% in KRd); with four treatment-related deaths occurring with IsaKRd (two COVID, one pneumonia, one pulmonary embolism) and one with KRd (septic shock).
“Treatment was tolerable with a toxicity profile that was similar to that in previous reports,” Dr. Gay said.
“In the context of these highly effective regimens that produce a high rate of response, the 10-6 MRD cutoff might be more informative than other result categories,” she added.
Longer follow-up will provide more insights in survival endpoints, and “the trial can potentially offer the opportunity to explore correlations between depth of MRD negativity and survival endpoints,” Dr. Gay noted.
Further commenting on the study, Irene Ghobrial, MD, of Medical Oncology, with the Dana-Farber Cancer Institute, Boston, said the results are encouraging.
“We’re seeing two phase three trials now showing us that indeed a CD38 antibody in addition to our triplet standards of care are making a huge difference in MRD response,” she said in an interview.
“So, I think the main message here is that the four-drug regimen is the way to go from now on in multiple myeloma.”
The study received funding from Sanofi and Amgen. Dr. Gay disclosed relationships with AbbVie; Bristol Myers Squibb/Celgene; Sanofi; Roche; GlaxoSmithKline; Pfizer; Oncopeptides; Takeda; Janssen; and Amgen. Dr. Mikhael reported ties with Amgen, BMS, Janssen, Sanofi and Takeda.
FROM ASH 2023
Sickle Cell Gene Therapy ‘Truly Transformative’
.
More specifically, a single infusion of lovo-cel led to complete resolution of vaso-occlusive events in 88% of patients, with 94% achieving complete resolution of severe events. All 10 adolescents in the study achieved complete resolution of vaso-occlusive events. Most patients remained free of vaso-occlusive events at their last follow-up.
“This is a one-time, truly transformative treatment with lovo-cel,” lead author Julie Kanter, MD, director of the adult sickle cell clinic at the University of Alabama in Birmingham, said in a media briefing at the annual meeting of the American Society of Hematology. The gene therapy can essentially eliminate vaso-occlusive events in patients with sickle cell disease and lead to normal hemoglobin levels, Dr. Kanter added.
For “anybody who has rounded on the inpatient floor and taken care of adolescents admitted with a pain crisis multiple times a year,” seeing these results “is so compelling,” commented Sarah O’Brien, MD, a pediatric hematologist at Nationwide Children’s Hospital in Columbus, Ohio, who moderated the briefing but was not involved in the study.
One and Done
Sickle cell disease, a debilitating and potentially life-threatening blood disorder, affects an estimated 100,000 people in the US.
People with the condition have a mutation in hemoglobin, which causes red blood cells to develop an abnormal sickle shape. These sickled cells block the flow of blood, ultimately depriving tissues of oxygen and leading to organ damage and severe pain, known as vaso-occlusive events.
On Dec. 8, the U.S. Food and Drug Administration (FDA) approved lovo-cel for patients aged 12 years or older with severe sickle cell disease alongside another gene-editing therapy called exagamglogene autotemcel or exa-cel (Casgevy, Vertex Pharmaceuticals and Crispr Therapeutics). The two therapies use different gene-editing approaches — exa-cel is the first to use the gene-editing tool CRISPR while lovo-cel uses a lentiviral vector.
Both are one-time, single-dose cell-based gene therapies.
With lovo-cel, patients first undergo a transfusion regimen and myeloablative conditioning with busulfan to collect cells that can then be genetically modified. A patient’s harvested cells are modified with an anti-sickling version of hemoglobin A, HbAT87Q. Patients then receive an infusion of these edited cells and remain in the hospital during engraftment and reconstitution.
Dr. Kanter presented long-term follow-up data on 47 patients enrolled in phase 1/2 and phase 3 studies of lovo-cel.
All patients had stable HbAT87Q levels from 6 months to their last follow-up at a median of 35.5 months.
Most patients achieved a durable globin response through their final follow-up visit.
Among the 34 evaluable patients, 88% had complete resolution of vaso-occlusive events 6 to 18 months after their infusion, including all 10 adolescent patients. Almost all patients (94%) achieved complete resolution of serious vaso-occlusive events.
In the few patients who experienced posttreatment vaso-occlusive events, these individuals still achieved major reductions in hospital admissions and hospital days.
Among 20 patients followed for at least 3 years, more than half had clinically meaningful improvements in pain intensity, pain interference, and fatigue.
Most treatment-related adverse events occurred within 1 year of lovo-cel infusions and were primarily related to busulfan conditioning. No cases of veno-occlusive liver disease, graft failure, or graft vs host disease occurred, and patients did not have complications related to the viral vector. No patients who had a history of stroke prior to lovo-cel therapy experienced a post-therapy stroke.
One patient died at baseline from significant cardiopulmonary disease related to sickle cell disease, but the death was considered unrelated to lovo-cel therapy.
To see a one-time treatment that essentially eradicates vaso-occlusive events is “really unparalleled,” said Steven Pipe, MD, from the University of Michigan School of Medicine in Ann Arbor, who presented data on a different study at the briefing.
However, Dr. Kanter noted, “it’s important to highlight that many of these individuals come into this therapy with significant disease and end-organ complications, and this will be something we will really need to follow long-term to understand how much this therapy can stabilize or reverse these complications.”
The studies were funded by bluebird bio. Dr. Kanter disclosed honoraria from the company and consulting/advising activities and receipt of research funding from multiple other entities. Dr. O’Brien disclosed consultancy for AstraZeneca, honoraria from Pharmacosmos, and research funding from Bristol Myers Squibb. Dr. Pipe disclosed consulting activities from multiple companies, not including bluebird bio.
A version of this article appeared on Medscape.com.
.
More specifically, a single infusion of lovo-cel led to complete resolution of vaso-occlusive events in 88% of patients, with 94% achieving complete resolution of severe events. All 10 adolescents in the study achieved complete resolution of vaso-occlusive events. Most patients remained free of vaso-occlusive events at their last follow-up.
“This is a one-time, truly transformative treatment with lovo-cel,” lead author Julie Kanter, MD, director of the adult sickle cell clinic at the University of Alabama in Birmingham, said in a media briefing at the annual meeting of the American Society of Hematology. The gene therapy can essentially eliminate vaso-occlusive events in patients with sickle cell disease and lead to normal hemoglobin levels, Dr. Kanter added.
For “anybody who has rounded on the inpatient floor and taken care of adolescents admitted with a pain crisis multiple times a year,” seeing these results “is so compelling,” commented Sarah O’Brien, MD, a pediatric hematologist at Nationwide Children’s Hospital in Columbus, Ohio, who moderated the briefing but was not involved in the study.
One and Done
Sickle cell disease, a debilitating and potentially life-threatening blood disorder, affects an estimated 100,000 people in the US.
People with the condition have a mutation in hemoglobin, which causes red blood cells to develop an abnormal sickle shape. These sickled cells block the flow of blood, ultimately depriving tissues of oxygen and leading to organ damage and severe pain, known as vaso-occlusive events.
On Dec. 8, the U.S. Food and Drug Administration (FDA) approved lovo-cel for patients aged 12 years or older with severe sickle cell disease alongside another gene-editing therapy called exagamglogene autotemcel or exa-cel (Casgevy, Vertex Pharmaceuticals and Crispr Therapeutics). The two therapies use different gene-editing approaches — exa-cel is the first to use the gene-editing tool CRISPR while lovo-cel uses a lentiviral vector.
Both are one-time, single-dose cell-based gene therapies.
With lovo-cel, patients first undergo a transfusion regimen and myeloablative conditioning with busulfan to collect cells that can then be genetically modified. A patient’s harvested cells are modified with an anti-sickling version of hemoglobin A, HbAT87Q. Patients then receive an infusion of these edited cells and remain in the hospital during engraftment and reconstitution.
Dr. Kanter presented long-term follow-up data on 47 patients enrolled in phase 1/2 and phase 3 studies of lovo-cel.
All patients had stable HbAT87Q levels from 6 months to their last follow-up at a median of 35.5 months.
Most patients achieved a durable globin response through their final follow-up visit.
Among the 34 evaluable patients, 88% had complete resolution of vaso-occlusive events 6 to 18 months after their infusion, including all 10 adolescent patients. Almost all patients (94%) achieved complete resolution of serious vaso-occlusive events.
In the few patients who experienced posttreatment vaso-occlusive events, these individuals still achieved major reductions in hospital admissions and hospital days.
Among 20 patients followed for at least 3 years, more than half had clinically meaningful improvements in pain intensity, pain interference, and fatigue.
Most treatment-related adverse events occurred within 1 year of lovo-cel infusions and were primarily related to busulfan conditioning. No cases of veno-occlusive liver disease, graft failure, or graft vs host disease occurred, and patients did not have complications related to the viral vector. No patients who had a history of stroke prior to lovo-cel therapy experienced a post-therapy stroke.
One patient died at baseline from significant cardiopulmonary disease related to sickle cell disease, but the death was considered unrelated to lovo-cel therapy.
To see a one-time treatment that essentially eradicates vaso-occlusive events is “really unparalleled,” said Steven Pipe, MD, from the University of Michigan School of Medicine in Ann Arbor, who presented data on a different study at the briefing.
However, Dr. Kanter noted, “it’s important to highlight that many of these individuals come into this therapy with significant disease and end-organ complications, and this will be something we will really need to follow long-term to understand how much this therapy can stabilize or reverse these complications.”
The studies were funded by bluebird bio. Dr. Kanter disclosed honoraria from the company and consulting/advising activities and receipt of research funding from multiple other entities. Dr. O’Brien disclosed consultancy for AstraZeneca, honoraria from Pharmacosmos, and research funding from Bristol Myers Squibb. Dr. Pipe disclosed consulting activities from multiple companies, not including bluebird bio.
A version of this article appeared on Medscape.com.
.
More specifically, a single infusion of lovo-cel led to complete resolution of vaso-occlusive events in 88% of patients, with 94% achieving complete resolution of severe events. All 10 adolescents in the study achieved complete resolution of vaso-occlusive events. Most patients remained free of vaso-occlusive events at their last follow-up.
“This is a one-time, truly transformative treatment with lovo-cel,” lead author Julie Kanter, MD, director of the adult sickle cell clinic at the University of Alabama in Birmingham, said in a media briefing at the annual meeting of the American Society of Hematology. The gene therapy can essentially eliminate vaso-occlusive events in patients with sickle cell disease and lead to normal hemoglobin levels, Dr. Kanter added.
For “anybody who has rounded on the inpatient floor and taken care of adolescents admitted with a pain crisis multiple times a year,” seeing these results “is so compelling,” commented Sarah O’Brien, MD, a pediatric hematologist at Nationwide Children’s Hospital in Columbus, Ohio, who moderated the briefing but was not involved in the study.
One and Done
Sickle cell disease, a debilitating and potentially life-threatening blood disorder, affects an estimated 100,000 people in the US.
People with the condition have a mutation in hemoglobin, which causes red blood cells to develop an abnormal sickle shape. These sickled cells block the flow of blood, ultimately depriving tissues of oxygen and leading to organ damage and severe pain, known as vaso-occlusive events.
On Dec. 8, the U.S. Food and Drug Administration (FDA) approved lovo-cel for patients aged 12 years or older with severe sickle cell disease alongside another gene-editing therapy called exagamglogene autotemcel or exa-cel (Casgevy, Vertex Pharmaceuticals and Crispr Therapeutics). The two therapies use different gene-editing approaches — exa-cel is the first to use the gene-editing tool CRISPR while lovo-cel uses a lentiviral vector.
Both are one-time, single-dose cell-based gene therapies.
With lovo-cel, patients first undergo a transfusion regimen and myeloablative conditioning with busulfan to collect cells that can then be genetically modified. A patient’s harvested cells are modified with an anti-sickling version of hemoglobin A, HbAT87Q. Patients then receive an infusion of these edited cells and remain in the hospital during engraftment and reconstitution.
Dr. Kanter presented long-term follow-up data on 47 patients enrolled in phase 1/2 and phase 3 studies of lovo-cel.
All patients had stable HbAT87Q levels from 6 months to their last follow-up at a median of 35.5 months.
Most patients achieved a durable globin response through their final follow-up visit.
Among the 34 evaluable patients, 88% had complete resolution of vaso-occlusive events 6 to 18 months after their infusion, including all 10 adolescent patients. Almost all patients (94%) achieved complete resolution of serious vaso-occlusive events.
In the few patients who experienced posttreatment vaso-occlusive events, these individuals still achieved major reductions in hospital admissions and hospital days.
Among 20 patients followed for at least 3 years, more than half had clinically meaningful improvements in pain intensity, pain interference, and fatigue.
Most treatment-related adverse events occurred within 1 year of lovo-cel infusions and were primarily related to busulfan conditioning. No cases of veno-occlusive liver disease, graft failure, or graft vs host disease occurred, and patients did not have complications related to the viral vector. No patients who had a history of stroke prior to lovo-cel therapy experienced a post-therapy stroke.
One patient died at baseline from significant cardiopulmonary disease related to sickle cell disease, but the death was considered unrelated to lovo-cel therapy.
To see a one-time treatment that essentially eradicates vaso-occlusive events is “really unparalleled,” said Steven Pipe, MD, from the University of Michigan School of Medicine in Ann Arbor, who presented data on a different study at the briefing.
However, Dr. Kanter noted, “it’s important to highlight that many of these individuals come into this therapy with significant disease and end-organ complications, and this will be something we will really need to follow long-term to understand how much this therapy can stabilize or reverse these complications.”
The studies were funded by bluebird bio. Dr. Kanter disclosed honoraria from the company and consulting/advising activities and receipt of research funding from multiple other entities. Dr. O’Brien disclosed consultancy for AstraZeneca, honoraria from Pharmacosmos, and research funding from Bristol Myers Squibb. Dr. Pipe disclosed consulting activities from multiple companies, not including bluebird bio.
A version of this article appeared on Medscape.com.
FROM ASH 2023
CAR T-Cell Therapy: Cure for Systemic Autoimmune Diseases?
A single infusion of autologous CD19-directed CAR T-cell therapy led to persistent, drug-free remission in 15 patients with life-threatening systemic lupus erythematosus, idiopathic inflammatory myositis, or systemic sclerosis, according to research presented at the American Society of Hematology annual meeting.
The responses persisted at 15 months median follow-up, with all patients achieving complete remission, reported Fabian Mueller, MD, of the Bavarian Cancer Research Center and Friedrich-Alexander University of Erlangen-Nuremberg, Bavaria, Germany.
The CAR T-cell treatment appears to provide an “entire reset of B cells,” possibly even a cure, for these 15 patients who had run out of treatment options and had short life expectancies, Dr. Mueller said. “It’s impressive that we have treated these patients.”
Some of the cases have been described previously — including in Annals of the Rheumatic Diseases earlier this year, Nature Medicine in 2022, and the New England Journal of Medicine in 2021.
Now with substantially longer follow-up, the investigators have gained a greater understanding of “the B-cell biology behind our treatment,” Dr. Mueller said. However, “we need longer follow-up to establish how effective the treatment is going to be in the long run.”
All 15 patients included in the analysis were heavily pretreated and had multi-organ involvement. Prior to CAR T-cell therapy, patients had a median disease duration of 3 years, ranging from 1 to as many as 20 years, and had failed a median of five previous treatments. Patients were young — a median age of 36 years — which is much younger than most oncology patients who undergo CAR T-cell therapy, Dr. Mueller said.
The 15 patients underwent typical lymphodepletion and were apheresed and treated with a single infusion of 1 x 106 CD19 CAR T cells per kg of body weight — an established safe dose used in a phase 1 trial of B cell malignancies.
The CAR T cells, manufactured in-house, expanded rapidly, peaking around day 9. B cells disappeared within 7 days and began to reoccur in peripheral blood in all patients between 60 and 180 days. However, no disease flares occurred, Dr. Mueller said.
After 3 months, eight patients with systemic lupus erythematosus showed no sign of disease activity and dramatic improvement in symptoms. Three patients with idiopathic inflammatory myositis experienced major improvements in symptoms and normalization of creatinine kinase levels, the most clinically relevant marker for muscle inflammation. And three of four patients with systemic sclerosis demonstrated major improvements in symptoms and no new disease activity. These responses lasted for a median of 15 months, and all patients stopped taking immunosuppressive drugs.
Patients also tolerated the CAR T-cell treatment well, especially compared with the adverse event profile in oncology patients. Only low-grade inflammatory CAR T-related side effects occurred, and few patients required support for B-cell-derived immune deficiency.
However, infectious complications occurred in 14 patients, including urinary tract and respiratory infections, over the 12-month follow-up. One patient was hospitalized for severe pneumonia a few weeks after CAR T therapy, and two patients experienced herpes zoster reactivations, including one at 6 months and one at 12 months following treatment.
During a press briefing at the ASH conference, Dr. Mueller addressed the “critical question” of patient selection for CAR T-cell therapy, especially in light of the recently announced US Food and Drug Administration investigation exploring whether CAR T cells can cause secondary blood cancers.
Although the T-cell malignancy risk complicates matters, CAR T cells appear to behave differently in patients with autoimmune diseases than those with cancer, he said.
“We don’t understand the biology” related to the malignancy risk yet, Dr. Mueller said, but the benefit for end-of-life patients with no other treatment option likely outweighs the risk. That risk-benefit assessment, however, is more uncertain for those with less severe autoimmune diseases.
For now, it’s important to conduct individual assessments and inform patients about the risk, Dr. Mueller said.
Dr. Mueller disclosed relationships with BMS, AstraZeneca, Gilead, Janssen, Miltenyi Biomedicine, Novartis, Incyte, Abbvie, Sobi, and BeiGene.
A version of this article appeared on Medscape.com.
A single infusion of autologous CD19-directed CAR T-cell therapy led to persistent, drug-free remission in 15 patients with life-threatening systemic lupus erythematosus, idiopathic inflammatory myositis, or systemic sclerosis, according to research presented at the American Society of Hematology annual meeting.
The responses persisted at 15 months median follow-up, with all patients achieving complete remission, reported Fabian Mueller, MD, of the Bavarian Cancer Research Center and Friedrich-Alexander University of Erlangen-Nuremberg, Bavaria, Germany.
The CAR T-cell treatment appears to provide an “entire reset of B cells,” possibly even a cure, for these 15 patients who had run out of treatment options and had short life expectancies, Dr. Mueller said. “It’s impressive that we have treated these patients.”
Some of the cases have been described previously — including in Annals of the Rheumatic Diseases earlier this year, Nature Medicine in 2022, and the New England Journal of Medicine in 2021.
Now with substantially longer follow-up, the investigators have gained a greater understanding of “the B-cell biology behind our treatment,” Dr. Mueller said. However, “we need longer follow-up to establish how effective the treatment is going to be in the long run.”
All 15 patients included in the analysis were heavily pretreated and had multi-organ involvement. Prior to CAR T-cell therapy, patients had a median disease duration of 3 years, ranging from 1 to as many as 20 years, and had failed a median of five previous treatments. Patients were young — a median age of 36 years — which is much younger than most oncology patients who undergo CAR T-cell therapy, Dr. Mueller said.
The 15 patients underwent typical lymphodepletion and were apheresed and treated with a single infusion of 1 x 106 CD19 CAR T cells per kg of body weight — an established safe dose used in a phase 1 trial of B cell malignancies.
The CAR T cells, manufactured in-house, expanded rapidly, peaking around day 9. B cells disappeared within 7 days and began to reoccur in peripheral blood in all patients between 60 and 180 days. However, no disease flares occurred, Dr. Mueller said.
After 3 months, eight patients with systemic lupus erythematosus showed no sign of disease activity and dramatic improvement in symptoms. Three patients with idiopathic inflammatory myositis experienced major improvements in symptoms and normalization of creatinine kinase levels, the most clinically relevant marker for muscle inflammation. And three of four patients with systemic sclerosis demonstrated major improvements in symptoms and no new disease activity. These responses lasted for a median of 15 months, and all patients stopped taking immunosuppressive drugs.
Patients also tolerated the CAR T-cell treatment well, especially compared with the adverse event profile in oncology patients. Only low-grade inflammatory CAR T-related side effects occurred, and few patients required support for B-cell-derived immune deficiency.
However, infectious complications occurred in 14 patients, including urinary tract and respiratory infections, over the 12-month follow-up. One patient was hospitalized for severe pneumonia a few weeks after CAR T therapy, and two patients experienced herpes zoster reactivations, including one at 6 months and one at 12 months following treatment.
During a press briefing at the ASH conference, Dr. Mueller addressed the “critical question” of patient selection for CAR T-cell therapy, especially in light of the recently announced US Food and Drug Administration investigation exploring whether CAR T cells can cause secondary blood cancers.
Although the T-cell malignancy risk complicates matters, CAR T cells appear to behave differently in patients with autoimmune diseases than those with cancer, he said.
“We don’t understand the biology” related to the malignancy risk yet, Dr. Mueller said, but the benefit for end-of-life patients with no other treatment option likely outweighs the risk. That risk-benefit assessment, however, is more uncertain for those with less severe autoimmune diseases.
For now, it’s important to conduct individual assessments and inform patients about the risk, Dr. Mueller said.
Dr. Mueller disclosed relationships with BMS, AstraZeneca, Gilead, Janssen, Miltenyi Biomedicine, Novartis, Incyte, Abbvie, Sobi, and BeiGene.
A version of this article appeared on Medscape.com.
A single infusion of autologous CD19-directed CAR T-cell therapy led to persistent, drug-free remission in 15 patients with life-threatening systemic lupus erythematosus, idiopathic inflammatory myositis, or systemic sclerosis, according to research presented at the American Society of Hematology annual meeting.
The responses persisted at 15 months median follow-up, with all patients achieving complete remission, reported Fabian Mueller, MD, of the Bavarian Cancer Research Center and Friedrich-Alexander University of Erlangen-Nuremberg, Bavaria, Germany.
The CAR T-cell treatment appears to provide an “entire reset of B cells,” possibly even a cure, for these 15 patients who had run out of treatment options and had short life expectancies, Dr. Mueller said. “It’s impressive that we have treated these patients.”
Some of the cases have been described previously — including in Annals of the Rheumatic Diseases earlier this year, Nature Medicine in 2022, and the New England Journal of Medicine in 2021.
Now with substantially longer follow-up, the investigators have gained a greater understanding of “the B-cell biology behind our treatment,” Dr. Mueller said. However, “we need longer follow-up to establish how effective the treatment is going to be in the long run.”
All 15 patients included in the analysis were heavily pretreated and had multi-organ involvement. Prior to CAR T-cell therapy, patients had a median disease duration of 3 years, ranging from 1 to as many as 20 years, and had failed a median of five previous treatments. Patients were young — a median age of 36 years — which is much younger than most oncology patients who undergo CAR T-cell therapy, Dr. Mueller said.
The 15 patients underwent typical lymphodepletion and were apheresed and treated with a single infusion of 1 x 106 CD19 CAR T cells per kg of body weight — an established safe dose used in a phase 1 trial of B cell malignancies.
The CAR T cells, manufactured in-house, expanded rapidly, peaking around day 9. B cells disappeared within 7 days and began to reoccur in peripheral blood in all patients between 60 and 180 days. However, no disease flares occurred, Dr. Mueller said.
After 3 months, eight patients with systemic lupus erythematosus showed no sign of disease activity and dramatic improvement in symptoms. Three patients with idiopathic inflammatory myositis experienced major improvements in symptoms and normalization of creatinine kinase levels, the most clinically relevant marker for muscle inflammation. And three of four patients with systemic sclerosis demonstrated major improvements in symptoms and no new disease activity. These responses lasted for a median of 15 months, and all patients stopped taking immunosuppressive drugs.
Patients also tolerated the CAR T-cell treatment well, especially compared with the adverse event profile in oncology patients. Only low-grade inflammatory CAR T-related side effects occurred, and few patients required support for B-cell-derived immune deficiency.
However, infectious complications occurred in 14 patients, including urinary tract and respiratory infections, over the 12-month follow-up. One patient was hospitalized for severe pneumonia a few weeks after CAR T therapy, and two patients experienced herpes zoster reactivations, including one at 6 months and one at 12 months following treatment.
During a press briefing at the ASH conference, Dr. Mueller addressed the “critical question” of patient selection for CAR T-cell therapy, especially in light of the recently announced US Food and Drug Administration investigation exploring whether CAR T cells can cause secondary blood cancers.
Although the T-cell malignancy risk complicates matters, CAR T cells appear to behave differently in patients with autoimmune diseases than those with cancer, he said.
“We don’t understand the biology” related to the malignancy risk yet, Dr. Mueller said, but the benefit for end-of-life patients with no other treatment option likely outweighs the risk. That risk-benefit assessment, however, is more uncertain for those with less severe autoimmune diseases.
For now, it’s important to conduct individual assessments and inform patients about the risk, Dr. Mueller said.
Dr. Mueller disclosed relationships with BMS, AstraZeneca, Gilead, Janssen, Miltenyi Biomedicine, Novartis, Incyte, Abbvie, Sobi, and BeiGene.
A version of this article appeared on Medscape.com.
FROM ASH 2023
In real world, patients with myeloma have worse outcomes
The analysis, which included nearly 4,000 patients with multiple myeloma, revealed that patients in a real-world setting demonstrated worse progression-free and overall survival on six of seven standard treatments compared with patients evaluated in randomized controlled trials.
Lead author Alissa Visram, MD, MPH, who spoke about the study at the annual meeting of the American Society of Hematology, said the findings will likely change the way she speaks to patients about their potential outcomes.
“I’ll probably present both numbers [from real-life and clinical-trial data] and give them a sense of the best-case scenario,” Dr. Visram said during an ASH media briefing. But she said she will also caution her patients that the real-world numbers reflect how people on these drugs actually fare.
The effectiveness of multiple myeloma drugs remains unclear outside the clinical trial setting, explained Dr. Visram, of the Division of Hematology at the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Outcomes from randomized controlled trials form the basis of drug approvals but many patients in the real world do not meet the “stringent” trial inclusion criteria.
Dr. Visram and colleagues launched the current study to better understand the potential differences between real-world and clinical trial outcomes. In the analysis, the researchers compared real-world outcomes among patients receiving seven standard multiple myeloma regimens covered by Ontario’s public health plan with patient outcomes reported in phase 3 randomized controlled trials.
The retrospective study included 3951 patients with newly diagnosed and refractory multiple myeloma treated from 2007 to 2020 in Ontario. Regimens for newly diagnosed transplant ineligible patients included lenalidomide plus dexamethasone and triple therapy with bortezomib, lenalidomide, and dexamethasone. Regimens for patients with relapsed disease included pomalidomide plus dexamethasone or carfilzomib plus dexamethasone as well as triple combinations including carfilzomib, lenalidomide, and dexamethasone.
Overall, Dr. Visram and colleagues found that patients in the real-world setting demonstrated worse overall survival for six of the seven regimens evaluated (pooled hazard ratio [HR], 1.75; P = .010).
The real-world patients also had worse progression-free survival for six of the seven regimens (pooled HR, 1.44; P = .034).
For these regimens, progression-free survival was at least 3-18 months longer in the clinical trial cohort, while median overall survival was at least 19 months longer compared with real-world patients, Dr. Visram explained.
The only regimen with comparable outcomes in the clinical trial and real-world settings was pomalidomide and dexamethasone, she said. One reason could be that patients receiving pomalidomide plus dexamethasone in the clinical trial setting had similar or more advanced disease than those in the real-world setting.
The study also found that adverse effects were similar between the clinical and real-world groups.
The next step, Dr. Visram said, would be to explore what’s driving the differences in outcomes.
Are patients in the real-world setting older or frailer? Do they have more advanced disease? Are providers using these regimens differently?
Mikkael A. Sekeres, MD, MS, explained that the difference likely comes down to the health of the patient.
Patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated,” Dr. Sekeres, of the Sylvester Comprehensive Cancer Center at the University of Miami, Florida, said in an earlier ASH press briefing.
Cynthia E. Dunbar, MD, noted that patients in clinical trials have other advantages as well.
“Patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects,” said Dr. Dunbar, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH. These patients also “might stay on the drug for longer, or they have nurses who are always encouraging them on how to make it through a toxicity.”
Dr. Dunbar said hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly.”
No study funding was reported. Dr. Visram reported consulting and honoraria relationships with Apotex, Janssen, and Sanofi. Other study authors reported multiple relationships with industry. Disclosures for Dr. Dunbar and Dr. Sekeres were unavailable.
A version of this article appeared on Medscape.com.
The analysis, which included nearly 4,000 patients with multiple myeloma, revealed that patients in a real-world setting demonstrated worse progression-free and overall survival on six of seven standard treatments compared with patients evaluated in randomized controlled trials.
Lead author Alissa Visram, MD, MPH, who spoke about the study at the annual meeting of the American Society of Hematology, said the findings will likely change the way she speaks to patients about their potential outcomes.
“I’ll probably present both numbers [from real-life and clinical-trial data] and give them a sense of the best-case scenario,” Dr. Visram said during an ASH media briefing. But she said she will also caution her patients that the real-world numbers reflect how people on these drugs actually fare.
The effectiveness of multiple myeloma drugs remains unclear outside the clinical trial setting, explained Dr. Visram, of the Division of Hematology at the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Outcomes from randomized controlled trials form the basis of drug approvals but many patients in the real world do not meet the “stringent” trial inclusion criteria.
Dr. Visram and colleagues launched the current study to better understand the potential differences between real-world and clinical trial outcomes. In the analysis, the researchers compared real-world outcomes among patients receiving seven standard multiple myeloma regimens covered by Ontario’s public health plan with patient outcomes reported in phase 3 randomized controlled trials.
The retrospective study included 3951 patients with newly diagnosed and refractory multiple myeloma treated from 2007 to 2020 in Ontario. Regimens for newly diagnosed transplant ineligible patients included lenalidomide plus dexamethasone and triple therapy with bortezomib, lenalidomide, and dexamethasone. Regimens for patients with relapsed disease included pomalidomide plus dexamethasone or carfilzomib plus dexamethasone as well as triple combinations including carfilzomib, lenalidomide, and dexamethasone.
Overall, Dr. Visram and colleagues found that patients in the real-world setting demonstrated worse overall survival for six of the seven regimens evaluated (pooled hazard ratio [HR], 1.75; P = .010).
The real-world patients also had worse progression-free survival for six of the seven regimens (pooled HR, 1.44; P = .034).
For these regimens, progression-free survival was at least 3-18 months longer in the clinical trial cohort, while median overall survival was at least 19 months longer compared with real-world patients, Dr. Visram explained.
The only regimen with comparable outcomes in the clinical trial and real-world settings was pomalidomide and dexamethasone, she said. One reason could be that patients receiving pomalidomide plus dexamethasone in the clinical trial setting had similar or more advanced disease than those in the real-world setting.
The study also found that adverse effects were similar between the clinical and real-world groups.
The next step, Dr. Visram said, would be to explore what’s driving the differences in outcomes.
Are patients in the real-world setting older or frailer? Do they have more advanced disease? Are providers using these regimens differently?
Mikkael A. Sekeres, MD, MS, explained that the difference likely comes down to the health of the patient.
Patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated,” Dr. Sekeres, of the Sylvester Comprehensive Cancer Center at the University of Miami, Florida, said in an earlier ASH press briefing.
Cynthia E. Dunbar, MD, noted that patients in clinical trials have other advantages as well.
“Patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects,” said Dr. Dunbar, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH. These patients also “might stay on the drug for longer, or they have nurses who are always encouraging them on how to make it through a toxicity.”
Dr. Dunbar said hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly.”
No study funding was reported. Dr. Visram reported consulting and honoraria relationships with Apotex, Janssen, and Sanofi. Other study authors reported multiple relationships with industry. Disclosures for Dr. Dunbar and Dr. Sekeres were unavailable.
A version of this article appeared on Medscape.com.
The analysis, which included nearly 4,000 patients with multiple myeloma, revealed that patients in a real-world setting demonstrated worse progression-free and overall survival on six of seven standard treatments compared with patients evaluated in randomized controlled trials.
Lead author Alissa Visram, MD, MPH, who spoke about the study at the annual meeting of the American Society of Hematology, said the findings will likely change the way she speaks to patients about their potential outcomes.
“I’ll probably present both numbers [from real-life and clinical-trial data] and give them a sense of the best-case scenario,” Dr. Visram said during an ASH media briefing. But she said she will also caution her patients that the real-world numbers reflect how people on these drugs actually fare.
The effectiveness of multiple myeloma drugs remains unclear outside the clinical trial setting, explained Dr. Visram, of the Division of Hematology at the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Outcomes from randomized controlled trials form the basis of drug approvals but many patients in the real world do not meet the “stringent” trial inclusion criteria.
Dr. Visram and colleagues launched the current study to better understand the potential differences between real-world and clinical trial outcomes. In the analysis, the researchers compared real-world outcomes among patients receiving seven standard multiple myeloma regimens covered by Ontario’s public health plan with patient outcomes reported in phase 3 randomized controlled trials.
The retrospective study included 3951 patients with newly diagnosed and refractory multiple myeloma treated from 2007 to 2020 in Ontario. Regimens for newly diagnosed transplant ineligible patients included lenalidomide plus dexamethasone and triple therapy with bortezomib, lenalidomide, and dexamethasone. Regimens for patients with relapsed disease included pomalidomide plus dexamethasone or carfilzomib plus dexamethasone as well as triple combinations including carfilzomib, lenalidomide, and dexamethasone.
Overall, Dr. Visram and colleagues found that patients in the real-world setting demonstrated worse overall survival for six of the seven regimens evaluated (pooled hazard ratio [HR], 1.75; P = .010).
The real-world patients also had worse progression-free survival for six of the seven regimens (pooled HR, 1.44; P = .034).
For these regimens, progression-free survival was at least 3-18 months longer in the clinical trial cohort, while median overall survival was at least 19 months longer compared with real-world patients, Dr. Visram explained.
The only regimen with comparable outcomes in the clinical trial and real-world settings was pomalidomide and dexamethasone, she said. One reason could be that patients receiving pomalidomide plus dexamethasone in the clinical trial setting had similar or more advanced disease than those in the real-world setting.
The study also found that adverse effects were similar between the clinical and real-world groups.
The next step, Dr. Visram said, would be to explore what’s driving the differences in outcomes.
Are patients in the real-world setting older or frailer? Do they have more advanced disease? Are providers using these regimens differently?
Mikkael A. Sekeres, MD, MS, explained that the difference likely comes down to the health of the patient.
Patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated,” Dr. Sekeres, of the Sylvester Comprehensive Cancer Center at the University of Miami, Florida, said in an earlier ASH press briefing.
Cynthia E. Dunbar, MD, noted that patients in clinical trials have other advantages as well.
“Patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects,” said Dr. Dunbar, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH. These patients also “might stay on the drug for longer, or they have nurses who are always encouraging them on how to make it through a toxicity.”
Dr. Dunbar said hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly.”
No study funding was reported. Dr. Visram reported consulting and honoraria relationships with Apotex, Janssen, and Sanofi. Other study authors reported multiple relationships with industry. Disclosures for Dr. Dunbar and Dr. Sekeres were unavailable.
A version of this article appeared on Medscape.com.
FROM ASH 2023
This test may guide AML therapy for Black pediatric patients
.
The score, dubbed ACS10 and initially highlighted in a 2022 report, predicts how well patients will respond to cytarabine based on their genetic make-up, and has the potential to personalize treatment for Black pediatric patients, a group that often has worse outcomes than White patients.
In the current study, presented at the annual meeting of the American Society of Hematology (ASH) , Black patients with low ACS10 scores had significantly worse outcomes compared with those with high scores when initially treated with low-dose cytarabine, daunorubicin, and etoposide.
The difference in outcomes disappeared, however, for patients who received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine.
The genetic traits revealed by the test likely help explain why Black patients with AML typically fare worse on certain regimens, Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute, commented in an ASH press preview briefing.
This study also suggests that clinicians should perform testing for genetic variants and biomarkers that impact outcomes “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity,” said Dr. Dunbar, also secretary of ASH.
The ACS10 test, derived from a combination of 10 single nucleotide polymorphisms, is not yet available, but one could be developed to help guide treatment decisions for clinicians, especially those in developing countries where AML treatment can be very expensive, said study lead author Jatinder Lamba, PhD, MSc, of the University of Florida College of Pharmacy, Gainesville, at an ASH press briefing on Thursday.
Prior research shows that Black pediatric patients with AML often have worse outcomes than White patients. A recent study , for instance, found Black patients with AML, especially those aged 18 to 29 years, had a higher early death rate compared with White patients (16% vs 3%) and significantly lower 5-year overall survival rates (22% vs 51%). The authors of this study suggested that genetic differences between young Black and White patients could help explain the disparity.
In the new analysis, Dr. Lamba and colleagues explored how outcomes by race and cytarabine pharmacogenomics varied in pediatric patients with AML.
The study included 86 Black patients and 359 White patients with newly diagnosed AML treated on two multi-institutional clinical trials. The patients received one of three initial treatments that included cytarabine: high-dose or low-dose cytarabine, daunorubicin, and etoposide, or clofarabine and cytarabine.
Most Black patients in the analysis (73%) had low ACS10 scores compared with 30% of White patients.
Unlike other recent reports, this study found that Black and White patients had similar complete remission rates following two courses of induction therapy (92.6% vs 95%) as well as similar rates of minimal residual disease negativity after one course (55.8% vs 55.4%).
Event-free survival (EFS) and overall survival rates were also similar, with 5-year EFS estimates at 58.3% for Black patients and 58.2% for White patients and overall survival rates at 63.8% vs 69.4%, respectively (P = .24).
However, when separating outcomes by ACS10 scores, Black patients with low scores had significantly worse EFS following low-dose cytarabine, daunorubicin, and etoposide compared with those with high ACS10 scores. And when these patients received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine induction therapy instead, the differences went away.
Overall, Black patients demonstrated significantly better EFS following treatment with clofarabine and cytarabine compared with the low-dose cytarabine triple therapy (hazard ratio, 0.17; P = .01). After adjusting for cofounders, clofarabine and cytarabine induction was the best treatment for Black patients with low ACS10 scores (HR for EFS, 0.2).
“Our results suggest that pharmacogenomics differences between Black and White patients should be considered when tailoring induction regimens to improve outcomes of Black patients and bridge the racial disparity gap in AML treatment,” the researchers concluded.
In developing countries, especially in Africa, starting patients on high-dose cytarabine, daunorubicin, and etoposide can lead to better results “without increasing much of the economic burden” since this treatment is the cheapest, Dr. Lamba said. “At the same time, if the patients have high ACS10 score, you can reduce their economic burden by giving them standard dose” cytarabine, daunorubicin, and etoposide and achieve similar results.
No study funding was reported. Dr. Lamba reported no relevant financial relationships, and three other authors reported various disclosures. Disclosures for Dr. Dunbar were unavailable..
A version of this article appeared on Medscape.com.
.
The score, dubbed ACS10 and initially highlighted in a 2022 report, predicts how well patients will respond to cytarabine based on their genetic make-up, and has the potential to personalize treatment for Black pediatric patients, a group that often has worse outcomes than White patients.
In the current study, presented at the annual meeting of the American Society of Hematology (ASH) , Black patients with low ACS10 scores had significantly worse outcomes compared with those with high scores when initially treated with low-dose cytarabine, daunorubicin, and etoposide.
The difference in outcomes disappeared, however, for patients who received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine.
The genetic traits revealed by the test likely help explain why Black patients with AML typically fare worse on certain regimens, Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute, commented in an ASH press preview briefing.
This study also suggests that clinicians should perform testing for genetic variants and biomarkers that impact outcomes “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity,” said Dr. Dunbar, also secretary of ASH.
The ACS10 test, derived from a combination of 10 single nucleotide polymorphisms, is not yet available, but one could be developed to help guide treatment decisions for clinicians, especially those in developing countries where AML treatment can be very expensive, said study lead author Jatinder Lamba, PhD, MSc, of the University of Florida College of Pharmacy, Gainesville, at an ASH press briefing on Thursday.
Prior research shows that Black pediatric patients with AML often have worse outcomes than White patients. A recent study , for instance, found Black patients with AML, especially those aged 18 to 29 years, had a higher early death rate compared with White patients (16% vs 3%) and significantly lower 5-year overall survival rates (22% vs 51%). The authors of this study suggested that genetic differences between young Black and White patients could help explain the disparity.
In the new analysis, Dr. Lamba and colleagues explored how outcomes by race and cytarabine pharmacogenomics varied in pediatric patients with AML.
The study included 86 Black patients and 359 White patients with newly diagnosed AML treated on two multi-institutional clinical trials. The patients received one of three initial treatments that included cytarabine: high-dose or low-dose cytarabine, daunorubicin, and etoposide, or clofarabine and cytarabine.
Most Black patients in the analysis (73%) had low ACS10 scores compared with 30% of White patients.
Unlike other recent reports, this study found that Black and White patients had similar complete remission rates following two courses of induction therapy (92.6% vs 95%) as well as similar rates of minimal residual disease negativity after one course (55.8% vs 55.4%).
Event-free survival (EFS) and overall survival rates were also similar, with 5-year EFS estimates at 58.3% for Black patients and 58.2% for White patients and overall survival rates at 63.8% vs 69.4%, respectively (P = .24).
However, when separating outcomes by ACS10 scores, Black patients with low scores had significantly worse EFS following low-dose cytarabine, daunorubicin, and etoposide compared with those with high ACS10 scores. And when these patients received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine induction therapy instead, the differences went away.
Overall, Black patients demonstrated significantly better EFS following treatment with clofarabine and cytarabine compared with the low-dose cytarabine triple therapy (hazard ratio, 0.17; P = .01). After adjusting for cofounders, clofarabine and cytarabine induction was the best treatment for Black patients with low ACS10 scores (HR for EFS, 0.2).
“Our results suggest that pharmacogenomics differences between Black and White patients should be considered when tailoring induction regimens to improve outcomes of Black patients and bridge the racial disparity gap in AML treatment,” the researchers concluded.
In developing countries, especially in Africa, starting patients on high-dose cytarabine, daunorubicin, and etoposide can lead to better results “without increasing much of the economic burden” since this treatment is the cheapest, Dr. Lamba said. “At the same time, if the patients have high ACS10 score, you can reduce their economic burden by giving them standard dose” cytarabine, daunorubicin, and etoposide and achieve similar results.
No study funding was reported. Dr. Lamba reported no relevant financial relationships, and three other authors reported various disclosures. Disclosures for Dr. Dunbar were unavailable..
A version of this article appeared on Medscape.com.
.
The score, dubbed ACS10 and initially highlighted in a 2022 report, predicts how well patients will respond to cytarabine based on their genetic make-up, and has the potential to personalize treatment for Black pediatric patients, a group that often has worse outcomes than White patients.
In the current study, presented at the annual meeting of the American Society of Hematology (ASH) , Black patients with low ACS10 scores had significantly worse outcomes compared with those with high scores when initially treated with low-dose cytarabine, daunorubicin, and etoposide.
The difference in outcomes disappeared, however, for patients who received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine.
The genetic traits revealed by the test likely help explain why Black patients with AML typically fare worse on certain regimens, Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute, commented in an ASH press preview briefing.
This study also suggests that clinicians should perform testing for genetic variants and biomarkers that impact outcomes “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity,” said Dr. Dunbar, also secretary of ASH.
The ACS10 test, derived from a combination of 10 single nucleotide polymorphisms, is not yet available, but one could be developed to help guide treatment decisions for clinicians, especially those in developing countries where AML treatment can be very expensive, said study lead author Jatinder Lamba, PhD, MSc, of the University of Florida College of Pharmacy, Gainesville, at an ASH press briefing on Thursday.
Prior research shows that Black pediatric patients with AML often have worse outcomes than White patients. A recent study , for instance, found Black patients with AML, especially those aged 18 to 29 years, had a higher early death rate compared with White patients (16% vs 3%) and significantly lower 5-year overall survival rates (22% vs 51%). The authors of this study suggested that genetic differences between young Black and White patients could help explain the disparity.
In the new analysis, Dr. Lamba and colleagues explored how outcomes by race and cytarabine pharmacogenomics varied in pediatric patients with AML.
The study included 86 Black patients and 359 White patients with newly diagnosed AML treated on two multi-institutional clinical trials. The patients received one of three initial treatments that included cytarabine: high-dose or low-dose cytarabine, daunorubicin, and etoposide, or clofarabine and cytarabine.
Most Black patients in the analysis (73%) had low ACS10 scores compared with 30% of White patients.
Unlike other recent reports, this study found that Black and White patients had similar complete remission rates following two courses of induction therapy (92.6% vs 95%) as well as similar rates of minimal residual disease negativity after one course (55.8% vs 55.4%).
Event-free survival (EFS) and overall survival rates were also similar, with 5-year EFS estimates at 58.3% for Black patients and 58.2% for White patients and overall survival rates at 63.8% vs 69.4%, respectively (P = .24).
However, when separating outcomes by ACS10 scores, Black patients with low scores had significantly worse EFS following low-dose cytarabine, daunorubicin, and etoposide compared with those with high ACS10 scores. And when these patients received high-dose cytarabine, daunorubicin, and etoposide or clofarabine and cytarabine induction therapy instead, the differences went away.
Overall, Black patients demonstrated significantly better EFS following treatment with clofarabine and cytarabine compared with the low-dose cytarabine triple therapy (hazard ratio, 0.17; P = .01). After adjusting for cofounders, clofarabine and cytarabine induction was the best treatment for Black patients with low ACS10 scores (HR for EFS, 0.2).
“Our results suggest that pharmacogenomics differences between Black and White patients should be considered when tailoring induction regimens to improve outcomes of Black patients and bridge the racial disparity gap in AML treatment,” the researchers concluded.
In developing countries, especially in Africa, starting patients on high-dose cytarabine, daunorubicin, and etoposide can lead to better results “without increasing much of the economic burden” since this treatment is the cheapest, Dr. Lamba said. “At the same time, if the patients have high ACS10 score, you can reduce their economic burden by giving them standard dose” cytarabine, daunorubicin, and etoposide and achieve similar results.
No study funding was reported. Dr. Lamba reported no relevant financial relationships, and three other authors reported various disclosures. Disclosures for Dr. Dunbar were unavailable..
A version of this article appeared on Medscape.com.
FROM ASH 2023
Relapsed DLBCL: With Complete Interim Response, SCT Outperforms CAR T
“In patients with relapsed DLBCL in a complete remission, treatment with auto-HCT is associated with a lower rate of relapse/progression, and a longer progression-free survival [versus CAR T therapy],” said first author Mazyar Shadman, MD, MPH, of the Division of Medical Oncology, University of Washington, Seattle.
“The data support utilization of auto-HCT in patients with relapsed LBCL achieving a complete response,” he said.
The findings were presented at the annual meeting of the American Society of Hematology in San Diego.
While approximately 60% of patients with DLBCL are successfully treated after an initial anthracycline-based and rituximab-containing chemotherapy regimen, those who do not improve have poorer outcomes, and CAR T-cell therapy has emerged as the standard of care for those patients, based on results from the ZUMA-7 and TRANSFORM clinical trials.
But with delays in accessing CAR T quite common, patients will often receive interim chemotherapy while awaiting referral to a CAR T center, and occasionally, usually unexpectedly, some will achieve a partial or complete response.
In previous research involving patients who achieved a partial remission in such interim cases, Dr. Shadman and colleagues demonstrated that auto-HCT had favorable outcomes, compared with those who received CAR T therapy.
For the new retrospective, real-world analysis, the authors compared outcomes with the treatment options among 360 patients between the ages of 18 and 75 who were enrolled in the Center for International Blood & Marrow Transplant Research registry and had received auto-HCT or CAR T therapy after achieving a complete remission following salvage chemotherapy.
Of those receiving CAR-T cell therapy, most (53.2%) received tisagenlecleucel (tisa-cel), followed by axicabtagene ciloleucel (axi-cel, 45.6%) and lisocabtagene maraleucel (liso-cel, 1.3%), between 2018 and 2021, while 281 patients were treated with auto-HCT between 2015 and 2021.
With a median follow-up of 49.7 months (range 3.0-94.4) for auto-HCT and 24.7 months (range 3.3-49.4) for CAR-T, a univariate analysis showed the rate of 2-year progression free survival was 66.2% in the auto-HCT group and 47.8% in the CAR T group (P < .001).
The results also favored auto-HCT for 2-year progression/relapse, with a cumulative incidence of 27.8% with auto-HCT versus 48% with CAR T (P < .001), and the 2-year overall survival was higher with auto-HCT (78.9% vs. 65.6%; P = .037).
After adjustment in multivariable analysis adjusting for relevant clinical variables, auto-HCT versus CAR T remained associated with a lower risk of relapse or progression (HR 2.18; P < .0001) and an improved progression-free survival (HR 1.83; P = .0011), with no significant differences in the risk of treatment-related mortality (HR 0.59; P = .36) or overall survival (HR 1.44; P = .12).
Deaths occurred among 85 patients in the auto-HCT group and 25 in the CAR T cohort, with lymphoma being the main cause of death in both groups (60% and 68%, respectively).
While 37 (13.2%) of auto-HCT patients later received subsequent CAR-T therapy, no patients receiving CAR-T had subsequent auto-HCT.
There were no differences between the CAR-T and auto-HST groups in rates of 2-year treatment-related mortality (4.1% vs. 5.9%; P = .673).
A subanalysis of those who had treatment failure at 12 months, (CAR-T = 57 and auto-HCT = 163) showed that those receiving CAR-T therapy had a higher 2-year relapse rate (46.3% vs. 25%; P < .001); an inferior 2-year progression-free survival rate (48.4% vs. 68.2%; P = .001) compared with auto-HCT, while there were no significant differences between the groups in terms of 2-year overall survival or treatment-related mortality.
After a multivariable analysis adjusting for relevant clinical factors, CAR-T therapy remained associated with higher risk of relapse (HR 2.18; P < .0001) and an inferior progression-free survival (HR 1.83; P = .0011) compared with auto-HCT, with no differences in the risk of treatment-related mortality (HR 0.59; P = .36) or overall survival (HR 1.44; P = .12).
“These results are consistent with our previously reported findings, indicating higher efficacy of auto-HCT compared with CAR T in patients with partial remission,” Dr. Shadman said.
In addition to the study’s being a retrospective analysis, limitations include that more than half of patients in the CAR T cohort received tisa-cel, which could have lower efficacy compared with other approved CAR T therapies, Dr. Shadman noted.
“A repeat analysis by including more patients treated with axi-cel or liso-cel may address this issue in the future,” he said.
Discussing the results in a press briefing, Dr. Shadman underscored that “there is no question the choice of therapy for these DLBCL patients with primary refractory disease should be second-line CAR T therapy — we are not suggesting that those patients should be sent for auto-HCT,” he said.
“What we are saying is, in real-world practice ... patients may need chemotherapy treatment in the interim (awaiting CAR T treatment), and we don’t expect these patients to respond to those cycles because they have already shown us that they don’t do well with chemotherapy — however some do respond and can go into complete remission.”
The question then becomes whether patients at that point will fare better with CAR T or auto-HCT, and the results indicate that “auto-HCT gives those patients a pretty solid remission that looks better than [that with] CAR T therapy.”
Dr. Shadman noted that the results serve to inform or confirm key clinical practices, including “in patients with late relapses, after 12 months, auto-HCT should remain the standard of care.
“In patients with primary refractory disease or early relapse, CAR T should be the goal of therapy and improving access to CAR T should remain a priority.
“In the subset of patients who achieve a CR with interim treatment, a discussion about the possibility of utilizing auto-HCT seems reasonable and can provide another curative option for some patients while keeping CAR-T as a backup treatment plan in case of auto-HCT failure.”
Commenting on the study, Jonathan W. Friedberg, MD, the Samuel Durand Professor of Medicine and director of the Wilmot Cancer Institute, University of Rochester, New York, said, “these findings confirm utility of auto-HCT in patients who achieve a CR.”
However, “the problem is that only a small fraction of patients achieve CR in this situation, and we do not know who they are going to be at time of relapse,” he told this news organization.
He agreed that “given robust randomized trials showing overall survival benefit of CAR-T compared to auto-HCT in patients with high risk relapsed DLBCL, CAR-T treatment should remain the current standard.
“However, these current results help to confirm the strategy for management of low- risk (late) relapses and indicate that auto-HCT still has a place for these patients if they achieve CR with salvage therapy.”
Dr. Shadman reported relationships with ADC therapeutics, Bristol Myers Squibb, Genmab, Lilly, Vincerx, Kite (Gilead), Janssen, Fate Therapeutics, MorphoSys/Incyte, AstraZeneca, BeiGene, Pharmacyclics, Mustang Bio, AbbVie, Genentech, MEI Pharma, Regeneron, and TG Therapeutics. Dr. Friedberg had no disclosures to report.
“In patients with relapsed DLBCL in a complete remission, treatment with auto-HCT is associated with a lower rate of relapse/progression, and a longer progression-free survival [versus CAR T therapy],” said first author Mazyar Shadman, MD, MPH, of the Division of Medical Oncology, University of Washington, Seattle.
“The data support utilization of auto-HCT in patients with relapsed LBCL achieving a complete response,” he said.
The findings were presented at the annual meeting of the American Society of Hematology in San Diego.
While approximately 60% of patients with DLBCL are successfully treated after an initial anthracycline-based and rituximab-containing chemotherapy regimen, those who do not improve have poorer outcomes, and CAR T-cell therapy has emerged as the standard of care for those patients, based on results from the ZUMA-7 and TRANSFORM clinical trials.
But with delays in accessing CAR T quite common, patients will often receive interim chemotherapy while awaiting referral to a CAR T center, and occasionally, usually unexpectedly, some will achieve a partial or complete response.
In previous research involving patients who achieved a partial remission in such interim cases, Dr. Shadman and colleagues demonstrated that auto-HCT had favorable outcomes, compared with those who received CAR T therapy.
For the new retrospective, real-world analysis, the authors compared outcomes with the treatment options among 360 patients between the ages of 18 and 75 who were enrolled in the Center for International Blood & Marrow Transplant Research registry and had received auto-HCT or CAR T therapy after achieving a complete remission following salvage chemotherapy.
Of those receiving CAR-T cell therapy, most (53.2%) received tisagenlecleucel (tisa-cel), followed by axicabtagene ciloleucel (axi-cel, 45.6%) and lisocabtagene maraleucel (liso-cel, 1.3%), between 2018 and 2021, while 281 patients were treated with auto-HCT between 2015 and 2021.
With a median follow-up of 49.7 months (range 3.0-94.4) for auto-HCT and 24.7 months (range 3.3-49.4) for CAR-T, a univariate analysis showed the rate of 2-year progression free survival was 66.2% in the auto-HCT group and 47.8% in the CAR T group (P < .001).
The results also favored auto-HCT for 2-year progression/relapse, with a cumulative incidence of 27.8% with auto-HCT versus 48% with CAR T (P < .001), and the 2-year overall survival was higher with auto-HCT (78.9% vs. 65.6%; P = .037).
After adjustment in multivariable analysis adjusting for relevant clinical variables, auto-HCT versus CAR T remained associated with a lower risk of relapse or progression (HR 2.18; P < .0001) and an improved progression-free survival (HR 1.83; P = .0011), with no significant differences in the risk of treatment-related mortality (HR 0.59; P = .36) or overall survival (HR 1.44; P = .12).
Deaths occurred among 85 patients in the auto-HCT group and 25 in the CAR T cohort, with lymphoma being the main cause of death in both groups (60% and 68%, respectively).
While 37 (13.2%) of auto-HCT patients later received subsequent CAR-T therapy, no patients receiving CAR-T had subsequent auto-HCT.
There were no differences between the CAR-T and auto-HST groups in rates of 2-year treatment-related mortality (4.1% vs. 5.9%; P = .673).
A subanalysis of those who had treatment failure at 12 months, (CAR-T = 57 and auto-HCT = 163) showed that those receiving CAR-T therapy had a higher 2-year relapse rate (46.3% vs. 25%; P < .001); an inferior 2-year progression-free survival rate (48.4% vs. 68.2%; P = .001) compared with auto-HCT, while there were no significant differences between the groups in terms of 2-year overall survival or treatment-related mortality.
After a multivariable analysis adjusting for relevant clinical factors, CAR-T therapy remained associated with higher risk of relapse (HR 2.18; P < .0001) and an inferior progression-free survival (HR 1.83; P = .0011) compared with auto-HCT, with no differences in the risk of treatment-related mortality (HR 0.59; P = .36) or overall survival (HR 1.44; P = .12).
“These results are consistent with our previously reported findings, indicating higher efficacy of auto-HCT compared with CAR T in patients with partial remission,” Dr. Shadman said.
In addition to the study’s being a retrospective analysis, limitations include that more than half of patients in the CAR T cohort received tisa-cel, which could have lower efficacy compared with other approved CAR T therapies, Dr. Shadman noted.
“A repeat analysis by including more patients treated with axi-cel or liso-cel may address this issue in the future,” he said.
Discussing the results in a press briefing, Dr. Shadman underscored that “there is no question the choice of therapy for these DLBCL patients with primary refractory disease should be second-line CAR T therapy — we are not suggesting that those patients should be sent for auto-HCT,” he said.
“What we are saying is, in real-world practice ... patients may need chemotherapy treatment in the interim (awaiting CAR T treatment), and we don’t expect these patients to respond to those cycles because they have already shown us that they don’t do well with chemotherapy — however some do respond and can go into complete remission.”
The question then becomes whether patients at that point will fare better with CAR T or auto-HCT, and the results indicate that “auto-HCT gives those patients a pretty solid remission that looks better than [that with] CAR T therapy.”
Dr. Shadman noted that the results serve to inform or confirm key clinical practices, including “in patients with late relapses, after 12 months, auto-HCT should remain the standard of care.
“In patients with primary refractory disease or early relapse, CAR T should be the goal of therapy and improving access to CAR T should remain a priority.
“In the subset of patients who achieve a CR with interim treatment, a discussion about the possibility of utilizing auto-HCT seems reasonable and can provide another curative option for some patients while keeping CAR-T as a backup treatment plan in case of auto-HCT failure.”
Commenting on the study, Jonathan W. Friedberg, MD, the Samuel Durand Professor of Medicine and director of the Wilmot Cancer Institute, University of Rochester, New York, said, “these findings confirm utility of auto-HCT in patients who achieve a CR.”
However, “the problem is that only a small fraction of patients achieve CR in this situation, and we do not know who they are going to be at time of relapse,” he told this news organization.
He agreed that “given robust randomized trials showing overall survival benefit of CAR-T compared to auto-HCT in patients with high risk relapsed DLBCL, CAR-T treatment should remain the current standard.
“However, these current results help to confirm the strategy for management of low- risk (late) relapses and indicate that auto-HCT still has a place for these patients if they achieve CR with salvage therapy.”
Dr. Shadman reported relationships with ADC therapeutics, Bristol Myers Squibb, Genmab, Lilly, Vincerx, Kite (Gilead), Janssen, Fate Therapeutics, MorphoSys/Incyte, AstraZeneca, BeiGene, Pharmacyclics, Mustang Bio, AbbVie, Genentech, MEI Pharma, Regeneron, and TG Therapeutics. Dr. Friedberg had no disclosures to report.
“In patients with relapsed DLBCL in a complete remission, treatment with auto-HCT is associated with a lower rate of relapse/progression, and a longer progression-free survival [versus CAR T therapy],” said first author Mazyar Shadman, MD, MPH, of the Division of Medical Oncology, University of Washington, Seattle.
“The data support utilization of auto-HCT in patients with relapsed LBCL achieving a complete response,” he said.
The findings were presented at the annual meeting of the American Society of Hematology in San Diego.
While approximately 60% of patients with DLBCL are successfully treated after an initial anthracycline-based and rituximab-containing chemotherapy regimen, those who do not improve have poorer outcomes, and CAR T-cell therapy has emerged as the standard of care for those patients, based on results from the ZUMA-7 and TRANSFORM clinical trials.
But with delays in accessing CAR T quite common, patients will often receive interim chemotherapy while awaiting referral to a CAR T center, and occasionally, usually unexpectedly, some will achieve a partial or complete response.
In previous research involving patients who achieved a partial remission in such interim cases, Dr. Shadman and colleagues demonstrated that auto-HCT had favorable outcomes, compared with those who received CAR T therapy.
For the new retrospective, real-world analysis, the authors compared outcomes with the treatment options among 360 patients between the ages of 18 and 75 who were enrolled in the Center for International Blood & Marrow Transplant Research registry and had received auto-HCT or CAR T therapy after achieving a complete remission following salvage chemotherapy.
Of those receiving CAR-T cell therapy, most (53.2%) received tisagenlecleucel (tisa-cel), followed by axicabtagene ciloleucel (axi-cel, 45.6%) and lisocabtagene maraleucel (liso-cel, 1.3%), between 2018 and 2021, while 281 patients were treated with auto-HCT between 2015 and 2021.
With a median follow-up of 49.7 months (range 3.0-94.4) for auto-HCT and 24.7 months (range 3.3-49.4) for CAR-T, a univariate analysis showed the rate of 2-year progression free survival was 66.2% in the auto-HCT group and 47.8% in the CAR T group (P < .001).
The results also favored auto-HCT for 2-year progression/relapse, with a cumulative incidence of 27.8% with auto-HCT versus 48% with CAR T (P < .001), and the 2-year overall survival was higher with auto-HCT (78.9% vs. 65.6%; P = .037).
After adjustment in multivariable analysis adjusting for relevant clinical variables, auto-HCT versus CAR T remained associated with a lower risk of relapse or progression (HR 2.18; P < .0001) and an improved progression-free survival (HR 1.83; P = .0011), with no significant differences in the risk of treatment-related mortality (HR 0.59; P = .36) or overall survival (HR 1.44; P = .12).
Deaths occurred among 85 patients in the auto-HCT group and 25 in the CAR T cohort, with lymphoma being the main cause of death in both groups (60% and 68%, respectively).
While 37 (13.2%) of auto-HCT patients later received subsequent CAR-T therapy, no patients receiving CAR-T had subsequent auto-HCT.
There were no differences between the CAR-T and auto-HST groups in rates of 2-year treatment-related mortality (4.1% vs. 5.9%; P = .673).
A subanalysis of those who had treatment failure at 12 months, (CAR-T = 57 and auto-HCT = 163) showed that those receiving CAR-T therapy had a higher 2-year relapse rate (46.3% vs. 25%; P < .001); an inferior 2-year progression-free survival rate (48.4% vs. 68.2%; P = .001) compared with auto-HCT, while there were no significant differences between the groups in terms of 2-year overall survival or treatment-related mortality.
After a multivariable analysis adjusting for relevant clinical factors, CAR-T therapy remained associated with higher risk of relapse (HR 2.18; P < .0001) and an inferior progression-free survival (HR 1.83; P = .0011) compared with auto-HCT, with no differences in the risk of treatment-related mortality (HR 0.59; P = .36) or overall survival (HR 1.44; P = .12).
“These results are consistent with our previously reported findings, indicating higher efficacy of auto-HCT compared with CAR T in patients with partial remission,” Dr. Shadman said.
In addition to the study’s being a retrospective analysis, limitations include that more than half of patients in the CAR T cohort received tisa-cel, which could have lower efficacy compared with other approved CAR T therapies, Dr. Shadman noted.
“A repeat analysis by including more patients treated with axi-cel or liso-cel may address this issue in the future,” he said.
Discussing the results in a press briefing, Dr. Shadman underscored that “there is no question the choice of therapy for these DLBCL patients with primary refractory disease should be second-line CAR T therapy — we are not suggesting that those patients should be sent for auto-HCT,” he said.
“What we are saying is, in real-world practice ... patients may need chemotherapy treatment in the interim (awaiting CAR T treatment), and we don’t expect these patients to respond to those cycles because they have already shown us that they don’t do well with chemotherapy — however some do respond and can go into complete remission.”
The question then becomes whether patients at that point will fare better with CAR T or auto-HCT, and the results indicate that “auto-HCT gives those patients a pretty solid remission that looks better than [that with] CAR T therapy.”
Dr. Shadman noted that the results serve to inform or confirm key clinical practices, including “in patients with late relapses, after 12 months, auto-HCT should remain the standard of care.
“In patients with primary refractory disease or early relapse, CAR T should be the goal of therapy and improving access to CAR T should remain a priority.
“In the subset of patients who achieve a CR with interim treatment, a discussion about the possibility of utilizing auto-HCT seems reasonable and can provide another curative option for some patients while keeping CAR-T as a backup treatment plan in case of auto-HCT failure.”
Commenting on the study, Jonathan W. Friedberg, MD, the Samuel Durand Professor of Medicine and director of the Wilmot Cancer Institute, University of Rochester, New York, said, “these findings confirm utility of auto-HCT in patients who achieve a CR.”
However, “the problem is that only a small fraction of patients achieve CR in this situation, and we do not know who they are going to be at time of relapse,” he told this news organization.
He agreed that “given robust randomized trials showing overall survival benefit of CAR-T compared to auto-HCT in patients with high risk relapsed DLBCL, CAR-T treatment should remain the current standard.
“However, these current results help to confirm the strategy for management of low- risk (late) relapses and indicate that auto-HCT still has a place for these patients if they achieve CR with salvage therapy.”
Dr. Shadman reported relationships with ADC therapeutics, Bristol Myers Squibb, Genmab, Lilly, Vincerx, Kite (Gilead), Janssen, Fate Therapeutics, MorphoSys/Incyte, AstraZeneca, BeiGene, Pharmacyclics, Mustang Bio, AbbVie, Genentech, MEI Pharma, Regeneron, and TG Therapeutics. Dr. Friedberg had no disclosures to report.
FROM ASH 2023