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CAR T-Cell: Do Benefits Still Outweigh Risks?
Importantly, most specialists agree, so far the risk appears no greater than the known risk of secondary primary malignancies that is well established with other cancer therapies.
“The data that we have so far suggest that the risk of secondary T-cell lymphoma in patients treated with CAR T-cells is similar to [that] of patients treated with other cancer therapies, [including] chemotherapy, radiation, transplantation,” Marco Ruella, MD, said in an interview. He reported on a case of a T-cell lymphoma occurring following CAR-T therapy at the University of Pennsylvania.
While his team is still investigating the development of such malignancies, “the FDA notice does not change our clinical practice and patients should be reassured that the benefit of CAR-T therapy significantly outweighs the potential risk of secondary malignancies including T-cell lymphoma,” said Dr. Ruella, scientific director of the Lymphoma Program, Division of Hematology and Oncology and Center for Cellular Immunotherapies, at the University of Pennsylvania, Philadelphia.
FDA: 28 Reports of Malignancies; 3 with Evidence of ‘Likely’ CAR T Involvement
Concerns were raised last November when the FDA announced in a safety communication that it was investigating the “serious risk of T-cell malignancy” following B-cell maturation antigen (BCMA)-directed or CD19-directed CAR T-cell immunotherapies, citing reports from clinical trials and/or postmarketing adverse event data sources. Subsequently, in January, the FDA called for the boxed warning on all approved BCMA- and CD19-targeted genetically modified autologous T-cell immunotherapies, which include: Abecma (idecabtagene vicleucel); Breyanzi (lisocabtagene maraleucel); Carvykti (ciltacabtagene autoleucel); Kymriah (tisagenlecleucel); Tecartus (brexucabtagene autoleucel); and Yescarta (axicabtagene ciloleucel).
“Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, the FDA continues to investigate the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death,” the FDA reported in discussing the safety warnings.
The cases were detailed in a report from FDA researchers published in the New England Journal of Medicine, noting that as of December 31, 2023, the FDA had become aware of 22 cases of T-cell cancers occurring following CAR T-cell treatment, including T-cell lymphoma, T-cell large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma.
Report coauthor Peter Marks, MD, PhD, of the FDA’s Center for Biologics Evaluation and Research in Silver Spring, Maryland, said in an interview that since the publication of their report, six new cases have emerged.
“As reported in the NEJM Perspective, there were 22 cases of T-cell malignancy after treatment with CAR T-cell immunotherapies as of December 31, 2023, but we have received additional reports and, as of February 9, 2024, FDA has now received 28 reports,” he said. “Note that as new cases are being reported, there will be updates to the total number of cases under ongoing review by FDA.”
The initial 22 cases all occurred relatively soon after treatment. Of 14 cases with sufficient data, all developed within 2 years of the CAR-T therapy, ranging from 1 to 19 months, with about half occurring in the first year after administration.
The cases involved five of the six FDA-approved CAR-T products, with the numbers too low to suggest an association with any particular product.
In three of the cases, the lymphoma was found in genetic testing to contain the CAR construction, “indicating that the CAR-T product was most likely involved in the development of the T-cell cancer,” according to the FDA researchers.
With inadequate genetic sampling in most of the remaining 19 cases, the association is less clear, however “the timing of several of the cases makes association a possibility,” Dr. Marks said. In their report, Dr. Marks and colleagues added that “determination of whether the T-cell cancer is associated with the CAR construct ... most likely won’t be possible for every case reported to date.”
Even if all the reported cases are assumed to be related to CAR-T treatment, the numbers still represent a very small proportion of the more than 27,000 doses of the six CAR-T therapies approved in the United States, the authors noted, but they cautioned that the numbers could indeed be higher than reported.
“Relying on postmarketing reporting may lead to underestimates of such cases,” they said.
Life-Long Monitoring Recommended
In response to the reports, the FDA is urging that clinicians’ monitoring of patients treated with CAR-T therapy should be lifelong.
“Patients and clinical trial participants receiving treatment with these products should be monitored lifelong for new malignancies,” Dr. Marks said.
“In the event that a new malignancy occurs following treatment with these products, contact the manufacturer to report the event and obtain instructions on collection of patient samples for testing for the presence of the CAR transgene.”
In addition, cases should be reported to the FDA, either by calling or through the FDA’s medical product safety reporting program.
T-Cell Malignancy Case Report
In describing the case at their medical center in the report in Nature Medicine, Dr. Ruella and colleagues said a T-cell lymphoma occurred in a patient with non-Hodgkin B-cell lymphoma 3 months after an anti-CD19 CAR T-cell treatment.
As a result, the team conducted a subsequent analysis of 449 patients treated with CAR-T therapy at the University of Pennsylvania center, and with a median follow-up of 10.3 months, 16 patients (3.6%) had developed a secondary primary malignancy, with a median onset time of 26.4 months for solid and 9.7 months for hematological malignancies.
The patient who had developed a T-cell lymphoma tested negative for CAR integration upon diagnosis, and regarding the other cancers, Dr. Ruella noted that “we have no indication that the secondary malignancies are directly caused by the CAR-T therapy.
“We have many patients with a very long follow-up beyond 5 and even 10 years,” he said. “In these patients, we don’t see an increased risk of T-cell lymphoma.”
‘Cautious Reassurance’ Urged in Discussion with Patients
With alarming headlines on the findings suggesting that CAR-T therapy may cause cancer, Rahul Banerjee, MD, and colleagues at the University of Washington, Seattle, recommend the use of “cautious reassurance” in discussing the issue with patients. In a paper published in January in Blood Advances, they suggest a three-part response: underscoring that the benefits of CAR T “far outweigh” the risks in relapsed/refractory malignancies, that the ‘one-and-done’ nature of CAR-T infusions provide meaningful improvements in quality of life, and that the active cancer at hand is “a much larger threat than a hypothetical cancer years later.”
In many cases, patients may only have months to live without CAR-T therapy and will have already had multiple prior lines of therapy, therefore the CAR-T treatment itself may provide time for the secondary primary cancers from any of the treatments to emerge, as experts have noted.
“One has to be alive to be diagnosed with a secondary primary malignancy, and it’s thus very possible that CAR-T may be creating a type of ‘immortal time bias’ wherein patients live long enough to experience the unfortunate sequelae of their previous therapies,” Dr. Banerjee explained in an interview.
Nevertheless, the potential for substantial improvements in quality of life with CAR-T therapy compared with traditional treatments addresses a top priority for patients, he added.
“For most patients with [for instance], myeloma, the ability of CAR-T to put them rapidly into a deep remission without the need for maintenance is an unheard-of potential for them,” Dr. Banerjee said.
“In multiple myeloma, no CAR-T therapy has (yet) demonstrated an overall survival benefit — but I think the substantial quality-of-life benefit stands by itself as a big reason why patients continue to prefer CAR-T.”
Keep Patients In Touch with CAR T Centers
In light of the concerns regarding the secondary malignancies, Dr. Banerjee underscored that CAR-T patients should be kept in close touch with centers that have CAR-T treatment expertise.
With most patients followed primarily at community practices where CAR-T therapy is not administered, “I’d strongly encourage my colleagues in community practices to refer all eligible patients to a CAR-T-capable center for evaluation regardless of what their risk of post-CAR-T secondary primary malignancies may be,” Dr. Banerjee urged.
“Based on the evidence we have currently, which includes the FDA’s updated information, there are many more unknowns about this potential secondary primary malignancy risk than knowns,” he said. “This is of course a much more nuanced issue than any one package insert can convey, and CAR-T experts at treating centers can have these conversations at length with eligible patients who are nervous about these recent updates.”
Dr. Ruella disclosed that he holds patents related to CD19 CAR T cells, as well as relationships with NanoString, Bristol Myers Squibb, GlaxoSmithKline, Scailyte, Bayer, AbClon, Oxford NanoImaging, CURIOX, and Beckman Coulter, and he was the scientific founder of viTToria Biotherapeutics. Dr. Banerjee reported ties with BMS, Caribou Biosciences, Genentech, Janssen, Karyopharm, Pfizer, Sanofi, SparkCures, Novartis, and Pack Health.
Importantly, most specialists agree, so far the risk appears no greater than the known risk of secondary primary malignancies that is well established with other cancer therapies.
“The data that we have so far suggest that the risk of secondary T-cell lymphoma in patients treated with CAR T-cells is similar to [that] of patients treated with other cancer therapies, [including] chemotherapy, radiation, transplantation,” Marco Ruella, MD, said in an interview. He reported on a case of a T-cell lymphoma occurring following CAR-T therapy at the University of Pennsylvania.
While his team is still investigating the development of such malignancies, “the FDA notice does not change our clinical practice and patients should be reassured that the benefit of CAR-T therapy significantly outweighs the potential risk of secondary malignancies including T-cell lymphoma,” said Dr. Ruella, scientific director of the Lymphoma Program, Division of Hematology and Oncology and Center for Cellular Immunotherapies, at the University of Pennsylvania, Philadelphia.
FDA: 28 Reports of Malignancies; 3 with Evidence of ‘Likely’ CAR T Involvement
Concerns were raised last November when the FDA announced in a safety communication that it was investigating the “serious risk of T-cell malignancy” following B-cell maturation antigen (BCMA)-directed or CD19-directed CAR T-cell immunotherapies, citing reports from clinical trials and/or postmarketing adverse event data sources. Subsequently, in January, the FDA called for the boxed warning on all approved BCMA- and CD19-targeted genetically modified autologous T-cell immunotherapies, which include: Abecma (idecabtagene vicleucel); Breyanzi (lisocabtagene maraleucel); Carvykti (ciltacabtagene autoleucel); Kymriah (tisagenlecleucel); Tecartus (brexucabtagene autoleucel); and Yescarta (axicabtagene ciloleucel).
“Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, the FDA continues to investigate the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death,” the FDA reported in discussing the safety warnings.
The cases were detailed in a report from FDA researchers published in the New England Journal of Medicine, noting that as of December 31, 2023, the FDA had become aware of 22 cases of T-cell cancers occurring following CAR T-cell treatment, including T-cell lymphoma, T-cell large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma.
Report coauthor Peter Marks, MD, PhD, of the FDA’s Center for Biologics Evaluation and Research in Silver Spring, Maryland, said in an interview that since the publication of their report, six new cases have emerged.
“As reported in the NEJM Perspective, there were 22 cases of T-cell malignancy after treatment with CAR T-cell immunotherapies as of December 31, 2023, but we have received additional reports and, as of February 9, 2024, FDA has now received 28 reports,” he said. “Note that as new cases are being reported, there will be updates to the total number of cases under ongoing review by FDA.”
The initial 22 cases all occurred relatively soon after treatment. Of 14 cases with sufficient data, all developed within 2 years of the CAR-T therapy, ranging from 1 to 19 months, with about half occurring in the first year after administration.
The cases involved five of the six FDA-approved CAR-T products, with the numbers too low to suggest an association with any particular product.
In three of the cases, the lymphoma was found in genetic testing to contain the CAR construction, “indicating that the CAR-T product was most likely involved in the development of the T-cell cancer,” according to the FDA researchers.
With inadequate genetic sampling in most of the remaining 19 cases, the association is less clear, however “the timing of several of the cases makes association a possibility,” Dr. Marks said. In their report, Dr. Marks and colleagues added that “determination of whether the T-cell cancer is associated with the CAR construct ... most likely won’t be possible for every case reported to date.”
Even if all the reported cases are assumed to be related to CAR-T treatment, the numbers still represent a very small proportion of the more than 27,000 doses of the six CAR-T therapies approved in the United States, the authors noted, but they cautioned that the numbers could indeed be higher than reported.
“Relying on postmarketing reporting may lead to underestimates of such cases,” they said.
Life-Long Monitoring Recommended
In response to the reports, the FDA is urging that clinicians’ monitoring of patients treated with CAR-T therapy should be lifelong.
“Patients and clinical trial participants receiving treatment with these products should be monitored lifelong for new malignancies,” Dr. Marks said.
“In the event that a new malignancy occurs following treatment with these products, contact the manufacturer to report the event and obtain instructions on collection of patient samples for testing for the presence of the CAR transgene.”
In addition, cases should be reported to the FDA, either by calling or through the FDA’s medical product safety reporting program.
T-Cell Malignancy Case Report
In describing the case at their medical center in the report in Nature Medicine, Dr. Ruella and colleagues said a T-cell lymphoma occurred in a patient with non-Hodgkin B-cell lymphoma 3 months after an anti-CD19 CAR T-cell treatment.
As a result, the team conducted a subsequent analysis of 449 patients treated with CAR-T therapy at the University of Pennsylvania center, and with a median follow-up of 10.3 months, 16 patients (3.6%) had developed a secondary primary malignancy, with a median onset time of 26.4 months for solid and 9.7 months for hematological malignancies.
The patient who had developed a T-cell lymphoma tested negative for CAR integration upon diagnosis, and regarding the other cancers, Dr. Ruella noted that “we have no indication that the secondary malignancies are directly caused by the CAR-T therapy.
“We have many patients with a very long follow-up beyond 5 and even 10 years,” he said. “In these patients, we don’t see an increased risk of T-cell lymphoma.”
‘Cautious Reassurance’ Urged in Discussion with Patients
With alarming headlines on the findings suggesting that CAR-T therapy may cause cancer, Rahul Banerjee, MD, and colleagues at the University of Washington, Seattle, recommend the use of “cautious reassurance” in discussing the issue with patients. In a paper published in January in Blood Advances, they suggest a three-part response: underscoring that the benefits of CAR T “far outweigh” the risks in relapsed/refractory malignancies, that the ‘one-and-done’ nature of CAR-T infusions provide meaningful improvements in quality of life, and that the active cancer at hand is “a much larger threat than a hypothetical cancer years later.”
In many cases, patients may only have months to live without CAR-T therapy and will have already had multiple prior lines of therapy, therefore the CAR-T treatment itself may provide time for the secondary primary cancers from any of the treatments to emerge, as experts have noted.
“One has to be alive to be diagnosed with a secondary primary malignancy, and it’s thus very possible that CAR-T may be creating a type of ‘immortal time bias’ wherein patients live long enough to experience the unfortunate sequelae of their previous therapies,” Dr. Banerjee explained in an interview.
Nevertheless, the potential for substantial improvements in quality of life with CAR-T therapy compared with traditional treatments addresses a top priority for patients, he added.
“For most patients with [for instance], myeloma, the ability of CAR-T to put them rapidly into a deep remission without the need for maintenance is an unheard-of potential for them,” Dr. Banerjee said.
“In multiple myeloma, no CAR-T therapy has (yet) demonstrated an overall survival benefit — but I think the substantial quality-of-life benefit stands by itself as a big reason why patients continue to prefer CAR-T.”
Keep Patients In Touch with CAR T Centers
In light of the concerns regarding the secondary malignancies, Dr. Banerjee underscored that CAR-T patients should be kept in close touch with centers that have CAR-T treatment expertise.
With most patients followed primarily at community practices where CAR-T therapy is not administered, “I’d strongly encourage my colleagues in community practices to refer all eligible patients to a CAR-T-capable center for evaluation regardless of what their risk of post-CAR-T secondary primary malignancies may be,” Dr. Banerjee urged.
“Based on the evidence we have currently, which includes the FDA’s updated information, there are many more unknowns about this potential secondary primary malignancy risk than knowns,” he said. “This is of course a much more nuanced issue than any one package insert can convey, and CAR-T experts at treating centers can have these conversations at length with eligible patients who are nervous about these recent updates.”
Dr. Ruella disclosed that he holds patents related to CD19 CAR T cells, as well as relationships with NanoString, Bristol Myers Squibb, GlaxoSmithKline, Scailyte, Bayer, AbClon, Oxford NanoImaging, CURIOX, and Beckman Coulter, and he was the scientific founder of viTToria Biotherapeutics. Dr. Banerjee reported ties with BMS, Caribou Biosciences, Genentech, Janssen, Karyopharm, Pfizer, Sanofi, SparkCures, Novartis, and Pack Health.
Importantly, most specialists agree, so far the risk appears no greater than the known risk of secondary primary malignancies that is well established with other cancer therapies.
“The data that we have so far suggest that the risk of secondary T-cell lymphoma in patients treated with CAR T-cells is similar to [that] of patients treated with other cancer therapies, [including] chemotherapy, radiation, transplantation,” Marco Ruella, MD, said in an interview. He reported on a case of a T-cell lymphoma occurring following CAR-T therapy at the University of Pennsylvania.
While his team is still investigating the development of such malignancies, “the FDA notice does not change our clinical practice and patients should be reassured that the benefit of CAR-T therapy significantly outweighs the potential risk of secondary malignancies including T-cell lymphoma,” said Dr. Ruella, scientific director of the Lymphoma Program, Division of Hematology and Oncology and Center for Cellular Immunotherapies, at the University of Pennsylvania, Philadelphia.
FDA: 28 Reports of Malignancies; 3 with Evidence of ‘Likely’ CAR T Involvement
Concerns were raised last November when the FDA announced in a safety communication that it was investigating the “serious risk of T-cell malignancy” following B-cell maturation antigen (BCMA)-directed or CD19-directed CAR T-cell immunotherapies, citing reports from clinical trials and/or postmarketing adverse event data sources. Subsequently, in January, the FDA called for the boxed warning on all approved BCMA- and CD19-targeted genetically modified autologous T-cell immunotherapies, which include: Abecma (idecabtagene vicleucel); Breyanzi (lisocabtagene maraleucel); Carvykti (ciltacabtagene autoleucel); Kymriah (tisagenlecleucel); Tecartus (brexucabtagene autoleucel); and Yescarta (axicabtagene ciloleucel).
“Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, the FDA continues to investigate the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death,” the FDA reported in discussing the safety warnings.
The cases were detailed in a report from FDA researchers published in the New England Journal of Medicine, noting that as of December 31, 2023, the FDA had become aware of 22 cases of T-cell cancers occurring following CAR T-cell treatment, including T-cell lymphoma, T-cell large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma.
Report coauthor Peter Marks, MD, PhD, of the FDA’s Center for Biologics Evaluation and Research in Silver Spring, Maryland, said in an interview that since the publication of their report, six new cases have emerged.
“As reported in the NEJM Perspective, there were 22 cases of T-cell malignancy after treatment with CAR T-cell immunotherapies as of December 31, 2023, but we have received additional reports and, as of February 9, 2024, FDA has now received 28 reports,” he said. “Note that as new cases are being reported, there will be updates to the total number of cases under ongoing review by FDA.”
The initial 22 cases all occurred relatively soon after treatment. Of 14 cases with sufficient data, all developed within 2 years of the CAR-T therapy, ranging from 1 to 19 months, with about half occurring in the first year after administration.
The cases involved five of the six FDA-approved CAR-T products, with the numbers too low to suggest an association with any particular product.
In three of the cases, the lymphoma was found in genetic testing to contain the CAR construction, “indicating that the CAR-T product was most likely involved in the development of the T-cell cancer,” according to the FDA researchers.
With inadequate genetic sampling in most of the remaining 19 cases, the association is less clear, however “the timing of several of the cases makes association a possibility,” Dr. Marks said. In their report, Dr. Marks and colleagues added that “determination of whether the T-cell cancer is associated with the CAR construct ... most likely won’t be possible for every case reported to date.”
Even if all the reported cases are assumed to be related to CAR-T treatment, the numbers still represent a very small proportion of the more than 27,000 doses of the six CAR-T therapies approved in the United States, the authors noted, but they cautioned that the numbers could indeed be higher than reported.
“Relying on postmarketing reporting may lead to underestimates of such cases,” they said.
Life-Long Monitoring Recommended
In response to the reports, the FDA is urging that clinicians’ monitoring of patients treated with CAR-T therapy should be lifelong.
“Patients and clinical trial participants receiving treatment with these products should be monitored lifelong for new malignancies,” Dr. Marks said.
“In the event that a new malignancy occurs following treatment with these products, contact the manufacturer to report the event and obtain instructions on collection of patient samples for testing for the presence of the CAR transgene.”
In addition, cases should be reported to the FDA, either by calling or through the FDA’s medical product safety reporting program.
T-Cell Malignancy Case Report
In describing the case at their medical center in the report in Nature Medicine, Dr. Ruella and colleagues said a T-cell lymphoma occurred in a patient with non-Hodgkin B-cell lymphoma 3 months after an anti-CD19 CAR T-cell treatment.
As a result, the team conducted a subsequent analysis of 449 patients treated with CAR-T therapy at the University of Pennsylvania center, and with a median follow-up of 10.3 months, 16 patients (3.6%) had developed a secondary primary malignancy, with a median onset time of 26.4 months for solid and 9.7 months for hematological malignancies.
The patient who had developed a T-cell lymphoma tested negative for CAR integration upon diagnosis, and regarding the other cancers, Dr. Ruella noted that “we have no indication that the secondary malignancies are directly caused by the CAR-T therapy.
“We have many patients with a very long follow-up beyond 5 and even 10 years,” he said. “In these patients, we don’t see an increased risk of T-cell lymphoma.”
‘Cautious Reassurance’ Urged in Discussion with Patients
With alarming headlines on the findings suggesting that CAR-T therapy may cause cancer, Rahul Banerjee, MD, and colleagues at the University of Washington, Seattle, recommend the use of “cautious reassurance” in discussing the issue with patients. In a paper published in January in Blood Advances, they suggest a three-part response: underscoring that the benefits of CAR T “far outweigh” the risks in relapsed/refractory malignancies, that the ‘one-and-done’ nature of CAR-T infusions provide meaningful improvements in quality of life, and that the active cancer at hand is “a much larger threat than a hypothetical cancer years later.”
In many cases, patients may only have months to live without CAR-T therapy and will have already had multiple prior lines of therapy, therefore the CAR-T treatment itself may provide time for the secondary primary cancers from any of the treatments to emerge, as experts have noted.
“One has to be alive to be diagnosed with a secondary primary malignancy, and it’s thus very possible that CAR-T may be creating a type of ‘immortal time bias’ wherein patients live long enough to experience the unfortunate sequelae of their previous therapies,” Dr. Banerjee explained in an interview.
Nevertheless, the potential for substantial improvements in quality of life with CAR-T therapy compared with traditional treatments addresses a top priority for patients, he added.
“For most patients with [for instance], myeloma, the ability of CAR-T to put them rapidly into a deep remission without the need for maintenance is an unheard-of potential for them,” Dr. Banerjee said.
“In multiple myeloma, no CAR-T therapy has (yet) demonstrated an overall survival benefit — but I think the substantial quality-of-life benefit stands by itself as a big reason why patients continue to prefer CAR-T.”
Keep Patients In Touch with CAR T Centers
In light of the concerns regarding the secondary malignancies, Dr. Banerjee underscored that CAR-T patients should be kept in close touch with centers that have CAR-T treatment expertise.
With most patients followed primarily at community practices where CAR-T therapy is not administered, “I’d strongly encourage my colleagues in community practices to refer all eligible patients to a CAR-T-capable center for evaluation regardless of what their risk of post-CAR-T secondary primary malignancies may be,” Dr. Banerjee urged.
“Based on the evidence we have currently, which includes the FDA’s updated information, there are many more unknowns about this potential secondary primary malignancy risk than knowns,” he said. “This is of course a much more nuanced issue than any one package insert can convey, and CAR-T experts at treating centers can have these conversations at length with eligible patients who are nervous about these recent updates.”
Dr. Ruella disclosed that he holds patents related to CD19 CAR T cells, as well as relationships with NanoString, Bristol Myers Squibb, GlaxoSmithKline, Scailyte, Bayer, AbClon, Oxford NanoImaging, CURIOX, and Beckman Coulter, and he was the scientific founder of viTToria Biotherapeutics. Dr. Banerjee reported ties with BMS, Caribou Biosciences, Genentech, Janssen, Karyopharm, Pfizer, Sanofi, SparkCures, Novartis, and Pack Health.
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
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
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
FDA investigates secondary cancers from CAR T-cell therapies
Secondary cancers are a known risk for this class of immunotherapies, known as B-cell maturation antigen (BCMA)–directed or CD19-directed autologous CAR T-cell therapies, and are included in the prescribing information for these drugs. However, the FDA has received 19 reports of secondary cancers, including CAR-positive lymphoma, since 2017, when the first CAR T-cell treatments were approved, according to Endpoints News.
Most of these reports came from the FDA’s postmarketing adverse event system and others from clinical trial data.
Although the overall benefits of these products continue to outweigh their potential risks, “FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action,” the agency said in a press release.
Currently approved products in this class include idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), brexucabtagene autoleucel (Tecartus), and axicabtagene ciloleucel (Yescarta).
“Patients and clinical trial participants receiving treatment with these products should be monitored life-long for new malignancies,” the FDA added.
Suspected adverse events, including T-cell cancers, should be reported by contacting the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
A version of this article first appeared on Medscape.com.
Secondary cancers are a known risk for this class of immunotherapies, known as B-cell maturation antigen (BCMA)–directed or CD19-directed autologous CAR T-cell therapies, and are included in the prescribing information for these drugs. However, the FDA has received 19 reports of secondary cancers, including CAR-positive lymphoma, since 2017, when the first CAR T-cell treatments were approved, according to Endpoints News.
Most of these reports came from the FDA’s postmarketing adverse event system and others from clinical trial data.
Although the overall benefits of these products continue to outweigh their potential risks, “FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action,” the agency said in a press release.
Currently approved products in this class include idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), brexucabtagene autoleucel (Tecartus), and axicabtagene ciloleucel (Yescarta).
“Patients and clinical trial participants receiving treatment with these products should be monitored life-long for new malignancies,” the FDA added.
Suspected adverse events, including T-cell cancers, should be reported by contacting the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
A version of this article first appeared on Medscape.com.
Secondary cancers are a known risk for this class of immunotherapies, known as B-cell maturation antigen (BCMA)–directed or CD19-directed autologous CAR T-cell therapies, and are included in the prescribing information for these drugs. However, the FDA has received 19 reports of secondary cancers, including CAR-positive lymphoma, since 2017, when the first CAR T-cell treatments were approved, according to Endpoints News.
Most of these reports came from the FDA’s postmarketing adverse event system and others from clinical trial data.
Although the overall benefits of these products continue to outweigh their potential risks, “FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action,” the agency said in a press release.
Currently approved products in this class include idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), brexucabtagene autoleucel (Tecartus), and axicabtagene ciloleucel (Yescarta).
“Patients and clinical trial participants receiving treatment with these products should be monitored life-long for new malignancies,” the FDA added.
Suspected adverse events, including T-cell cancers, should be reported by contacting the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
A version of this article first appeared on Medscape.com.
T-cell cancers: CAR T therapy to the rescue?
As Baylor College of Medicine’s Max Mamonkin, PhD, noted in a presentation, patients with conditions such as T-cell lymphoma and T-cell acute lymphoblastic leukemia (ALL) have limited treatment options and grim prognoses. “This is an area with huge unmet need,” he said. “They don’t have options that patients with B-cell malignancies have, like [CAR T-cell therapy] and bispecifics.”
One big challenge is that CAR-targeted antigens in T-cell blood cancers are shared by both normal and malignant T-cells, he said. That poses a risk during therapy that the engineered cells will target each other with “disastrous consequences.”
Research by his team and others have shown that gene editing can help the cells to stop engaging in “fratricide,” Dr. Mamonkin said.
The problem is “it’s much easier to do gene editing on the bench and much harder to translate it into the clinic,” especially in light of limitations posed by the Food and Drug administration, he said. “We started to think about alternative methods to get this approach to the clinic.”
One strategy is to use pharmacologic inhibition via the Bruton’s tyrosine kinase inhibitors ibrutinib and dasatinib to mute the tendency of CAR T toward self-destruction. When tested in mice, “the unedited cells not just persisted, they expanded with sustained anti-leukemic activity and significantly prolonged their lives even more than the knock-out [gene-edited] cells.”
The research has now moved to human subjects. In 2021, researchers at Texas Children’s Hospital and Houston Methodist Hospital launched a clinical trial to test CD7 CAR T-cell therapy with CD28 in 21 patients with CD7-positive T-cell lymphoma. The initial part of the transplant-enabling CRIMSON-NE study is expected to be completed by mid-2024, and patients will be followed for 15 years.
Early results show that CD7 CAR T-cells have persisted in the blood of patients over weeks and months, Dr. Mamonkin said. In eight patients, “we’re seeing good evidence of activity,” with two patients reaching complete remissions.
The findings suggest that CD7 can be targeted in T-cell malignancies, he said. What about CD5? A similar study known as MAGENTA is testing CD5 CAR T-cell therapy with CD28 in T-cell leukemia and lymphoma in 42 patients. The phase 1 trial began in 2017. It’s expected to be completed by 2024 and to track patients for 15 years.
Results so far have been positive with complete remission achieved in three of nine patients with T-cell lymphoma; two remained in remission for more than 4 years.
Results in T-cell ALL improved after researchers adjusted the manufacturing of the cells. As for durability in these patients, “we try to bridge them to transplantation as soon as possible.”
As for side effects overall, there wasn’t much immune effector cell-associated neurotoxicity syndrome, and the CD7 approach seems to be more inflammatory, he said.
The presentation didn’t address the potential cost of the therapies. CAR T-cell therapy can cost between $500,000 and $1 million. Medicare covers it, but Medicaid may not depending on the state, and insurers may refuse to pay for it.
Dr. Mamonkin disclosed ties with Allogene, Amgen, Fate, Galapagos, March Bio, and NKILT.
As Baylor College of Medicine’s Max Mamonkin, PhD, noted in a presentation, patients with conditions such as T-cell lymphoma and T-cell acute lymphoblastic leukemia (ALL) have limited treatment options and grim prognoses. “This is an area with huge unmet need,” he said. “They don’t have options that patients with B-cell malignancies have, like [CAR T-cell therapy] and bispecifics.”
One big challenge is that CAR-targeted antigens in T-cell blood cancers are shared by both normal and malignant T-cells, he said. That poses a risk during therapy that the engineered cells will target each other with “disastrous consequences.”
Research by his team and others have shown that gene editing can help the cells to stop engaging in “fratricide,” Dr. Mamonkin said.
The problem is “it’s much easier to do gene editing on the bench and much harder to translate it into the clinic,” especially in light of limitations posed by the Food and Drug administration, he said. “We started to think about alternative methods to get this approach to the clinic.”
One strategy is to use pharmacologic inhibition via the Bruton’s tyrosine kinase inhibitors ibrutinib and dasatinib to mute the tendency of CAR T toward self-destruction. When tested in mice, “the unedited cells not just persisted, they expanded with sustained anti-leukemic activity and significantly prolonged their lives even more than the knock-out [gene-edited] cells.”
The research has now moved to human subjects. In 2021, researchers at Texas Children’s Hospital and Houston Methodist Hospital launched a clinical trial to test CD7 CAR T-cell therapy with CD28 in 21 patients with CD7-positive T-cell lymphoma. The initial part of the transplant-enabling CRIMSON-NE study is expected to be completed by mid-2024, and patients will be followed for 15 years.
Early results show that CD7 CAR T-cells have persisted in the blood of patients over weeks and months, Dr. Mamonkin said. In eight patients, “we’re seeing good evidence of activity,” with two patients reaching complete remissions.
The findings suggest that CD7 can be targeted in T-cell malignancies, he said. What about CD5? A similar study known as MAGENTA is testing CD5 CAR T-cell therapy with CD28 in T-cell leukemia and lymphoma in 42 patients. The phase 1 trial began in 2017. It’s expected to be completed by 2024 and to track patients for 15 years.
Results so far have been positive with complete remission achieved in three of nine patients with T-cell lymphoma; two remained in remission for more than 4 years.
Results in T-cell ALL improved after researchers adjusted the manufacturing of the cells. As for durability in these patients, “we try to bridge them to transplantation as soon as possible.”
As for side effects overall, there wasn’t much immune effector cell-associated neurotoxicity syndrome, and the CD7 approach seems to be more inflammatory, he said.
The presentation didn’t address the potential cost of the therapies. CAR T-cell therapy can cost between $500,000 and $1 million. Medicare covers it, but Medicaid may not depending on the state, and insurers may refuse to pay for it.
Dr. Mamonkin disclosed ties with Allogene, Amgen, Fate, Galapagos, March Bio, and NKILT.
As Baylor College of Medicine’s Max Mamonkin, PhD, noted in a presentation, patients with conditions such as T-cell lymphoma and T-cell acute lymphoblastic leukemia (ALL) have limited treatment options and grim prognoses. “This is an area with huge unmet need,” he said. “They don’t have options that patients with B-cell malignancies have, like [CAR T-cell therapy] and bispecifics.”
One big challenge is that CAR-targeted antigens in T-cell blood cancers are shared by both normal and malignant T-cells, he said. That poses a risk during therapy that the engineered cells will target each other with “disastrous consequences.”
Research by his team and others have shown that gene editing can help the cells to stop engaging in “fratricide,” Dr. Mamonkin said.
The problem is “it’s much easier to do gene editing on the bench and much harder to translate it into the clinic,” especially in light of limitations posed by the Food and Drug administration, he said. “We started to think about alternative methods to get this approach to the clinic.”
One strategy is to use pharmacologic inhibition via the Bruton’s tyrosine kinase inhibitors ibrutinib and dasatinib to mute the tendency of CAR T toward self-destruction. When tested in mice, “the unedited cells not just persisted, they expanded with sustained anti-leukemic activity and significantly prolonged their lives even more than the knock-out [gene-edited] cells.”
The research has now moved to human subjects. In 2021, researchers at Texas Children’s Hospital and Houston Methodist Hospital launched a clinical trial to test CD7 CAR T-cell therapy with CD28 in 21 patients with CD7-positive T-cell lymphoma. The initial part of the transplant-enabling CRIMSON-NE study is expected to be completed by mid-2024, and patients will be followed for 15 years.
Early results show that CD7 CAR T-cells have persisted in the blood of patients over weeks and months, Dr. Mamonkin said. In eight patients, “we’re seeing good evidence of activity,” with two patients reaching complete remissions.
The findings suggest that CD7 can be targeted in T-cell malignancies, he said. What about CD5? A similar study known as MAGENTA is testing CD5 CAR T-cell therapy with CD28 in T-cell leukemia and lymphoma in 42 patients. The phase 1 trial began in 2017. It’s expected to be completed by 2024 and to track patients for 15 years.
Results so far have been positive with complete remission achieved in three of nine patients with T-cell lymphoma; two remained in remission for more than 4 years.
Results in T-cell ALL improved after researchers adjusted the manufacturing of the cells. As for durability in these patients, “we try to bridge them to transplantation as soon as possible.”
As for side effects overall, there wasn’t much immune effector cell-associated neurotoxicity syndrome, and the CD7 approach seems to be more inflammatory, he said.
The presentation didn’t address the potential cost of the therapies. CAR T-cell therapy can cost between $500,000 and $1 million. Medicare covers it, but Medicaid may not depending on the state, and insurers may refuse to pay for it.
Dr. Mamonkin disclosed ties with Allogene, Amgen, Fate, Galapagos, March Bio, and NKILT.
FROM SITC 2023
DLBCL treatment options: CAR T outperforms ASCT
NEW YORK – according to evidence presented at the 2023 Lymphoma, Leukemia, and Myeloma Congress.
DLBCL is characterized by the National Institutes of Health as an aggressive malignancy and the most common lymphoma. Research presented at the conference indicated that 60%70% of patients were cured with six to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP).
“In the past, if a relapsed of refractory DLBCL patient couldn’t get a transplant, they were likely headed for palliative care. CAR T-cell therapy is no longer experimental. Not only can we offer it to patients who are ineligible for transplant (and manage the side effects), the treatment has proven to offer better overall survival and cure rates, even in patients who eligible for ASCT,” said presenter Jason Westin, MD, director of the lymphoma clinical research program at the University of Texas MD Anderson Cancer Center, Houston.
The ZUMA-7 phase 3trial among patients with early r/r DLBCL demonstrated the superiority of CAR T-cell therapy with the agent, axicabtagene ciloleucel (YESCARTA, Kita Pharma) versus standard of care (chemoimmunotherapy followed by high-dose chemotherapy and ASCT). Those in the axicabtagene ciloleucel (axi-cel) group had a median progression free survival (PFS) of 14.7 months and an estimated 4-year overall survival (OS) rate of 54.6% compared to 3.7 months and 46% in the control group.
Patients treated with axi-cel experienced a higher rate of adverse events (AE) grade 3 of higher, compared with the ACST group (91% vs. 83%) Furthermore, patients who received axi-cel had cytokine release syndrome (6%) and neurologic events in (21%) grade 3 or higher, compared with 0% and less than 1% in the ASCT group.
At the conference, Dr. Westin’s copanelist Jennifer Amengual, MD, of Columbia University Irving Medical Center, New York, interpreted the data on adverse events (AEs) from ZUMA-7 to mean that if a patient is especially susceptible to CAR T side effects, then ASCT could be preferred. She also outlined a second strategy that shows promise when a patient has either failed CAR T and ASCT or whose frailty demands an approach that avoids AEs.
Dr. Amengual cited a study in which patients with r/r DLBCL were treated with the bispecific antibody glofitamab (Columvi/Roche), which induced a complete response in 39% of patients at a median follow-up of 12.6 months and a 12-month PFS rate of 37%. Those treated with the agent experienced cytokine release syndrome and neurologic events grade 3 or higher, at a rate of 4% and 3% respectively.
“Efforts to make off-the-shelf CAR T therapy are ongoing. With some fine-tuning the PFS and OS with bispecific antibodies will likely approach or exceed both CAR T and ACST. The fact that they could come right off the shelf, rather than having to be tailor made for each patient, gives them a huge advantage in terms of cost and availability, while maintaining what appears to be an excellent safety profile” said Morton Colman, MD, professor of medicine at Weill Cornell Medicine, New York, and chair of the 2023 Lymphoma, Leukemia, and Myeloma Congress.
Dr. Amengual disclosed ties with Astra Zeneca and Incyte. Dr. Westin reported ties with Abbie, ADC therapeutics, AstraZeneca, Bristol-Myers Squibb, Genentech, GenMad, Hanssen, Kite/Gilead, Morphosys/Incyte, Novartis, Nurix, Regeneron, and SeaGen. Dr. Coleman had no disclosures.
NEW YORK – according to evidence presented at the 2023 Lymphoma, Leukemia, and Myeloma Congress.
DLBCL is characterized by the National Institutes of Health as an aggressive malignancy and the most common lymphoma. Research presented at the conference indicated that 60%70% of patients were cured with six to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP).
“In the past, if a relapsed of refractory DLBCL patient couldn’t get a transplant, they were likely headed for palliative care. CAR T-cell therapy is no longer experimental. Not only can we offer it to patients who are ineligible for transplant (and manage the side effects), the treatment has proven to offer better overall survival and cure rates, even in patients who eligible for ASCT,” said presenter Jason Westin, MD, director of the lymphoma clinical research program at the University of Texas MD Anderson Cancer Center, Houston.
The ZUMA-7 phase 3trial among patients with early r/r DLBCL demonstrated the superiority of CAR T-cell therapy with the agent, axicabtagene ciloleucel (YESCARTA, Kita Pharma) versus standard of care (chemoimmunotherapy followed by high-dose chemotherapy and ASCT). Those in the axicabtagene ciloleucel (axi-cel) group had a median progression free survival (PFS) of 14.7 months and an estimated 4-year overall survival (OS) rate of 54.6% compared to 3.7 months and 46% in the control group.
Patients treated with axi-cel experienced a higher rate of adverse events (AE) grade 3 of higher, compared with the ACST group (91% vs. 83%) Furthermore, patients who received axi-cel had cytokine release syndrome (6%) and neurologic events in (21%) grade 3 or higher, compared with 0% and less than 1% in the ASCT group.
At the conference, Dr. Westin’s copanelist Jennifer Amengual, MD, of Columbia University Irving Medical Center, New York, interpreted the data on adverse events (AEs) from ZUMA-7 to mean that if a patient is especially susceptible to CAR T side effects, then ASCT could be preferred. She also outlined a second strategy that shows promise when a patient has either failed CAR T and ASCT or whose frailty demands an approach that avoids AEs.
Dr. Amengual cited a study in which patients with r/r DLBCL were treated with the bispecific antibody glofitamab (Columvi/Roche), which induced a complete response in 39% of patients at a median follow-up of 12.6 months and a 12-month PFS rate of 37%. Those treated with the agent experienced cytokine release syndrome and neurologic events grade 3 or higher, at a rate of 4% and 3% respectively.
“Efforts to make off-the-shelf CAR T therapy are ongoing. With some fine-tuning the PFS and OS with bispecific antibodies will likely approach or exceed both CAR T and ACST. The fact that they could come right off the shelf, rather than having to be tailor made for each patient, gives them a huge advantage in terms of cost and availability, while maintaining what appears to be an excellent safety profile” said Morton Colman, MD, professor of medicine at Weill Cornell Medicine, New York, and chair of the 2023 Lymphoma, Leukemia, and Myeloma Congress.
Dr. Amengual disclosed ties with Astra Zeneca and Incyte. Dr. Westin reported ties with Abbie, ADC therapeutics, AstraZeneca, Bristol-Myers Squibb, Genentech, GenMad, Hanssen, Kite/Gilead, Morphosys/Incyte, Novartis, Nurix, Regeneron, and SeaGen. Dr. Coleman had no disclosures.
NEW YORK – according to evidence presented at the 2023 Lymphoma, Leukemia, and Myeloma Congress.
DLBCL is characterized by the National Institutes of Health as an aggressive malignancy and the most common lymphoma. Research presented at the conference indicated that 60%70% of patients were cured with six to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP).
“In the past, if a relapsed of refractory DLBCL patient couldn’t get a transplant, they were likely headed for palliative care. CAR T-cell therapy is no longer experimental. Not only can we offer it to patients who are ineligible for transplant (and manage the side effects), the treatment has proven to offer better overall survival and cure rates, even in patients who eligible for ASCT,” said presenter Jason Westin, MD, director of the lymphoma clinical research program at the University of Texas MD Anderson Cancer Center, Houston.
The ZUMA-7 phase 3trial among patients with early r/r DLBCL demonstrated the superiority of CAR T-cell therapy with the agent, axicabtagene ciloleucel (YESCARTA, Kita Pharma) versus standard of care (chemoimmunotherapy followed by high-dose chemotherapy and ASCT). Those in the axicabtagene ciloleucel (axi-cel) group had a median progression free survival (PFS) of 14.7 months and an estimated 4-year overall survival (OS) rate of 54.6% compared to 3.7 months and 46% in the control group.
Patients treated with axi-cel experienced a higher rate of adverse events (AE) grade 3 of higher, compared with the ACST group (91% vs. 83%) Furthermore, patients who received axi-cel had cytokine release syndrome (6%) and neurologic events in (21%) grade 3 or higher, compared with 0% and less than 1% in the ASCT group.
At the conference, Dr. Westin’s copanelist Jennifer Amengual, MD, of Columbia University Irving Medical Center, New York, interpreted the data on adverse events (AEs) from ZUMA-7 to mean that if a patient is especially susceptible to CAR T side effects, then ASCT could be preferred. She also outlined a second strategy that shows promise when a patient has either failed CAR T and ASCT or whose frailty demands an approach that avoids AEs.
Dr. Amengual cited a study in which patients with r/r DLBCL were treated with the bispecific antibody glofitamab (Columvi/Roche), which induced a complete response in 39% of patients at a median follow-up of 12.6 months and a 12-month PFS rate of 37%. Those treated with the agent experienced cytokine release syndrome and neurologic events grade 3 or higher, at a rate of 4% and 3% respectively.
“Efforts to make off-the-shelf CAR T therapy are ongoing. With some fine-tuning the PFS and OS with bispecific antibodies will likely approach or exceed both CAR T and ACST. The fact that they could come right off the shelf, rather than having to be tailor made for each patient, gives them a huge advantage in terms of cost and availability, while maintaining what appears to be an excellent safety profile” said Morton Colman, MD, professor of medicine at Weill Cornell Medicine, New York, and chair of the 2023 Lymphoma, Leukemia, and Myeloma Congress.
Dr. Amengual disclosed ties with Astra Zeneca and Incyte. Dr. Westin reported ties with Abbie, ADC therapeutics, AstraZeneca, Bristol-Myers Squibb, Genentech, GenMad, Hanssen, Kite/Gilead, Morphosys/Incyte, Novartis, Nurix, Regeneron, and SeaGen. Dr. Coleman had no disclosures.
AT LLM CONGRESS 2023
Frontline myeloma treatments: ASCT vs. CAR T
“In an otherwise healthy treatment-naive patient with multiple myeloma, to ensure the best chances of overall survival, I would always recommend standard of care consolidation therapy of chemotherapy + ASCT,” said Sergio Giralt, MD, of New York’s Memorial Sloan Kettering Cancer Center, debating the merits of ASCT versus CAR T as consolidation therapy at the Lymphoma, Leukemia & Myeloma (LLM) Congress 2023 in New York.
Final results from the phase II GRIFFIN trial highlight the benchmarks that CAR T-cell therapy would need to reach to achieve equivalence with ASCT. At a 4-year follow-up, newly diagnosed MM patients who received daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) followed by ASCT + D-RVd consolidation, and daratumumab maintenance, had a progression-free survival (PFS) rate of 87.3%, 92.7% overall survival (OS) rate, and 50% achieved minimal residual disease negativity.
Dr. Adriana Rossi, MD, assistant professor of medicine, Icahn School of Medicine at Mount Sinai, New York, cited a convergence of evidence suggesting that CAR T could achieve impressive results as a consolidation therapy in fit patients with MM, including: CARTITUDE 1 and CARTITUDE 4, which studied CAR T in RR MM patients. However, due to the fact that no head-to-head study of CAR T vs. ASCT as consolidation therapy in otherwise healthy MM patients exists, “There is not enough long-term data to support the equivalence CAR T with ASCT,” Dr. Giralt concluded.
Dr. Rossi further advocated for considering CAR T as a consolidation treatment because of the risks of secondary malignancies associated with ACST maintenance regimens.
Dr. Giralt rebutted this argument by citing data about averse events (AE) in studies of CAR-T therapies in RR MM patients like KarMMa-2, in which grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 94.6%, 45.9%, and 37.8% of patients respectively. Furthermore, 2 of 37 patients in KarMMA died (1 pneumonia, 1 pseudomonal sepsis), while rates of death from AEs related to ASCT occur in less than 1% of patients, according to Dr. Giralt.
Beyond a dearth of evidence thus far about the long term PFS, OS, and safety profile superiority of CAR-T therapies, compared with ASCT in treatment-naive MM patients, Dr. Giralt also noted the facts that CAR T-cell therapies are expensive and require manufacturing infrastructure also demonstrate that they cannot be easily adopted everywhere, even as a third-line therapy.
“In many places like Morocco, where I practice, we do not have access to CAR-T therapies,” said Sadia Zafad, MD, of the Clinique Al Madina Hematology and Oncology Center in Casablanca, Morocco. Dr. Zafad attended the debate.
A lack of access to CAR T is also a problem in the United States, where wait times for the therapy can stretch up to 6 months, getting insurance approval is challenging, and many patients simply don’t live near a center where CAR T-cell therapy is available. Citing all these factors, Dr. Giralt concluded: “Even if CAR T can be shown to have the same results as transplant, it is much more resource-intensive than transplant, and insurers are going to start saying there’s no necessary benefit. We have yet to use value as a primary end point, but as cancer care gets more and more expensive, that’s going to come up more, for CAR T and other novel therapies.”
Dr. Giralt reported relationships with Actinuum, Amgen, BMS, Celgene, Crisper, J&J, Jazz, Kite, Miltenyi, Novartis, Sanofi, and Takeda. Dr. Rossi disclosed ties with Adaptive, BMS, Celgene, JNJ, Sanofi & Genzyme. Dr. Zafad reported no disclosures.
“In an otherwise healthy treatment-naive patient with multiple myeloma, to ensure the best chances of overall survival, I would always recommend standard of care consolidation therapy of chemotherapy + ASCT,” said Sergio Giralt, MD, of New York’s Memorial Sloan Kettering Cancer Center, debating the merits of ASCT versus CAR T as consolidation therapy at the Lymphoma, Leukemia & Myeloma (LLM) Congress 2023 in New York.
Final results from the phase II GRIFFIN trial highlight the benchmarks that CAR T-cell therapy would need to reach to achieve equivalence with ASCT. At a 4-year follow-up, newly diagnosed MM patients who received daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) followed by ASCT + D-RVd consolidation, and daratumumab maintenance, had a progression-free survival (PFS) rate of 87.3%, 92.7% overall survival (OS) rate, and 50% achieved minimal residual disease negativity.
Dr. Adriana Rossi, MD, assistant professor of medicine, Icahn School of Medicine at Mount Sinai, New York, cited a convergence of evidence suggesting that CAR T could achieve impressive results as a consolidation therapy in fit patients with MM, including: CARTITUDE 1 and CARTITUDE 4, which studied CAR T in RR MM patients. However, due to the fact that no head-to-head study of CAR T vs. ASCT as consolidation therapy in otherwise healthy MM patients exists, “There is not enough long-term data to support the equivalence CAR T with ASCT,” Dr. Giralt concluded.
Dr. Rossi further advocated for considering CAR T as a consolidation treatment because of the risks of secondary malignancies associated with ACST maintenance regimens.
Dr. Giralt rebutted this argument by citing data about averse events (AE) in studies of CAR-T therapies in RR MM patients like KarMMa-2, in which grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 94.6%, 45.9%, and 37.8% of patients respectively. Furthermore, 2 of 37 patients in KarMMA died (1 pneumonia, 1 pseudomonal sepsis), while rates of death from AEs related to ASCT occur in less than 1% of patients, according to Dr. Giralt.
Beyond a dearth of evidence thus far about the long term PFS, OS, and safety profile superiority of CAR-T therapies, compared with ASCT in treatment-naive MM patients, Dr. Giralt also noted the facts that CAR T-cell therapies are expensive and require manufacturing infrastructure also demonstrate that they cannot be easily adopted everywhere, even as a third-line therapy.
“In many places like Morocco, where I practice, we do not have access to CAR-T therapies,” said Sadia Zafad, MD, of the Clinique Al Madina Hematology and Oncology Center in Casablanca, Morocco. Dr. Zafad attended the debate.
A lack of access to CAR T is also a problem in the United States, where wait times for the therapy can stretch up to 6 months, getting insurance approval is challenging, and many patients simply don’t live near a center where CAR T-cell therapy is available. Citing all these factors, Dr. Giralt concluded: “Even if CAR T can be shown to have the same results as transplant, it is much more resource-intensive than transplant, and insurers are going to start saying there’s no necessary benefit. We have yet to use value as a primary end point, but as cancer care gets more and more expensive, that’s going to come up more, for CAR T and other novel therapies.”
Dr. Giralt reported relationships with Actinuum, Amgen, BMS, Celgene, Crisper, J&J, Jazz, Kite, Miltenyi, Novartis, Sanofi, and Takeda. Dr. Rossi disclosed ties with Adaptive, BMS, Celgene, JNJ, Sanofi & Genzyme. Dr. Zafad reported no disclosures.
“In an otherwise healthy treatment-naive patient with multiple myeloma, to ensure the best chances of overall survival, I would always recommend standard of care consolidation therapy of chemotherapy + ASCT,” said Sergio Giralt, MD, of New York’s Memorial Sloan Kettering Cancer Center, debating the merits of ASCT versus CAR T as consolidation therapy at the Lymphoma, Leukemia & Myeloma (LLM) Congress 2023 in New York.
Final results from the phase II GRIFFIN trial highlight the benchmarks that CAR T-cell therapy would need to reach to achieve equivalence with ASCT. At a 4-year follow-up, newly diagnosed MM patients who received daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) followed by ASCT + D-RVd consolidation, and daratumumab maintenance, had a progression-free survival (PFS) rate of 87.3%, 92.7% overall survival (OS) rate, and 50% achieved minimal residual disease negativity.
Dr. Adriana Rossi, MD, assistant professor of medicine, Icahn School of Medicine at Mount Sinai, New York, cited a convergence of evidence suggesting that CAR T could achieve impressive results as a consolidation therapy in fit patients with MM, including: CARTITUDE 1 and CARTITUDE 4, which studied CAR T in RR MM patients. However, due to the fact that no head-to-head study of CAR T vs. ASCT as consolidation therapy in otherwise healthy MM patients exists, “There is not enough long-term data to support the equivalence CAR T with ASCT,” Dr. Giralt concluded.
Dr. Rossi further advocated for considering CAR T as a consolidation treatment because of the risks of secondary malignancies associated with ACST maintenance regimens.
Dr. Giralt rebutted this argument by citing data about averse events (AE) in studies of CAR-T therapies in RR MM patients like KarMMa-2, in which grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 94.6%, 45.9%, and 37.8% of patients respectively. Furthermore, 2 of 37 patients in KarMMA died (1 pneumonia, 1 pseudomonal sepsis), while rates of death from AEs related to ASCT occur in less than 1% of patients, according to Dr. Giralt.
Beyond a dearth of evidence thus far about the long term PFS, OS, and safety profile superiority of CAR-T therapies, compared with ASCT in treatment-naive MM patients, Dr. Giralt also noted the facts that CAR T-cell therapies are expensive and require manufacturing infrastructure also demonstrate that they cannot be easily adopted everywhere, even as a third-line therapy.
“In many places like Morocco, where I practice, we do not have access to CAR-T therapies,” said Sadia Zafad, MD, of the Clinique Al Madina Hematology and Oncology Center in Casablanca, Morocco. Dr. Zafad attended the debate.
A lack of access to CAR T is also a problem in the United States, where wait times for the therapy can stretch up to 6 months, getting insurance approval is challenging, and many patients simply don’t live near a center where CAR T-cell therapy is available. Citing all these factors, Dr. Giralt concluded: “Even if CAR T can be shown to have the same results as transplant, it is much more resource-intensive than transplant, and insurers are going to start saying there’s no necessary benefit. We have yet to use value as a primary end point, but as cancer care gets more and more expensive, that’s going to come up more, for CAR T and other novel therapies.”
Dr. Giralt reported relationships with Actinuum, Amgen, BMS, Celgene, Crisper, J&J, Jazz, Kite, Miltenyi, Novartis, Sanofi, and Takeda. Dr. Rossi disclosed ties with Adaptive, BMS, Celgene, JNJ, Sanofi & Genzyme. Dr. Zafad reported no disclosures.
AT LLM CONGRESS 2023
Dispelling clinicians’ misconceptions about sickle cell disease
Affecting more than 20 million people globally and 100,000 people nationwide, SCD is the most common inherited blood disorder in the United States. It occurs largely but not exclusively among people of African descent.
Patients with SCD develop crescent-shaped or “sickled” red blood cells that, unlike normally round cells, can potentially block blood flow and thus cause a host of problems ranging from a risk of stroke or infections to sometimes severe pain crises, called vaso-occlusive episodes.
To help ward off such complications, some key preventative measures and an array of therapies have become available in recent years: Newborn screening and prophylaxis, including the introduction of pneumococcal vaccines, have substantially reduced rates of invasive pneumococcal infection, which previously accounted for 32% of all causes of death in patients with SCD under the age of 20.
And while hydroxyurea was the only medication from 1998 to 2017 to alleviate acute pain episodes in SCD, newer options have become available in recent years, with l-glutamine, voxelotor, and crizanlizumab gaining FDA approval to further help prevent the episodes.
However, studies show that many if not most patients fail to receive adequate treatment, with one recent report indicating that, between 2016 and 2020, hydroxyurea was prescribed to fewer than 25% of patients with SCD, and fewer than 4% of people with the disease who experience chronic pain episodes had prescriptions for the newer FDA-approved drugs.
Myths and truths
To help clarify some common misconceptions that contribute to the problems, Lewis Hsu, MD, PhD, chief medical officer of the Sickle Cell Disease Association of America, detailed some of the most prevalent and persistent myths among clinicians about SCD:
Pain level
Myths: Firstly, that sickle cell pain is not that bad, and patients therefore don’t really need opioid pain treatment, and secondly, that sickle cell pain is measurable by lab tests, such as the number of sickled red blood cells on a blood smear, reticulocytes, or hemoglobin level.
Truths: “Sickle cell vaso-occlusive pain can be very severe – a 10 on a scale of 10 – but the pain is usually only known by subjective report,” said Dr. Hsu, a pediatric hematologist who serves as director of the Sickle Cell Center and professor of pediatrics for the University of Illinois at Chicago.
“No lab test can be used to measure pain,” he said. “Other lab tests can be abnormal, and some have statistical correlation with lifetime severity of disease course, but the lab tests are not for determination of acute level of pain or absence of pain.”
Blacks only
Myth: SCD only affects Black people.
Truth: People who have sickle cell disease from many ethnic backgrounds and skin colors.
“Around the Mediterranean, there are sickle cell patients from Greece, Turkey, Italy, and Spain. Some are blond and blue-eyed. People in India and Pakistan have sickle cell disease,” Dr. Hsu explained.
In addition, “people from the Arabian Peninsula have sickle cell disease; some Malaysians have sickle cell disease; one child who is about third generation in Hong Kong has sickle cell disease.”
Parental link
Myth: Sickle cell disease only occurs in individuals both of whose parents have the sickle gene.
Truth: “There are types of sickle cell disease [involving] a sickle cell gene from one parent and a gene for hemoglobin C from the other parent,” Dr. Hsu noted. “Others inherited one sickle gene [from one parent] and inherited from the other parent a gene for beta thalassemia. Others involve an inherited sickle gene and hemoglobin E; others have inherited one sickle gene and inherited a gene for hemoglobin D-Punjab, while others have sickle and hemoglobin O-Arab.”
Effects beyond pain
Myth: A person who is not having sickle cell pain is otherwise not significantly affected by their disease.
Truth: “Organs can be damaged silently every day,” Dr. Hsu said. “Kidney failure, retina damage, and pulmonary hypertension are the most notable of organ systems that can suffer damage for a long time without symptoms, then develop symptoms when it is too late to intervene.”
“For this reason, individuals with sickle cell disease should have regular expert care for health maintenance that is disease specific,” Dr. Hsu added.
Consult guidelines
One final concern is a basic failure to utilize critical information sources and guidelines, especially by primary care providers and/or other nonspecialists from whom patients with SCD may often seek treatment. “Awareness of these guidelines is low,” Dr. Hsu said.
Key resources that can be helpful include evidence-based guidelines developed by an expert panel of the National Heart, Lung, and Blood Institute, and the American Society of Hematology has a Pocket Guide app on management of sickle cell disease.
Another key resource being highlighted in September, which is National Sickle Cell Disease Awareness Month, is the NHLBI’s comprehensive website, providing information ranging from fact sheets on the disease and treatments to social media resources and inspiring stories of people with SCD.
“We are trying to bring more sickle cell information and case studies into medical school curricula, nursing curricula, social workers and community health workers awareness, [and] apps and online guidelines are proliferating,” Dr. Hsu says.
He goes on to say, “We need more recognition and resources from insurance providers that quality care for sickle cell disease is measured and rewarded.”
Dr. Hsu coauthored “Hope and Destiny: The Patient and Parent’s Guide to Sickle Cell Disease and Sickle Cell Trait.” He reported relationships with Novartis, Emmaus, Forma Therapeutic, Dupont/Nemours Children’s Hospital, Hilton Publishing, Asklepion, Bayer, CRISPR/Vertex, Cyclerion, Pfizer, and Aruvant.
Affecting more than 20 million people globally and 100,000 people nationwide, SCD is the most common inherited blood disorder in the United States. It occurs largely but not exclusively among people of African descent.
Patients with SCD develop crescent-shaped or “sickled” red blood cells that, unlike normally round cells, can potentially block blood flow and thus cause a host of problems ranging from a risk of stroke or infections to sometimes severe pain crises, called vaso-occlusive episodes.
To help ward off such complications, some key preventative measures and an array of therapies have become available in recent years: Newborn screening and prophylaxis, including the introduction of pneumococcal vaccines, have substantially reduced rates of invasive pneumococcal infection, which previously accounted for 32% of all causes of death in patients with SCD under the age of 20.
And while hydroxyurea was the only medication from 1998 to 2017 to alleviate acute pain episodes in SCD, newer options have become available in recent years, with l-glutamine, voxelotor, and crizanlizumab gaining FDA approval to further help prevent the episodes.
However, studies show that many if not most patients fail to receive adequate treatment, with one recent report indicating that, between 2016 and 2020, hydroxyurea was prescribed to fewer than 25% of patients with SCD, and fewer than 4% of people with the disease who experience chronic pain episodes had prescriptions for the newer FDA-approved drugs.
Myths and truths
To help clarify some common misconceptions that contribute to the problems, Lewis Hsu, MD, PhD, chief medical officer of the Sickle Cell Disease Association of America, detailed some of the most prevalent and persistent myths among clinicians about SCD:
Pain level
Myths: Firstly, that sickle cell pain is not that bad, and patients therefore don’t really need opioid pain treatment, and secondly, that sickle cell pain is measurable by lab tests, such as the number of sickled red blood cells on a blood smear, reticulocytes, or hemoglobin level.
Truths: “Sickle cell vaso-occlusive pain can be very severe – a 10 on a scale of 10 – but the pain is usually only known by subjective report,” said Dr. Hsu, a pediatric hematologist who serves as director of the Sickle Cell Center and professor of pediatrics for the University of Illinois at Chicago.
“No lab test can be used to measure pain,” he said. “Other lab tests can be abnormal, and some have statistical correlation with lifetime severity of disease course, but the lab tests are not for determination of acute level of pain or absence of pain.”
Blacks only
Myth: SCD only affects Black people.
Truth: People who have sickle cell disease from many ethnic backgrounds and skin colors.
“Around the Mediterranean, there are sickle cell patients from Greece, Turkey, Italy, and Spain. Some are blond and blue-eyed. People in India and Pakistan have sickle cell disease,” Dr. Hsu explained.
In addition, “people from the Arabian Peninsula have sickle cell disease; some Malaysians have sickle cell disease; one child who is about third generation in Hong Kong has sickle cell disease.”
Parental link
Myth: Sickle cell disease only occurs in individuals both of whose parents have the sickle gene.
Truth: “There are types of sickle cell disease [involving] a sickle cell gene from one parent and a gene for hemoglobin C from the other parent,” Dr. Hsu noted. “Others inherited one sickle gene [from one parent] and inherited from the other parent a gene for beta thalassemia. Others involve an inherited sickle gene and hemoglobin E; others have inherited one sickle gene and inherited a gene for hemoglobin D-Punjab, while others have sickle and hemoglobin O-Arab.”
Effects beyond pain
Myth: A person who is not having sickle cell pain is otherwise not significantly affected by their disease.
Truth: “Organs can be damaged silently every day,” Dr. Hsu said. “Kidney failure, retina damage, and pulmonary hypertension are the most notable of organ systems that can suffer damage for a long time without symptoms, then develop symptoms when it is too late to intervene.”
“For this reason, individuals with sickle cell disease should have regular expert care for health maintenance that is disease specific,” Dr. Hsu added.
Consult guidelines
One final concern is a basic failure to utilize critical information sources and guidelines, especially by primary care providers and/or other nonspecialists from whom patients with SCD may often seek treatment. “Awareness of these guidelines is low,” Dr. Hsu said.
Key resources that can be helpful include evidence-based guidelines developed by an expert panel of the National Heart, Lung, and Blood Institute, and the American Society of Hematology has a Pocket Guide app on management of sickle cell disease.
Another key resource being highlighted in September, which is National Sickle Cell Disease Awareness Month, is the NHLBI’s comprehensive website, providing information ranging from fact sheets on the disease and treatments to social media resources and inspiring stories of people with SCD.
“We are trying to bring more sickle cell information and case studies into medical school curricula, nursing curricula, social workers and community health workers awareness, [and] apps and online guidelines are proliferating,” Dr. Hsu says.
He goes on to say, “We need more recognition and resources from insurance providers that quality care for sickle cell disease is measured and rewarded.”
Dr. Hsu coauthored “Hope and Destiny: The Patient and Parent’s Guide to Sickle Cell Disease and Sickle Cell Trait.” He reported relationships with Novartis, Emmaus, Forma Therapeutic, Dupont/Nemours Children’s Hospital, Hilton Publishing, Asklepion, Bayer, CRISPR/Vertex, Cyclerion, Pfizer, and Aruvant.
Affecting more than 20 million people globally and 100,000 people nationwide, SCD is the most common inherited blood disorder in the United States. It occurs largely but not exclusively among people of African descent.
Patients with SCD develop crescent-shaped or “sickled” red blood cells that, unlike normally round cells, can potentially block blood flow and thus cause a host of problems ranging from a risk of stroke or infections to sometimes severe pain crises, called vaso-occlusive episodes.
To help ward off such complications, some key preventative measures and an array of therapies have become available in recent years: Newborn screening and prophylaxis, including the introduction of pneumococcal vaccines, have substantially reduced rates of invasive pneumococcal infection, which previously accounted for 32% of all causes of death in patients with SCD under the age of 20.
And while hydroxyurea was the only medication from 1998 to 2017 to alleviate acute pain episodes in SCD, newer options have become available in recent years, with l-glutamine, voxelotor, and crizanlizumab gaining FDA approval to further help prevent the episodes.
However, studies show that many if not most patients fail to receive adequate treatment, with one recent report indicating that, between 2016 and 2020, hydroxyurea was prescribed to fewer than 25% of patients with SCD, and fewer than 4% of people with the disease who experience chronic pain episodes had prescriptions for the newer FDA-approved drugs.
Myths and truths
To help clarify some common misconceptions that contribute to the problems, Lewis Hsu, MD, PhD, chief medical officer of the Sickle Cell Disease Association of America, detailed some of the most prevalent and persistent myths among clinicians about SCD:
Pain level
Myths: Firstly, that sickle cell pain is not that bad, and patients therefore don’t really need opioid pain treatment, and secondly, that sickle cell pain is measurable by lab tests, such as the number of sickled red blood cells on a blood smear, reticulocytes, or hemoglobin level.
Truths: “Sickle cell vaso-occlusive pain can be very severe – a 10 on a scale of 10 – but the pain is usually only known by subjective report,” said Dr. Hsu, a pediatric hematologist who serves as director of the Sickle Cell Center and professor of pediatrics for the University of Illinois at Chicago.
“No lab test can be used to measure pain,” he said. “Other lab tests can be abnormal, and some have statistical correlation with lifetime severity of disease course, but the lab tests are not for determination of acute level of pain or absence of pain.”
Blacks only
Myth: SCD only affects Black people.
Truth: People who have sickle cell disease from many ethnic backgrounds and skin colors.
“Around the Mediterranean, there are sickle cell patients from Greece, Turkey, Italy, and Spain. Some are blond and blue-eyed. People in India and Pakistan have sickle cell disease,” Dr. Hsu explained.
In addition, “people from the Arabian Peninsula have sickle cell disease; some Malaysians have sickle cell disease; one child who is about third generation in Hong Kong has sickle cell disease.”
Parental link
Myth: Sickle cell disease only occurs in individuals both of whose parents have the sickle gene.
Truth: “There are types of sickle cell disease [involving] a sickle cell gene from one parent and a gene for hemoglobin C from the other parent,” Dr. Hsu noted. “Others inherited one sickle gene [from one parent] and inherited from the other parent a gene for beta thalassemia. Others involve an inherited sickle gene and hemoglobin E; others have inherited one sickle gene and inherited a gene for hemoglobin D-Punjab, while others have sickle and hemoglobin O-Arab.”
Effects beyond pain
Myth: A person who is not having sickle cell pain is otherwise not significantly affected by their disease.
Truth: “Organs can be damaged silently every day,” Dr. Hsu said. “Kidney failure, retina damage, and pulmonary hypertension are the most notable of organ systems that can suffer damage for a long time without symptoms, then develop symptoms when it is too late to intervene.”
“For this reason, individuals with sickle cell disease should have regular expert care for health maintenance that is disease specific,” Dr. Hsu added.
Consult guidelines
One final concern is a basic failure to utilize critical information sources and guidelines, especially by primary care providers and/or other nonspecialists from whom patients with SCD may often seek treatment. “Awareness of these guidelines is low,” Dr. Hsu said.
Key resources that can be helpful include evidence-based guidelines developed by an expert panel of the National Heart, Lung, and Blood Institute, and the American Society of Hematology has a Pocket Guide app on management of sickle cell disease.
Another key resource being highlighted in September, which is National Sickle Cell Disease Awareness Month, is the NHLBI’s comprehensive website, providing information ranging from fact sheets on the disease and treatments to social media resources and inspiring stories of people with SCD.
“We are trying to bring more sickle cell information and case studies into medical school curricula, nursing curricula, social workers and community health workers awareness, [and] apps and online guidelines are proliferating,” Dr. Hsu says.
He goes on to say, “We need more recognition and resources from insurance providers that quality care for sickle cell disease is measured and rewarded.”
Dr. Hsu coauthored “Hope and Destiny: The Patient and Parent’s Guide to Sickle Cell Disease and Sickle Cell Trait.” He reported relationships with Novartis, Emmaus, Forma Therapeutic, Dupont/Nemours Children’s Hospital, Hilton Publishing, Asklepion, Bayer, CRISPR/Vertex, Cyclerion, Pfizer, and Aruvant.
FDA approves motixafortide for stem cell mobilization in myeloma
The success of autologous stem cell transplantation (ASCT) depends on adequate mobilization of stem cells during the treatment process. Collection of a sufficient number of stem cells to perform two transplantations is recommended. However, in up to 47% of patients, collecting target numbers of hematopoietic stem cells for ASCT after one apheresis session remains a challenge, BioLineRx explained in a press release today, announcing the approval.
The goal of combining motixafortide with filgrastim is to mobilize stem cells more reliably than filgrastim can alone, with fewer days of apheresis sessions and fewer doses of filgrastim.
“We believe [motixafortide] will play a critical role in addressing unmet needs and introduce a new treatment paradigm for” patients with multiple myeloma, CEO Philip Serlin said in the release.
The drug approval was based on the GENESIS trial, which randomized 122 patients to either motixafortide plus filgrastim or placebo plus filgrastim.
BioLineRx said the trial included patients considered representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with about 70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy.
Motixafortide plus filgrastim enabled 67.5% of patients to achieve the stem cell collection goal of 6 million or more CD34+ cells/kg within two apheresis sessions, versus 9.5% of patients receiving the placebo plus filgrastim regimen. Additionally, 92.5% of patients reached the stem cell collection goal in up to two apheresis sessions in the motixafortide arm and 21.4% in the placebo arm.
However, “the data are descriptive and were not statistically powered nor prespecified. The information should be cautiously interpreted,” the company said.
Serious adverse reactions occurred in 5.4% of patients in the motixafortide arm, including vomiting, injection-site reaction, hypersensitivity reaction, injection-site cellulitis, hypokalemia, and hypoxia. The most common adverse reactions, occurring in more than 20% of patients, were injection site reactions (pain, erythema, and pruritus), pruritus, flushing, and back pain.
Labeling for the subcutaneous injection is available online.
A version of this article first appeared on Medscape.com.
The success of autologous stem cell transplantation (ASCT) depends on adequate mobilization of stem cells during the treatment process. Collection of a sufficient number of stem cells to perform two transplantations is recommended. However, in up to 47% of patients, collecting target numbers of hematopoietic stem cells for ASCT after one apheresis session remains a challenge, BioLineRx explained in a press release today, announcing the approval.
The goal of combining motixafortide with filgrastim is to mobilize stem cells more reliably than filgrastim can alone, with fewer days of apheresis sessions and fewer doses of filgrastim.
“We believe [motixafortide] will play a critical role in addressing unmet needs and introduce a new treatment paradigm for” patients with multiple myeloma, CEO Philip Serlin said in the release.
The drug approval was based on the GENESIS trial, which randomized 122 patients to either motixafortide plus filgrastim or placebo plus filgrastim.
BioLineRx said the trial included patients considered representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with about 70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy.
Motixafortide plus filgrastim enabled 67.5% of patients to achieve the stem cell collection goal of 6 million or more CD34+ cells/kg within two apheresis sessions, versus 9.5% of patients receiving the placebo plus filgrastim regimen. Additionally, 92.5% of patients reached the stem cell collection goal in up to two apheresis sessions in the motixafortide arm and 21.4% in the placebo arm.
However, “the data are descriptive and were not statistically powered nor prespecified. The information should be cautiously interpreted,” the company said.
Serious adverse reactions occurred in 5.4% of patients in the motixafortide arm, including vomiting, injection-site reaction, hypersensitivity reaction, injection-site cellulitis, hypokalemia, and hypoxia. The most common adverse reactions, occurring in more than 20% of patients, were injection site reactions (pain, erythema, and pruritus), pruritus, flushing, and back pain.
Labeling for the subcutaneous injection is available online.
A version of this article first appeared on Medscape.com.
The success of autologous stem cell transplantation (ASCT) depends on adequate mobilization of stem cells during the treatment process. Collection of a sufficient number of stem cells to perform two transplantations is recommended. However, in up to 47% of patients, collecting target numbers of hematopoietic stem cells for ASCT after one apheresis session remains a challenge, BioLineRx explained in a press release today, announcing the approval.
The goal of combining motixafortide with filgrastim is to mobilize stem cells more reliably than filgrastim can alone, with fewer days of apheresis sessions and fewer doses of filgrastim.
“We believe [motixafortide] will play a critical role in addressing unmet needs and introduce a new treatment paradigm for” patients with multiple myeloma, CEO Philip Serlin said in the release.
The drug approval was based on the GENESIS trial, which randomized 122 patients to either motixafortide plus filgrastim or placebo plus filgrastim.
BioLineRx said the trial included patients considered representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with about 70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy.
Motixafortide plus filgrastim enabled 67.5% of patients to achieve the stem cell collection goal of 6 million or more CD34+ cells/kg within two apheresis sessions, versus 9.5% of patients receiving the placebo plus filgrastim regimen. Additionally, 92.5% of patients reached the stem cell collection goal in up to two apheresis sessions in the motixafortide arm and 21.4% in the placebo arm.
However, “the data are descriptive and were not statistically powered nor prespecified. The information should be cautiously interpreted,” the company said.
Serious adverse reactions occurred in 5.4% of patients in the motixafortide arm, including vomiting, injection-site reaction, hypersensitivity reaction, injection-site cellulitis, hypokalemia, and hypoxia. The most common adverse reactions, occurring in more than 20% of patients, were injection site reactions (pain, erythema, and pruritus), pruritus, flushing, and back pain.
Labeling for the subcutaneous injection is available online.
A version of this article first appeared on Medscape.com.