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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.