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High Marks for New CAR T Toxicity Grading Tool
“Hematotoxicity after CAR T is common and clinically relevant, but it also remains poorly understood [with] a high degree of heterogeneity in terms of grading its clinical management,” said first author Kai Rejeski, MD, in presenting on the findings at the 6th European CAR T-cell Meeting, held in Spain and jointly sponsored by the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA).
“We hope that this novel grading system helps with this by enabling harmonized reporting using the same nomenclature and allowing the comparison of the expected incidence rates of grade 3 or higher [hematological toxicities] across several disease entities and CAR T products,” said Dr. Rejeski, of the Adult BMT (Blood Marrow Transplant) and Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York City.
ICAHT Grading System
In a recent meta-analysis, Dr. Rejeski and his team found that infections are the cause of as many as 49% of non–relapse related deaths after CAR T-cell therapy, representing the most common cause of death and numbering significantly more than the more prominent causes of cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity (ICANS), which paradoxically have been the focus of significantly more research. In addition, the authors have reported substantial inconsistency among CAR T centers in the grading and management of the post–CAR T cytopenias that can cause those infections, underscoring the need for better guidelines.
“The narrative around CAR T toxicity has long centered on CRS and ICANS as novel and prototypical side effects with distinct management protocols,” Dr. Rejeski said in an interview. “However, it is cytopenias and the associated infections that drive nonrelapse mortality after CAR T.”
To address the need, the EHA and EBMT established the grading system for Immune Effector Cell–Associated HematoToxicity (ICAHT) that is applicable across disease types, indications, and treatment settings.
The details of the grading system were published in September 2023 in the journal Blood. The new system, which specifically focuses on neutrophil count and timing, importantly addresses the biphasic nature of ICAHT by distinguishing “early” ICAHT, occurring within 30 days of the CAR T administration, and “late” ICAHT, occurring more that 30 days following the treatment.
By contrast, conventional grading scales for CAR T–related cytopenias, such as the Common Terminology Criteria for Adverse Events (CTCAE) scale, “neither reflect the unique quality of post–CAR T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia,” the authors report in the study.
Real-World Evaluation
To assess the ICAHT grading system’s relevance in a real-world clinical setting of CAR T-cell therapy recipients, Dr. Rejeski and colleagues conducted a multicenter observational study, published in January 2024 in Blood Advances.
The study involved 549 patients at 12 international CAR T centers treated with BCMA- or CD19- directed CAR T therapy for relapsed/refractory B-cell malignancies.
Of the patients, 112 were treated for multiple myeloma (MM), 334 for large B cell lymphoma (LBCL), and 103 for mantle cell lymphoma (MCL).
Using the grading system, grade 3 (severe) or 4 (life-threatening) ICAHT (n = 125), was found to be strongly associated with key factors including a cumulative duration of severe neutropenia (P < .0001), the presence of multilineage cytopenias, such as severe thrombocytopenia (90%, compared with 46% in nonsevere ICAHT) and severe anemia (92% vs 49%; both P < .001), as well as the use of platelet and red blood cell transfusions.
Grade 3 or higher ICAHT was more common in patients with MCL (28%), compared with LBCL (23%) and MM (15%).
Key factors at baseline that were independently associated with severe ICAHT after multivariate adjustment included the presence of bone marrow infiltration, increased serum LDH levels, elevated CAR-HEMATOTOX scores (all P < .001), and receipt of CD28z costimulatory domain products, including axi-cel or brexu-cel (P = .01).
Those with grade 3 or higher ICAHT scores had a significantly higher rate of severe infections, compared with lower ICAHT scores (49% vs 13%; P < .0001), as well as increased nonrelapse mortality (14% vs 4.5%; P < .0001), primarily attributable to fatal infections.
Survival outcomes were also worse with grade 3 or higher ICAHT, including significantly lower rates of 1-year progression-free survival (35% vs 51%) and 1-year overall survival (52% vs 73%; both P < .0001).
Grade 3 or higher ICAHT was also significantly associated with prolonged hospital stays (median 21 vs 16 days; P < .0001).
However, contrary to findings from some previous studies, the current study showed no association between ICAHT severity and the prior administration of autologous stem cell transplant.
The number of prior treatment lines was not associated with grade 3 or higher ICAHT. However, grade 3 or higher CRS was more common as a cotoxicity (15% vs 5% without severe ICAHT), as was severe ICANS (26% vs 13%; both P < .001).
Notably, ICAHT grading showed superiority in the prediction of severe infections, compared with CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant).
While mild to moderate toxicity after CAR T-cell therapy has been associated with more favorable outcomes, the poor survival rates associated with severe ICAHT “underscore that high-grade toxicity and inferior treatment outcomes often go hand-in-hand,” the authors write.
Conversely, “the patients with grade 1 or 2 ICAHT exhibited excellent treatment outcomes in our study,” they point out.
Recommendations in Clinical Practice
For clinical guidance, the ICAHT grading system provides best practice recommendations based on severity for diagnostic work-up and management, such as measures including use of granulocyte-colony stimulating factor (G-CSF), anti-infective prophylaxis and stem cell boosts.
The authors add that preinfusion scoring systems, including the CAR-HEMATOTOX prognostic score, may be optimized by ICAHT grading in terms of modeling for severe or life-threatening ICAHT as an important endpoint.
“We have had an absence of the standardized severity-based guidelines that we know very well for CRS and ICANS, both in terms of the diagnostic work-up and the grading but also the management,” Dr. Rejeski said at the meeting.
“We hope that the new ICAHT grading focuses future research efforts to not only understand this important side effect better, but also develop specific management strategies that mitigate the risk of infections in high-risk patients,” Dr. Rejeski added.
“The multiply validated CAR-HEMATOTOX score, assessed at time of lymphodepletion, may be helpful in this regard,” he added.
An accompanying editorial published with the guidelines underscored that “this is the first such guideline by a major organization and is a much-needed development for the management of this important CAR T-cell–associated toxicity.”
The improved standardized reporting of ICAHT “could also inform hematotoxicity management protocols,” said the editorial authors, David Qualls, MD, of the Memorial Sloan Kettering Cancer Center in New York City and Caron Jacobson, MD, of the Dana-Farber Cancer Institute, in Boston, Massachusetts.
“While providing comprehensive recommendations for ICAHT, the EHA/EBMT guidelines also highlight important gaps in our current knowledge of ICAHT, which are significant,” the editorial authors add.
Further commenting, Ulrich Jaeger, MD, a professor of hematology at the Medical University of Vienna, Vienna, Austria, agreed that the research fills an important need in post–CAR T-cell therapy management.
“Dr. Rejeski´s work is really seminal in the field and confirmed by validation cohorts in other centers,” he said in an interview. “I think the story is absolutely clear. It will be of increasing importance, with more patients surviving. [The system] will have to be adapted to novel indications as well.”
Dr. Rejeski disclosed ties with Kite/Gilead, Novartis, GMS/Celgene, and Pierre-Fabre. Jaeger reports relationships with Novartis, Gilead Sciences, Celgene/BMS, Janssen, Roche, Miltenyi Biotec, and Innovative Medicines Initiative.
“Hematotoxicity after CAR T is common and clinically relevant, but it also remains poorly understood [with] a high degree of heterogeneity in terms of grading its clinical management,” said first author Kai Rejeski, MD, in presenting on the findings at the 6th European CAR T-cell Meeting, held in Spain and jointly sponsored by the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA).
“We hope that this novel grading system helps with this by enabling harmonized reporting using the same nomenclature and allowing the comparison of the expected incidence rates of grade 3 or higher [hematological toxicities] across several disease entities and CAR T products,” said Dr. Rejeski, of the Adult BMT (Blood Marrow Transplant) and Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York City.
ICAHT Grading System
In a recent meta-analysis, Dr. Rejeski and his team found that infections are the cause of as many as 49% of non–relapse related deaths after CAR T-cell therapy, representing the most common cause of death and numbering significantly more than the more prominent causes of cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity (ICANS), which paradoxically have been the focus of significantly more research. In addition, the authors have reported substantial inconsistency among CAR T centers in the grading and management of the post–CAR T cytopenias that can cause those infections, underscoring the need for better guidelines.
“The narrative around CAR T toxicity has long centered on CRS and ICANS as novel and prototypical side effects with distinct management protocols,” Dr. Rejeski said in an interview. “However, it is cytopenias and the associated infections that drive nonrelapse mortality after CAR T.”
To address the need, the EHA and EBMT established the grading system for Immune Effector Cell–Associated HematoToxicity (ICAHT) that is applicable across disease types, indications, and treatment settings.
The details of the grading system were published in September 2023 in the journal Blood. The new system, which specifically focuses on neutrophil count and timing, importantly addresses the biphasic nature of ICAHT by distinguishing “early” ICAHT, occurring within 30 days of the CAR T administration, and “late” ICAHT, occurring more that 30 days following the treatment.
By contrast, conventional grading scales for CAR T–related cytopenias, such as the Common Terminology Criteria for Adverse Events (CTCAE) scale, “neither reflect the unique quality of post–CAR T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia,” the authors report in the study.
Real-World Evaluation
To assess the ICAHT grading system’s relevance in a real-world clinical setting of CAR T-cell therapy recipients, Dr. Rejeski and colleagues conducted a multicenter observational study, published in January 2024 in Blood Advances.
The study involved 549 patients at 12 international CAR T centers treated with BCMA- or CD19- directed CAR T therapy for relapsed/refractory B-cell malignancies.
Of the patients, 112 were treated for multiple myeloma (MM), 334 for large B cell lymphoma (LBCL), and 103 for mantle cell lymphoma (MCL).
Using the grading system, grade 3 (severe) or 4 (life-threatening) ICAHT (n = 125), was found to be strongly associated with key factors including a cumulative duration of severe neutropenia (P < .0001), the presence of multilineage cytopenias, such as severe thrombocytopenia (90%, compared with 46% in nonsevere ICAHT) and severe anemia (92% vs 49%; both P < .001), as well as the use of platelet and red blood cell transfusions.
Grade 3 or higher ICAHT was more common in patients with MCL (28%), compared with LBCL (23%) and MM (15%).
Key factors at baseline that were independently associated with severe ICAHT after multivariate adjustment included the presence of bone marrow infiltration, increased serum LDH levels, elevated CAR-HEMATOTOX scores (all P < .001), and receipt of CD28z costimulatory domain products, including axi-cel or brexu-cel (P = .01).
Those with grade 3 or higher ICAHT scores had a significantly higher rate of severe infections, compared with lower ICAHT scores (49% vs 13%; P < .0001), as well as increased nonrelapse mortality (14% vs 4.5%; P < .0001), primarily attributable to fatal infections.
Survival outcomes were also worse with grade 3 or higher ICAHT, including significantly lower rates of 1-year progression-free survival (35% vs 51%) and 1-year overall survival (52% vs 73%; both P < .0001).
Grade 3 or higher ICAHT was also significantly associated with prolonged hospital stays (median 21 vs 16 days; P < .0001).
However, contrary to findings from some previous studies, the current study showed no association between ICAHT severity and the prior administration of autologous stem cell transplant.
The number of prior treatment lines was not associated with grade 3 or higher ICAHT. However, grade 3 or higher CRS was more common as a cotoxicity (15% vs 5% without severe ICAHT), as was severe ICANS (26% vs 13%; both P < .001).
Notably, ICAHT grading showed superiority in the prediction of severe infections, compared with CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant).
While mild to moderate toxicity after CAR T-cell therapy has been associated with more favorable outcomes, the poor survival rates associated with severe ICAHT “underscore that high-grade toxicity and inferior treatment outcomes often go hand-in-hand,” the authors write.
Conversely, “the patients with grade 1 or 2 ICAHT exhibited excellent treatment outcomes in our study,” they point out.
Recommendations in Clinical Practice
For clinical guidance, the ICAHT grading system provides best practice recommendations based on severity for diagnostic work-up and management, such as measures including use of granulocyte-colony stimulating factor (G-CSF), anti-infective prophylaxis and stem cell boosts.
The authors add that preinfusion scoring systems, including the CAR-HEMATOTOX prognostic score, may be optimized by ICAHT grading in terms of modeling for severe or life-threatening ICAHT as an important endpoint.
“We have had an absence of the standardized severity-based guidelines that we know very well for CRS and ICANS, both in terms of the diagnostic work-up and the grading but also the management,” Dr. Rejeski said at the meeting.
“We hope that the new ICAHT grading focuses future research efforts to not only understand this important side effect better, but also develop specific management strategies that mitigate the risk of infections in high-risk patients,” Dr. Rejeski added.
“The multiply validated CAR-HEMATOTOX score, assessed at time of lymphodepletion, may be helpful in this regard,” he added.
An accompanying editorial published with the guidelines underscored that “this is the first such guideline by a major organization and is a much-needed development for the management of this important CAR T-cell–associated toxicity.”
The improved standardized reporting of ICAHT “could also inform hematotoxicity management protocols,” said the editorial authors, David Qualls, MD, of the Memorial Sloan Kettering Cancer Center in New York City and Caron Jacobson, MD, of the Dana-Farber Cancer Institute, in Boston, Massachusetts.
“While providing comprehensive recommendations for ICAHT, the EHA/EBMT guidelines also highlight important gaps in our current knowledge of ICAHT, which are significant,” the editorial authors add.
Further commenting, Ulrich Jaeger, MD, a professor of hematology at the Medical University of Vienna, Vienna, Austria, agreed that the research fills an important need in post–CAR T-cell therapy management.
“Dr. Rejeski´s work is really seminal in the field and confirmed by validation cohorts in other centers,” he said in an interview. “I think the story is absolutely clear. It will be of increasing importance, with more patients surviving. [The system] will have to be adapted to novel indications as well.”
Dr. Rejeski disclosed ties with Kite/Gilead, Novartis, GMS/Celgene, and Pierre-Fabre. Jaeger reports relationships with Novartis, Gilead Sciences, Celgene/BMS, Janssen, Roche, Miltenyi Biotec, and Innovative Medicines Initiative.
“Hematotoxicity after CAR T is common and clinically relevant, but it also remains poorly understood [with] a high degree of heterogeneity in terms of grading its clinical management,” said first author Kai Rejeski, MD, in presenting on the findings at the 6th European CAR T-cell Meeting, held in Spain and jointly sponsored by the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA).
“We hope that this novel grading system helps with this by enabling harmonized reporting using the same nomenclature and allowing the comparison of the expected incidence rates of grade 3 or higher [hematological toxicities] across several disease entities and CAR T products,” said Dr. Rejeski, of the Adult BMT (Blood Marrow Transplant) and Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York City.
ICAHT Grading System
In a recent meta-analysis, Dr. Rejeski and his team found that infections are the cause of as many as 49% of non–relapse related deaths after CAR T-cell therapy, representing the most common cause of death and numbering significantly more than the more prominent causes of cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity (ICANS), which paradoxically have been the focus of significantly more research. In addition, the authors have reported substantial inconsistency among CAR T centers in the grading and management of the post–CAR T cytopenias that can cause those infections, underscoring the need for better guidelines.
“The narrative around CAR T toxicity has long centered on CRS and ICANS as novel and prototypical side effects with distinct management protocols,” Dr. Rejeski said in an interview. “However, it is cytopenias and the associated infections that drive nonrelapse mortality after CAR T.”
To address the need, the EHA and EBMT established the grading system for Immune Effector Cell–Associated HematoToxicity (ICAHT) that is applicable across disease types, indications, and treatment settings.
The details of the grading system were published in September 2023 in the journal Blood. The new system, which specifically focuses on neutrophil count and timing, importantly addresses the biphasic nature of ICAHT by distinguishing “early” ICAHT, occurring within 30 days of the CAR T administration, and “late” ICAHT, occurring more that 30 days following the treatment.
By contrast, conventional grading scales for CAR T–related cytopenias, such as the Common Terminology Criteria for Adverse Events (CTCAE) scale, “neither reflect the unique quality of post–CAR T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia,” the authors report in the study.
Real-World Evaluation
To assess the ICAHT grading system’s relevance in a real-world clinical setting of CAR T-cell therapy recipients, Dr. Rejeski and colleagues conducted a multicenter observational study, published in January 2024 in Blood Advances.
The study involved 549 patients at 12 international CAR T centers treated with BCMA- or CD19- directed CAR T therapy for relapsed/refractory B-cell malignancies.
Of the patients, 112 were treated for multiple myeloma (MM), 334 for large B cell lymphoma (LBCL), and 103 for mantle cell lymphoma (MCL).
Using the grading system, grade 3 (severe) or 4 (life-threatening) ICAHT (n = 125), was found to be strongly associated with key factors including a cumulative duration of severe neutropenia (P < .0001), the presence of multilineage cytopenias, such as severe thrombocytopenia (90%, compared with 46% in nonsevere ICAHT) and severe anemia (92% vs 49%; both P < .001), as well as the use of platelet and red blood cell transfusions.
Grade 3 or higher ICAHT was more common in patients with MCL (28%), compared with LBCL (23%) and MM (15%).
Key factors at baseline that were independently associated with severe ICAHT after multivariate adjustment included the presence of bone marrow infiltration, increased serum LDH levels, elevated CAR-HEMATOTOX scores (all P < .001), and receipt of CD28z costimulatory domain products, including axi-cel or brexu-cel (P = .01).
Those with grade 3 or higher ICAHT scores had a significantly higher rate of severe infections, compared with lower ICAHT scores (49% vs 13%; P < .0001), as well as increased nonrelapse mortality (14% vs 4.5%; P < .0001), primarily attributable to fatal infections.
Survival outcomes were also worse with grade 3 or higher ICAHT, including significantly lower rates of 1-year progression-free survival (35% vs 51%) and 1-year overall survival (52% vs 73%; both P < .0001).
Grade 3 or higher ICAHT was also significantly associated with prolonged hospital stays (median 21 vs 16 days; P < .0001).
However, contrary to findings from some previous studies, the current study showed no association between ICAHT severity and the prior administration of autologous stem cell transplant.
The number of prior treatment lines was not associated with grade 3 or higher ICAHT. However, grade 3 or higher CRS was more common as a cotoxicity (15% vs 5% without severe ICAHT), as was severe ICANS (26% vs 13%; both P < .001).
Notably, ICAHT grading showed superiority in the prediction of severe infections, compared with CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant).
While mild to moderate toxicity after CAR T-cell therapy has been associated with more favorable outcomes, the poor survival rates associated with severe ICAHT “underscore that high-grade toxicity and inferior treatment outcomes often go hand-in-hand,” the authors write.
Conversely, “the patients with grade 1 or 2 ICAHT exhibited excellent treatment outcomes in our study,” they point out.
Recommendations in Clinical Practice
For clinical guidance, the ICAHT grading system provides best practice recommendations based on severity for diagnostic work-up and management, such as measures including use of granulocyte-colony stimulating factor (G-CSF), anti-infective prophylaxis and stem cell boosts.
The authors add that preinfusion scoring systems, including the CAR-HEMATOTOX prognostic score, may be optimized by ICAHT grading in terms of modeling for severe or life-threatening ICAHT as an important endpoint.
“We have had an absence of the standardized severity-based guidelines that we know very well for CRS and ICANS, both in terms of the diagnostic work-up and the grading but also the management,” Dr. Rejeski said at the meeting.
“We hope that the new ICAHT grading focuses future research efforts to not only understand this important side effect better, but also develop specific management strategies that mitigate the risk of infections in high-risk patients,” Dr. Rejeski added.
“The multiply validated CAR-HEMATOTOX score, assessed at time of lymphodepletion, may be helpful in this regard,” he added.
An accompanying editorial published with the guidelines underscored that “this is the first such guideline by a major organization and is a much-needed development for the management of this important CAR T-cell–associated toxicity.”
The improved standardized reporting of ICAHT “could also inform hematotoxicity management protocols,” said the editorial authors, David Qualls, MD, of the Memorial Sloan Kettering Cancer Center in New York City and Caron Jacobson, MD, of the Dana-Farber Cancer Institute, in Boston, Massachusetts.
“While providing comprehensive recommendations for ICAHT, the EHA/EBMT guidelines also highlight important gaps in our current knowledge of ICAHT, which are significant,” the editorial authors add.
Further commenting, Ulrich Jaeger, MD, a professor of hematology at the Medical University of Vienna, Vienna, Austria, agreed that the research fills an important need in post–CAR T-cell therapy management.
“Dr. Rejeski´s work is really seminal in the field and confirmed by validation cohorts in other centers,” he said in an interview. “I think the story is absolutely clear. It will be of increasing importance, with more patients surviving. [The system] will have to be adapted to novel indications as well.”
Dr. Rejeski disclosed ties with Kite/Gilead, Novartis, GMS/Celgene, and Pierre-Fabre. Jaeger reports relationships with Novartis, Gilead Sciences, Celgene/BMS, Janssen, Roche, Miltenyi Biotec, and Innovative Medicines Initiative.
FROM THE 6TH EUROPEAN CAR T-CELL MEETING
B-ALL: CAR-T Outperforms Novel Therapies
“This is the first time there is a real-world comparison of CAR-T cell therapy versus other treatments in the era of other novel therapies such as inotuzumab or tyrosine kinase inhibitors (TKIs),” said first author Alexandros Rampotas, MD, of the University College London Hospital NHS Foundation Trust. “The study was looking retrospectively at patients treated in the UK, but the results should be applicable to most countries where similar treatments are available.”
Dr. Rampotas presented the research at the 6th European CAR T-cell Meeting jointly sponsored by the Society for Blood and Marrow Transplantation and the European Hematology Association.
Outcomes when patients with B-ALL relapse after allo-HCT treatment are generally very poor, and while the advent of CAR T-cell therapy has provided significant improvements, additional novel targeted therapies have also joined the field to further improve outcomes.
With no prior studies directly comparing outcomes between the various treatment options in a real-world setting, Dr. Rampotas and colleagues conducted a retrospective analysis of posttransplant relapsed B-ALL cases at six major transplant centers in the United Kingdom between 2010 and 2022.
Of 93 patients with sufficient data for the analysis, 17 had been treated with CAR T-cell therapy: 4 with UCART19, 1 with CD22 CAR T-cell, and 12 with the CD19-directed CAR T-cell products tisagenlecleucel (Kymriah) or obecabtagene autoleucel (obe-cel).
Among the remaining 75 patients who received non-CAR T-cell therapies, 24 received TKIs, 11 received blinatumumab, 12 received inotuzumab, 10 received intensive chemotherapy, 3 received intensive chemotherapy and TKI therapy, 14 received palliative/supportive regimens and 1 had a second allo-HCT following relapse from the first.
The median time from relapse to treatment was 2.8 months in the CAR T-cell therapy group, and 0.32 months for those receiving non-CAR T-cell therapies.
“The 2.8-month time-to-treat is quite expected as CAR T-cells can take a while to manufacture and be infused,” Dr. Rampotas noted. “This also comes with the bias that the patients who did receive them were likely fitter and could wait for that long.”
Patients receiving CAR T-cell therapy were also younger (median age 26 versus 47 in the non-CAR T-cell group) but the CAR T-cell group had higher risk disease and had a median of 2 prior lines of therapy versus 1 in the non-CAR T-cell group.
With a median follow-up of 24.8 months, patients receiving CAR T-cell therapy had significantly better rates of overall survival (OS), with 31 months compared with the non-CAR T-cell therapy OS of just 6.4 months (P = .0147).
The patients treated with CAR T-cell therapy also had improved progression-free survival (PFS) over the non-CAR T-cell patients (16.7 vs 3.7 months; P = .0001).
The superior outcomes in the CAR T-cell group remained consistent after exclusion of patients who received palliative approaches.
“In the realm of numerous innovative therapies for B-ALL, CAR Ts have now, for the first time, exhibited superior outcomes over alternative approaches in posttransplant relapsed B-ALL in the real world,” the authors reported. “The clear superior PFS and OS should encourage the use of more CAR T-cell therapies for this challenging cohort, while further improvements are imperative to enhance outcomes.”
In the meantime, “patients who relapse post transplant with B-ALL should be referred for CAR-T cell therapy as it is a superior treatment to other available options,” Dr. Rampotas said.
Dr. Rampotas discloses receiving conference fees from Gilead.
“This is the first time there is a real-world comparison of CAR-T cell therapy versus other treatments in the era of other novel therapies such as inotuzumab or tyrosine kinase inhibitors (TKIs),” said first author Alexandros Rampotas, MD, of the University College London Hospital NHS Foundation Trust. “The study was looking retrospectively at patients treated in the UK, but the results should be applicable to most countries where similar treatments are available.”
Dr. Rampotas presented the research at the 6th European CAR T-cell Meeting jointly sponsored by the Society for Blood and Marrow Transplantation and the European Hematology Association.
Outcomes when patients with B-ALL relapse after allo-HCT treatment are generally very poor, and while the advent of CAR T-cell therapy has provided significant improvements, additional novel targeted therapies have also joined the field to further improve outcomes.
With no prior studies directly comparing outcomes between the various treatment options in a real-world setting, Dr. Rampotas and colleagues conducted a retrospective analysis of posttransplant relapsed B-ALL cases at six major transplant centers in the United Kingdom between 2010 and 2022.
Of 93 patients with sufficient data for the analysis, 17 had been treated with CAR T-cell therapy: 4 with UCART19, 1 with CD22 CAR T-cell, and 12 with the CD19-directed CAR T-cell products tisagenlecleucel (Kymriah) or obecabtagene autoleucel (obe-cel).
Among the remaining 75 patients who received non-CAR T-cell therapies, 24 received TKIs, 11 received blinatumumab, 12 received inotuzumab, 10 received intensive chemotherapy, 3 received intensive chemotherapy and TKI therapy, 14 received palliative/supportive regimens and 1 had a second allo-HCT following relapse from the first.
The median time from relapse to treatment was 2.8 months in the CAR T-cell therapy group, and 0.32 months for those receiving non-CAR T-cell therapies.
“The 2.8-month time-to-treat is quite expected as CAR T-cells can take a while to manufacture and be infused,” Dr. Rampotas noted. “This also comes with the bias that the patients who did receive them were likely fitter and could wait for that long.”
Patients receiving CAR T-cell therapy were also younger (median age 26 versus 47 in the non-CAR T-cell group) but the CAR T-cell group had higher risk disease and had a median of 2 prior lines of therapy versus 1 in the non-CAR T-cell group.
With a median follow-up of 24.8 months, patients receiving CAR T-cell therapy had significantly better rates of overall survival (OS), with 31 months compared with the non-CAR T-cell therapy OS of just 6.4 months (P = .0147).
The patients treated with CAR T-cell therapy also had improved progression-free survival (PFS) over the non-CAR T-cell patients (16.7 vs 3.7 months; P = .0001).
The superior outcomes in the CAR T-cell group remained consistent after exclusion of patients who received palliative approaches.
“In the realm of numerous innovative therapies for B-ALL, CAR Ts have now, for the first time, exhibited superior outcomes over alternative approaches in posttransplant relapsed B-ALL in the real world,” the authors reported. “The clear superior PFS and OS should encourage the use of more CAR T-cell therapies for this challenging cohort, while further improvements are imperative to enhance outcomes.”
In the meantime, “patients who relapse post transplant with B-ALL should be referred for CAR-T cell therapy as it is a superior treatment to other available options,” Dr. Rampotas said.
Dr. Rampotas discloses receiving conference fees from Gilead.
“This is the first time there is a real-world comparison of CAR-T cell therapy versus other treatments in the era of other novel therapies such as inotuzumab or tyrosine kinase inhibitors (TKIs),” said first author Alexandros Rampotas, MD, of the University College London Hospital NHS Foundation Trust. “The study was looking retrospectively at patients treated in the UK, but the results should be applicable to most countries where similar treatments are available.”
Dr. Rampotas presented the research at the 6th European CAR T-cell Meeting jointly sponsored by the Society for Blood and Marrow Transplantation and the European Hematology Association.
Outcomes when patients with B-ALL relapse after allo-HCT treatment are generally very poor, and while the advent of CAR T-cell therapy has provided significant improvements, additional novel targeted therapies have also joined the field to further improve outcomes.
With no prior studies directly comparing outcomes between the various treatment options in a real-world setting, Dr. Rampotas and colleagues conducted a retrospective analysis of posttransplant relapsed B-ALL cases at six major transplant centers in the United Kingdom between 2010 and 2022.
Of 93 patients with sufficient data for the analysis, 17 had been treated with CAR T-cell therapy: 4 with UCART19, 1 with CD22 CAR T-cell, and 12 with the CD19-directed CAR T-cell products tisagenlecleucel (Kymriah) or obecabtagene autoleucel (obe-cel).
Among the remaining 75 patients who received non-CAR T-cell therapies, 24 received TKIs, 11 received blinatumumab, 12 received inotuzumab, 10 received intensive chemotherapy, 3 received intensive chemotherapy and TKI therapy, 14 received palliative/supportive regimens and 1 had a second allo-HCT following relapse from the first.
The median time from relapse to treatment was 2.8 months in the CAR T-cell therapy group, and 0.32 months for those receiving non-CAR T-cell therapies.
“The 2.8-month time-to-treat is quite expected as CAR T-cells can take a while to manufacture and be infused,” Dr. Rampotas noted. “This also comes with the bias that the patients who did receive them were likely fitter and could wait for that long.”
Patients receiving CAR T-cell therapy were also younger (median age 26 versus 47 in the non-CAR T-cell group) but the CAR T-cell group had higher risk disease and had a median of 2 prior lines of therapy versus 1 in the non-CAR T-cell group.
With a median follow-up of 24.8 months, patients receiving CAR T-cell therapy had significantly better rates of overall survival (OS), with 31 months compared with the non-CAR T-cell therapy OS of just 6.4 months (P = .0147).
The patients treated with CAR T-cell therapy also had improved progression-free survival (PFS) over the non-CAR T-cell patients (16.7 vs 3.7 months; P = .0001).
The superior outcomes in the CAR T-cell group remained consistent after exclusion of patients who received palliative approaches.
“In the realm of numerous innovative therapies for B-ALL, CAR Ts have now, for the first time, exhibited superior outcomes over alternative approaches in posttransplant relapsed B-ALL in the real world,” the authors reported. “The clear superior PFS and OS should encourage the use of more CAR T-cell therapies for this challenging cohort, while further improvements are imperative to enhance outcomes.”
In the meantime, “patients who relapse post transplant with B-ALL should be referred for CAR-T cell therapy as it is a superior treatment to other available options,” Dr. Rampotas said.
Dr. Rampotas discloses receiving conference fees from Gilead.
FROM THE 6TH EUROPEAN CAR T-CELL MEETING
MM:New Tool Gauges Post–CAR T Relapse Risk
“To our knowledge, this large multicenter study is the first report to identify patients with RRMM at high risk of early relapse after CAR-T,” the authors report in the study, published February 15 in the Journal of Clinical Oncology.
“We saw that early relapse within 5 months from infusion was significantly associated with very poor outcomes, and disease-, treatment-, and inflammation-specific variables were independent predictors of early relapse,” first author Nico Gagelmann, MD, of the University Medical Center Hamburg-Eppendorf, in Hamburg, Germany, explained in presenting the findings at the 6th European CAR T-cell Meeting jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association. CAR-T therapy has revolutionized the treatment of RRMM, with the idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) CAR-T therapies approved for the condition. However, the treatment is far from a cure, with nearly 50% of patients relapsing and having progression of disease within the first year after infusion, prompting a need to better understand the risk factors for who may or may not progress.
With a lack of a universal model to help with those predictions across products and populations, Dr. Gagelmann and colleagues conducted a retrospective observational study utilizing data from 136 patients at seven CAR-T centers in Europe and 133 patients at three centers in the US who had received either commercial or academically produced anti-BCMA CAR-T.
Of the patients, 171 were infused with ide-cel, 38 with cilta-cel, and 60 with an academic CAR-T therapy. The patients had a median age of 63, and extramedullary disease was more common in the US cohort (48%) versus European (35%; P = .04).
Notably, the response rates between the European and US cohorts were similar, despite various differences between the cohorts, including differences in ethnicities and a lower body mass index (BMI) in the European cohort versus US (BMI 25 vs 28, respectively; P < .001). There were also no significant differences in responses between the CAR-T treatments.
The overall response rate was 87% and was comparable between the European and US groups, with complete responses occurring among 48% of patients in Europe and 49% in the US group.
Their measurable residual disease (MRD) negativity rate at any time was 29% and 37%, respectively, and rates of complete response at day 30 were 29% and 26%, respectively. The rate of progression-free survival at 12 months was 40% for the entire cohort, with a rate of 45% in the European group and 34% in the US group (P = .09). Overall survival rates at 12 months were 79% and 65%, respectively (P = .11).
The patients had a median time to relapse of 5 months, and the 5-month incidence of relapse was identical, at 24% in each cohort.
Of those patients, overall survival at 12 months was low, at 30% in the European cohort and 14% in the US group.
“Early relapse within the first 5 months clearly identified patients with poor survival across the cohort,” Dr. Gagelmann said.
Key Risk Factors Identified
Key factors found after multivariate adjustment to be independently predictive of early relapse or progression included extramedullary disease or plasma cell leukemia, being refractory to lenalidomide, having high-risk cytogenetics, and having increased age- and sex-adjusted ferritin at the time of lymphodepletion.
With each of the risk factors valued at 1 point, the MyCARe model ranked scores of 0-1 points as low-risk, 2-3 as intermediate risk, and a score above 4 was considered high-risk.
Based on the model, the risk of early relapse within 5 months among those scored as low risk was 7%, for intermediate risk, 27% (hazard ratio [HR], 3.27 vs low-risk; P < .001), and for high risk, 53% (HR, 7.89 vs low-risk; P < .001), with outcomes overall comparable between the two geographic groups. Importantly, the model maintained utility for patients who did and did not receive salvage therapies; however, “more studies are needed to identify the optimal post–CAR-T approach,” the authors write.
Dr. Gagelmann added that older age was significantly associated with improved progression-free survival in the US cohort, with a 12-month progression-free survival of 27% among patients under 65 versus 43% for those over 65 (P = .03). However, age was not found to be associated with similar outcomes in the European cohort.
The authors note that the MyCARe model outperformed the CAR-HEMATOTOX and more recent disease-specific R2-ISS risk-stratification tools regarding prediction of relapse/progression and progression-free survival.
However, with CAR-HEMATOTOX developed to predict side effects and non-relapse mortality, “our results demonstrate that both scores independently predict different outcomes after anti–BCMA CAR-T in RRMM,” the authors report. Therefore, “they can be used complimentarily to predict complications (CAR-HEMATOTOX) and relapse/progression-free survival (MyCARe model).”
Importantly, the authors add that the tool may help in patient selection for earlier treatment.
“As ide-cel and cilta-cel have shown astonishing efficacy for earlier treatment lines, our model might also be validated for such patients,” the authors note in the study. They conclude that the study provides “the first Euro-American cartography of the efficacy and safety profile of current CAR-T, showing comparable results.”
“We also built the MyCARe model, which can predict early relapse, response, and survival and may facilitate patient selection in this very challenging setting,” the authors report.
Hope for Interventions Based on Patients’ Risk
Commenting on the study, Rahul Banerjee, MD, an assistant professor with the Division of Hematology and Oncology, University of Washington, Seattle, underscored that “we need more cross-border research like this in the myeloma field.”
“Clinically, my hope that this will help us tailor post–CAR-T interventions according to each patient’s risk profile,” he said.
Risk factors such as the presence of extramedullary disease, plasma cell leukemia, or high-risk cytogenetics are expected; however, Dr. Banerjee said the inclusion of increased ferritin before CAR-T was “an interesting new risk factor that we’ve also heard about from our colleagues in the lymphoma space.”
Ferritin perturbations can indicate many things, but high ferritin can be a sign of elevated inflammation at baseline,” he explained. “These patients may have a hyperinflammatory phenotype of their myeloma which can predispose T-cells to exhaustion,” Dr. Banerjee said.
“Exhausted T-cells at collection mean exhausted CAR T-cells at infusion, and so the negative prognostic significance of elevated ferritin — which we don’t always check before CAR-T — makes sense.”
While the authors suggest a potential benefit of the MyCAR3 model in identifying patients who could benefit from other novel therapies at relapse, Dr. Banerjee suggests another possibility. “I’d take this a step further and suggest future studies of this MyCARe model to identify patients who might benefit from post–CAR-T maintenance,” he said.
“The ‘one-and-done’ nature of CAR-T in terms of not requiring further myeloma therapy after infusion is a powerful benefit for patients, but there are some patients who may benefit from low-dose pomalidomide or iberdomide/mezigdomide maintenance to help keep the myeloma at bay and to promote T-cell fitness,” Dr. Banerjee explained. “This risk model may identify patients to prioritize for such types of clinical trials in the future.”
Caveats include that factors beyond the baseline features (used for the risk model) can further influence outcomes,” Dr. Banerjee noted.
“Risk stratification is inherently a dynamic process over time,” he said, questioning, for instance, “what about patients who achieve measurable residual disease negativity [MRD] at day +28 after CAR-T cell? Does the achievement of MRD negativity ‘erase’ a high-risk MyCARe score? We’ll need future studies to tell.”
An overriding take-home message for clinicians should be to simply refer eligible patients to a CAR-T capable center as soon as possible for evaluation.
“In the lymphoma world, they have a nice adage for this: ‘If they recur, you should refer,’ ” he said. “I’d suggest the same here. By no means will we move to CAR-T therapy for every patient at first relapse. However, based on their MyCARe score and other risk factors, there may be patients we prioritize for CAR-T first versus CAR-T with maintenance versus clinical trials.”
Dr. Gagelmann reported relationships with BMS, Pfizer, Stemline, MorphoSys, and Kite. Dr. Banerjee disclosed ties with BMS, Caribou Biosciences, Genentech, Janssen, Karyopharm, Pfizer, Sanofi, SparkCures, Novartis, and Pack Health.
“To our knowledge, this large multicenter study is the first report to identify patients with RRMM at high risk of early relapse after CAR-T,” the authors report in the study, published February 15 in the Journal of Clinical Oncology.
“We saw that early relapse within 5 months from infusion was significantly associated with very poor outcomes, and disease-, treatment-, and inflammation-specific variables were independent predictors of early relapse,” first author Nico Gagelmann, MD, of the University Medical Center Hamburg-Eppendorf, in Hamburg, Germany, explained in presenting the findings at the 6th European CAR T-cell Meeting jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association. CAR-T therapy has revolutionized the treatment of RRMM, with the idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) CAR-T therapies approved for the condition. However, the treatment is far from a cure, with nearly 50% of patients relapsing and having progression of disease within the first year after infusion, prompting a need to better understand the risk factors for who may or may not progress.
With a lack of a universal model to help with those predictions across products and populations, Dr. Gagelmann and colleagues conducted a retrospective observational study utilizing data from 136 patients at seven CAR-T centers in Europe and 133 patients at three centers in the US who had received either commercial or academically produced anti-BCMA CAR-T.
Of the patients, 171 were infused with ide-cel, 38 with cilta-cel, and 60 with an academic CAR-T therapy. The patients had a median age of 63, and extramedullary disease was more common in the US cohort (48%) versus European (35%; P = .04).
Notably, the response rates between the European and US cohorts were similar, despite various differences between the cohorts, including differences in ethnicities and a lower body mass index (BMI) in the European cohort versus US (BMI 25 vs 28, respectively; P < .001). There were also no significant differences in responses between the CAR-T treatments.
The overall response rate was 87% and was comparable between the European and US groups, with complete responses occurring among 48% of patients in Europe and 49% in the US group.
Their measurable residual disease (MRD) negativity rate at any time was 29% and 37%, respectively, and rates of complete response at day 30 were 29% and 26%, respectively. The rate of progression-free survival at 12 months was 40% for the entire cohort, with a rate of 45% in the European group and 34% in the US group (P = .09). Overall survival rates at 12 months were 79% and 65%, respectively (P = .11).
The patients had a median time to relapse of 5 months, and the 5-month incidence of relapse was identical, at 24% in each cohort.
Of those patients, overall survival at 12 months was low, at 30% in the European cohort and 14% in the US group.
“Early relapse within the first 5 months clearly identified patients with poor survival across the cohort,” Dr. Gagelmann said.
Key Risk Factors Identified
Key factors found after multivariate adjustment to be independently predictive of early relapse or progression included extramedullary disease or plasma cell leukemia, being refractory to lenalidomide, having high-risk cytogenetics, and having increased age- and sex-adjusted ferritin at the time of lymphodepletion.
With each of the risk factors valued at 1 point, the MyCARe model ranked scores of 0-1 points as low-risk, 2-3 as intermediate risk, and a score above 4 was considered high-risk.
Based on the model, the risk of early relapse within 5 months among those scored as low risk was 7%, for intermediate risk, 27% (hazard ratio [HR], 3.27 vs low-risk; P < .001), and for high risk, 53% (HR, 7.89 vs low-risk; P < .001), with outcomes overall comparable between the two geographic groups. Importantly, the model maintained utility for patients who did and did not receive salvage therapies; however, “more studies are needed to identify the optimal post–CAR-T approach,” the authors write.
Dr. Gagelmann added that older age was significantly associated with improved progression-free survival in the US cohort, with a 12-month progression-free survival of 27% among patients under 65 versus 43% for those over 65 (P = .03). However, age was not found to be associated with similar outcomes in the European cohort.
The authors note that the MyCARe model outperformed the CAR-HEMATOTOX and more recent disease-specific R2-ISS risk-stratification tools regarding prediction of relapse/progression and progression-free survival.
However, with CAR-HEMATOTOX developed to predict side effects and non-relapse mortality, “our results demonstrate that both scores independently predict different outcomes after anti–BCMA CAR-T in RRMM,” the authors report. Therefore, “they can be used complimentarily to predict complications (CAR-HEMATOTOX) and relapse/progression-free survival (MyCARe model).”
Importantly, the authors add that the tool may help in patient selection for earlier treatment.
“As ide-cel and cilta-cel have shown astonishing efficacy for earlier treatment lines, our model might also be validated for such patients,” the authors note in the study. They conclude that the study provides “the first Euro-American cartography of the efficacy and safety profile of current CAR-T, showing comparable results.”
“We also built the MyCARe model, which can predict early relapse, response, and survival and may facilitate patient selection in this very challenging setting,” the authors report.
Hope for Interventions Based on Patients’ Risk
Commenting on the study, Rahul Banerjee, MD, an assistant professor with the Division of Hematology and Oncology, University of Washington, Seattle, underscored that “we need more cross-border research like this in the myeloma field.”
“Clinically, my hope that this will help us tailor post–CAR-T interventions according to each patient’s risk profile,” he said.
Risk factors such as the presence of extramedullary disease, plasma cell leukemia, or high-risk cytogenetics are expected; however, Dr. Banerjee said the inclusion of increased ferritin before CAR-T was “an interesting new risk factor that we’ve also heard about from our colleagues in the lymphoma space.”
Ferritin perturbations can indicate many things, but high ferritin can be a sign of elevated inflammation at baseline,” he explained. “These patients may have a hyperinflammatory phenotype of their myeloma which can predispose T-cells to exhaustion,” Dr. Banerjee said.
“Exhausted T-cells at collection mean exhausted CAR T-cells at infusion, and so the negative prognostic significance of elevated ferritin — which we don’t always check before CAR-T — makes sense.”
While the authors suggest a potential benefit of the MyCAR3 model in identifying patients who could benefit from other novel therapies at relapse, Dr. Banerjee suggests another possibility. “I’d take this a step further and suggest future studies of this MyCARe model to identify patients who might benefit from post–CAR-T maintenance,” he said.
“The ‘one-and-done’ nature of CAR-T in terms of not requiring further myeloma therapy after infusion is a powerful benefit for patients, but there are some patients who may benefit from low-dose pomalidomide or iberdomide/mezigdomide maintenance to help keep the myeloma at bay and to promote T-cell fitness,” Dr. Banerjee explained. “This risk model may identify patients to prioritize for such types of clinical trials in the future.”
Caveats include that factors beyond the baseline features (used for the risk model) can further influence outcomes,” Dr. Banerjee noted.
“Risk stratification is inherently a dynamic process over time,” he said, questioning, for instance, “what about patients who achieve measurable residual disease negativity [MRD] at day +28 after CAR-T cell? Does the achievement of MRD negativity ‘erase’ a high-risk MyCARe score? We’ll need future studies to tell.”
An overriding take-home message for clinicians should be to simply refer eligible patients to a CAR-T capable center as soon as possible for evaluation.
“In the lymphoma world, they have a nice adage for this: ‘If they recur, you should refer,’ ” he said. “I’d suggest the same here. By no means will we move to CAR-T therapy for every patient at first relapse. However, based on their MyCARe score and other risk factors, there may be patients we prioritize for CAR-T first versus CAR-T with maintenance versus clinical trials.”
Dr. Gagelmann reported relationships with BMS, Pfizer, Stemline, MorphoSys, and Kite. Dr. Banerjee disclosed ties with BMS, Caribou Biosciences, Genentech, Janssen, Karyopharm, Pfizer, Sanofi, SparkCures, Novartis, and Pack Health.
“To our knowledge, this large multicenter study is the first report to identify patients with RRMM at high risk of early relapse after CAR-T,” the authors report in the study, published February 15 in the Journal of Clinical Oncology.
“We saw that early relapse within 5 months from infusion was significantly associated with very poor outcomes, and disease-, treatment-, and inflammation-specific variables were independent predictors of early relapse,” first author Nico Gagelmann, MD, of the University Medical Center Hamburg-Eppendorf, in Hamburg, Germany, explained in presenting the findings at the 6th European CAR T-cell Meeting jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association. CAR-T therapy has revolutionized the treatment of RRMM, with the idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) CAR-T therapies approved for the condition. However, the treatment is far from a cure, with nearly 50% of patients relapsing and having progression of disease within the first year after infusion, prompting a need to better understand the risk factors for who may or may not progress.
With a lack of a universal model to help with those predictions across products and populations, Dr. Gagelmann and colleagues conducted a retrospective observational study utilizing data from 136 patients at seven CAR-T centers in Europe and 133 patients at three centers in the US who had received either commercial or academically produced anti-BCMA CAR-T.
Of the patients, 171 were infused with ide-cel, 38 with cilta-cel, and 60 with an academic CAR-T therapy. The patients had a median age of 63, and extramedullary disease was more common in the US cohort (48%) versus European (35%; P = .04).
Notably, the response rates between the European and US cohorts were similar, despite various differences between the cohorts, including differences in ethnicities and a lower body mass index (BMI) in the European cohort versus US (BMI 25 vs 28, respectively; P < .001). There were also no significant differences in responses between the CAR-T treatments.
The overall response rate was 87% and was comparable between the European and US groups, with complete responses occurring among 48% of patients in Europe and 49% in the US group.
Their measurable residual disease (MRD) negativity rate at any time was 29% and 37%, respectively, and rates of complete response at day 30 were 29% and 26%, respectively. The rate of progression-free survival at 12 months was 40% for the entire cohort, with a rate of 45% in the European group and 34% in the US group (P = .09). Overall survival rates at 12 months were 79% and 65%, respectively (P = .11).
The patients had a median time to relapse of 5 months, and the 5-month incidence of relapse was identical, at 24% in each cohort.
Of those patients, overall survival at 12 months was low, at 30% in the European cohort and 14% in the US group.
“Early relapse within the first 5 months clearly identified patients with poor survival across the cohort,” Dr. Gagelmann said.
Key Risk Factors Identified
Key factors found after multivariate adjustment to be independently predictive of early relapse or progression included extramedullary disease or plasma cell leukemia, being refractory to lenalidomide, having high-risk cytogenetics, and having increased age- and sex-adjusted ferritin at the time of lymphodepletion.
With each of the risk factors valued at 1 point, the MyCARe model ranked scores of 0-1 points as low-risk, 2-3 as intermediate risk, and a score above 4 was considered high-risk.
Based on the model, the risk of early relapse within 5 months among those scored as low risk was 7%, for intermediate risk, 27% (hazard ratio [HR], 3.27 vs low-risk; P < .001), and for high risk, 53% (HR, 7.89 vs low-risk; P < .001), with outcomes overall comparable between the two geographic groups. Importantly, the model maintained utility for patients who did and did not receive salvage therapies; however, “more studies are needed to identify the optimal post–CAR-T approach,” the authors write.
Dr. Gagelmann added that older age was significantly associated with improved progression-free survival in the US cohort, with a 12-month progression-free survival of 27% among patients under 65 versus 43% for those over 65 (P = .03). However, age was not found to be associated with similar outcomes in the European cohort.
The authors note that the MyCARe model outperformed the CAR-HEMATOTOX and more recent disease-specific R2-ISS risk-stratification tools regarding prediction of relapse/progression and progression-free survival.
However, with CAR-HEMATOTOX developed to predict side effects and non-relapse mortality, “our results demonstrate that both scores independently predict different outcomes after anti–BCMA CAR-T in RRMM,” the authors report. Therefore, “they can be used complimentarily to predict complications (CAR-HEMATOTOX) and relapse/progression-free survival (MyCARe model).”
Importantly, the authors add that the tool may help in patient selection for earlier treatment.
“As ide-cel and cilta-cel have shown astonishing efficacy for earlier treatment lines, our model might also be validated for such patients,” the authors note in the study. They conclude that the study provides “the first Euro-American cartography of the efficacy and safety profile of current CAR-T, showing comparable results.”
“We also built the MyCARe model, which can predict early relapse, response, and survival and may facilitate patient selection in this very challenging setting,” the authors report.
Hope for Interventions Based on Patients’ Risk
Commenting on the study, Rahul Banerjee, MD, an assistant professor with the Division of Hematology and Oncology, University of Washington, Seattle, underscored that “we need more cross-border research like this in the myeloma field.”
“Clinically, my hope that this will help us tailor post–CAR-T interventions according to each patient’s risk profile,” he said.
Risk factors such as the presence of extramedullary disease, plasma cell leukemia, or high-risk cytogenetics are expected; however, Dr. Banerjee said the inclusion of increased ferritin before CAR-T was “an interesting new risk factor that we’ve also heard about from our colleagues in the lymphoma space.”
Ferritin perturbations can indicate many things, but high ferritin can be a sign of elevated inflammation at baseline,” he explained. “These patients may have a hyperinflammatory phenotype of their myeloma which can predispose T-cells to exhaustion,” Dr. Banerjee said.
“Exhausted T-cells at collection mean exhausted CAR T-cells at infusion, and so the negative prognostic significance of elevated ferritin — which we don’t always check before CAR-T — makes sense.”
While the authors suggest a potential benefit of the MyCAR3 model in identifying patients who could benefit from other novel therapies at relapse, Dr. Banerjee suggests another possibility. “I’d take this a step further and suggest future studies of this MyCARe model to identify patients who might benefit from post–CAR-T maintenance,” he said.
“The ‘one-and-done’ nature of CAR-T in terms of not requiring further myeloma therapy after infusion is a powerful benefit for patients, but there are some patients who may benefit from low-dose pomalidomide or iberdomide/mezigdomide maintenance to help keep the myeloma at bay and to promote T-cell fitness,” Dr. Banerjee explained. “This risk model may identify patients to prioritize for such types of clinical trials in the future.”
Caveats include that factors beyond the baseline features (used for the risk model) can further influence outcomes,” Dr. Banerjee noted.
“Risk stratification is inherently a dynamic process over time,” he said, questioning, for instance, “what about patients who achieve measurable residual disease negativity [MRD] at day +28 after CAR-T cell? Does the achievement of MRD negativity ‘erase’ a high-risk MyCARe score? We’ll need future studies to tell.”
An overriding take-home message for clinicians should be to simply refer eligible patients to a CAR-T capable center as soon as possible for evaluation.
“In the lymphoma world, they have a nice adage for this: ‘If they recur, you should refer,’ ” he said. “I’d suggest the same here. By no means will we move to CAR-T therapy for every patient at first relapse. However, based on their MyCARe score and other risk factors, there may be patients we prioritize for CAR-T first versus CAR-T with maintenance versus clinical trials.”
Dr. Gagelmann reported relationships with BMS, Pfizer, Stemline, MorphoSys, and Kite. Dr. Banerjee disclosed ties with BMS, Caribou Biosciences, Genentech, Janssen, Karyopharm, Pfizer, Sanofi, SparkCures, Novartis, and Pack Health.
FROM THE 6TH EUROPEAN CAR T-CELL MEETING