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“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.
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Melville</byline> <bylineText>NANCY MELVILLE</bylineText> <bylineFull>NANCY MELVILLE</bylineFull> <bylineTitleText>MDedge News</bylineTitleText> <USOrGlobal/> <wireDocType/> <newsDocType/> <journalDocType/> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:imng"> <name>IMNG Medical Media</name> <rightsInfo> <copyrightHolder> <name>Frontline Medical News</name> </copyrightHolder> <copyrightNotice>Copyright (c) 2015 Frontline Medical News, a Frontline Medical Communications Inc. company. All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>A new grading system designed to improve the assessment of hematological toxicities following chimeric antigen receptor (CAR) T-cell therapy shows utility for a</metaDescription> <articlePDF/> <teaserImage/> <teaser>A real-world study demonstrates the benefits of a new grading system to assess hematotoxicities across disease types following CAR T-cell therapies.</teaser> <title>High Marks for New CAR T Toxicity Grading Tool</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>hemn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">18</term> </publications> <sections> <term canonical="true">53</term> <term>39313</term> </sections> <topics> <term>59374</term> <term canonical="true">195</term> <term>61821</term> <term>243</term> <term>250</term> <term>341</term> <term>27442</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>High Marks for New CAR T Toxicity Grading Tool</title> <deck/> </itemMeta> <itemContent> <p class="Normal">FROM THE 6TH EUROPEAN CAR T-CELL MEETING</p> <p><span class="tag metaDescription">A new grading system designed to improve the assessment of hematological toxicities following chimeric antigen receptor (CAR) T-cell therapy shows utility for a real-world population, providing much-needed standardization and guidance for management of the potentially life-threatening events. </span><br/><br/>“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).<br/><br/>“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.</p> <h2>ICAHT Grading System</h2> <p>In a recent <span class="Hyperlink"><a href="https://ash.confex.com/ash/2023/webprogram/Paper187516.html">meta-analysis</a>, </span>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 <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10145722/">reported</a></span> 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.<br/><br/>“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.”<br/><br/>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. <br/><br/>The details of the grading system were <span class="Hyperlink"><a href="https://ashpublications.org/blood/article/142/10/865/496185/Immune-effector-cell-associated-hematotoxicity-EHA">published in September</a></span> 2023 in the journal <em>Blood</em>. 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.<br/><br/>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.</p> <h2>Real-World Evaluation</h2> <p>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, <span class="Hyperlink"><a href="https://ashpublications.org/bloodadvances/article/doi/10.1182/bloodadvances.2023011767/506970/Applying-the-EHA-EBMT-Grading-for-ICAHT-after-CAR">published in January</a></span> 2024 in <em>Blood Advances</em>.<br/><br/>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.<br/><br/>Of the patients, 112 were treated for multiple myeloma (MM), 334 for large B cell lymphoma (LBCL), and 103 for mantle cell lymphoma (MCL).<br/><br/>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 (<em>P</em> < .0001), the presence of multilineage cytopenias, such as severe thrombocytopenia (90%, compared with 46% in nonsevere ICAHT) and severe anemia (92% vs 49%; both <em>P</em> < .001), as well as the use of platelet and red blood cell transfusions.<br/><br/>Grade 3 or higher ICAHT was more common in patients with MCL (28%), compared with LBCL (23%) and MM (15%).<br/><br/>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 <em>P</em> < .001), and receipt of CD28z costimulatory domain products, including axi-cel or brexu-cel (<em>P</em> = .01).<br/><br/>Those with grade 3 or higher ICAHT scores had a significantly higher rate of severe infections, compared with lower ICAHT scores (49% vs 13%; <em>P</em> < .0001), as well as increased nonrelapse mortality (14% vs 4.5%; <em>P</em> < .0001), primarily attributable to fatal infections.<br/><br/>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 <em>P</em> < .0001). <br/><br/>Grade 3 or higher ICAHT was also significantly associated with prolonged hospital stays (median 21 vs 16 days; <em>P</em> < .0001). <br/><br/>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.<br/><br/>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 <em>P</em> < .001).<br/><br/>Notably, ICAHT grading showed superiority in the prediction of severe infections, compared with CTCAE grading (c-index 0.73 vs 0.55, <em>P</em> < .0001 vs nonsignificant). <br/><br/>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.<br/><br/>Conversely, “the patients with grade 1 or 2 ICAHT exhibited excellent treatment outcomes in our study,” they point out.</p> <h2>Recommendations in Clinical Practice</h2> <p>For clinical guidance, the <span class="Hyperlink"><a href="https://ashpublications.org/blood/article/142/10/865/496185/Immune-effector-cell-associated-hematotoxicity-EHA">ICAHT grading system</a></span> 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.<br/><br/>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.<br/><br/>“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.<br/><br/>“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. <br/><br/>“The multiply validated CAR-HEMATOTOX score, assessed at time of lymphodepletion, may be helpful in this regard,” he added.<br/><br/>An accompanying <span class="Hyperlink"><a href="https://ashpublications.org/blood/article/142/10/859/497740/A-road-map-for-navigating-CAR-T-hematotoxicity">editorial</a></span> 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.”<br/><br/>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.<br/><br/>“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.<br/><br/>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.<br/><br/>“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.”<br/><br/>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.<span class="end"/></p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
FROM THE 6TH EUROPEAN CAR T-CELL MEETING