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Observational Study
. 2024 Apr 23;8(8):1857-1868.
doi: 10.1182/bloodadvances.2023011767.

Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality

Kai Rejeski  1   2   3   4 , Yucai Wang  5 , Doris K Hansen  6 , Gloria Iacoboni  7 , Emmanuel Bachy  8 , Radhika Bansal  5 , Olaf Penack  3   9 , Fabian Müller  10 , Wolfgang Bethge  11 , Javier Munoz  12 , Razan Mohty  6 , Veit L Bücklein  1   2 , Pere Barba  7 , Frederick L Locke  6 , Yi Lin  5 , Michael D Jain  6 , Marion Subklewe  1   2   3
Affiliations
Observational Study

Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality

Kai Rejeski et al. Blood Adv. .

Abstract

Cytopenias represent the most common side effect of CAR T-cell therapy (CAR-T) and can predispose for severe infectious complications. Current grading systems, such as the Common Terminology Criteria for Adverse Events (CTCAE), neither reflect the unique quality of post-CAR-T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia. For this reason, a novel EHA/EBMT consensus grading was recently developed for Immune Effector Cell-Associated HematoToxicity (ICAHT). In this multicenter, observational study, we applied the grading system to a large real-world cohort of 549 patients treated with BCMA- or CD19-directed CAR-T for refractory B-cell malignancies (112 multiple myeloma [MM], 334 large B-cell lymphoma [LBCL], 103 mantle cell lymphoma [MCL]) and examined the clinical sequelae of severe (≥3°) ICAHT. The ICAHT grading was strongly associated with the cumulative duration of severe neutropenia (r = 0.92, P < .0001), the presence of multilineage cytopenias, and the use of platelet and red blood cell transfusions. We noted an increased rate of severe ICAHT in patients with MCL vs those with LBCL and MM (28% vs 23% vs 15%). Severe ICAHT was associated with a higher rate of severe infections (49% vs 13%, P < .0001), increased nonrelapse mortality (14% vs 4%, P < .0001), and inferior survival outcomes (1-year progression-free survival: 35% vs 51%, 1-year overall survival: 52% vs 73%, both P < .0001). Importantly, the ICAHT grading demonstrated superior capacity to predict severe infections compared with the CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant). Taken together, these data highlight the clinical relevance of the novel grading system and support the reporting of ICAHT severity in clinical trials evaluating CAR-T therapies.

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Conflict of interest statement

Conflict-of-interest disclosure: K.R. reports research funding, advisory, honoraria and travel support from Kite/Gilead; honoraria from Novartis; consultancy, honoraria from Bristol Myers Squibb (BMS)/Celgene; and travel support from Pierre Fabre. Y.W. reports research funding (to institution) from Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, and Genmab; advisory board (compensation to institution) from Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, and AstraZeneca; consultancy (compensation to institution) from InnoCare and AbbVie; and honorarium (to institution) from Kite/Gilead. D.K.H. reports consulting or advisory role and research funding from BMS; and research funding from Adaptive Biotech. G.I. reports honoraria and travel support from Novartis, Kite/Gilead, BMS, AbbVie, Autolus, Sandoz, Miltenyi, and AstraZeneca. E.B. reports consultancy/honoraria from Novartis, Kite/Gilead, Roche, Takeda, and Incyte; research funding (paid to institution) from Amgen; and travel and personal fees from Roche and Incyte. O.P. has received honoraria or travel support from Astellas, Gilead, Jazz, MSD, Neovii Biotech, Novartis, Pfizer and Therakos. He has received research support from Gilead, Incyte, Jazz, Neovii Biotech and Takeda. He is a member of advisory boards to Jazz, Gilead, MSD, Omeros, Priothera, Shionogi and SOBI. F.M. reports travel support, advisory/honoraria from Novartis/Kite Gilead. W.B. reports consulting for and received honoraria from Novartis, Gilead; and consulting for and research funding from Miltenyi. J.M reports consulting for Pharmacyclics/AbbVie, Bayer, Gilead/Kite, BeiGene, Pfizer, Janssen, Celgene/BMS, Kyowa, Alexion, Fosun Kite, Seattle Genetics, Karyopharm, Aurobindo, Verastem, Genmab, Genentech/Roche, ADC Therapeutics, Epizyme, BeiGene, Novartis, MorphoSys/Incyte, MEI, TG Therapeutics, AstraZeneca, and Eli Lilly; research funding from Bayer, Gilead/Kite, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium, Novartis, BeiGene; and honoraria from Targeted Oncology, OncView, Curio, Physicians' Education Resource, and Seattle Genetics. V.L.B. received honoraria from Amgen, Pfizer, Kite/Gilead; research funding from Celgene, Kite/Gilead; honoraria from Kite/Gilead; Novartis; and served in a consultancy/advisory at Novartis, BMS, and Takeda. P.B. reports advisory role at Allogene, Amgen, BMS/Celgene, Kite/Gilead, Incyte, Novartis, and Pierre Fabre; consultancy at Jazz Pharmaceuticals, Miltenyi Biomedicine, Nektar, Novartis, and Pierre Fabre. F.L.L. has a scientific advisory role with A2, Allogene, Amgen, bluebird bio, BMS/Celgene, Calibr, Caribou, Cellular Biomedicine Group, Cowen, Daiichi Sankyo, EcoR1, Emerging Therapy Solutions, GammaDelta Therapeutics, Gerson Lehrman Group, Iovance, Kite Pharma, Janssen, Legend Biotech, Novartis, Sana, Takeda, Wugen, and Umoja; receives research support from Kite/Gilead, Novartis, BMS, 2seventy Bio, and Allogene; and reports that his institution holds unlicensed patents in his name in the field of cellular immunotherapy. Y.L. received research funding from Kite/Gilead, BMS, Janssen, Merck, Takeda, and 2seventy Bio; has consultancy/advisory role at Novartis, BMS, Janssen, Gamida Cells, NexImmune, NekTar Biotherapeutics, Pfizer, and Kite/Gilead; is on the data and safety monitoring board of Pfizer and Sorrento; and reports that all funds were to institution, no personal compensation. M.D.J. reports consultancy/advisory for Kite/Gilead and Myeloid Therapeutics; and research funding from Kite/Gilead, Incyte, and Loxo@Lilly. M.S. receives industry research support from Amgen, BMS/Celgene, Gilead, Janssen, Miltenyi Biotec, Novartis, Roche, Seattle Genetics, and Takeda; serves as a consultant/advisor to AvenCell, CDR-Life, Ichnos Sciences, Incyte Biosciences, Janssen, Miltenyi Biotec, Molecular Partners, Novartis, Pfizer; and Takeda; and serves on the speakers’ bureau at Amgen, AstraZeneca, BMS/Celgene, Gilead, GSK, Janssen, Novartis, Pfizer, Roche, and Takeda. None of the mentioned conflicts of interest were related to financing of the content of this manuscript. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
ICAHT severity across disease entities. (A-D) Relative distribution of ICAHT severity grades across the entire study population (A) and for patients with relapsed/refractory (r/r) LBCL (B), mantle cell lymphoma (C), and MM (D).
Figure 2.
Figure 2.
Impact of ICAHT severity on the duration of severe neutropenia and neutrophil recovery phenotypes. (A) Median duration of severe neutropenia (ANC <500/μL) between CAR-T infusion and day 60 by ICAHT severity grade. Whiskers indicate the 95% CI. (B) Distribution of neutrophil recovery phenotypes for each ICAHT grade (“quick” [Q] vs “intermittent” [I]vs “aplastic” [A]; for definitions see Rejeski et al11).
Figure 3.
Figure 3.
Severe ICAHT is associated with an increased rate of infection. (A-B) Relative distribution of infection grades for all infection subtypes (A) and for bacterial infections only (B) comparing patients without (grade 0-2) vs with severe ICAHT (grade ≥3). The respective infection grades (1-5°) are color-coded; P values were determined by χ2 test. A table summarizes the rate of severe infections (grade 3 or higher) and severe bacterial infections by ICAHT severity (P value as determined by Fisher exact test).
Figure 4.
Figure 4.
ICAHT severity is associated with increased NRM and extended hospital duration. (A) 1-year nonrelapse mortality (NRM) according to ICAHT severity. The p-value of the Mantel-Cox log-rank test comparing severe vs nonsevere ICAHT is depicted. (B) Overview of the determined causes of death unrelated to lymphoma progression across all time points for the entire study cohort (total n = 560 patients).
Figure 5.
Figure 5.
Superior discrimination for severe infections with the novel ICAHT grading compared with CTCAE grading. (A) Receiver operating characteristic (ROC) analysis studying the influence of the ICAHT (pink) and CTCAE (blue) grading on the binary outcome of severe infection during the first 90 days after CAR T-cell infusion. The area under the curve (AUC) and P value are provided. (B) Relative distribution of severity grades for CTCAE grading of neutropenia (top) vs ICAHT grading (bottom). The P value of the χ2 test is depicted.
Figure 6.
Figure 6.
Patients with severe ICAHT show poor survival outcomes. (A-B) Kaplan-Meier estimates of PFS (A) and OS (B) comparing patients with grade 3-4 ICAHT (red) vs absent or grade 1-2 ICAHT (green). The P value of the log-rank test is shown on the bottom right of the graph. The median PFS and OS in months and HR of the univariate Cox regression model are superimposed above each graph. (C-D) Subgroup analysis of PFS (C) and OS (D) stratified by 3 ICAHT severity groups. Absent hematotoxicity (grade 0, blue) was compared with mild-to-moderate (grade 1-2, dark green) and severe-to-life-threatening ICAHT (grade 3-4, yellow). The P value of the log-rank test and the HRs using absent ICAHT (grade 0) as the reference are depicted.
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