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

Abstract

CAR-T cell therapy; Infections; Mortality

Terapia con células CAR-T; Infecciones; Mortalidad

Teràpia amb cèl·lules CAR-T; Infeccions; Mortalitat

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.

K.R. received a fellowship from the School of Oncology of the German Cancer Consortium and was funded by the Else Kröner Forschungskolleg within the Munich Clinician Scientist Program. This work was supported by a grant within the Gilead Research Scholar Program (to K.R. and M.S.), grant funds from a translational group of the Bavarian Center for Cancer Research (BZKF, to K.R., F.M. and M.S), and the Bruno and Helene Jöster Foundation (to K.R. and M.S.). This work was also supported by a Deutsche Forschungsgemeinschaft (German Research Foundation) research grant provided within the Sonderforschungbereich SFB-TRR 338/1 2021 – 452881907, and DFG research grant 451580403 (to M.S.). The work was further supported by the Bavarian Elite Graduate Training Network (to M.S.), the Wilhelm Sander-Stiftung (to M.S., project no. 2018.087.1), the Else Kröner-Fresenius-Stiftung (to M.S.), and the Bavarian Center for Cancer Research. M.D.J. acknowledges funding from the Bankhead-Coley Cancer Research Program and the Mark Foundation.