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Hematological toxicity is the most common adverse event after chimeric antigen receptor (CAR) T-cell therapy. Cytopenias can be profound and long-lasting and can predispose for severe infectious complications. In a recent worldwide survey, we demonstrated that there remains considerable heterogeneity in regard to current practice patterns. Here, we sought to build consensus on the grading and management of immune effector cell-associated hematotoxicity (ICAHT) after CAR T-cell therapy. For this purpose, a joint effort between the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA) involved an international panel of 36 CAR T-cell experts who met in a series of virtual conferences, culminating in a 2-day meeting in Lille, France. On the basis of these deliberations, best practice recommendations were developed. For the grading of ICAHT, a classification system based on depth and duration of neutropenia was developed for early (day 0-30) and late (after day +30) cytopenia. Detailed recommendations on risk factors, available preinfusion scoring systems (eg, CAR-HEMATOTOX score), and diagnostic workup are provided. A further section focuses on identifying hemophagocytosis in the context of severe hematotoxicity. Finally, we review current evidence and provide consensus recommendations for the management of ICAHT, including growth factor support, anti-infectious prophylaxis, transfusions, autologous hematopoietic stem cell boost, and allogeneic hematopoietic cell transplantation. In conclusion, we propose ICAHT as a novel toxicity category after immune effector cell therapy, provide a framework for its grading, review literature on risk factors, and outline expert recommendations for the diagnostic workup and short- and long-term management., (© 2023 by The American Society of Hematology.)

Background: Several commercial and academic autologous chimeric antigen receptor T-cell (CAR-T) products targeting CD19 have been approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia, high-grade B-cell lymphoma and mantle cell lymphoma. Products for other diseases such as multiple myeloma and follicular lymphoma are likely to be approved by the European Medicines Agency in the near future., Design: The European Society for Blood and Marrow Transplantation (EBMT)-Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association collaborated to draft best practice recommendations based on the current literature to support health care professionals in delivering consistent, high-quality care in this rapidly moving field., Results: Thirty-six CAR-T experts (medical, nursing, pharmacy/laboratory) assembled to draft recommendations to cover all aspects of CAR-T patient care and supply chain management, from patient selection to long-term follow-up, post-authorisation safety surveillance and regulatory issues., Conclusions: We provide practical, clinically relevant recommendations on the use of these high-cost, logistically complex therapies for haematologists/oncologists, nurses and other stakeholders including pharmacists and health sector administrators involved in the delivery of CAR-T in the clinic., Competing Interests: Disclosure PJH—Janssen, Takeda, Amgen, Celgene, Alnylam. CR—Novartis, Gilead, BMS. PB—Neovii, Riemser, Medac, Novartis, Gilead, Celgene BMS, Miltenyi, Jazz, Riemser, Amgen, Servier. GWB—Kite/Gilead, Novartis, Celgene/BMS and FamicordTx. HB—Novartis and Celgene. CB—Intellia Therapeutics, TxCell, Novartis, GSK, Molmed, Kite/Gilead, Miltenyi, Kiadis, QuellTx, Janssen, Allogene. CC—Sanofi SA, Miltenyi Biotech, Fresenius Kabi, Gilead, Novartis, Celgene, Terumo BCT, Bellicum Pharmaceuticals, Janssen. RE—Kite Gilead, BMS Celgene, Janssen. FSG—Novartis, Kite/Gilead, Celgene/BMS, Pfizer, Incyte, Amgen, Takeda, and Roche. UJ—Novartis, Janssen, Gilead, BMS, Miltenyi. MH—T-CURX GmbH. MJK—BMS/Celgene, Kite/Gilead, Miltenyi Biotec, Novartis, Roche. UK—AstraZeneca, Affimed, Glycostem, GammaDelta, Zelluna. JK—Novartis, Miltenyi Biotech, Gadeta, Gilead/BMS. SM—Celgene/BMS, Novartis, DNA Prime SA, Gilead/KITE, Miltenyi, Immunicum. MM—Sanofi, Jazz, Amgen, Takeda, Novartis, Janssen, Celgene, Adaptive Biotechnologies, Astellas, Pfizer, Stemline, GSK, outside the submitted work. JM—Kite/Gilead, Jazz, Janssen, and Mallinckrodt. CR—Kite/Gilead, Novartis, Celgene/BMS, Janssen. RS—Novartis, Gilead, Janssen. JAS—Gilead, Jazz, Janssen, Mallinckrodt, Medac. JS—MSD, Gilead, Pfizer, Kite, Novartis, TEVA. MS—Amgen, Gilead, Miltenyi Biotec, Morphosys, Roche, Seattle Genetics, BMS, Celgene, Pfizer, Novartis, Roche, Janssen, Novartis. CT—BMS/Celgene, Abbvie, Takeda, Roche, Novartis, Gilead/Kyte, Incyte, Novartis, Cellectis, Amgen, Sanofi, Janssen, AstraZeneca, ADC Therapeutics. MT—Gilead/KITE, Regeneron, Roche, Novartis, Janssen, Celgene/BMS. JGG—Abbvie, Amgen, Astra Zeneca, BMS, Janssen, Kite/Gilead, Morphosys, Novartis, Takeda. NK—AOP Phama, Novartis, Amgen, Sanofi, Neovii, JAZZ, Gilead/Kite, Celgene, Riemser. HE—Janssen, BMS/Celgene, Amgen, Sanofi, GSK, Novartis, Takeda. IY-A—Kite/Gilead, Novartis, Celgene/BMS and Janssen. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20-27%) and a median OS of 3.3 months (95% CI: 2.8-3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36-50%) and a median OS of 6.1 months (95% CI: 4.2-7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67-4.31) and improved OS (HR=0.536, 95% CI: 0.394-0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data.