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Background: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group. Methods: This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance. Results and conclusion: The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic. © 2022 The Authors

CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34+CD22+CD19− (pre)-leukemic cells represent an “early progenitor origin-related” mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19−CD22+ cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34+CD19−CD22+ cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34+CD19−CD22+ cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34+CD19−CD22+ progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19− relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged., The work in P.M. and C.B.’s Laboratory was supported by the European Research Council (CoG-2014-646903, PoC-2018-811220) and the Spanish Ministry of Economy and Competitiveness (SAF2016-80481R, PID2019-108160RB-I00) (P.M.); the ISCIII (ISCIII/FEDER, PI17/01028 and PI20/00822), the Spanish Association against Cancer (AECC), and the FERO Foundation (C.B.). P.M. and J.M.R. acknowledge the support of ISCIII-RICORS within the Next Generation EU program (Plan de Recuperación, Transformación y Resiliencia). N.E. is supported by Cancer Research UK and a Children and Young People’s Cancer Innovation Award (DRCPGM\100058). A.R. is supported by a Wellcome Trust Clinical Research Career Development Fellowship (216632/Z/19/Z). A.O. was supported by ISCIII (PI19/011183). F.S. was supported by AGAUR/Generalitat de Catalunya (SGR288). The single-cell transcriptomic analysis was supported by MRC Discovery award MRCDA 0816-11 and the MRC WIMM Single Cell Facility and MRC-funded Oxford Consortium for Single-Cell Biology (MR/M00919X/1) provided assistance.