CD34+CD19−CD22+ B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies
Clara Bueno, Susana Barrera, Álex Bataller, Valentín Ortiz‐Maldonado, Natalina Elliot, Sorcha O’Byrne, Guanlin Wang, Montse Rovira, Francisco Gutiérrez‐Agüera, Juan L. Trincado, María González‐González, Mireia Morgades, Marc Sorigué, Paloma Bárcena, Samanta Romina Zanetti, Montserrat Torrebadell, Nerea Vega‐García, Susana Rives, Mar Mallo, Françesc Solé, Adam J. Mead, Irene Roberts, Supat Thongjuea, Bethan Psaila, Manel Juan, Julio Delgado, Álvaro Urbano-Ispizúa, Josep‐María Ribera, Alberto Órfão, Anindita Roy, Pablo Menéndez
Abstract
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.