Immunotherapies targeting CD19 have completely changed the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initially remarkable complete remission (CR) rates, many patients eventually relapse. Patients with B-ALL who have been effectively treated with CD19-directed T cells ultimately relapse, suggesting that preexisting CD34+CD22+CD19 (pre)-leukemic cells constitute an “early progenitor origin-related” mechanism driving phenotypic escape from CD19-directed immunotherapies. 

For a study, researchers showed that during B-cell development, CD22 expression comes before CD19 expression. CD34+CD19CD22+ cells are identified in ∼70% of B-ALL patients’ diagnostic and relapsed bone marrow samples, and their frequency rises twofold in patients with B-ALL in CR following CD19 CAR T-cell treatment. Before treatment, the median number of CD34+CD19CD22+ cells was thrice greater in patients with B-ALL who relapsed following CD19-directed immunotherapy (median follow-up, 24 months). 

Fluorescence in situ hybridization study of flow-sorted cell populations and xenograft modeling indicated that CD34+CD19CD22+ cells contain the genetic defects identified at diagnosis and induce leukemogenesis in vivo. The findings supported ongoing clinical trials aiming at CD19/CD22 dual targeting as a strategy for minimizing CD19 relapses by implying that preleukemic CD34+CD19CD22+ progenitors underpin phenotypic escape following CD19-directed immunotherapies. 

It was recommended that CD34/CD19/CD22 immunophenotyping be used in clinical laboratories for initial diagnosis and ongoing monitoring of patients with B-ALL receiving CD19-targeted treatment.