Hematopoietic stem cell involvement in BCR-ABL1- positive ALL as a potential mechanism of resistance to blinatumomab therapy.

The bispecific T-cell engager blinatumomab targeting CD19 can induce complete remission in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, some patients ultimately relapse with loss of CD19 antigen on leukemic cells, which has been established as a novel mechanism to escape CD19-specific immunotherapies. Here, we provide evidence that CD19-negative (CD19 ^- ) relapse after CD19-directed therapy in BCP-ALL may be a result of the selection of preexisting CD19 ^- malignant progenitor cells. We present 2 BCR-ABL1 fusion-positive BCP-ALL patients with CD19 ^- myeloid lineage relapse after blinatumomab therapy and show BCR-ABL1 positivity in their hematopoietic stem cell (HSC)/progenitor/myeloid compartments at initial diagnosis by fluorescence in situ hybridization after cell sorting. By using the same approach with 25 additional diagnostic samples from patients with BCR-ABL1- positive BCP-ALL, we identified HSC involvement in 40% of the patients. Patients (6 of 8) with major BCR-ABL1 transcript encoding P210 ^BCR-ABL1 mainly showed HSC involvement, whereas in most of the patients (9 of 12) with minor BCR-ABL1 transcript encoding P190 ^BCR-ABL1 , only the CD19 ⁺ leukemia compartments were BCR-ABL1 positive ( P = .02). Our data are of clinical importance, because they indicate that both CD19 ⁺ cells and CD19 ^- precursors should be targeted to avoid CD19 ^- relapses in patients with BCR-ABL1- positive ALL.
(© 2017 by The American Society of Hematology.)