Hematopoietic stem cell involvement in 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 fusion-positive BCP-ALL patients with CD19 myeloid lineage relapse after blinatumomab therapy and show 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 positive BCP-ALL, we identified HSC involvement in 40% of the patients. Patients (6 of 8) with major transcript encoding P210 mainly showed HSC involvement, whereas in most of the patients (9 of 12) with minor transcript encoding P190, only the CD19 leukemia compartments were positive ( = .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 positive ALL.