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

Inga Nagel, Marius Bartels, Johannes Duell, Hans-Heinrich Oberg, Sandra Ussat, Henrike Bruckmueller, Oliver Ottmann, Heike Pfeifer, Heiko Trautmann, Nicola Gökbuget, Almuth Caliebe, Dieter Kabelitz, Michael Kneba, Heinz-August Horst, Dieter Hoelzer, Max S. Topp, Ingolf Cascorbi, Reiner Siebert and Monika Brüggemann

Key Points

  • BCR-ABL1–positive cells outside the B-lineage compartment are found in 40% of adult patients with BCR-ABL1–positive BCP-ALL.

  • Selection of preexisting CD19 subclones is a potential source of tumor escape after CD19-targeted therapies in adult Philadelphia chromosome–positive ALL.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

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 P210BCR-ABL1 mainly showed HSC involvement, whereas in most of the patients (9 of 12) with minor BCR-ABL1 transcript encoding P190BCR-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.

  • Submitted May 4, 2017.
  • Accepted July 27, 2017.
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