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

• Published in: Blood 2017-11, Vol.130 (18), p.2027-2031
• Main Authors: Nagel, Inga, Bartels, Marius, Duell, Johannes, Oberg, Hans-Heinrich, Ussat, Sandra, Bruckmueller, Henrike, Ottmann, Oliver, Pfeifer, Heike, Trautmann, Heiko, Gökbuget, Nicola, Caliebe, Almuth, Kabelitz, Dieter, Kneba, Michael, Horst, Heinz-August, Hoelzer, Dieter, Topp, Max S., Cascorbi, Ingolf, Siebert, Reiner, Brüggemann, Monika
• Format: Article
• Language: English
• Subjects: Adult; Antibodies, Bispecific - therapeutic use; Blast Crisis - pathology; Brief Report; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl - metabolism; Hematopoietic Stem Cells - metabolism; Humans; Immunophenotyping; Lymphoid Neoplasia; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2017-05-782888

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. •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.