In two B-cell precursor acute lymphoblastic leukemia patients who relapsed after CD19-targeting blinatumomab, Nagel et al. used fluorescent in situ hybridization with BCR-ABL probes to demonstrate that relapsing cells were due to CD19- BCR-ABL1-positive hematopoietic stem cell progenitor and myeloid lineage cells, suggesting that combination therapies are needed to target both CD19+ leukemic B cells and CD19- malignant precursor cells.
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 escape mechanism to CD19-specific immunotherapies. Here, we provide evidence that CD19-negative relapse after CD19-directed therapy in BCP-ALL may be due to selection of preexisting CD19-negative malignant progenitor cells. We present two BCR-ABL1-fusion-positive BCP-ALL patients with CD19-negative 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. Using the same approach in 25 additional diagnostic samples of patients with BCR-ABL1-positive BCP-ALL, HSC involvement was identified in 40% of the patients. Patients with major-BCR-ABL1 transcript encoding P210BCR-ABL1 mainly showed HSC involvement (6/8), whereas in most of the patients with minor-BCR-ABL1 transcript encoding P190BCR-ABL1 only the CD19-positive leukemia compartments were BCR-ABL1-positive (9/12) (p=0.02). Our data are of clinical importance, because they indicate that not only CD19-positive cells, but also CD19-negative precursors should be targeted to avoid CD19-negative relapses in patients with BCR-ABL1-positive ALL.
Author Info: (1) Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. (2) Department of Hematology, University
Author Info: (1) Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. (2) Department of Hematology, University Hospital Schleswig-Holstein, Kiel, Germany. (3) Department of Internal Medicine II, Universitaetsklinikum, Wuerzburg, Germany. (4) Institute of Immunology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. (5) Institute of Immunology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. (6) Institute of Experimental and Clinical Pharmacology, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. (7) Division of Cancer and Genetics, Dept. of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom. (8) 2nd Medical Department, University Hospital, Frankfurt, Germany. (9) Department of Hematology, University Hospital Schleswig-Holstein, Kiel, Germany. (10) 2nd Medical Department, University Hospital, Frankfurt, Germany. (11) Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. (12) Institute of Immunology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. (13) Department of Hematology, University Hospital Schleswig-Holstein, Kiel, Germany. (14) Department of Hematology, University Hospital Schleswig-Holstein, Kiel, Germany. (15) 2nd Medical Department, University Hospital, Frankfurt, Germany. (16) Department of Internal Medicine II, Universitaetsklinikum, Wuerzburg, Germany. (17) Institute of Experimental and Clinical Pharmacology, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. (18) Institute of Human Genetics, University Hospital of Ulm & University Ulm, Germany. (19) Department of Hematology, University Hospital Schleswig-Holstein, Kiel, Germany; m.brueggemann@med2.uni-kiel.de.
