title: Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking.
abstract: The CD19 antigen is a promising target for immunotherapy of acute lymphoblastic leukemia (ALL), but CD19-relapses remain a major challenge in about 10% to 20% of patients. Here, we analyzed 4 CD19-ALL relapses after treatment with the CD19/CD3 bispecific T-cell engager (BiTE) blinatumomab. Three were on-drug relapses, with the CD19-escape variant first detected after only 2 treatment courses. In 1 patient, the CD19-clone appeared as a late relapse 19 months after completion of blinatumomab treatment. All 4 cases showed a cellular phenotype identical to the primary diagnosis except for CD19 negativity. This argued strongly in favor of an isolated molecular event and against a common lymphoid CD19-progenitor cell or myeloid lineage shift driving resistance. A thorough molecular workup of 1 of the cases with early relapse confirmed this hypothesis by revealing a disrupted CD19 membrane export in the post-endoplasmic reticulum compartment as molecular basis for blinatumomab resistance.
authors: Department of Oncology and Hematology, Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Friederike
authors: F
authors: Braig
authors: Department of Oncology and Hematology, Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Anna
authors: A
authors: Brandt
authors: Hematology/Oncology, Department of Internal Medicine II, and.
authors: Mariele
authors: M
authors: Goebeler
authors: Rheumatology/Clinical Immunology, University Hospital of Würzburg, Würzburg, Germany.
authors: Hans-Peter
authors: HP
authors: Tony
authors: Research Institute Children's Cancer Center, Hamburg, Germany.|Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Anna-Katharina
authors: AK
authors: Kurze
authors: Research Institute Children's Cancer Center, Hamburg, Germany.|Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Peter
authors: P
authors: Nollau
authors: Hematology/Oncology, Department of Internal Medicine II, and.
authors: Thomas
authors: T
authors: Bumm
authors: Division of Medicine, Clinic III, Hematology, Oncology and Palliative Medicine, University of Rostock, Rostock, Germany; and.
authors: Sebastian
authors: S
authors: Böttcher
authors: Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Würzburg, Germany.
authors: Ralf C
authors: RC
authors: Bargou
authors: Department of Oncology and Hematology, Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Mascha
authors: M
authors: Binder
mesh_terms: D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific / Q000627:therapeutic use; D018941:Antigens, CD19 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport
chemical_list: D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D000970:Antineoplastic Agents; C000604811:CD19 molecule, human; C510808:blinatumomab