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: Friederike Braig, Anna Brandt, Mariele Goebeler, Hans-Peter Tony, Anna-Katharina Kurze, Peter Nollau, Thomas Bumm, Sebastian Böttcher, Ralf C Bargou, Mascha Binder
• Journal: Blood (Blood) Vol. 129 Issue 1 Pg. 100-104 (01 05 2017) ISSN: 1528-0020 [Electronic] United States
• PMID: 27784674 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by The American Society of Hematology.

Chemical References

• Antibodies, Bispecific
• Antigens, CD19
• Antineoplastic Agents
• CD19 molecule, human
• blinatumomab

Topics

• Adult
• Aged
• Antibodies, Bispecific (therapeutic use)
• Antigens, CD19 (metabolism)
• Antineoplastic Agents (therapeutic use)
• Blotting, Western
• Cell Membrane (metabolism)
• Drug Resistance, Neoplasm (physiology)
• Female
• Flow Cytometry
• Humans
• Male
• Middle Aged
• Neoplasm Recurrence, Local (metabolism, pathology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (metabolism, pathology)
• Protein Transport