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Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking

Friederike Braig, Anna Brandt, Mariele Goebeler, Hans-Peter Tony, Anna-Katharina Kurze, Peter Nollau, Thomas Bumm, Sebastian Böttcher, Ralf C. Bargou and Mascha Binder

Key Points

  • CD19 relapses are a major challenge in about 10% to 20% of patients treated with blinatumomab.

  • Molecular workup of 1 case revealed a disrupted CD19 membrane export as the basis for blinatumomab resistance.

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

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.

  • Submitted May 25, 2016.
  • Accepted October 11, 2016.
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