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

TY - JOUR

T1 - Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking

AU - Braig, Friederike

AU - Brandt, Anna

AU - Goebeler, Mariele

AU - Tony, Hans-Peter

AU - Kurze, Anna-Katharina

AU - Nollau, Peter

AU - Bumm, Thomas

AU - Böttcher, Sebastian

AU - Bargou, Ralf C

AU - Binder, Mascha

N1 - Copyright © 2016 American Society of Hematology.

PY - 2017/1/5

Y1 - 2017/1/5

N2 - The CD19 antigen is a promising target for immunotherapy of acute lymphoblastic leukemia (ALL), but CD19-negative relapses remain a major challenge in about 10-20% of patients. Here, we analyzed four CD19-negative ALL relapses after treatment with the CD19/CD3 bispecific T-cell engager blinatumomab. Three were on-drug relapses, with the CD19-negative escape variant first detected after only two treatment courses. In one patient, the CD19-negative clone appeared as a late relapse 19 months after completion of blinatumomab treatment. All four 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-negative progenitor cell or myeloid lineage shift driving resistance. A thorough molecular workup of one 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.

AB - The CD19 antigen is a promising target for immunotherapy of acute lymphoblastic leukemia (ALL), but CD19-negative relapses remain a major challenge in about 10-20% of patients. Here, we analyzed four CD19-negative ALL relapses after treatment with the CD19/CD3 bispecific T-cell engager blinatumomab. Three were on-drug relapses, with the CD19-negative escape variant first detected after only two treatment courses. In one patient, the CD19-negative clone appeared as a late relapse 19 months after completion of blinatumomab treatment. All four 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-negative progenitor cell or myeloid lineage shift driving resistance. A thorough molecular workup of one 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.

U2 - 10.1182/blood-2016-05-718395

DO - 10.1182/blood-2016-05-718395

M3 - SCORING: Journal article

C2 - 27784674

VL - 129

SP - 100

EP - 104

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 1

ER -