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Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy

Kevin A. Hay, Jordan Gauthier, Alexandre V. Hirayama, Jenna M. Voutsinas, Qian Wu, Daniel Li, Ted A. Gooley, Sindhu Cherian, Xueyan Chen, Barbara S. Pender, Reed M. Hawkins, Aesha Vakil, Rachel N. Steinmetz, Gary Schoch, Aude G. Chapuis, Brian G. Till, Hans-Peter Kiem, Jorge D. Ramos, Mazyar Shadman, Ryan D. Cassaday, Utkarsh H. Acharya, Stanley R. Riddell, David G. Maloney and Cameron J. Turtle

Key Points

  • Baseline platelet count, lactate dehydrogenase, and lymphodepletion regimen impact EFS in patients in MRD-negative CR after CD19 CAR T-cell.

  • Allogeneic HCT after CD19 CAR T-cell therapy is well tolerated and may improve EFS.

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

Abstract

Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease–negative (MRD-negative) complete remission (CR) rates in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR T-cell therapy have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase 1/2 clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR T-cell therapy at our institution. Forty-five (85%) of 53 patients who received CD19 CAR T-cell therapy and were evaluable for response achieved MRD-negative CR by high-resolution flow cytometry. With a median follow-up of 30.9 months, event-free survival (EFS) and overall survival (OS) were significantly better in the patients who achieved MRD-negative CR compared with those who did not (median EFS, 7.6 vs 0.8 months; P < .0001; median OS, 20.0 vs 5.0 months; P = .014). In patients who achieved MRD-negative CR by flow cytometry, absence of the index malignant clone by IGH deep sequencing was associated with better EFS (P = .034). Stepwise multivariable modeling in patients achieving MRD-negative CR showed that lower prelymphodepletion lactate dehydrogenase concentration (hazard ratio [HR], 1.38 per 100 U/L increment increase), higher prelymphodepletion platelet count (HR, 0.74 per 50 000/μL increment increase), incorporation of fludarabine into the lymphodepletion regimen (HR, 0.25), and allogeneic hematopoietic cell transplantation (HCT) after CAR T-cell therapy (HR, 0.39) were associated with better EFS. These data allow identification of patients at higher risk of relapse after CAR T-cell immunotherapy who might benefit from consolidation strategies such as allogeneic HCT. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

  • Submitted November 7, 2018.
  • Accepted January 28, 2019.
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