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

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

  • The baseline platelet count and LDH, and lymphodepletion regimen impact EFS in patients in MRD-negative CR after CD19 CAR-T cells.

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

Abstract

Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease-negative complete remission (MRD-negative CR) rates in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR-T cells have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase I/II clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR-T cells (NCT01865617, www.clinicaltrials.gov) at our institution. Forty-five of 53 (85%) 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 to 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 lower pre-lymphodepletion LDH concentration (hazard ratio, HR 1.38 per 100U/L increment increase), higher pre-lymphodepletion 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 like allogeneic HCT.

  • Submitted November 8, 2018.
  • Accepted January 28, 2019.