Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR-T cells.
Hay KA , Gauthier J , Hirayama AV , Voutsinas JM , Wu Q , Li D , Gooley TA , Cherian S , Chen X , Pender BS , Hawkins RM , Vakil A , Steinmetz RN , Schoch G , Chapuis AG , Till BG , Kiem HP , Ramos JD , Shadman M , Cassaday RD , Acharya UH , Riddell SR ,
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.
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