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, Cameron J Turtle, 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, Cameron J Turtle
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.
Conflict of interest statement
Conflict-of-interest disclosure: K.A.H. has served on ad hoc advisory boards for Celgene. D.L. is an employee of and has equity interests in Juno Therapeutics (a Celgene company). B.G.T. received research funding from Mustang Biopharma and has patents licensed to Mustang Biopharma. H.-P.K. served as a consultant for Rocket Pharmaceuticals, Homology Medicine, and Magenta. J.D.R. is an employee of and has equity ownership in Seattle Genetics. M.S. received research funding from Acerta Pharma, Beigene, Celgene, Genentech, Gilead Sciences, Mustang Biopharma, Pharmacyclics, and TG Therapeutics and served as a consultant for Qilu Puget Sound Biotherapeutics, AbbVie, Genentech, Verastem, and AstraZeneca. R.D.C. received research funding from Amgen, Incyte, Kite (a Gilead Company), Merck, Pfizer, and Seattle Genetics and served as a consultant for Adaptive Biotechnologies, Pfizer, Amgen, and Jazz Pharmaceuticals. U.H.A. received research funding from Juno Therapeutics. S.R.R. served as an advisor and has equity interests in Juno Therapeutics, Adaptive Biotechnologies, and Nohla Therapeutics. D.G.M. received research funding from GlaxoSmithKline and Juno Therapeutics. C.J.T. received research funding from Juno Therapeutics and Nektar Therapeutics, has patents licensed to Juno Therapeutics, serves on scientific advisory boards, has equity ownership in Caribou Biosciences, Eureka Therapeutics, and Precision Biosciences, and has served on ad hoc advisory boards for Aptevo, Juno Therapeutics, Kite, Nektar Therapeutics, and Novartis. The remaining authors declare no competing financial interests.
© 2019 by The American Society of Hematology.
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Source: PubMed