Liora M Schultz1, Christina Baggott2, Snehit Prabhu3, Holly L Pacenta4,5, Christine L Phillips6,7, Jenna Rossoff8, Heather E Stefanski9, Julie-An Talano10, Amy Moskop10, Steven P Margossian11, Michael R Verneris12, Gary Douglas Myers13, Nicole A Karras14, Patrick A Brown15, Muna Qayed16, Michelle Hermiston17, Prakash Satwani18, Christa Krupski6,7, Amy K Keating12, Rachel Wilcox13, Cara A Rabik19, Vanessa A Fabrizio20,21, Rayne H Rouce22, Vasant Chinnabhandar9, Michael Kunicki2, Valentin V Barsan1, A Yasemin Goksenin17, Yimei Li23, Sharon Mavroukakis2, Emily Egeler2, Kevin J Curran20,21, Crystal L Mackall24,25, Theodore W Laetsch4,26,27. 1. Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA. 2. Stanford University School of Medicine, Stanford, CA. 3. Stanford University School of Medicine, Stanford Cancer Institute, Stanford, CA. 4. Department of Pediatrics, The University of Texas Southwestern Medical Center/Children's Health, Dallas, TX. 5. Division of Hematology and Oncology, Cook Children's Medical Center, Fort Worth, TX. 6. Department of Pediatrics, University of Cincinnati, Cincinnati, OH. 7. Cincinnati Children's Hospital Medical Center, Cancer and Blood Disease Institute, Cincinnati, OH. 8. Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL. 9. Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN. 10. Division of Hematology/Oncology/Blood and Marrow Transplantation, Department of Pediatrics, Medical College of Wisconsin and Children's Wisconsin, Wauwatosa, WI. 11. Harvard Medical School, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Pediatric Hematology-Oncology, Boston, MA. 12. University of Colorado School of Medicine, Children's Hospital of Colorado, Aurora, CO. 13. Children's Mercy Hospital, University of Missouri Kansas City, Kansas City, MO. 14. Department of Pediatrics, City of Hope National Medical Center, Duarte, CA. 15. Department of Oncology, Sidney Kimmel Cancer Center at John Hopkins School of Medicine, Baltimore, MD. 16. Emory University and Children's Healthcare of Atlanta, Druid Hills, GA. 17. University of California San Francisco Benioff Children's Hospital, San Francisco, CA. 18. Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, Columbia University Medical Center, New York, NY. 19. Division of Hematologic Malignancies I, Center for Drug Evaluation and Research (CDER), FDA, Silver Spring, MD. 20. Department of Pediatrics, Memorial Sloan Kettering Cancer Center. 21. Department of Pediatrics, Weill Cornell Medical College, New York, NY. 22. Texas Children's Cancer Center, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX. 23. Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 24. Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford, CA. 25. Department of Medicine, Division of Blood and Bone Marrow Transplantation, Stanford University School of Medicine, Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford, CA. 26. Department of Pediatrics and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 27. Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.
Abstract
PURPOSE: Tisagenlecleucel is a CD19-specific chimeric antigen receptor T-cell therapy, US Food and Drug Administration-approved for children, adolescents, and young adults (CAYA) with relapsed and/or refractory (RR) B-cell acute lymphoblastic leukemia (B-ALL). The US Food and Drug Administration registration for tisagenlecleucel was based on a complete response (CR) rate of 81%, 12-month overall survival (OS) of 76%, and event-free survival (EFS) of 50%. We report clinical outcomes and analyze covariates of outcomes after commercial tisagenlecleucel. METHODS: We conducted a retrospective, multi-institutional study of CAYA with RR B-ALL across 15 US institutions, who underwent leukapheresis shipment to Novartis for commercial tisagenlecleucel. A total of 200 patients were included in an intent-to-treat response analysis, and 185 infused patients were analyzed for survival and toxicity. RESULTS: Intent-to-treat analysis demonstrates a 79% morphologic CR rate (95% CI, 72 to 84). The infused cohort had an 85% CR (95% CI, 79 to 89) and 12-month OS of 72% and EFS of 50%, with 335 days of median follow-up. Notably, 48% of patients had low-disease burden (< 5% bone marrow lymphoblasts, no CNS3, or other extramedullary disease), or undetectable disease, pretisagenlecleucel. Univariate and multivariate analyses associate high-disease burden (HB, ≥ 5% bone marrow lymphoblasts, CNS3, or non-CNS extramedullary) with inferior outcomes, with a 12-month OS of 58% and EFS of 31% compared with low-disease burden (OS; 85%, EFS; 70%) and undetectable disease (OS; 95%, EFS; 72%; P < .0001 for OS and EFS). Grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 21% and 7% overall and 35% and 9% in patients with HB, respectively. CONCLUSION: Commercial tisagenlecleucel in CAYA RR B-ALL demonstrates efficacy and tolerability. This first analysis of commercial tisagenlecleucel stratified by disease burden identifies HB preinfusion to associate with inferior OS and EFS and increased toxicity.
PURPOSE: Tisagenlecleucel is a CD19-specific chimeric antigen receptor T-cell therapy, US Food and Drug Administration-approved for children, adolescents, and young adults (CAYA) with relapsed and/or refractory (RR) B-cell acute lymphoblastic leukemia (B-ALL). The US Food and Drug Administration registration for tisagenlecleucel was based on a complete response (CR) rate of 81%, 12-month overall survival (OS) of 76%, and event-free survival (EFS) of 50%. We report clinical outcomes and analyze covariates of outcomes after commercial tisagenlecleucel. METHODS: We conducted a retrospective, multi-institutional study of CAYA with RR B-ALL across 15 US institutions, who underwent leukapheresis shipment to Novartis for commercial tisagenlecleucel. A total of 200 patients were included in an intent-to-treat response analysis, and 185 infused patients were analyzed for survival and toxicity. RESULTS: Intent-to-treat analysis demonstrates a 79% morphologic CR rate (95% CI, 72 to 84). The infused cohort had an 85% CR (95% CI, 79 to 89) and 12-month OS of 72% and EFS of 50%, with 335 days of median follow-up. Notably, 48% of patients had low-disease burden (< 5% bone marrow lymphoblasts, no CNS3, or other extramedullary disease), or undetectable disease, pretisagenlecleucel. Univariate and multivariate analyses associate high-disease burden (HB, ≥ 5% bone marrow lymphoblasts, CNS3, or non-CNS extramedullary) with inferior outcomes, with a 12-month OS of 58% and EFS of 31% compared with low-disease burden (OS; 85%, EFS; 70%) and undetectable disease (OS; 95%, EFS; 72%; P < .0001 for OS and EFS). Grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 21% and 7% overall and 35% and 9% in patients with HB, respectively. CONCLUSION: Commercial tisagenlecleucel in CAYA RR B-ALL demonstrates efficacy and tolerability. This first analysis of commercial tisagenlecleucel stratified by disease burden identifies HB preinfusion to associate with inferior OS and EFS and increased toxicity.
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