Regina M Myers1, Agne Taraseviciute2,3, Seth M Steinberg4, Adam J Lamble5, Jennifer Sheppard6, Bonnie Yates7, Alexandra E Kovach2, Brent Wood2, Michael J Borowitz8, Maryalice Stetler-Stevenson9, Constance M Yuan9, Vinodh Pillai1, Toni Foley7, Perry Chung1, Lee Chen2, Daniel W Lee10, Colleen Annesley5, Amanda DiNofia1, Stephan A Grupp1, Samuel John6, Deepa Bhojwani11, Patrick A Brown12, Theodore W Laetsch1,6, Lia Gore13, Rebecca A Gardner5, Susan R Rheingold1, Michael A Pulsipher2, Nirali N Shah7. 1. Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA. 2. Section of Transplantation and Cellular Therapy, Children's Hospital Los Angeles Cancer and Blood Disease Institute, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA. 3. Current affiliation: Janssen Research & Development, LLC, Raritan, NJ. 4. Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD. 5. Division of Hematology and Oncology University of Washington, Seattle Children's Hospital, Seattle, WA. 6. Division of Pediatric Hematology-Oncology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX. 7. National Cancer Institute/Center for Cancer Research, Pediatric Oncology Branch, National Institutes of Health, Bethesda, MD. 8. Department of Pathology, Johns Hopkins Hospital, Baltimore, MD. 9. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD. 10. Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Virginia, Charlottesville, VA. 11. Division of Hematology/Oncology, Children's Hospital Los Angeles Cancer and Blood Disease Institute, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA. 12. Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD. 13. Pediatric Heme/Onc/BMT-CT, University of Colorado, Children's Hospital Colorado, Aurora, CO.
Abstract
PURPOSE: CD19-targeted chimeric antigen receptor T cells (CD19-CAR) and blinatumomab effectively induce remission in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) but are also associated with CD19 antigen modulation. There are limited data regarding the impact of prior blinatumomab exposure on subsequent CD19-CAR outcomes. PATIENTS AND METHODS: We conducted a multicenter, retrospective review of children and young adults with relapsed or refractory ALL who received CD19-CAR between 2012 and 2019. Primary objectives addressed 6-month relapse-free survival (RFS) and event-free survival (EFS), stratified by blinatumomab use. Secondary objectives included comparison of longer-term survival outcomes, complete remission rates, CD19 modulation, and identification of factors associated with EFS. RESULTS: Of 420 patients (median age, 12.7 years; interquartile range, 7.1-17.5) treated with commercial tisagenlecleucel or one of three investigational CD19-CAR constructs, 77 (18.3%) received prior blinatumomab. Blinatumomab-exposed patients more frequently harbored KMT2A rearrangements and underwent a prior stem-cell transplant than blinatumomab-naïve patients. Among patients evaluable for CD19-CAR response (n = 412), blinatumomab nonresponders had lower complete remission rates to CD19-CAR (20 of 31, 64.5%) than blinatumomab responders (39 of 42, 92.9%) or blinatumomab-naive patients (317 of 339, 93.5%), P < .0001. Following CD19-CAR, blinatumomab nonresponders had worse 6-month EFS (27.3%; 95% CI, 13.6 to 43.0) compared with blinatumomab responders (66.9%; 95% CI, 50.6 to 78.9; P < .0001) or blinatumomab-naïve patients (72.6%; 95% CI, 67.5 to 77; P < .0001) and worse RFS. High-disease burden independently associated with inferior EFS. CD19-dim or partial expression (preinfusion) was more frequently seen in blinatumomab-exposed patients (13.3% v 6.5%; P = .06) and associated with lower EFS and RFS. CONCLUSION: With the largest series to date in pediatric CD19-CAR, and, to our knowledge, the first to study the impact of sequential CD19 targeting, we demonstrate that blinatumomab nonresponse and high-disease burden were independently associated with worse RFS and EFS, identifying important indicators of long-term outcomes following CD19-CAR.
PURPOSE: CD19-targeted chimeric antigen receptor T cells (CD19-CAR) and blinatumomab effectively induce remission in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) but are also associated with CD19 antigen modulation. There are limited data regarding the impact of prior blinatumomab exposure on subsequent CD19-CAR outcomes. PATIENTS AND METHODS: We conducted a multicenter, retrospective review of children and young adults with relapsed or refractory ALL who received CD19-CAR between 2012 and 2019. Primary objectives addressed 6-month relapse-free survival (RFS) and event-free survival (EFS), stratified by blinatumomab use. Secondary objectives included comparison of longer-term survival outcomes, complete remission rates, CD19 modulation, and identification of factors associated with EFS. RESULTS: Of 420 patients (median age, 12.7 years; interquartile range, 7.1-17.5) treated with commercial tisagenlecleucel or one of three investigational CD19-CAR constructs, 77 (18.3%) received prior blinatumomab. Blinatumomab-exposed patients more frequently harbored KMT2A rearrangements and underwent a prior stem-cell transplant than blinatumomab-naïve patients. Among patients evaluable for CD19-CAR response (n = 412), blinatumomab nonresponders had lower complete remission rates to CD19-CAR (20 of 31, 64.5%) than blinatumomab responders (39 of 42, 92.9%) or blinatumomab-naive patients (317 of 339, 93.5%), P < .0001. Following CD19-CAR, blinatumomab nonresponders had worse 6-month EFS (27.3%; 95% CI, 13.6 to 43.0) compared with blinatumomab responders (66.9%; 95% CI, 50.6 to 78.9; P < .0001) or blinatumomab-naïve patients (72.6%; 95% CI, 67.5 to 77; P < .0001) and worse RFS. High-disease burden independently associated with inferior EFS. CD19-dim or partial expression (preinfusion) was more frequently seen in blinatumomab-exposed patients (13.3% v 6.5%; P = .06) and associated with lower EFS and RFS. CONCLUSION: With the largest series to date in pediatric CD19-CAR, and, to our knowledge, the first to study the impact of sequential CD19 targeting, we demonstrate that blinatumomab nonresponse and high-disease burden were independently associated with worse RFS and EFS, identifying important indicators of long-term outcomes following CD19-CAR.
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