Preinfusion factors impacting relapse immunophenotype following CD19 CAR T cells

Author:

Lamble Adam J.1ORCID,Myers Regina M.2ORCID,Taraseviciute Agne3,John Samuel4,Yates Bonnie5,Steinberg Seth M.6,Sheppard Jennifer4,Kovach Alexandra E.7ORCID,Wood Brent7ORCID,Borowitz Michael J.8,Stetler-Stevenson Maryalice9,Yuan Constance M.9ORCID,Pillai Vinodh2ORCID,Foley Toni5,Chung Perry2,Chen Lee2,Lee Daniel W.10ORCID,Annesley Colleen1,DiNofia Amanda2,Grupp Stephan A.2,Verneris Michael R.11,Gore Lia11ORCID,Laetsch Theodore W.24,Bhojwani Deepa12,Brown Patrick A.13ORCID,Pulsipher Michael A.14ORCID,Rheingold Susan R.2ORCID,Gardner Rebecca A.1,Shah Nirali N.5ORCID

Affiliation:

1. 1Division of Hematology/Oncology, University of Washington, Seattle Children's Hospital, Seattle, WA

2. 2Division of Oncology, Cell Therapy and Transplant Section, Children's Hospital of Philadelphia, Philadelphia, PA

3. 3Section 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

4. 4Division of Pediatric Hematology/Oncology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX

5. 5National Cancer Institute/Center for Cancer Research, Pediatric Oncology Branch, National Institutes of Health, Bethesda, MD

6. 6Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD

7. 7Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA

8. 8Department of Pathology, Johns Hopkins Hospital, Baltimore, MD

9. 9Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD

10. 10Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Virginia, Charlottesville, VA

11. 11Pediatric Hematology/Oncology/BMT-CT, University of Colorado, Children's Hospital Colorado, Aurora, CO

12. 12Division 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

13. 13Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD

14. 14Division of Hematology and Oncology, Primary Children’s Hospital, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT

Abstract

Abstract Relapse following chimeric antigen receptor (CAR) T-cell therapy directed against CD19 for relapsed/refractory B-acute lymphoblastic leukemia (r/r B-ALL) remains a significant challenge. Three main patterns of relapse predominate: CD19 positive (CD19pos) relapse, CD19 negative (CD19neg) relapse, and lineage switch (LS). Development and validation of risk factors that predict relapse phenotype could help define potential pre- or post-CAR T-cell infusion interventions aimed at decreasing relapse. Our group sought to extensively characterize preinfusion risk factors associated with the development of each relapse pattern via a multicenter, retrospective review of children and young adults with r/r B-ALL treated with a murine-based CD19-CAR construct. Of 420 patients treated with CAR, 166 (39.5%) relapsed, including 83 (50%) CD19pos, 68 (41%) CD19neg, and 12 (7.2%) LS relapses. A greater cumulative number of prior complete remissions was associated with CD19pos relapses, whereas high preinfusion disease burden, prior blinatumomab nonresponse, older age, and 4-1BB CAR construct were associated with CD19neg relapses. The presence of a KMT2A rearrangement was the only preinfusion risk factor associated with LS. The median overall survival following a post-CAR relapse was 11.9 months (95% CI, 9-17) and was particularly dismal in patients experiencing an LS, with no long-term survivors following this pattern of relapse. Given the poor outcomes for those with post-CAR relapse, study of relapse prevention strategies, such as consolidative hematopoietic stem cell transplantation, is critical and warrants further investigation on prospective clinical trials.

Publisher

American Society of Hematology

Subject

Hematology

Reference35 articles.

1. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia;Maude;N Engl J Med,2018

2. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study;Shah;Lancet,2021

3. Mechanisms of resistance to CAR T cell therapy;Shah;Nat Rev Clin Oncol,2019

4. Blinatumomab nonresponse and high-disease burden are associated with inferior outcomes after CD19-CAR for B-ALL;Myers;J Clin Oncol,2021

5. Disease burden affects outcomes in pediatric and young adult B-cell lymphoblastic leukemia after commercial tisagenlecleucel: a pediatric real-world chimeric antigen receptor consortium report;Schultz;J Clin Oncol,2021

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