Abstract
CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with relapsed/refractory B-cell malignancies; however, it is associated with toxicities including cytokine release syndrome (CRS), neurotoxicity, and impaired hematopoietic recovery. The latter is associated with high-grade cytopenias requiring extended growth factor or transfusional support, potentially leading to additional complications such as infection or hemorrhage. To date, the factors independently associated with hematologic toxicity have not been well characterized. To address this deficit, we retrospectively analyzed 173 patients who received defined-composition CD19 CAR T-cell therapy in a phase 1/2 clinical trial (https://clinicaltrials.gov; NCT01865617), with primary end points of absolute neutrophil count and platelet count at day-28 after CAR T-cell infusion. We observed cumulative incidences of neutrophil and platelet recovery of 81% and 75%, respectively, at 28 days after infusion. Hematologic toxicity was noted in a significant subset of patients, with persistent neutropenia in 9% and thrombocytopenia in 14% at last follow-up. Using debiased least absolute shrinkage selector and operator regression analysis for high-dimensional modeling and considering patient-, disease-, and treatment-related variables, we identified increased CRS severity as an independent predictor for decreased platelet count and lower prelymphodepletion platelet count as an independent predictor of both decreased neutrophil and platelet counts after CD19 CAR T-cell infusion. Furthermore, multivariable models including CRS-related cytokines identified associations between higher peak serum concentrations of interleukin-6 and lower day-28 cell counts; in contrast, higher serum concentrations of transforming growth factor-β1 were associated with higher counts. Our findings suggest that patient selection and improved CRS management may improve hematopoietic recovery after CD19 CAR T-cell therapy.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2055-2068 |
| Number of pages | 14 |
| Journal | Blood Advances |
| Volume | 6 |
| Issue number | 7 |
| DOIs | |
| State | Published - Apr 12 2022 |
Bibliographical note
Funding Information:Conflict-of-interest disclosure: A.V.H. received honoraria from Bristol Myers Squibb and Novartis and research support from Juno Therapeutics, a Bristol Myers Squibb company. D.G.M. received research funding from Kite Pharma, Juno Therapeutics, a Celgene company, and Celgene and honoraria for participation on advisory boards for Kite Pharma, Gilead, Genentech, Novartis, and Eureka. C.J.T. receives research funding from Juno Therapeutics, Nektar Therapeutics, Minerva, TCR2, and AstraZeneca; serves on scientific advisory boards and has options in Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, and ArsenalBio; serves on scientific advisory boards for T-CURX and Century Therapeutics; has served on advisory boards for Nektar Therapeutics, Allogene, Kite/Gilead, Novartis, Humanigen, PACT Pharma, Amgen, and Astra Zeneca; and has patents licensed to Juno Therapeutics. J.G. has received honoraria from Larvol, Eusa-pharma, JMP, and Multerra Bio; has received research support from Juno Therapeutics, a Bristol Myers Squibb company, and Sobi; and has served on an advisory board for JNJ/Legend Biotech. The remaining authors declare no competing financial interests.
Funding Information:
This work was supported by National Institutes of Health, National Cancer Institute grants R01CA136551, R35CA197734,
Publisher Copyright:
© 2022 by The American Society of Hematology.
Keywords
- Antigens, CD19
- Cell Count
- Clinical Trials, Phase I as Topic
- Clinical Trials, Phase II as Topic
- Cytokine Release Syndrome/etiology
- Humans
- Immunotherapy, Adoptive/adverse effects
- Recurrence
- Retrospective Studies
- Thrombocytopenia/etiology
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural