@article{6d314f83508346e08336ec4621bccff7,
title = "Vitamin D Insufficiency and Clinical Outcomes with Chimeric Antigen Receptor T-Cell Therapy in Large B-cell Lymphoma",
abstract = "Vitamin D insufficiency is a potentially modifiable risk factor for poor outcomes in newly diagnosed large B-cell lymphoma (LBCL). However, the role of circulating vitamin D concentrations in relapsed/refractory LBCL treated with CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) is currently unknown. This was a single-center, observational study that evaluated the association of pre-CAR-T 25-hydroxyvitamin D (25-OHD) status with 100-day complete response, progression-free survival, overall survival, and CAR-T–related toxicity in 111 adult relapsed/refractory LBCL patients. Vitamin D insufficiency was defined as ≤30 ng/mL in accordance with the Endocrine Society guidelines. The median pre-CAR-T 25-hydroxyvitamin D concentration was 24 ng/mL (interquarile range = 18-34). Vitamin D–insufficient patients (≤30 ng/mL; n = 73 [66%]) were significantly younger than their vitamin D–replete (>30 ng/mL; n = 38 [34%]) counterparts (P= .039). The vitamin D–insufficient cohort was enriched for de novo LBCL as the histological subtype (P= .026) and had a higher proportion of tisagenlecleucel as the CAR-T product (P= .049). There were no other significant differences in the baseline characteristics between the two groups. In vitamin D–insufficient compared to –replete patients, 100-day complete response was 55% versus 76% (P= .029), and 2-year overall survival was 41% versus 71% (P= .061), respectively. In multivariate analysis, vitamin D insufficiency remained significantly associated with 100-day complete response (odds ratio 2.58 [1.05-6.83]; P= .045) and overall survival (hazard ratio 2.24 [1.08-4.66], P= .030). In recipients of tisagenlecleucel, vitamin D insufficiency was associated with significantly lower cell viability of the infused CAR-T product (P= .015). Finally, pretreatment vitamin D insufficiency did not predict for subsequent CAR-T–related toxicity. This is the first report to demonstrate that vitamin D insufficiency is associated with inferior clinical outcomes in CAR-T recipients. Further study into the mechanistic insights of this finding, and the potential role of vitamin D supplementation to optimize CAR-T are warranted.",
keywords = "CAR-T, Large B-cell lymphoma, Prognostic biomarker, Vitamin D",
author = "Karthik Nath and Tomas, {Ana Alarcon} and Jessica Flynn and Fein, {Joshua A.} and Anna Alperovich and Theodora Anagnostou and Batlevi, {Connie Lee} and Dahi, {Parastoo B.} and Fingrut, {Warren B.} and Giralt, {Sergio A.} and Lin, {Richard J.} and Palomba, {M. Lia} and Peled, {Jonathan U.} and Gilles Salles and Sauter, {Craig S.} and Michael Scordo and Ellen Fraint and Elise Feuer and Nishi Shah and Slingerland, {John B.} and Sean Devlin and Shah, {Gunjan L.} and Gaurav Gupta and Perales, {Miguel Angel} and Roni Shouval",
note = "Funding Information: Financial disclosure: Supported by the Memorial Sloan Kettering Cancer Center Core Grant (P30 CA008748) from the National Institutes of Health/National Cancer Institute. RS was supported by the American Society of Transplantation and Cellular Therapy New Investigator Award, the American Society of Hematology Fellow Scholar Award, a grant from the Long Island Sound Chapter, Swim Across America, the Robert Hirschhorn Award, and the Memorial Sloan Kettering Steven Greenberg Lymphoma Research Award. A.A.T. was supported by a grant from the Alfonso Martin Escudero Foundation. J.A.F. was supported by a grant from the American Society of Hematology. Conflict of interest statement: R.S. reports a Consulting or Advisory Role withMedexus and MyBiotics. C.L.B. reports Stock and Other Ownership Interests with Moderna Therapeutics, Novavax, Pfizer, Bristol Myers Squibb, Regeneron, Viatris; Honoraria from DAVA Oncology; a Consulting or Advisory Role with LifeSci Capital, GLG, Juno Therapeutics, Celgene, Seattle Genetics, Kite, a Gilead company, TG Therapeutics, Karyopharm Therapeutics. Research Funding: Janssen Biotech (Inst), Novartis (Inst), Epizyme (Inst), Xynomic Pharma (Inst), Bayer (Inst), Roche (Inst), Autolus (Inst). P.B.D. reports a Consulting or Advisory Role with Kite, a Gilead company. S.A.G. reports Honoraria from Celgene, Takeda, Amgen, Jazz Pharmaceuticals, Sanofi; a Consulting or Advisory Role with Celgene, Takeda, Sanofi, Jazz Pharmaceuticals, Amgen, Janssen, Actinuum, Bristol Myers Squibb, Johnson & Johnson, and Pfizer; Research Funding from Celgene (Inst), Miltenyi Biotec, Johnson & Johnson, Amgen, Actinuum, and Sanofi; Travel, Accommodations or Expenses from Celgene, Sanofi, Amgen, and Jazz Pharmaceuticals. G.S. reports Honoraria from Roche/Genentech, Janssen, Celgene, Gilead Sciences, Novartis, AbbVie, and MorphoSys; a Consulting or Advisory Role with Roche/Genentech, Gilead Sciences, Janssen, Celgene, Novartis, MorphoSys, Epizyme, Alimera Sciences, Genmab, Debiopharm Group, Velosbio, BMS, BeiGene, Incyte, Miltenyi Biotec, and Ipsen. C.S.S. reports a Consulting or Advisory Role with Spectrum Pharmaceuticals, Juno Therapeutics, Sanofi, Gilead Sciences, Novartis, Precision BioSciences, Gamida Cell, Karyopharm Therapeutics, GlaxoSmithKline, and Genmab; Research Funding from Juno Therapeutics (Inst), Sanofi (Inst), Precision BioSciences (Inst), BMS (Inst), and Actinium Pharmaceuticals (Inst); Travel, Accommodations, and Expenses from Juno Therapeutics, Sanofi, Gilead Sciences, and Novartis. M.S. reports Honoraria from i3 CME; a Consulting or Advisory Role with McKinsey & Company, Angiocrine Bioscience, and Omeros; Research Funding from Angiocrine Bioscience and Omeros (Inst); Travel, Accommodations, and Expenses from Kite/Gilead. G.L.S. reports Research Funding from Amgen (Inst) and Janssen (Inst). M-A.P. reports Stock and Other Ownership Interests with NexImmune and Omeros; Honoraria from MorphoSys; a Consulting or Advisory Role with Incyte, Merck, Servier/Pfizer, NexImmune, Novartis, MolMed, Medigene, Takeda, Nektar, AbbVie, Cidara Therapeutics, Celgene, Kite/Gilead, Bristol Myers Squibb, Omeros, and Vor Biopharma; Research Funding from Incyte (Inst), Miltenyi Biotec (Inst), Novartis (Inst), Kite, a Gilead company (Inst), and Nektar (Inst). M.L.P. reports Stock and Other Ownership Interests with Seres Therapeutics (I); Honoraria from Flagship Biosciences (I), Evelo Therapeutics (I), Jazz Pharmaceuticals (I), Therakos (I), Amgen (I), Merck (I), and Seres Therapeutics (I); a Consulting or Advisory Role with Flagship Biosciences (I), Novartis (I), Evelo Therapeutics (I), Jazz Pharmaceuticals (I), Therakos (I), Amgen (I), Merck (I), Seres Therapeutics (I), Kite, a Gilead company, Novartis, BeiGene, and Synthekine; Research Funding from Seres Therapeutics (I); Patents, Royalties, Other Intellectual Property: Intellectual Property Rights (I), Juno intellectual property rights (Inst). J.U.P. reports Research funding, intellectual property fees, and travel reimbursement from Seres Therapeutics; Consulting fees from DaVolterra, CSL Behring, and MaaT Pharma; Advisory board and holds equity in Postbiotics Plus Research. K.N. R.S. A.A.T, J.F. G.G and M-A.P. conceived and designed the analysis; A.A.T. A.A. T.A. W.B.F. E.Fraint, N.S. collected the data; J.B.S. J.A.F, C.L.B. P.B.D. S.A.G, R.J.L. M.L.P. J.U.P, G.S. C.S.S, M.S. G.L.S. E.Feurer, G.G contributed data or analysis tools; J.F. S.D. R.S performed analysis of the data; K.N, R.S. wrote the paper; all authors critically reviewed the manuscript. Financial disclosure: See Acknowledgments on page XXXX. Funding Information: Financial disclosure: Supported by the Memorial Sloan Kettering Cancer Center Core Grant ( P30 CA008748 ) from the National Institutes of Health/National Cancer Institute. RS was supported by the American Society of Transplantation and Cellular Therapy New Investigator Award, the American Society of Hematology Fellow Scholar Award, a grant from the Long Island Sound Chapter, Swim Across America, the Robert Hirschhorn Award, and the Memorial Sloan Kettering Steven Greenberg Lymphoma Research Award. A.A.T. was supported by a grant from the Alfonso Martin Escudero Foundation. J.A.F. was supported by a grant from the American Society of Hematology. Publisher Copyright: {\textcopyright} 2022 The American Society for Transplantation and Cellular Therapy",
year = "2022",
month = nov,
doi = "10.1016/j.jtct.2022.08.001",
language = "English (US)",
volume = "28",
pages = "751.e1--751.e7",
journal = "Transplantation and Cellular Therapy",
issn = "2666-6375",
publisher = "Elsevier BV",
number = "11",
}