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LYMPHOMA

Impact of conditioning chemotherapy on lymphocyte kinetics and outcomes in LBCL patients treated with CAR T-cell therapy

Leukemia volume 36, pages 2669–2677 (2022)Cite this article

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Abstract

Conditioning chemotherapy (CCT) has been shown to be essential for optimal efficacy of chimeric antigen receptor (CAR) T-cell therapy. Here, we determined whether the change in absolute lymphocyte count, referred to as delta lymphocyte index (DLIx), may serve as a surrogate marker for pharmacodynamic effects of CCT and whether it associated with germline genetic variants in patients with large B-cell lymphoma (LBCL). One-hundred and seventy-one patients were included, of which 86 (50%) received bridging therapy post-leukapheresis. Median DLIx was 0.5 × 109/L (range, 0.01–2.75 × 109/L) and was significantly higher in patients who achieved complete response (p = 0.04). On multivariate analysis, low DLIx was associated only with use of bridging therapy (odds ratio 0.4, 95% CI 0.2–0.8, p = 0.007). Low DLIx was independently associated with shorter progression-free (p = 0.02) and overall survival (p = 0.02). DLIx was associated with genetic variations related to drug metabolism and macrophage biology such as ABCB1, MISP and CPVL. The impact of CCT on lymphocyte count is affected by use of bridging therapy but change in lymphocyte count is independently associated with efficacy. Studies aimed at investigating macrophage biology in this setting may suggest strategies to increase the efficacy of CCT and improve outcomes.

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Fig. 1: Factors associated with DLIx and efficacy outcomes.
Fig. 2: Change in plasma levels of IL-7 and IL-15 between day -5 and day 0 according to DLIx.
Fig. 3: Association between germline genetic variation and DLIx.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This research is supported in part by the University of Texas MD Anderson Cancer Center B-cell Lymphoma Moonshot (SSN) and The University of Texas MD Anderson Cancer Center Support Grant from National Institutes of Health (P30 CA016672) and by the Shirley Stein Scientific Endowment Research Award. PS salary is supported by the Lymphoma Research Foundation Career Development Award, the Leukemia Lymphoma Society Career Development Program, the Kite Gilead Scholar in Clinical Research Award, the Sabin Fellowship Award, and by the R21 NIH grant. The MD Anderson Lymphoma Tissue Bank is supported by the KW Cares Foundation.

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  1. These authors contributed equally: Paolo Strati, Andrew P. Jallouk, Michelle A. T. Hildebrandt, Sattva S. Neelapu.

Authors and Affiliations

  1. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Paolo Strati, Andrew P. Jallouk, Kaberi Das, Hua-Jay Cherng, Sairah Ahmed, Hun J. Lee, Swaminathan P. Iyer, Ranjit Nair, Loretta J. Nastoupil, Raphael E. Steiner, Haleigh Mistry, Brittany Pulsifer, Mansoor Noorani, Christopher R. Flowers, Jason R. Westin, Michelle A. T. Hildebrandt & Sattva S. Neelapu

  2. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Paolo Strati

  3. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Ryan Sun & Jaihee Choi

  4. Department of Epidemiolog, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Chad D. Huff & Yao Yu

  5. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Neeraj Saini, Elizabeth J. Shpall & Partow Kebriaei

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Contributions

APJ analyzed data, and wrote the paper; SA, HJL, SPY, RN, LJN, RES, EJS, PK, CRF, and JRW provided clinical care to patients and coauthored the paper; HM, BP and MN collected clinical data and coauthored the paper; KD, HJC, and NS performed cytokine analysis and co-authored the paper; CDH, YY, and MATH performed genetic analysis and coauthored the paper; RS and JC provided statistical support and coauthored the paper; PS and SSN designed the study, analyzed the data, provided clinical care to patients, and wrote the paper.

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Correspondence to Paolo Strati.

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Competing interests

PS is a consultant or has served on advisory boards for Kite Gilead, Sobi, Roche-Genentech, Hutchinson MediPharma, ADC Therapeutics, Incyte Morphosys, and TG Therapeutics, and received research funds from Sobi, Astrazeneca-Acerta, ADC Therapeutics, and ALX Oncology. SSN has received personal fees from Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Sellas Life Sciences, Cell Medica/Kuur/Athenex, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics, Bluebird Bio, and Sana Biotechnology; research support from Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics, Allogene Therapeutics, Precision Biosciences, Acerta, and Adicet Bio; royalties from Takeda Pharmaceuticals; and has intellectual property related to cell therapy.

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Strati, P., Jallouk, A.P., Sun, R. et al. Impact of conditioning chemotherapy on lymphocyte kinetics and outcomes in LBCL patients treated with CAR T-cell therapy. Leukemia 36, 2669–2677 (2022). https://doi.org/10.1038/s41375-022-01704-z

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