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Multicenter Study
. 2025 Jul;39(7):1714-1722.
doi: 10.1038/s41375-025-02605-7. Epub 2025 Apr 24.

Myeloid neoplasms after CD19-directed CAR T cells therapy in long-term B-cell lymphoma responders, a rising risk over time?

Nicolas Gazeau #  1 , David Beauvais #  2 , Rémi Tilmont  2 , Micha Srour  2 , Emmanuelle Ferrant  3 , Violaine Safar  3 , Ludovic Fouillet  4 , Pascale Flandrin-Gresta  5 , Nicolas Gower  2 , Paul Chauvet  2   6 , Nicolas Duployez  7 , Benjamin Podvin  7 , Julie Demaret  8 , Sarah Huet  9 , Pierre Sujobert  9 , Hervé Ghesquières  3 , Gandhi Damaj  10 , Emmanuel Bachy  3 , Franck Morschhauser  2 , Ibrahim Yakoub-Agha  2   11 , Maël Heiblig  3 , Pierre Sesques  3
Affiliations
Multicenter Study

Myeloid neoplasms after CD19-directed CAR T cells therapy in long-term B-cell lymphoma responders, a rising risk over time?

Nicolas Gazeau et al. Leukemia. 2025 Jul.

Abstract

Therapy-related myeloid neoplasms (t-MN), including myelodysplastic neoplasms (t-MDS) and acute myeloid leukemia (t-AML), have emerged as significant late complications after CAR T cell therapy. We retrospectively analyzed 539 patients with B cell lymphoma treated with CD19 directed CAR T cell therapy across four French centers. Cumulative incidences of t-MN was estimated with relapse or death treated as competing risk. Univariate and propensity score matching (PSM) analyses were conducted to assess risk factors with age and the number of prior treatments as covariates. After a median follow-up of 25 months, the cumulative incidence of t-MN was 4.5% at 2 years. T-MN occurred predominantly as t-MDS (62%) and t-AML (38%) with high cytogenetic risk. Median overall survival after t-MN diagnosis was 4.5 months. In univariate analysis, older age (p < 0.01), higher MCV (p < 0.01), and higher ICANS grade (p = 0.04) were associated with increased risk of t-MN. After PSM, MCV and ICANS grade remained significant risk factors. CAR T cell products with CD28 co-stimulatory domains trended towards higher t-MN risk (p = 0.09). NGS analysis showed that 85.7% of t-MN had pre-existing mutations, most commonly TP53. This study highlights t-MN as a severe late complication of CAR T cell therapy. MCV and ICANS grade were identified as key risk factors.

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Conflict of interest statement

Competing interests: NGa, RT, MS, GD, NGo, LF, PFG, ND, BP, JD, SH, PS, HG, MH, PS have no COI. DB declares honorariua for Kite/Gilead and Novartis, EF declares consultancy for Astra Zeneca, Beigene, Janssen and honoraria for Astra Zeneca, Beigene, Janssen, Cilag, Abbvie, Gilead, VS declares consultancy for Kite/ Gilead, Beigene, BMS, Janssen and other from Janssen, EB declares consultancy, honoraria, and membership on an entity’s Board of Directors or advisory committees from AbbVie, Roche, and Takeda; research funding from Amgen; honoraria and membership on an entity’s Board of Directors or advisory committees from BeiGene and Incyte; honoraria, other personal fees, and research funding from Bristol Myers Squibb; consultancy and honoraria from Janssen; honoraria and other personal fees from Novartis and Pfizer; honoraria from ADC Therapeutics; and consultancy, honoraria, and other personal fees from Kite, a Gilead Company, FM declares consultancy, honoraria, and membership on an entity’s Board of Directors or advisory committees from Kite/Gilead Sciences, Bristol Myers Squibb, AbbVie, Epizyme, AstraZeneca, Novartis, and Genmab; consultancy and membership on an entity’s Board of Directors or advisory committees from Servier; consultancy, honoraria, and other payments for expert testimony and scientific lectures from Roche/Genentech; and honoraria from Chugai and Eisai, IYA declares honoraria from KITE, BMS, Novartis, Miltenyi Biomedecine.

Figures

Fig. 1
Fig. 1. Non-relapse mortality (NRM) and therapy-related myeloid neoplasms (t-MN) incidences curves.
a Incidence of NRM. b Incidence of NRM caused by infection, t-MN or other causes. c Incidence of t-MN with death and relapse treat as competing risk. d Incidence of t-AML and t-MDS with death and relapse treat as competing risk. e Incidence of t-MN depending of the CAR T cell used. f Incidence of t-MN depending of the co-stimulatory domain of the CAR T cells (4-1BB or CD28).
Fig. 2
Fig. 2
Individual courses of therapy-related myeloid neoplasms (8-MN) patients from CAR T cells infusion.
Fig. 3
Fig. 3
Overall survival of the t-MN cohort, from t-MN diagnosis.
Fig. 4
Fig. 4
Clonal evolution before and after CAR T cell infusion.
See this image and copyright information in PMC

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