T Cell Lymphoma and Secondary Primary Malignancy Risk After Commercial CAR T Cell Therapy

We report a T cell lymphoma (TCL) occurring 3 months after anti-CD19 chimeric antigen receptor (CAR) T cell immunotherapy for non-Hodgkin B cell lymphoma. The TCL was diagnosed from a thoracic lymph node upon surgery for lung cancer. The TCL exhibited CD8 cytotoxic phenotype and a JAK3 variant, while the CAR transgene was very low. The T cell clone was identified at low levels in the blood before CAR T infusion and in lung cancer. To assess the overall risk of secondary primary malignancy after commercial CAR T (CD19, BCMA), we analyzed 449 patients treated at the University of Pennsylvania. At a median follow-up of 10.3 months, 16 patients (3.6%) had a secondary primary malignancy. The median onset time was 26.4 and 9.7 months for solid and hematological malignancies, respectively. The projected 5-year cumulative incidence is 15.2% for solid and 2.3% for hematological malignancies. Overall, one case of TCL was observed, suggesting a low risk of TCL after CAR T.

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References

Thomas A, Mailankody S, Korde N, Kristinsson S, Turesson I, Landgren O . Second malignancies after multiple myeloma: from 1960s to 2010s. Blood. 2012; 119(12):2731-7. PMC: 3327452. DOI: 10.1182/blood-2011-12-381426. View

Travis L, Curtis R, Glimelius B, Holowaty E, van Leeuwen F, Lynch C . Second cancers among long-term survivors of non-Hodgkin's lymphoma. J Natl Cancer Inst. 1993; 85(23):1932-7. DOI: 10.1093/jnci/85.23.1932. View

Sacchi S, Marcheselli L, Bari A, Marcheselli R, Pozzi S, Luminari S . Secondary malignancies after treatment for indolent non-Hodgkin's lymphoma: a 16-year follow-up study. Haematologica. 2008; 93(3):398-404. DOI: 10.3324/haematol.12120. View

Kim H, Jeon M, Yu E, Kim D, Choi C, Ko Y . Composite follicular lymphoma and classic Hodgkin lymphoma. J Pathol Transl Med. 2021; 56(1):57-60. PMC: 8743806. DOI: 10.4132/jptm.2021.10.09. View

Aoyama Y, Tsunemine H, Kodaka T, Oda N, Matsuoka H, Itoh T . Plasmablastic lymphoma with unfavorable chromosomal abnormalities related to plasma cell myeloma: A borderline case between plasmablastic lymphoma and plasmablastic plasma cell myeloma. J Clin Exp Hematop. 2017; 57(1):37-39. PMC: 6144273. DOI: 10.3960/jslrt.16020. View

Chihara D, Dores G, Flowers C, Morton L . The bidirectional increased risk of B-cell lymphoma and T-cell lymphoma. Blood. 2021; 138(9):785-789. PMC: 8414260. DOI: 10.1182/blood.2020010497. View

Schaapveld M, Aleman B, van Eggermond A, Janus C, Krol A, van der Maazen R . Second Cancer Risk Up to 40 Years after Treatment for Hodgkin's Lymphoma. N Engl J Med. 2015; 373(26):2499-511. DOI: 10.1056/NEJMoa1505949. View

Goel H, Rahul E, Gupta I, Chopra A, Ranjan A, Gupta A . Molecular and genomic landscapes in secondary & therapy related acute myeloid leukemia. Am J Blood Res. 2021; 11(5):472-497. PMC: 8610791. View

Demoor-Goldschmidt C, De Vathaire F . Review of risk factors of secondary cancers among cancer survivors. Br J Radiol. 2018; 92(1093):20180390. PMC: 6435077. DOI: 10.1259/bjr.20180390. View

10.

Ragon B, Shah M, DSouza A, Estrada-Merly N, Gowda L, George G . Impact of second primary malignancy post-autologous transplantation on outcomes of multiple myeloma: a CIBMTR analysis. Blood Adv. 2023; 7(12):2746-2757. PMC: 10275699. DOI: 10.1182/bloodadvances.2022009138. View

11.

Brown J, Yeckes H, Friedberg J, Neuberg D, Kim H, Nadler L . Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol. 2005; 23(10):2208-14. DOI: 10.1200/JCO.2005.05.158. View

12.

Chong E, Ruella M, Schuster S . Five-Year Outcomes for Refractory B-Cell Lymphomas with CAR T-Cell Therapy. N Engl J Med. 2021; 384(7):673-674. DOI: 10.1056/NEJMc2030164. View

13.

Zhao W, Wang B, Chen L, Fu W, Xu J, Liu J . Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2). J Hematol Oncol. 2022; 15(1):86. PMC: 9261106. DOI: 10.1186/s13045-022-01301-8. View

14.

Steffin D, Muhsen I, Hill L, Ramos C, Ahmed N, Hegde M . Long-term follow-up for the development of subsequent malignancies in patients treated with genetically modified IECs. Blood. 2022; 140(1):16-24. PMC: 9346960. DOI: 10.1182/blood.2022015728. View

15.

Cappell K, Sherry R, Yang J, Goff S, Vanasse D, McIntyre L . Long-Term Follow-Up of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy. J Clin Oncol. 2020; 38(32):3805-3815. PMC: 7655016. DOI: 10.1200/JCO.20.01467. View

16.

Ruella M, Xu J, Barrett D, Fraietta J, Reich T, Ambrose D . Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med. 2018; 24(10):1499-1503. PMC: 6511988. DOI: 10.1038/s41591-018-0201-9. View

17.

Micklethwaite K, Gowrishankar K, Gloss B, Li Z, Street J, Moezzi L . Investigation of product-derived lymphoma following infusion of piggyBac-modified CD19 chimeric antigen receptor T cells. Blood. 2021; 138(16):1391-1405. PMC: 8532197. DOI: 10.1182/blood.2021010858. View

18.

Bishop D, Clancy L, Simms R, Burgess J, Mathew G, Moezzi L . Development of CAR T-cell lymphoma in 2 of 10 patients effectively treated with piggyBac-modified CD19 CAR T cells. Blood. 2021; 138(16):1504-1509. DOI: 10.1182/blood.2021010813. View

19.

Fraietta J, Nobles C, Sammons M, Lundh S, Carty S, Reich T . Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature. 2018; 558(7709):307-312. PMC: 6320248. DOI: 10.1038/s41586-018-0178-z. View

20.

Shah N, Qin H, Yates B, Su L, Shalabi H, Raffeld M . Clonal expansion of CAR T cells harboring lentivector integration in the CBL gene following anti-CD22 CAR T-cell therapy. Blood Adv. 2019; 3(15):2317-2322. PMC: 6693002. DOI: 10.1182/bloodadvances.2019000219. View