Late Effects of CAR T-Cell Therapy in Lymphoma

There are reports of delayed neurotoxicity, with confusion, disorientation, and expressive aphasia, 6 months following CAR T-cell therapy, these authors note | Image Credit: ArtemisDiana-stock.adobe.com

A recent study published in Frontiers in Oncology offers a comprehensive review of the long-term complications following chimeric antigen receptor T-cell therapy (CAR T), specifically anti-CD19 CAR T (CART19) for lymphoma. The study focuses on the late adverse events that occur or persist beyond 1 month after CART19.¹

Although the short-term complications of CAR T, such as cytokine release syndrome, infection risk, and myelotoxicity, are well studied, the long-term complications need to be further characterized.² "Because it is the first gene therapy approach–based therapy approved by the FDA as standard of care, there is a need for long-term follow-up of adverse events following CAR T to better delineate the possible late complications of this groundbreaking therapy," the authors state.

In this new analysis, they review the late adverse events associated with CART19 for relapsed/refractory B-cell non-Hodgkin lymphoma.

The study used published data from pivotal trials and real-world experiences with CART19 for adults with lymphoma. Several key late events associated with CART19, including cytopenias, are discussed. The overall prevalence of grade 3/4 cytopenia beyond 30 days occurs in 30% to 40% of patients and beyond 90 days in 3% to 22% of patients.³ There is no evidence-based standard of care in how to manage prolonged cytopenia post CAR T, and the approach should be tailored to the individual patient. Most cases of cytopenia will resolve with time; therefore, intervention should be considered only for patients with persistent and clinically relevant cytopenia.

B-cell aplasia, hypogammaglobulinemia, and low CD4+ counts are common adverse effects of CART19. The study reports that at 3 months post infusion, up to 60% of patients had low immunoglobulin G(IgG) levels, and up to 50% still had IgG levels below 400 mg/dL at 1 year without intravenous Ig (IVIG) replacement.⁴ In clinical practice, the percentage of patients requiring IVIG replacement varies from 27% to 38%. Low CD4+ T-cell count can persist for more than 1 year, with a median CD4 count of 150 to 250 cells/mm³ at 1-year post infusion. However, CD4+ counts have remained as low as 150 cells/mm³ at 18 months. Infections beyond the initial month from CART19 are not frequent and rarely severe, but they become more prevalent and severe when patients receive subsequent therapies for their underlying disease. Most infections (80%) were treated on an outpatient basis, with the most common infections being upper respiratory tract infections (48%) and lower respiratory infections (23%).

There is ongoing concern about the potential risk of secondary malignancies due to CART19's genetic editing nature. Few reports of T-cell lymphoma have been made, but there have been many reports of myeloid neoplasms following CAR T. "Myeloid neoplasm is not rare post CAR T, but unclear causality given [the] heavily pretreated patient population is already at risk for therapy-related myeloid neoplasm," the authors conclude.

There are reports of delayed neurotoxicity after 6 months of CAR T, with confusion, disorientation, and expressive aphasia. However, most studies showed a slight decline or no relevant neurocognitive impairment after CAR T.

"There is an unmet need to investigate strategies to prevent and treat post-CART19 prolonged cytopenia," the authors suggest. Although CART19 is associated with significant long-term effects, such as prolonged cytopenia, hypogammaglobulinemia, and infections, they can mostly be managed with a low risk of nonrelapse mortality.

References

1. Cordeiro AC, Durisek G, Batista MV, Schmidt J, de Lima M, Bezerra E. Late events after anti-CD19 CAR T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma. Front Oncol. 2024;14:1404351. doi:10.3389/fonc.2024.1404351

2. Cordeiro A, Bezerra ED, Hirayama AV, et al. Late events after treatment with CD19-targeted chimeric antigen receptor modified T cells. Biol Blood Marrow Transplant. 2020;26(1):26-33. doi:10.1016/j.bbmt.2019.08.003

3. Jain T, Olson TS, Locke FL. How I treat cytopenias after CAR T-cell therapy. Blood. 2023;141(20):2460-2469. doi:10.1182/blood.2022017415

4. Logue JM, Zucchetti E, Bachmeier CA, et al. Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma. Haematologica. 2021;106(4):978-986. doi:10.3324/haematol.2019.238634