# At the Crossroads of Lineage: Secondary Malignancies After CAR-Based Immunotherapy

## TL;DR

This paper reviews the rare occurrence of secondary cancers after CAR T-cell therapy for lymphomas and suggests these are mostly due to prior treatments rather than the therapy itself.

## Contribution

The paper provides a review of reported cases of secondary malignancies after CAR T-cell therapy and evaluates their possible causes.

## Key findings

- Secondary T-cell lymphomas after CAR T-cell therapy are rare, occurring in low single-digit percentages.
- Most secondary malignancies are likely due to background risk and prior treatments rather than direct CAR T-cell therapy effects.
- Ongoing research and registry follow-up are needed to better understand these rare events.

## Abstract

Non-Hodgkin lymphomas (NHL), including diffuse large B-cell lymphoma (DLBCL), remain prevalent; hence, it is of utmost importance to find new treatments. Chimeric antigen receptor (CAR) T-cell therapy has shown tremendous promise in recent years. While this new therapy has shown admirable results, there have been clinically significant side effects, such as the emergence of secondary cancers following CAR T-cell therapy. Regardless of CAR T-cell therapy, patients with DLBCL are known to develop secondary malignancies, including T-cell lymphomas (TCL), in some rare cases. This review aims to summarize current evidence on reported second primary malignancies following CAR T-cell therapy.

CD19-directed chimeric antigen receptor (CAR) T-cell therapies have been instrumental in improving outcomes of refractory or relapsed B-cell malignancies. However, there have been safety concerns due to recent reports of second primary malignancies (SPMs) related to CAR T-cell therapies. We reviewed articles from Embase, PubMed, and Cochrane Library records and included SPM case reports as well as cohort studies. Across published cohorts, secondary cutaneous or peripheral T-cell lymphoma (PTCL) after diffuse large B-cell lymphomas (DLBCLs) have been reported at low incidence (generally in the low single-digit percentage range). While CAR T-cell therapy is associated with these rare secondary malignancies and lineage-switch events primarily described in acute leukemia, they are clinically significant and have resulted in increased surveillance. The currently available evidence suggests that most secondary malignancies after CAR T-cell therapy are due to background risk and prior treatment exposures rather than direct CAR T-cell therapy induced oncogenesis. However, rare CAR T-cell therapy-associated second primary T-cell malignancies have been reported. To properly define incidence, mechanisms, and risk factors for CAR T-cell therapy-associated malignancies, continued prospective registry follow-up and additional research will be needed.