Incidence of Secondary Malignancy after Treatment with Anti-CD19 and Anti-BCMA Chimeric Antigen Receptor T-Cell Therapies
Authors: Jones Can , Fares Amneh A , Martinez Diana , Logue Jennifer M , Silva Rondon Carlos , Vargas Madueno Fernando , Nguyen Nina , Fernandez Hugo Francisco , Chavez Julio C. , Sandoval-Sus Jose 
Published: December 2024

Background:
Chimeric antigen receptor (CAR) T-cell therapy is a novel treatment option for various hematological malignancies in the relapse/refractory (R/R) setting, including B-cell non-Hodgkin Lymphoma (NHL), B-cell acute lymphoblastic leukemia (B-ALL), and multiple myeloma (MM). To date there are six CAR T-cell products approved: axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel), ciltacabtagene autoleucel (cilta-cel), idecabtagene vicleucel (ide-cel), lisocabtagene maraleucel (liso-cel) and tisagenlecleucel (tisa-cel). The positive clinical outcomes of these cellular therapies shifted the paradigm of these diseases; however, they are associated with important adverse events (AEs). Recently, reports of secondary primary malignancies (SPMs) after CAR T-cell therapy have raised concern. This study aims to quantify the incidence of SPMs after anti-CD19 and anti-BCMA CAR T-cell therapy.
Method:
We conducted a pooled analysis comprising patients who received anti-CD19 and anti-BCMA CAR T-cell therapy for R/R B-cell NHL, B-ALL, and MM. A search was performed using the terms secondary malignancy, CAR T-cell, and hematologic malignancy from PubMed, Embase, and conference abstracts from 1/1/2017 to 6/1/2024. We included articles reporting patients diagnosed with SPMs after CAR T-cell therapy. Studies of CAR T-cell therapy for solid tumors and SPMs diagnosed before CAR T-cell therapy were excluded.
Result:
A total of 20 studies (11 registry trials and 9 retrospective studies) were included in our analysis. Out of 17,693 patients treated with CAR T-cell therapy, 557 (3.15%) encompassed children and young adults between the ages of 3 and 21 years old. The remainder of the patients ranged from 57 to 66 years of age. The overall incidence of SPMs after CAR T-cell therapy was 4.43% (784/17,693). The most common SPM was myelodysplastic syndrome (1.58%; 280/17,693), followed by acute myeloid leukemia (0.69%; 122/17,693) and skin neoplasms (0.58%; 102/17,693). Skin neoplasms included squamous cell carcinoma, basal cell carcinoma, and melanoma. However, half of the studies did not mention or categorize skin cancer as a SPM. Notably, 26 (0.15%; 26/17,693) T-cell lymphoma cases were reported, which included five peripheral T-cell lymphomas and three CAR T-cell lymphomas (one derived from cilta-cel and two derived from piggyBac transposon-mediated CD19 CAR T-cells).
Conclusion:
As a result of our pooled analysis, the overall incidence of SPMs after CAR T-cell therapy is aligned with prior FDA reports (4.43% vs 4.32%), which is an important but small proportion of CAR-T-related AEs. Importantly, the incidence of CAR-positive lymphomas was extremely low (0.01%), which is similar to other reports. SPM after CAR-T is a rare and pertinent complication but should not deter the rational use of these therapies in the appropriate patients. Prospective studies of structured monitoring and screening programs should be designed to further quantify, characterize, prevent, and treat SPM in patients receiving CAR T-cell therapies.