Systematic Review of Secondary Primary Malignancies (SPMs) in Patients Treated with Chimeric Antigen Receptor T-Cell (CAR-T) Therapies
Authors: Agha Mounzer E , McGregor Sarah , De Braganca Kevin C , Lengil Tamar , Alegria Victoria , De Wiest Denise , Perciavalle Matthew , Potluri Ravi , Ranjan Sandip , Mohamed Ahmed , Pai Helen , Bixby Todd , Qureshi Zaina P , Voorhees Peter M. 
Published: December 2024

Introduction
CAR-T therapies have demonstrated transformative efficacy in inducing durable remissions in approved indications. However, patients eligible for these therapies are often heavily pretreated, putting them at risk of developing secondary primary malignancies (SPMs). The FDA has raised concerns of an added risk of SPMs from CAR-T treatments, in particular the risk of T-cell malignancies. We aimed to catalog the occurrence of SPMs in patients treated with CAR-T therapies, and if SPMs were ascribed to the CAR-T therapy.
Methods
A systematic literature review was conducted in accordance with PRISMA guidelines in MEDLINE, Embase and the Cochrane Library and conference proceedings through May 17, 2024 to identify evidence on SPMs reported in English from studies of CAR-T therapies in approved indications across multiple myeloma, lymphomas, and leukemias. Data on rate of SPMs, nature of SPMs, deaths due to SPMs, and whether the SPMs were attributed to the CAR-T therapy, were extracted. No restrictions were applied on study type or geography. Retrieved records were screened for eligibility by two reviewers independently against pre-defined PICOS criteria.
Results
89 unique publications, based on 27 clinical trials, 39 observational studies, 5 case series/reports, and 3 based on SPMs reported in the FDA Adverse Event Reporting System (FAERS) database, met the inclusion criteria. 47 studies involved patients with lymphomas (34 in large B-cell lymphoma [LBCL], 16 in other non-Hodgkin's lymphomas [NHLs]), 14 in leukemias (11 in acute lymphoblastic leukemia [ALL]), and 14 in multiple myeloma (MM). Rates of SPMs ranged from 0.0-30.8% of those treated with CAR-T therapy (median 4.2%, inter-quartile range [IQR] 2.2-7.4%). In LBCL, the range was 0.0-30.8%, with a median of 4.7% and IQR 2.1-8.2%; in other NHLs, it was 2.0-11.9%, 3.6%, and 3.0-5.0% respectively; in MM, it was 0.0-20.6%, 5.9%, and 4.6-9.7%, respectively; and in ALL, it was 0.6-28.6%, 2.2%, and 1.4-2.5%, respectively. The number of SPMs per affected patient ranged from 1.0-1.7 (median 1.0). Not counting studies reporting only myeloid SPMs, hematologic SPMs accounted for a median of 46% of SPMs across indications (35% in LBCL, 33% in other NHLs, 33% in MM, and 100% in ALL). Of 45 studies that reported on T-cell malignancies, 6 studies reported a total of 15 cases.
In randomized trials, rates of SPM were comparable between CAR-T and comparator arms (in lymphomas, 4.7% with axi-cel vs 1.8% with comparator [ZUMA-7]; 3.3% with liso-cel vs 7.6% [TRANSFORM]; in MM, 6.7% with ide-cel vs. 4.0% [KarMMa-3], 4.3% with cilta-cel vs. 6.7% [CARTITUDE-4]). Any hematological SPMs were 1.8% vs 0.0% (ZUMA-7), 2.2% vs 0.0% (KarMMA-3), 1.4% vs 0.0% (CARTITUDE-4).
Time from CAR-T infusion to diagnosis of SPM, where reported, is quite variable - from 2-80 months in lymphomas/leukemias, and 8-32 months in MM.
Of the 32 studies that reported deaths due to SPMs, such deaths accounted for 0.2-4.8% of all CAR-T treated patients (median: 1.8%, IQR 0.9-3.2%). In 22 lymphoma studies, SPM-related deaths ranged from 0.2-4.0%, and from 0.8-4.8% in 6 MM studies.
Of the 32 studies and 4 case reviews that assessed potential causes of the 232 SPMs, 136 cases were deemed unrelated to the CAR-T therapy by the investigator - in such cases, SPMs were attributed to prior therapies, or to patient risk factors such as advanced age, history of smoking or genetic factors. In a further 62 cases, investigators did not attribute the SPMs to CAR-T therapy. In 26 cases, the cause was unclear. The remaining 8 cases reported in 5 studies/reviews attributed SPMs to the administered CAR-T therapy - 7 of these were in lymphomas, and one in MM. The attributions for hematologic SPMs, where identified, were similar to those for any SPM.
Conclusion
SPMs reported were often not attributed to CAR-T therapy, likely due to co-existing risk factors like prior chemotherapy, radiation and advanced age. In RCTs, CAR-T therapies were not associated with an increased risk of overall SPMs in studied indications, but the rates of hematologic SPMs, while low, were numerically higher in the CAR T arms. T-cell malignancies have been uncommonly reported to date. Ongoing evaluations will continue to ensure the capture of emerging cases regardless of attribution.