Second Primary Malignancies after CAR T-Cell Therapy: A Systemic Review
Authors: Shahzad Moazzam , Qasim Hana , Ponvilawan Ben , Amin Muhammad Kashif , Zulfiqar Fizza , Ismail Areeba , Ishaq Muhammad Uzair , Irfan Sohaib , Vyas Abhinav , Khamees Ibrahim , Ihsan Rida , Chaudhary Sibgha Gull , Anwar Iqra , Ahmed Nausheen , Shune Leyla O. , Abdallah Al-Ola , McGuirk Joseph P. , Mushtaq Muhammad Umair 
Published: December 2024

Introduction: Chimeric antigen receptor (CAR) T-cell therapy has shown significant promise in treating hematologic malignancies. However, the emergence of second primary malignancies post-therapy is a growing concern. This systematic review aimed to evaluate the types and timing of second primary malignancies following CAR T-cell therapy and explore potential underlying mechanisms.

Methods: Following PRISMA, we searched Embase, Medline, Pubmed, CENTRAL, and Clinicaltrials.gov databases using search terms related to “CAR-T therapy” and “secondary malignancy.” After screening 10,440 articles, 17 studies were shortlisted with patients who received CAR T-cell therapy and developed second primary malignancies after the treatment. The inter-study variance was calculated using the Der Simonian-Laird Estimator. We assessed heterogeneity in the meta-analysis with the I2 statistics. Patient characteristics were collected and reported descriptively. The mortality rates among the included patients from each study were extracted to calculate the pooled mortality rate with 95% confidence intervals (CI). R version 4.3.2 and “meta” package version 7.0-0 were used for the statistical analysis.

Results: A total of 71 patients were included who developed second primary malignancies after CAR T-cell therapy, with 38% females and 62% males, and the ages ranging from 21 to 85 years. The primary malignancies included non-Hodgkin lymphoma (73.1%), chronic lymphocytic leukemia (13.4%), acute lymphoblastic leukemia (7.5%), and multiple myeloma (6%). Patients had undergone 2-9 lines of therapy before receiving CAR T-cell therapy. The CAR T-cell targets were CD19 (93%) or BCMA (7%). Second primary malignancies observed included myelodysplastic syndromes (38.0%), non-melanoma skin cancer (15.5%), acute myeloid leukemia (9.9%), diffuse large B-cell lymphoma (9.9%), T-cell lymphoma (5.6%), melanoma (2.8%), sarcoma (4.2%), multiple myeloma (4.2%), prostate cancer (4.2%), non-small cell lung cancer (4.2), and bladder cancer (1.4%), with a time of onset 1-16 months post-CAR T-cell therapy. Potential mechanisms discussed for second primary malignancies include CAR overexpression, prolonged stimulation through CAR leading to secondary mutations, prior extensive treatment with multiple DNA-damaging chemotherapy regimens, and selective pressure on malignant cells by CAR-T therapy, resulting in cell trans-differentiation or transformation. Among the eight studies that reported mortality data, the pooled death rate was 42% (95% CI 23-64%, I2= 19%).

Conclusion: This review identifies second primary malignancies such as myelodysplastic syndromes, acute myeloid leukemia, T-cell lymphomas, and non-melanoma skin cancers post-CAR T-cell therapy, typically occurring within 1-16 months with a high mortality rate. These findings highlight the need for long-term monitoring and further research to mitigate these risks, ensuring the therapy's safety and efficacy.