In light of recent FDA black box warnings regarding secondary malignancies following CAR-T cell therapy, researchers at Stanford University have conducted a comprehensive analysis of post-CAR-T myeloid neoplasms, presenting their findings at the 66th American Society of Hematology (ASH) Annual Meeting.
Comparative Analysis with Traditional Treatment-Related Malignancies
Dr. Mark Hamilton, a hematology-oncology and bone marrow transplant fellow at Stanford University, led the investigation of 17 post-CAR-T treatment-related myeloid malignancies. The research team found striking similarities between these cases and myeloid neoplasms occurring after autologous transplants, particularly in overall survival rates and karyotypic characteristics.
"The myeloid neoplasms we're seeing after CAR-T cell therapy appear to follow similar patterns to those we've observed in other contexts, such as post-autologous transplant or post-chemotherapy cases," explained Dr. Hamilton.
Molecular Insights and Risk Factors
The molecular analysis revealed a strong association with TP53 gene mutations, especially in cases involving myelodysplastic syndrome (MDS) or MDS progression to acute myeloid leukemia (AML). Significantly, the research demonstrated that mutations associated with these neoplasms were present prior to CAR-T cell infusion in the form of clonal hematopoiesis.
Key findings showed that patients receiving multiple cellular therapies faced higher susceptibility to developing these malignancies, likely due to increased opportunities for DNA damage to their bone marrow. The study also found that pre-infusion clonal hematopoiesis was remarkably common among patients, though this alone did not reliably predict who would develop treatment-related myeloid neoplasms.
Clinical Implications for Treatment Decisions
Despite the presence of FDA black box warnings, the research suggests that the detection of clonal hematopoiesis mutations should not automatically disqualify patients from receiving CAR-T cell therapy. Dr. Hamilton emphasized, "We don't see any evidence that patients with lymphoma should be denied a life-saving therapy because they have the presence of these mutations prior to infusion."
Study Limitations and Future Research
The research team acknowledged several limitations, including its single-institution nature and focus primarily on CD19 CAR-T cells, specifically axicabtagene ciloleucel. They noted the need for broader multi-institutional studies to better understand these post-CAR hematologic neoplasms at national and global levels.
The study utilized advanced techniques, including deep sequencing and minimal residual disease (MRD) tracing, which currently exceed standard clinical capabilities. While researchers observed some instances of CAR T-cells integrating into clonal hematopoiesis mutations, this phenomenon appeared relatively rare and not immediately concerning, though it warrants further investigation.
