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30 Genomic changes appearing post-CART therapy pose diagnostic challenges

Year: 2025

Type: article

Abstract: Chimeric antigen receptor (CAR) T-cells targeted to B-cell maturation antigen (BCMA) are a promising new treatment for relapsed or refractory multiple myeloma (MM), although there have been documented associated toxicities and risks of secondary malignancies. Critical to their medical management is the identification and characterization of genomic changes that may arise in patients receiving CAR-T therapy. We describe a 57-year-old male with high-risk multiple myeloma, who received standard chemotherapy followed by multiple interval therapies, an autologous peripheral blood stem cell transplant (one year after diagnosis) and CAR-T (ciltacabtagene autoleucel-cilta-cel) therapy (two years after transplant). Two bispecific immunotherapies, Teclistamab and Talquetamab, were administered 8 and 10 months post CAR-T, respectively. Two weeks after the last immunotherapy infusion, he presented with acute leukocytosis with a WBC of 210x109/L. Flow cytometry identified 94% abnormal T cells in bone marrow and blood that expressed CD2, CD3, CD5 (partial), CD7 (partial), CD8 (partial), and CD45 but lacked expression of CD4, CD16, CD56, and CD57. The bone marrow biopsy confirmed >95% involvement by an abnormal T-cell proliferation. A diagnosis of PTCL-NOS, with leukemic presentation was made. Multiple genetic analyses including karyotyping, FISH, chromosomal microarray, NGS and PCR were applied. T cell receptor gene rearrangement PCR showed a clonal T-cell population. Chromosomal analysis showed clonal abnormalities including a duplication of 6p and gain of X. Importantly, microarray showed a microdeletion of TET2 and additional copy number abnormalities. NGS identified loss of function pathogenic variants in one allele of TET2 and in one allele of CHEK2. The deletion of one TET2 allele concomitant with mutation of the homologous allele indicates biallelic loss of function. Our multidisciplinary clinical team suspects that the abnormalities of TET2 are likely associated with this patient’s CAR-T therapy. Published functional data suggest that biallelic depletion of TET2 in CAR-T cells may promote their hyperproliferation, providing a proliferative advantage to antigen-independent CAR-T cells and possibly enhancing T cell memory. However, the roles that other genetic changes in TET2 depleted CAR-T cells (such as a CHEK2 mutation, gain of X, 6p duplication and other copy number abnormalities in the present patient) play in this hyperproliferation of T-cells is unclear. The stimulatory action of bispecific immunotherapies in this setting is also incompletely understood. Both the chromosomal microarray and NGS analyses were critical to identifying the clonal changes responsible for the abnormal leukocytosis. Identifying specific genomic changes associated with CAR-T therapy is critical for accurate diagnosis of patients with abnormal clonal processes and will become more critical as this therapy is expanded to more diseases.

Source: American Journal of Clinical Pathology

DOI: 10.1093/ajcp/aqaf121.457