Introduction:
T-cell lymphoma (TCL) derived from CAR-T cells is a rare event (2 cases reported) in multiple myeloma (MM) patients receiving ciltacabtagene autoleucel (cilta-cel). Here, we present an enterotropic CAR+TCL post-cilta-cel, with unique genomic features.
Methods:
The presence of CAR+ cells in tissue/blood was assessed by flow cytometry (CAR-FACS). T-cell receptor clonality was assessed by high-throughput sequencing (TCR-HTS). Mutational profiling and CAR transgene insertion site analysis was performed by whole exome/genome sequencing (WES/WGS).
Results & Conclusions:
A 50 y/o male with MM received cilta-cel. On day(D)59, he developed profuse diarrhea, which progressively worsened to 4-6 L/day. He received steroids and infliximab without resolution. Endoscopies on D137 revealed dense T-cell infiltration in the lamina propria (predominately CD8+/TCRb+/TRBC1-). At this time, TCL was suspected. CAR-FACS on D199 duodenum biopsy showed CD8+CAR+ T-cells (35% of CD45+ cells) and double-negative (DN) CAR+ T-cells (16%). Similar findings were observed from ileum. TCR-HTS showed 2 dominant nonproductive TCRg and 2 dominant TCRb sequences (one of which was productive). Retrospectively, these sequences were also dominant as early as in D97 ileum. Interestingly, these TCR sequences were also detected from D207 peripheral blood but not from pre-treatment sample. WES on D137 duodenal biopsy revealed SH2B3 L390P at allele frequency 23%, which was not detected from the pre-treatment sample. WGS on FACS-sorted CD8+CAR+ T-cells revealed CAR gene inserted in a protooncogene TFCP2. These findings shed insight into CAR-derived lymphomagenesis, and further investigation is needed.
