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We report a case of chimeric antigen receptor (CAR)+ peripheral T-cell lymphoma (PTCL) following anti-BCMA CAR-T therapy in a patient with multiple myeloma (MM), treated successfully using a personalized approach. Secondary malignancies after CAR-T, including CAR+ T-cell lymphomas, are very rare, and optimal management remains undefined.1–3 Among reported cases with an aggressive clinical course, skin involvement has been common (Table S1 in the Supplementary Appendix), which, in our patient, was associated with CCR4 overexpression.

ndary malignancies after CAR-T, including CAR+ T-cell lymphomas, are very rare, and optimal management remains undefined.1–3 Among reported cases with an aggressive clinical course, skin involvement has been common (Table S1 in the Supplementary Appendix), which, in our patient, was associated with CCR4 overexpression. A 51-year-old man developed erythematous facial lesions and lymphocytosis six months after receiving ciltacabtagene autoleucel. PET/CT revealed hypermetabolic lesions in the nose and cheeks. Biopsies of skin and bone marrow confirmed a CAR+ double-negative (CD4−/CD8−) PTCL (Figure 1, Figure S1–2). Multimodal characterization was performed. Single-cell RNA and T-cell receptor sequencing distinguished malignant from healthy T cells, identifying high expression of CCR4 (validated by flow cytometry) and other pro-survival cytokines and receptors (Figures S1–4). CCR4, a skin-homing chemokine receptor typically expressed in cutaneous T-cell lymphomas (CTCL), is rarely upregulated in PTCL and may portend poor outcomes. Comparison of single-cell transcriptomics with banked CTCL samples revealed a unique transcriptional profile (Figure S3). An ex-vivo screen of 166 FDA-approved drugs identified anthracyclines as a tumor-specific vulnerability (Figure S5). Based on these findings, the patient was treated with the anti-CCR4 mogamulizumab in combination with liposomal doxorubicin and gemcitabine4, achieving complete remission, after which the treatment was discontinued (Figure 1, Figure S5). Maintenance therapy with peginterferon alfa-2a and extracorporeal photochemotherapy was attempted, but stopped after about two months for persistent cytopenia. The patient remains in remission after more than 10 months of follow-up. While the molecular data supported CCR4 targeting, the individual contribution of each component of our treatment regimen cannot be determined without prospective validation. However, our studies identify CCR4 as a possible target for CAR-related toxicity, including PTCL, particularly in the setting of skin involvement.

hile the molecular data supported CCR4 targeting, the individual contribution of each component of our treatment regimen cannot be determined without prospective validation. However, our studies identify CCR4 as a possible target for CAR-related toxicity, including PTCL, particularly in the setting of skin involvement. Whole genome sequencing demonstrated CAR vector integration within intron 6 of TIA1, with concordant absence of TIA1 expression by immunohistochemistry (Figure 1, Figure S2). This represents at least the second case of insertion into a known or putative tumor suppressor gene. Additional heterozygous truncating mutations in TET2 and EZH2, absent in pre-CAR-T samples, were also identified. These are frequently associated with clonal hematopoiesis and T-cell lymphomas and may have contributed to driving transformation. The heterozygous mutation of TET2 contrasts with other reported cases and preclinical data, where biallelic disruption of TET2 was associated with proliferation and tissue infiltration.5 RNA-seq further revealed the upregulation of MYC and PI3K/AKT signaling pathways (Figure S6).

contributed to driving transformation. The heterozygous mutation of TET2 contrasts with other reported cases and preclinical data, where biallelic disruption of TET2 was associated with proliferation and tissue infiltration.5 RNA-seq further revealed the upregulation of MYC and PI3K/AKT signaling pathways (Figure S6). As more patients receive CAR-T therapy, awareness of secondary malignancies is essential. Screening for clonal hematopoiesis before CAR-T and post-treatment monitoring may help identify patients at higher risk. Future work should dissect the interplay of vector integration, acquired (epi)genetic lesions, cytokine-driven proliferation, and serial infections in driving T-cell transformation/lymphomagenesis (Figure S7). We demonstrate that treatment based on genomic, phenotypic, and functional profiling can provide an effective therapeutic strategy in these rare but serious cases.