In a case presentation published in The New England Journal of Medicine, targeted treatment was successful for chimeric antigen receptor (CAR)-positive peripheral T-cell lymphoma developed after CAR T-cell therapy for multiple myeloma.
Using advanced genomic, phenotypic, and functional profiling techniques, the researchers and report authors from The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai found that CCR4 is a possible target for CAR T-cell therapy–related toxicities, including peripheral T-cell lymphoma, and that treatment with an anti-CCR4 antibody–based regimen may be considered for patients who develop these rare secondary cancers after CAR T-cell therapy.
“This is the first reported case of successfully using targeted therapy to treat a CAR-positive T-cell lymphoma,” said senior author Samir Parekh, MD, Director of the Center of Excellence for Multiple Myeloma at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. “It highlights the importance of monitoring for secondary cancers and leveraging precision medicine to respond quickly when they emerge.”
Case Report
The report showed that the patient, a 51-year-old man, received ciltacabtagene autoleucel for multiple myeloma. About 6 months later, he developed erythematous facial lesions and lymphocytosis as well as hypermetabolic lesions in the nose and cheeks found through PET/CT scans. He was diagnosed with CAR-positive, CD4-negative, and CD8-negative peripheral T-cell lymphoma.
Researchers performed multimodal characterization as well as single-cell RNA and T-cell receptor sequencing, which helped to identify a high degree of CCR4 expression, which is typically expressed in cutaneous T-cell lymphomas and is associated with a poor prognosis in peripheral T-cell lymphomas. They further found that the patient had a unique single-cell transcriptional profile compared with samples of cutaneous T-cell lymphoma.
They conducted an ex vivo screen of 166 drugs approved by the U.S. Food and Drug Administration to identify agents that may have antitumor activity for this patient’s case. They found the tumor was sensitive to anthracyclines and administered mogamulizumab plus liposomal doxorubicin and gemcitabine. This treatment resulted in a complete remission. After treatment was discontinued, the patient was given maintenance therapy of pegylated interferon α-2a and extracorporeal photochemotherapy, but it was discontinued after about 2 months because of persistent cytopenia. After more than 10 months of follow-up, the patient is still in remission.
Through whole-genome sequencing, the team found there was CAR vector integration within the TIA1 gene, which reportedly has only been seen once before, and heterozygous truncating mutations in TET2 and EZH2, which are associated with clonal hematopoiesis and T-cell lymphomas. Upregulation of MYC and PI3K/AKT signaling pathways was also observed.
The researchers noted CCR4 may be a target for such secondary cancers after CAR T-cell therapy, but prospective validation is needed. Aleman et al noted in the published report that screening patients for clonal hematopoiesis prior to receiving CAR T-cell therapy may help to identify patients at high risk for developing secondary cancers.
Disclosure: Funding was provided by the National Institutes of Health, the Leukemia & Lymphoma Society (now Blood Cancer United), and other philanthropic contributions. For full disclosures of the study authors, visit nejm.org.
