Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study

• DOI: 10.1182/blood.2020009004
• Publication Date: 2020-11-10T22:58:20Z
• Authors: Lorenzo Falchi; Helen Ma; Sandra Klein; Jennifer K. Lue; Francesca Montanari; Enrica Marchi; Changchun Deng; Hye A. Kim; Aishling Rada; Alice T. Jacob; Cristina Kinahan; Mark M. Francescone; Craig R. Soderquist; David C. Park; Govind Bhagat; Renu Nandakumar; Daniel Menezes; Luigi Scotto; Lubomir Sokol; Andrei R. Shustov; Owen A. O’Connor
• Keywords: Adult; Aged, 80 and over; Male; Antibiotics, Antineoplastic; Lymphoma, T-Cell, Peripheral; DNA Methylation; Middle Aged; 3. Good health; Histone Deacetylase Inhibitors; 03 medical and health sciences; Treatment Outcome; 0302 clinical medicine; Depsipeptides; Antineoplastic Combined Chemotherapy Protocols; Mutation; Azacitidine; Humans; Female; Aged

Abstract Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in preclinical models of T-cell lymphoma. In a phase 1 trial, we found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL. Patients who were treatment naïve or who had R/R PTCL received azacytidine 300 mg once per day on days 1 to 14, and romidepsin 14 mg/m2 on days 8, 15, and 22 every 35 days. The primary objective was overall response rate (ORR). Targeted next-generation sequencing was performed on tumor samples to correlate mutational profiles and response. Among 25 enrolled patients, the ORR and complete response rates were 61% and 48%, respectively. However, patients with T-follicular helper cell (tTFH) phenotype exhibited higher ORR (80%) and complete remission rate (67%). The most frequent grade 3 to 4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), and anemia (16%). At a median follow-up of 13.5 months, the median progression-free survival, duration of response, and overall survival were 8.0 months, 20.3 months, and not reached, respectively. The median progression-free survival and overall survival were 8.0 months and 20.6 months, respectively, in patients with R/R disease. Patients with tTFH enjoyed a particularly long median survival (median not reached). Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation. Combined azacytidine and romidepsin are highly active in PTCL patients and could serve as a platform for novel regimens in this disease. This trial was registered at www.clinicaltrials.gov as #NCT01998035.