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TARGETING THE PERIPHERAL T‐CELL LYMPHOMA (PTCL) EPIGENOME WITH ORAL 5‐AZACYTIDINE AND ROMIDEPSIN: RESULTS AND CLINICAL‐MOLECULAR CORRELATIONS FROM A PHASE 2 STUDY

2019; Wiley; Volume: 37; Issue: S2 Linguagem: Inglês

10.1002/hon.135_2629

1099-1069

Lorenzo Falchi, Jennifer Kimberly Lue, Francesca Montanari, Enrica Marchi, Jennifer E. Amengual, Ahmed Sawas, Changchun Deng, Karen Khan, H.A. Kim, Aishling M. Rada, Michelle Malanga, Mark Francescone, Craig R. Soderquist, D.C. Park, Govind Bhagat, Lubomir Sokol, Andrei R. Shustov, Owen A. O’Connor,

Lymphoma Diagnosis and Treatment

Introduction: PTCL exhibit pervasive dysfunction of epigenetic operations. This may be a targetable vulnerability, as demonstrated by the single-agent activity of histone deacetylase inhibitors (HDACi) and hypomethylating agents (HMA). We previously showed marked synergism between HDACi and HMA in T-cell lymphoma lines, accompanied by the modulation of >900 unique genes with the combination, but not the single agents. In a recently completed phase-1 study we observed encouraging activity of combined oral 5-azacytidine (AZA) and romidepsin (ROMI) in T-cell lymphoma patients. Here, we report the first analysis of the phase-2 portion of that study. Methods: Patients with newly diagnosed (ND) or relapsed/refractory (R/R) PTCL were eligible for enrollment. The recommended phase-2 dose from the phase-1 trial was AZA 300 mg daily days 1-14 and ROMI 14 mg/ms days 8, 15, 22 every 35 days. The primary objective was overall response rate (ORR). Other endpoints were progression-free survival (PFS) and duration of response (DOR). We performed targeted next-generation sequencing (NGS) of pre-treatment tumor samples to correlate epigenetic gene mutations and response. Results: Among 25 enrolled patients the median age was 63 years [42-88] and the M:F ratio was 14:11. 11 patients were ND and 14 were R/R, with a median of 2 prior therapies [1-6], 17 patients had AITL or PTCL-TFH, 3 PTCL-NOS, and 4 other subtypes (1 each of ALCL, ATLL, EATL, and ENKTL). 19 patients are evaluable for response and 5 are pending evaluation (complete data will be presented). The ORR was 68% (13/19), including 42% complete responses (CR) (8/19). Among 8 evaluable ND patients the ORR and CR were 75% and 37%, respectively, while among 11 R/R patients these were 64% and 45%, respectively. Notably, among 11 evaluable patients with AITL (9) or PTCL-TFH (2), 10 responded, and 6 achieved a CR. 23 patients are evaluable for toxicity. The most frequent hematologic G3-4 AE were thrombocytopenia (39%) and neutropenia (39%). The most frequent non-hematologic G3-4 AE included lung infection (17%) and febrile neutropenia (13%). Other common G1-2 toxicities included anemia, diarrhea, fatigue, nausea, and vomiting. No patients discontinued therapy due to AE. At a median follow-up of 5.8 months [0.3-23.1], the median DOR has not been reached (1.8-20.0+ months) and the median PFS for the entire population, ND and R/R patients is 7.9 months, 7.9 months, and not reached, respectively. Two patients have died, one due to progressive disease, one due to unknown cause. Pre-treatment tumor samples are available for 17 patients, 13 of whom are evaluable for response: all patients had at least one mutation in an epigenetic gene. Importantly, 9/10 patients with a TET2 mutation responded, whereas only 1 of 3 patients with wild-type TET2 responded. Conclusions: The AZA-ROMI combination is well tolerated and highly active in PTCL patients, particularly AITL or PTCL-TFH. TET2 mutations may portend a higher likelihood of response. Sequencing data from the entire study population will be presented (NCT01998035). Keywords: epigenetics; peripheral T-cell lymphomas (PTCL); romidepsin (RD). Disclosures: Amengual, J: Research Funding: Appia Pharmaceuticals. Sokol, L: Honoraria: Celgene, Spectrum Pharmaceuticals, Seattle Genetics. Shustov, A: Honoraria: Portola Pharmaceuticals, Kyowa-Hakko-Kirin; Research Funding: Spectrum Pharmaceuticals. O'Connor, O: Honoraria: Celgene; Research Funding: Celgene.