Multicenter phase 2 study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL

Jia Ruan, Alison Moskowitz, Neha Mehta-Shah, Lubomir Sokol, Zhengming Chen, Nikita Kotlov, Grigorii Nos, Maria Sorokina, Vladislav Maksimov, Andrea Sboner, Michael Sigouros, Koen van Besien, Steven Horwitz, Sarah C. Rutherford, Erin Mulvey, Maria V. Revuelta, Jenny Xiang, Alicia Alonso, Ari Melnick, Olivier ElementoGiorgio Inghirami, John P. Leonard, Leandro Cerchietti, Peter Martin

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Peripheral T-cell lymphomas (PTCL) with T-follicular helper phenotype (PTCL-TFH) has recurrent mutations affecting epigenetic regulators, which may contribute to aberrant DNA methylation and chemoresistance. This phase 2 study evaluated oral azacitidine (CC-486) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as initial treatment for PTCL. CC-486 at 300 mg daily was administered for 7 days before C1 of CHOP, and for 14 days before CHOP C2-6. The primary end point was end-of-treatment complete response (CR). Secondary end points included safety and survival. Correlative studies assessed mutations, gene expression, and methylation in tumor samples. Grade 3 to 4 hematologic toxicities were mostly neutropenia (71%), with febrile neutropenia uncommon (14%). Nonhematologic toxicities included fatigue (14%) and gastrointestinal symptoms (5%). In 20 evaluable patients, CR was 75%, including 88.2% for PTCL-TFH (n = 17). The 2-year progression-free survival (PFS) was 65.8% for all and 69.2% for PTCL-TFH, whereas 2-year overall survival (OS) was 68.4% for all and 76.1% for PTCL-TFH. The frequencies of the TET2, RHOA, DNMT3A, and IDH2 mutations were 76.5%, 41.1%, 23.5%, and 23.5%, respectively, with TET2 mutations significantly associated with CR (P = .007), favorable PFS (P = .004) and OS (P = .015), and DNMT3A mutations associated with adverse PFS (P = .016). CC-486 priming contributed to the reprograming of the tumor microenvironment by upregulation of genes related to apoptosis (P < .01) and inflammation (P < .01). DNA methylation did not show significant shift. This safe and active regimen is being further evaluated in the ALLIANCE randomized study A051902 in CD30-negative PTCL. This trial was registered at www.clinicaltrials.gov as #NCT03542266.

Original languageEnglish
Pages (from-to)2194-2205
Number of pages12
JournalBlood
Volume141
Issue number18
DOIs
StatePublished - May 4 2023

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