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

Author(s): ¹Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY;²Memorial Sloan Kettering Cancer Center, New York, NY;³Washington University in St. Louis, St. Louis, MO;⁴Moffitt Cancer Center, Tampa, FL;⁵BostonGene Corporation, Waltham, MA

Source: Blood (2023) 141 (18): 2194–2205

Dr. Anjan Patel's Thoughts

Not a common disease and not a randomized study, but very good responses seen in oral-Vidaza + CHOP for PTCL.

KEY POINTS

Addition of oral azacitidine to CHOP as initial therapy is safe, and induces high rates of CR in patients with PTCL-TFH. Integrative analyses suggest that azacitidine priming promotes apoptosis and inflammation within the lymphoma tumor microenvironment.

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.

Author Affiliations

Jia Ruan¹;Alison Moskowitz²;Neha Mehta-Shah³;Lubomir Sokol4Zhengming Chen¹;Nikita Kotlov⁵;Grigorii Nos⁵;Maria Sorokina⁵;Vladislav Maksimov⁵;Andrea Sboner¹;Michael Sigouros¹;Koen van Besien¹;Steven Horwitz²;Sarah C. Rutherford¹;Erin Mulvey¹;Maria V. Revuelta¹;Jenny Xiang¹;Alicia Alonso¹;Ari Melnick¹;Olivier Elemento¹;Giorgio Inghirami¹;John P. Leonard¹;Leandro Cerchietti¹;Peter Martin¹

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