Oral Azacitidine Plus CHOP Demonstrates Safety, Efficacy for Patients With Peripheral T-Cell Lymphomas With T-Follicular Helper Phenotype

Results From a Phase 2 Trial

Findings from a phase 2 trial published in Blood indicated that the combination of oral azacitidine (CC-486) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as initial treatment demonstrated high efficacy among patients with peripheral T-cell lymphomas (PTCL) with T-follicular helper phenotype (TFH). 

According to Jia Ruan, MD, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY, and coauthors, “Peripheral T-cell lymphomas with T-follicular helper phenotype has recurrent mutations affecting epigenetic regulators, which may contribute to aberrant DNA methylation and chemoresistance,” making patients in this group less likely to respond to treatment. 

This study aimed to evaluate the efficacy of the combination of oral azacitidine and CHOP as a potential initial treatment for PTCL-TFH. The primary endpoint was the end-of-treatment complete response (CR), and the secondary endpoints included safety and survival measures. 

A total of 20 evaluable patients with PTCL were enrolled in this trial and administered azacitidine orally at 300 mg daily for 7 days before cycle 1 of CHOP and for 14 days before cycles 2 to 6 of CHOP. Correlative studies were conducted to assess mutations, gene expression, and methylation patterns in tumor samples. 

The combination treatment showed promising efficacy outcomes, with a complete response rate of 75% among all patients. Among patients diagnosed with PTCL-TFH, the complete response rate was 88.2% (n = 17), indicating that this combination was especially effective for this group. The 2-year progression-free survival was 65.8% among all patients and 69.2% among patients with PTCL-TFH. The 2-year overall survival was 68.4% among all patients and 76.1% among patients with PTCL-TFH. 

Notably, mutational analyses revealed that TET2 mutations (76.5%) were significantly linked to complete response (P = .007), favorable progression-free survival (P = .004), and overall survival (P = .015). Conversely, DNMT3A mutations (23.5%) were linked to adverse progression-free survival (P = .016). These findings provide valuable insights into potential biomarkers for treatment prognosis among patients with PTCL-TFH.

The study authors observed that CC-486 priming affected the reprogramming of the tumor microenvironment by upregulation of genes related to apoptosis (P  < .01) and inflammation (P < .01). No significant shift was demonstrated by DNA methylation. Relatedly, “Integrative analyses suggest that azacitidine priming promotes apoptosis and inflammation within the lymphoma tumor microenvironment,” they noted. 

As for adverse events, the most common grade 3 to 4 hematologic toxicity observed was neutropenia (71%), with febrile neutropenia being less frequent (14%). Non-hematologic toxicities included fatigue (14%) and gastrointestinal symptoms (5%).

Dr Ruan et al concluded, “Addition of oral azacitidine to CHOP as initial therapy is safe, and induces high rates of [complete response] in patients with PTCL-TFH.”

“This safe and active regimen is being further evaluated in the ALLIANCE randomized study A051902 in CD30-negative PTCL,” they added. 

Source:  

Ruan J, Moskowitz A, Mehta-Shah N, et al; Multicenter phase 2 study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL. Blood 2023; 141 (18): 2194–2205. doi:10.1182/blood.2022018254