High Rates of Remission with the Initial Treatment of Oral Azacitidine Plus CHOP for Peripheral T-Cell Lymphoma (PTCL): Clinical Outcomes and Biomarker Analysis of a Multi-Center Phase II Study

INTRODUCTION:

Nodal PTCL with T-follicular helper phenotype (PTCL-TFH), which includes angioimmunoblastic T-cell lymphoma, is characterized by recurrent mutations affecting epigenetic regulators. Azacitidine, a DNA demethylating agent, has shown clinical activity as a single agent and in combination in R/R PTCL. We report the mature findings, including survival outcome and biomarker analysis, of the first study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL (ClinicalTrials.gov - NCT03542266).

METHODS:

This phase 2 study prioritized enrollment of PTCL-TFH. Subjects received CHOP on day 1 of each cycle for 6 cycles. Oral azacitidine (aza) priming at 300 mg daily was administered for 7 days prior to C1 of CHOP, and for 14 days before CHOP C2-6. The primary endpoint was CR per 2014 IWG criteria. Secondary endpoints included ORR, safety and survival. Correlative biomarker studies assessed mutation profile by whole exome NGS with germline control, genome-wide DNA methylation sequencing by RRBS, and gene expression by RNA-sequencing of paired tumor samples before and after aza priming prior to C1D1 chemotherapy. Survivals were estimated by Kaplan-Meier analysis, and log-rank tests were performed to correlate biomarkers to survival outcomes.

RESULTS:

A total of 21 subjects with previously untreated PTCL, including 17 with PTCL-TFH (81%), 3 with PTCL-NOS (14%), were enrolled and received treatment at 4 centers. The median age was 66 years (range 22-77), 19 (90%) had stage III/IV disease, 10 (48%) had elevated LDH, 7 (35%) had bone marrow involvement, and 9 (43%) had IPI 3-5. Treatment-emergent grade 3-4 hematologic toxicities included neutropenia (71%), thrombocytopenia (10%) and anemia (14%), with febrile neutropenia uncommon (14%). Grade 3-4 non-hematologic toxicities included fatigue (14%), hyponatremia (14%), diarrhea (5%), anorexia (5%), vomiting (5%), rash (5%), and elevated ALT (4.8%). There was no treatment-related mortality on study. As of July 2021 at a median follow-up of 21 months (range 16-30 months), 20 subjects were evaluable for primary endpoint, with one withdrawal after cycle 1. The end-of-treatment responses were all CRs, including CR at 75% (90%CI of 54.4 - 89.6%) for all evaluable patients (n=20) and 88.2% for PTCL-TFH (n=17). The 2-yr PFS was 65.8% (95%CI of 43.4-88.1%) for all patients, and 69.2% (95%CI of 46.7-91.7%) for PTCL-TFH. The 2-yr OS was 68% (95%CI of 46.7-89.2%) for all patients, and 75.6% (95%CI of 54.8-96.5%) for PTCL-TFH. The median PFS was estimated at 36 months (95%CI: 8 months - not reached). Consolidative stem cell transplant was performed in 10 subjects (9 auto and 1 allo), which did not impact PFS or OS. Mutational status was determined in 17 patients. The frequencies of the TET2, RHOA, DNMT3A, and IDH2 mutations were 76.5%, 41.1%, 23.5% and 23.5%, respectively, with RHOA and IDH2 mutations occurring in the hotspot positions (RHOA G17V, IDH2 R172G/T). For all patients, TET2 mutations were significantly associated with CR (p=0.007), favorable PFS (p=0.004) and OS (p=0.015), while DNMT3A mutations were associated with adverse PFS (p=0.016). Within the PTCL-TFH subgroup, TET2 mutations were associated with favorable PFS (p=0.014). RNAseq and RRBS assays were performed in 5 paired tumor samples before and after aza priming. Differentially upregulated genes revealed enrichment of gene sets related to apoptosis (p<0.01) and inflammation (p<0.01). Gene expression-based cell subtype deconvolution revealed a decreasing trend in TFH lymphoma cells, proliferation rate, as well as TCRB clonality in response to aza treatment, while DNA methylation did not show significant shift. Clonal evolution with emergence of DNMT3A mutant clones in a paired baseline-relapse samples in an early relapse patient suggested possible resistance mechanism.

CONCLUSIONS:

This study demonstrates that priming with oral azacitidine (CC486) in combination with CHOP as initial therapy is safe, effective, and produces sustained remission in PTCL-TFH subtype. Epigenetic priming with azacitidine appears to inhibit the proliferation of TFH lymphoma cells, providing potential synergistic mechanism of action with chemotherapy. This active combination will be further evaluated in the upcoming ALLIANCE/ US Intergroup randomized study A051902, comparing oral azacitidine-CHO(E)P vs duvelisib-CHO(E)P against CHO(E)P in CD30 negative PTCL.

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