Duvelisib/Azacitidine Combo Shows Encouraging Activity in T-Cell Lymphoma

Oral duvelisib (Copiktra) combined with oral azacitidine (Onureg) had a manageable safety profile and encouraging activity in patients with relapsed/refractory mature T-cell lymphoma (TCL), particularly among those with a T-follicular-helper (TFH) phenotype, according to results from a phase 1 trial (NCT05065866) published in Hematological Oncology.

The maximum tolerated dose (MTD) was established as duvelisib at 50 mg twice daily for the first 2 cycles, followed by 25 mg twice daily, combined with oral azacitidine at 100 mg daily on days 1 through 14 of each 28-day cycle. Dose escalation was halted at dose level 3 following 2 dose-limiting toxicities (DLTs) of grade 3 transaminitis; both were reversible with protocol-specified drug interruption, with transaminases returning to grade 1 or lower within a median of approximately 2 weeks. Therapy was resumed at a reduced dose in eligible patients.

Among all patients (n = 14), the most common hematologic toxicities of any grade were leukopenia (50%), neutropenia (43%), thrombocytopenia (43%), and anemia (43%). Grade 3/4 events included neutropenia (29%), anemia (21%), increased aspartate aminotransferase (AST; 21%), and increased alanine aminotransferase (ALT; 14%). The most common non-hematologic toxicities were nausea (71%), increased AST (57%), vomiting (43%), and increased ALT (43%); most gastrointestinal and other non-hematologic events were grade 1/2 and manageable with supportive care. Treatment discontinuation occurred in 2 patients due to grade 3 transaminitis at dose cohort 3 and in 1 patient due to rash after 19 cycles of therapy.

Efficacy data were available for 13 evaluable patients. The overall response rate (ORR) was 46% (n = 6), including a complete response (CR) rate of 31% (n = 4) and a partial response (PR) rate of 15% (n = 2); 1 patient was unevaluable. All 4 evaluable patients with a nodal TFH-lineage phenotype achieved a CR. The median progression-free survival (PFS) was 2.2 months (95% CI, 1.8-not estimable [NE]), and the median overall survival (OS) was 10.2 months (95% CI, 6.3-NE).

The median duration of response (DOR) was not reached; among the 6 responders, 1 patient who had PTCL not otherwise specified (PTCL-NOS) and achieved a PR had documented progression, at 2.5 months, while 3 were censored at the time of allogeneic transplant and 2 remained in ongoing CR off therapy. Three patients, including 2 with angioimmunoblastic T-cell lymphoma in CR and 1 with PTCL-NOS in PR, proceeded directly from study therapy to allogeneic hematopoietic stem-cell transplantation.

“This phase 1 trial supports the continued exploration of duvelisib combined with oral azacitidine as a novel therapeutic option for relapsed/refractory mature T-cell lymphoma, especially in TFH phenotype populations. Further clinical trials are warranted to confirm these preliminary findings and to optimize patient selection and dosing strategies,” Hayder Saeed, MD, associate member of the Department of Malignant Hematology at Moffitt Cancer Center, wrote in the publication with study coinvestigators.

In the open-label, 3+3 dose-escalation study of oral duvelisib, a dual PI3K-δ/γ inhibitor, plus oral azacitidine in patients with histologically confirmed, measurable, previously treated mature TCL, those with prior PI3K inhibitor exposure were excluded. Investigators screened 17 patients and enrolled 14, with a median age of 63.5 years (range, 44-72) and a median of 2 prior therapies (range, 1-21); 78% had primary refractory disease. The most common subtypes were PTCL-NOS (35%; n = 5) and TFH phenotype (28%; n = 4).

The primary end point of the study was the MTD of duvelisib plus oral azacitidine. Secondary end points included ORR, disease control rate, DOR, PFS, and OS. Additionally, exploratory end points assessed T-cell composition changes, including phosphorylated AKT (pAKT) levels in peripheral CD3-positive T cells.

Pharmacodynamic analyses showed greater on-treatment suppression of pAKT during combination therapy than during the single-agent duvelisib phase, consistent with preclinical data supporting combined PI3K inhibition and hypomethylation. Regulatory T cell dynamics differed between responders and non-responders, though the authors noted this finding is confounded by unequal on-treatment exposure time.

The investigators acknowledged limitations including the small sample size, selection bias inherent to phase 1 trials, and limited follow-up duration. They also noted that global DNA-methylation pharmacodynamics were not assessed.

Reference

Saeed H, Varela MM, Sahakian E, et al. A phase 1 trial of duvelisib and oral azacitidine in relapsed/refractory T-cell lymphoma. Hematol Oncol. Published August 3, 2026. doi:10.1002/hon.70235