Background
Phase II, single-arm, multicenter study (largest single-arm PI3K inhibitor PTCL study). 123 patients with relapsed/refractory PTCL after ≥1 prior therapy. Duvelisib is a dual PI3K-δ/γ inhibitor; PI3K-δ is enriched in T-cells and PI3K-γ supports the tumor microenvironment. AITL is characterized by PI3K pathway activation (TET2, RHOA, IDH2 mutations), providing strong rationale.
Interventions and follow up
Regimen: Duvelisib 75 mg PO twice daily × 2 cycles (induction), then 25 mg PO twice daily continuously until progression, in R/R PTCL
Primary endpoint: Overall response rate (independent review committee)
Median follow-up: ~24 months
Primary endpoint: Overall response rate (independent review committee)
Median follow-up: ~24 months
Results
ORR (primary, all PTCL): 48% (95% CI 38–57%)
CR rate (all PTCL): 33.3%
AITL subgroup ORR: 62.2%
AITL subgroup CR: 51.4%
AITL median PFS: 8.3 months
PTCL-NOS ORR: 43%
CR rate (all PTCL): 33.3%
AITL subgroup ORR: 62.2%
AITL subgroup CR: 51.4%
AITL median PFS: 8.3 months
PTCL-NOS ORR: 43%
Adverse events
Hematologic: Grade ≥3 neutropenia 28%
Gastrointestinal/hepatic: Grade ≥3 diarrhea/colitis 10%; grade ≥3 transaminase elevation 6.5%
Infectious/pulmonary: Grade ≥3 infections 25% (including hepatitis reactivation, PCP; prophylaxis required); pneumonitis any grade 13% (grade ≥3 4%)
Overall: Grade ≥3 AEs 74%; discontinuation for AEs 18.7%
Gastrointestinal/hepatic: Grade ≥3 diarrhea/colitis 10%; grade ≥3 transaminase elevation 6.5%
Infectious/pulmonary: Grade ≥3 infections 25% (including hepatitis reactivation, PCP; prophylaxis required); pneumonitis any grade 13% (grade ≥3 4%)
Overall: Grade ≥3 AEs 74%; discontinuation for AEs 18.7%
Conclusions
Duvelisib achieved a 48% ORR overall in R/R PTCL, with particularly strong activity in AITL (62.2% ORR, 51.4% CR), among the highest single-agent response rates reported in AITL, establishing PI3K inhibition as a key strategy in TFH-phenotype T-cell lymphomas.
Key Limitations
Single-arm Phase II with no randomized comparator. PI3K inhibitor-class toxicities (diarrhea/colitis, infections, hepatotoxicity, pneumonitis) require vigilant monitoring and PCP prophylaxis. The 75 mg to 25 mg dose step-down adds complexity. The compelling AITL benefit requires validation in a randomized setting.
Clinical Context
PRIMO results published in JCO 2026. Duvelisib received accelerated FDA approval for R/R CLL/SLL and FL; the FL indication was voluntarily withdrawn in 2023 over safety concerns, and it is not FDA-approved for PTCL. TFH-phenotype PTCL (AITL and PTCL with TFH markers) is increasingly recognized as biologically distinct and responsive to epigenetic/PI3K-targeted therapy. ESMO lists PI3K inhibition among emerging targeted approaches for AITL.
References