Duvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase 
(PI3K)-δ/γ isoforms currently in clinical development. PI3K-δ/γ inhibition may 
directly inhibit malignant T-cell growth, making duvelisib a promising candidate 
for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. 
Inhibition of either isoform may also contribute to clinical responses by 
modulating nonmalignant immune cells. We investigated these dual effects in a 
TCL cohort from a phase 1, open-label study of duvelisib in patients with 
relapsed or refractory PTCL (n = 16) and CTCL (n = 19), along with in vitro and 
in vivo models of TCL. The overall response rates in patients with PTCL and CTCL 
were 50.0% and 31.6%, respectively (P = .32). There were 3 complete responses, 
all among patients with PTCL. Activity was seen across a wide spectrum of 
subtypes. The most frequently observed grade 3 and 4 adverse events were 
transaminase increases (40% alanine aminotransferase, 17% aspartate 
aminotransferase), maculopapular rash (17%), and neutropenia (17%). Responders 
and nonresponders had markedly different changes in serum cytokine profiles 
induced by duvelisib. In vitro, duvelisib potently killed 3 of 4 TCL lines with 
constitutive phospho-AKT (pAKT) vs 0 of 7 lines lacking pAKT (P = .024) and 
exceeded cell killing by the PI3K-δ-specific inhibitor idelalisib. 
Administration of duvelisib to mice engrafted with a PTCL patient-derived 
xenograft resulted in a shift among tumor-associated macrophages from the 
immunosuppressive M2-like phenotype to the inflammatory M1-like phenotype. In 
summary, duvelisib demonstrated promising clinical activity and an acceptable 
safety profile in relapsed/refractory TCL, as well as preclinical evidence of 
both tumor cell-autonomous and immune-mediated effects. This trial was 
registered at www.clinicaltrials.gov as #NCT01476657.