Deep clinical responses and limited inflammatory toxicity in patients with relapsed/refractory T-cell lymphomas receiving Duvelisib and Romidepsin

PI3K-d inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities leading to market withdrawals. We previously demonstrated single-agent activity of the PI3K-dg duvelisib in T-cell lymphomas that was associated with inflammatory adverse events. We conducted a phase Ib/IIa study of duvelisib in combination with either romidepsin or bortezomib in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. Among those with peripheral T-cell lymphomas (PTCL), secondary endpoings of overall and complete response rates of duvelisib and romidepsin were 56% and 44% respectively with less grade 3/4 hepatotoxicity (14%) compared to the 40% rate of grade 3/4 transaminase elevation seen in our prior study with duvelisib monotherapy. Correlative analyses demonstrated enhanced response rates in patients with a follicular helper T-cell subtype. Finally, the attenuated hepatotoxicity seen in this study was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. These findings support further development of combined PI3K and HDAC inhibition in T-cell lymphomas and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations.