Paper Details

ABSTRACT

Introduction: Both duvelisib (duv), a phosphoinositive-3-kinase (PI3K)-γδ inhibitor, and ruxolitinib (rux), a Janus kinase (JAK)-1/2 inhibitor, are effective agents for peripheral T cell lymphoma (PTCL) and cutaneous T cell lymphoma (CTCL). In prior studies, PI3K signaling activation predicted for resistance to rux while JAK/signal transducer and activator of transcription (STAT) signaling activation predicted for resistance to duv-based therapy (Moskowitz, et al.  Blood 2021; Horwitz, et al. Nature Medicine 2024).  Building on these observations, we conducted a phase I study assessing dual-targeting of JAK and PI3K with rux plus duv for PTCL and CTCL. Maximum tolerated dose was determined to be rux 20mg po BID plus duv 25mg PO BID and among a total of 49 patients (pts) enrolled, ORR and CR rate were 41% and 24%, respectively (Moskowitz, et al. ASH 2024).  Particularly encouraging activity was observed among 5 pts with T-prolymphocytic leukemia (T-PLL), of whom 3 (60%) experienced a response, including 2 with prolonged responses lasting 24 and 36 mos. To confirm the preliminary efficacy observed, we expanded the study to enroll an additional 10 pts with T-PLL. Reported here are results for all pts with T-PLL.

Methods: This is an investigator-initiated multi-center study for pts with PTCL or CTCL that included an expansion cohort for pts with T-PLL. A sample size of 15 pts was chosen to allow, according to the Wilson score method, for a narrower 95% C.I of 48-89%, assuming similar efficacy is observed. Pts with treatment naïve or relapsed or refractory (rel/ref) T-PLL were eligible.  Treatment consisted of rux 20mg PO BID plus duv 25mg PO BID until progression or intolerance. Prophylaxis against herpes zoster and pneumocystis pneumonia (PJP) was required. The primary objective was to estimate the ORR (combined rates of complete response and partial response) and disease control rate (DCR; combined rates of complete response, partial response, and stable disease [SD] lasting at least 6 mos) using the global response score for T-PLL.

Results: 14 pts enrolled and 1 pt is currently in screening. Among 14 pts treated, median age at enrollment was 66 years (range, 63-87), 57% were female, 79% were white, 14% black, and 7% unknown. Median number of prior therapies was 0 (range 0-6); 8 pts were treatment-naïve. Two pts previously underwent allogeneic stem cell transplant and 1 previously underwent autologous stem cell transplant.  

Treatment-related grade 3 drug-related adverse events included neutropenia (7% G3, 14% G4), anemia (7% G3), lung infection (7% G3), and hypertension (7% G3).

Thirteen pts are evaluable for response (1 is too early). Five pts achieved objective response, all partial, leading to an ORR of 37% (95% C.I 14-68%). Three pts had stable disease (SD) of whom 2 had SD > 6 months (11.1 mos and 23.6 mos), leading to a disease control rate (DCR) of 54% (95% C.I. 25%-81%).

Median time to best response was 1.8 mos (1.8-10.1 mos). Median progression free survival (PFS) was 12.9 (95% C.I 1.8-NR) mos and median duration of response (DOR) was 17.7 (4.7-NR) mos. Among the 8 treatment-naïve pts, ORR was 63%, DCR 75%, and median PFS and DOR were 17.9 (9-NR) and 17.7 (4.7-NR) mos, respectively. In contrast, among 5 previously treated pts, 1 pt with 1 prior line of therapy (alemtuzumab) had SD >6 mos (23.6 mos) while the rest experienced no response to rux/duv.     

Genetic studies showed that 7 pts had disease with activating JAK3-mutations (including 1 pt with a JAK1 mutation), 2 had STAT5B-mutations, and 1 had a JAK1-mutation. Among pts with JAK3-muations, 2 (29%) achieved PR and 4 (57%) achieved disease control. Of the 2 pts with STAT5B mutations, both achieved PR. No responses were seen among the 2 pts with JAK1 mutations.

Conclusion:  Rux 20mg BID plus duv 25mg BID has encouraging efficacy in T-PLL with ORR of 37% and DCR of 54%. All responses were partial, but they were durable with median DOR of 17.7 mos. Higher efficacy was observed among treatment-naïve pts (ORR of 63% and DCR of 75%) as well as pts whose disease harbored JAK3 or STAT5B mutations. The toxicity profile was manageable with low rates of typical PI3Ki-related toxicities such as hepatitis, rash, or colitis, which were possibly diminished by ruxolitinib. In conclusion, rux/duv represents a durable, well tolerated option for pts with T-PLL who are not eligible for standard treatment with alemtuzumab followed by allogeneic stem cell transplant.