Phase 1B pilot study of itacitinib with alemtuzumab in patients with T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm with an aggressive clinical course. Overall prognosis is poor, and treatment relies on alemtuzumab because of inadequate response to conventional chemotherapy. Three-quarters of cases harbor activating mutations in the JAK-STAT pathway (, , , ). We report safety and efficacy from a phase 1B study evaluating the combination of the JAK1 inhibitor itacitinib with alemtuzumab. Patients (N = 15) were aged >18 years, with treatment-naïve (n = 8) or relapsed/refractory (n = 7) T-PLL with adequate organ function, European Cooperative Oncology Group Performance Status ≤2, and platelet >30 × 10/μL. Cycle 1 included a lead-in phase with itacitinib monotherapy days 1-14. Beginning day 15, patients also received alemtuzumab 30mg IV 3 times weekly for up to 4 (28-day) cycles or until best response. At best response, up to 8 cycles of maintenance with single-agent itacitinib was allowed. Median age was 65 years (range, 39-83). Ten patients (67%) had complex cytogenetics, 11 (73%) had chromosome 14 abnormality, and 13 (87%) were positive by fluorescence in situ hybridization. Among frontline patients, overall response rate (ORR) was 88% (complete remission [CR]: 75%), median event-free survival (EFS) and overall survival (OS) were 11.6 and 19.5 months, respectively. Three frontline patients proceeded to allogeneic stem cell transplantation. The ORR in the relapsed/refractory cohort was 57% (CR: 43%), whereas median EFS and OS were 11.1 months. Most (85%) adverse events were grade 1 to 2 and none were attributed to itacitinib. Continued studies evaluating JAK inhibitors in patients with T-PLL are warranted. This trial was registered at www.clinicaltrials.gov as #NCT03989466.