A Phase Ib Pilot Study of Itacitinib Combined with Alemtuzumab in Patients with T-Cell Prolymphocytic Leukemia (T-PLL)

Background: T-cell prolymphocytic leukemia (T-PLL) is a rare, mature T-cell neoplasm often characterized by an aggressive clinical course including rapid lymphocyte proliferation, progressive lymphadenopathy and organomegaly, pleural and pericardial effusions, skin manifestations, and severe B-symptoms. Overall prognosis has been poor, with inadequate response to conventional chemotherapy and limited efficacy of allo stem cell transplant (SCT). The CD52 monoclonal antibody alemtuzumab (CAMPATH) has been the most effective therapy for T-PLL, but responses are not durable. Molecular characterization of T-PLL has recently found up to 76% of cases harboring activating mutations in the JAK-STAT pathway (JAK1, JAK3, STAT5b, IL2RG). We hypothesized that the combination of the JAK1 inhibitor itacitinib with CAMPATH could target activated JAK-STAT signaling and provide clinical benefit.

Methods: This is a phase Ib study for pts ≥ 18 years with T-PLL with adequate organ function, ECOG performance status ≤ 2, and platelets ≥ 30,000. Patients (Pts) with newly diagnosed or previously treated T-PLL were eligible. The study had a 3+3 dose de-escalation design, starting at an itacitinib dose of 200 mg daily and de-escalating if the dose was above the MTD. De-escalation was not required. During cycle 1, pts received itacitinib alone on Days 1-14 to assess single-agent activity; starting on cycle 1 Day 15 and beyond, pts received the addition of CAMPATH 30 mg IV every other day, after a 3-day ramp up. Pts continued on the combination of CAMPATH + itacitinib for up to 4 cycles or until best response. At the time of best response, pts could proceed with maintenance therapy with single-agent itacitinib for up to 8 cycles. Primary objective was safety and efficacy of the combination. Secondary endpoints included response, EFS, and OS.

Results: 13 pts were enrolled on study. Baseline characteristics are shown in Table 1. The median age was 64 yrs (range, 39-83). 7 pts (54%) were newly diagnosed and 6 pts (46%) were previously treated, with a median of 2 (1-3) prior therapies, including 2 (33%) with prior SCT. Nine (69%) pts had complex karyotype, 8 (62%) had chromosome 14 abnormality by conventional cytogenetics, and 6 (46%) pts had TCL1 positivity by FISH. Mutations detected by NGS are summarized in Table 1, with 5/7 (71%) tested pts having activating mutations in the JAK-STAT pathway. Pts received a median of 4 cycles (1-11) of therapy on protocol, including a median of 2 (1-4) combinations cycles and a median of 1 (0-7) maintenance cycles. Of 6 evaluable frontline pts, there were 3 (50%) complete remissions (CR), all MRD (-) by flow cytometry, and 3 (50%) partial remissions (PR) for an overall response rate of 100%. Of 6 evaluable previously-treated pts, there were 2 (33%) CR, all MRD (-) by flow cytometry, 1 (17%) PR, and 1 (17%) early death in a pt that declined transfusions, for an ORR 50%. The median number of cycles to best response were 2 (1-4) and 1 (1-2) in the frontline and salvage cohorts, respectively. While no objective responses were observed in WBC or lymph nodes during the 2 week window of single-agent itacitinib, pts experienced improvement in B-symptoms, splenomegaly, appetite, and rash during this period prior to CAMPATH. The regimen was well tolerated. The most common grade 3/4 AEs on study were lung infection (4), allergic reaction (2), other infection (2), neutropenic fever (1), and kidney injury (1). No AEs were attributed to single-agent itacitinib. 3 of the 6 (50%) responding frontline pts went on to allogeneic SCT, 1 patient (81 years old) died after 11 cycles on protocol of unknown cause, and 2 pts are ongoing on protocol. The median OS was not reached and 8.5 m in the frontline and salvage cohorts, respectively. The median EFS was 11.7 m and 7.8 m in the frontline and salvage cohorts, respectively.

Conclusion: The combination of itacitinib and CAMPATH in pts with T-PLL was safe and well tolerated with no dose-limiting toxicities at the starting itacitinib dose of 200 mg daily. Single-agent itacitinib was associated with patient reported improvements in B-symptoms, rash, appetite, and exam findings of reduced splenomegaly. Response rates with the combination were similar to historical expectations in frontline and salvage, but OS and EFS appear favorable, with short follow up. Further study of the combination without a 2-week window (of itacitinib alone) and with objective measurement of patient reported symptoms is planned.

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