P1194: A PHASE IB TRIAL OF ITACITINIB COMBINED WITH ALEMTUZUMAB IN PATIENTS WITH T-CELL PROLYMPHOCYTIC LEUKEMIA (T-PLL)

Abstract

Background: T-cell prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm with an aggressive clinical course including rapid lymphocyte proliferation, progressive organomegaly, lymphadenopathy, 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. Three quarters of cases of T-PLL harbor activating mutations in the JAK-STAT pathway (JAK1, JAK3, STAT5b, IL2RG). Aims: We designed astudy to evaluate the combination of the JAK1 inhibitor itacitinib with CAMPATH to target activated JAK-STAT signaling. Methods: 15 pts were enrolled (Table 1). 8 pts (53%) were newly diagnosed and 7 pts (47%) were previously treated, with a median of 1 (1-3) prior therapies, including 2 (33%) with prior SCT. 10 pts (67%) had chromosome 14 abnormality by conventional cytogenetics, and 6/6 (100%) pts tested by FISH had TCL1 positivity. 5/7 (71%) tested pts having activating mutations in the JAK-STAT pathway. Pts received a median of 4 cycles (1-12) of therapy, including a median of 2 (1-4) combination cycles and a median of 3 (0-10) maintenance cycles. Of 8 evaluable frontline pts, there were 4 (50%) complete remissions (CR), all MRD (-) by flow cytometry, and 3 (38%) partial remissions (PR) for an overall response rate of 88%. Of 7 evaluable previously-treated pts, there were 3 (43%) CR, all MRD (-) by flow cytometry, 1 (14%) PR, 2 non responders (29%), and 1 (17%) early death in a pt that declined transfusions, for an ORR 57%. 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, 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 (3), 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 18.6 m and 8.5 m in the frontline and salvage cohorts, respectively. Results: Single-agent itacitinib was associated with patient reported improvements in B-symptoms, rash, appetite, and reduced splenomegaly. Response rates with the combination were encouraging in frontline and salvage, with favorable OS. Further study of the combination without a 2-week window (of itacitinib alone) and with objective measurement of patient reported symptoms is planned. Image:Summary/Conclusion: The combination of itacitinib 200 mg daily and CAMPATH in pts with T-PLL was safe and well tolerated with no dose-limiting toxicities. 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 encouraging in frontline and salvage, with favorable OS. Further study of the combination without a 2-week window (of itacitinib alone) and with objective measurement of patient reported symptoms is planned.