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Ruxolitinib Plus Azacitidine Tolerable for Advanced Phase MPN, Post-MPN AML
Ruxolitinib in combination with azacitidine was well-tolerated and showed comparable safety among patients with advanced phase myeloproliferative neoplasms (MPN-AP) /post-MPN AML (MPN-BP), according to findings from the 1250 Phazar trial being presented by Mark W. Drummond, PhD, FRCPath, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom, at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.
According to Dr Drummond et al, the purpose of this trial was to determine the maximum tolerated dose (MTD), safety profile, and clinical activity of ruxolitinib plus azacitidine.
“Treatments for 'accelerated phase' MPNs (MPN-AP, 10-19% blasts)/post-MPN AML (MPN-BP, ≥20% blasts) are limited. Most patients are precluded from potentially curative hematopoietic stem cell transplantation (HSCT). For HSCT ineligible patients, azacitidine is licensed to treat high-risk MDS or AML," they wrote.
Researchers used a modified two-stage continual reassessment method with an expansion cohort at the MTD to find the MTD of ruxolitinib with azacitidine. Cohorts of 3 to 5 patients were enrolled and given a fixed dose of azacitidine 75mg s/c for 7 days (5-2-2 schedule) of a 28-day cycle with continuous administration of oral ruxolitinib (dose levels 0, 1, 2 and 3 = 10, 15, 20 and 25 mg BD respectively). Dose-limiting toxicity (DLT) was defined as a grade 3 or 4 non-hematological toxicity during treatment cycle 1.
Over 12 months, clinical activity was evaluated through assessment of bone marrow response after 3 and 6 treatment cycles, as well as progression-free survival (PFS) leukemia-free survival (LFS), and overall survival (OS)
Of the 34 advanced MPN patients enrolled in this study, driver mutation status was available for 25 (74%) patients. Of those 25 patients, 17 (68%) carried canonical mutations in JAK2, 4 (16%) in CALR, and 4 (16%) were triple-negative.
The MTD of ruxolitinib in combination with azacitidine was determined to be 25mg BD, with 21 patients receiving the MTD, while three patients received 10 and 15mg BD and four patients received 20mg BD. While no DLTs were reported during phase 1 of the study, 1 DLT at dose level 3 was reported during the expansion phase (grade 3 febrile neutropenia), the patient's ruxolitinib dose was lowered from 25 to 20 mg BD.
20 out of the 34 total patients were able to be evaluated for disease response. After 3 and 6 cycles, the best responses from MPN-AP patients included 1 complete remission (CR), 4 marrow CR, 1 partial remission, 4 with stable disease (SD), and 3 with progressive disease. While responses for MPN-BP patients included 4 acute leukemia response-partial and 3 SD.
The median response duration for MPN-AP was 322 days, and for MPN-BP, it was 199 days. None of the 14 RBC transfusion-dependent patients achieved RBC transfusion independence, while 4 of the 7 (57.1%) patients dependent on platelet transfusions achieved platelet transfusion independence after 3 cycles, 1 (14.3%) persisted through 6 cycles.
At 12 months, median PFS was 42.1% (95% CI: 17.9, 64.7), LFS was 26.4% (95% CI: 6.5, 52.2) and OS was 42.4% (95% CI: 23.8, 59.8).
A total of 601 adverse events (AEs) were reported, with 16.3% being grade 3 and 3.5% grade 4, anemia and febrile neutropenia being the most common. 77 serious AEs were reported, 50.6% of those are believed to be trial-related. The most common AEs reported were febrile neutropenia (29.4%), sepsis (14.7%), and infections and infestations (14.7%)
"Of evaluable patients 10 of 20 achieved a PR or CR. The OS compares favourably with historical cohorts and clinically meaningful responses were achieved for transfusion independence," Drummond and colleagues added.
"Such combinations should be further explored, potentially with higher dose RUX. An expanded molecular analysis including responses is presented as a separate abstract," they concluded.—Alexandra Graziano
Drummond MW, Gaskell C, Claire Harrison C, et al. Phazar: A Phase Ib Study to Assess the Safety and Tolerability of Ruxolitinib in Combination with Azacitidine in Advanced Phase Myeloproliferative Neoplasms (MPN), Including Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukaemia (AML) Arising from MPN [ISRCTN16783472]. Presented at: the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 1250.
