A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms

Abstract

Ruxolitinib and azacytidine target distinct disease manifestations of myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs). Patients with MDS/MPNs initially received ruxolitinib BID (doses based on platelets count), continuously in 28-day cycles for the first 3 cycles. Azacytidine 25 mg/m² (Day 1-5) intravenously or subcutaneously was recommended to be added to each cycle starting cycle 4 and could be increased to 75 mg/m² (Days 1-5) for disease control. Azacytidine could be started earlier than cycle 4 and/or at higher dose in patients with rapidly proliferative disease or with elevated blasts. Thirty-five patients were treated (MDS/MPN-U, n =14; CMML, n =17; aCML, n =4), with a median follow-up of 15.2 months (range, 1.0-41.5). All patients were evaluable by the 2015 international consortium proposal of response criteria for MDS/MPNs (ICP MDS/MPN) and 20 (57%) responded. Nine patients (45%) responded after the addition of azacytidine. A greater than 50% reduction in palpable splenomegaly at 24 weeks was noted in 9/14 (64%) patients. Responders more frequently were JAK2-mutated (P = .02) and had splenomegaly (P = .03) compared to nonresponders. New onset grade 3/4 anemia and thrombocytopenia occurred in 18 (51%) and 19 (54%) patients, respectively, but required therapy discontinuation in only 1 (3%) patient. Patients with MDS/MPN-U had better median survival compared to CMML and aCML (26.5 vs 15.1 vs 8 months; P = .034). The combination of ruxolitinib and azacytidine was well-tolerated with an ICP MDS/MPN-response rate of 57% in patients with MDS/MPNs. The survival benefit was most prominent in patients with MDS/MPN-U.

Trial registration: ClinicalTrials.gov NCT01787487.

FIGURE 1

(A) depicts the percentage of change in spleen volume during therapy. Of the 12 patients with baseline splenomegaly palpable >5 cm below costal margin, 9 (64%) showed clinical improvement with >50% reduction of spleen volume when treated with AZA 1 RUX, at a median time of 1.8 months (range, 0.7–7.3 months), including 4 patients with 100% decrease from baseline. One patient achieved 45% reduction of splenomegaly, while 2 patients did not have any clinical improvement of spleen volume. (B) Overall survival, per diagnosis cohort, of patients with MDS/MPN treated with ruxolitinib and azacytidine. Kaplan–Meier estimates. (C) Overall survival of patients with MDS/MPN who have achieved clinical response in general compared to those who had no response; Kaplan–Meier analysis. mOS: Median overall survival [Color figure can be viewed at wileyonlinelibrary.com]