A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis

Abstract

Ruxolitinib (RUX)-based combinations may provide benefit for patients with myelofibrosis (MF). In this open-label, nonrandomized, prospective phase 2 study, patients with MF initially received RUX twice per day continuously in 28-day cycles for the first 3 cycles. Azacitidine (AZA) 25 mg/m2 (days 1-5) was added starting with cycle 4 and could be subsequently increased to 75 mg/m2 (days 1-5). Forty-six patients were enrolled with a median follow-up of 28 months (range, 4-50+ months). An International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) response was achieved in 33 patients (72%), with a median time to response of 1.8 months (range, 0.7-19.0 months). One-fourth (7 of 33) of the IWG-MRT responses occurred after the addition of AZA. A reduction of >50% in palpable spleen length at 24 weeks and at any time on the study was achieved in 62% and 71% of the evaluable patients, respectively. Among patients who achieved a >50% reduction in spleen length at 24 weeks, 95% had maintained it at 48 weeks. Notably, improvements in bone marrow reticulin fibrosis grade occurred in 57% of the patients at 24 months. Treatment discontinuations as a result of drug-related toxicities occurred in 4 patients (9%), all as a result of cytopenias. New onset grade 3 to 4 anemia and thrombocytopenia occurred in 35% and 26% of patients, respectively. RUX and AZA were safe, with encouraging spleen response rates and improvement in bone marrow fibrosis in patients with MF. This trial was registered at www.clinicaltrials.gov as #NCT01787487.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Palpable spleen length changes at any time on study. A waterfall plot showing the best percentage of palpable spleen length changes at any time during therapy among the 34 patients with baseline palpable splenomegaly >5 cm below costal margin.

Figure 2.

BM histomorphologic changes at 24 and 48 months. A bar graph showing the percentage of evaluable patients who had improvement, stabilization, or progression in BM reticulin fibrosis, collagen, and osteosclerosis at 24 and 48 months compared with pretherapy. Changes in BM histomorphology (upper panel) at 24 months and (lower panel) at 48 months. BM response was classified as improvement, stabilization, or worsening. Patients with baseline BM fibrosis grade 3 were excluded from this analysis because progression and stabilization were not defined. Numerator identifies patients with a grade different than that at pretherapy. The denominator identifies eligible patients included in the analysis (eg, excludes patients with BM fibrosis grade 3 for worsening).

Figure 3.

Median hemoglobin and platelet levels for patients receiving combination therapy. Changes over time in (A) median hemoglobin and (B) median platelets for all available patients at the given time point.

Figure 4.

Kaplan-Meier curves showing OS for all patients enrolled on study. OS during study for all patients (A) not censored for allogeneic SCT and (B) censored for allogeneic SCT. OS stratified by (C) achievement of clinical improvement in spleen length, (D) achievement of any IWG-MRT response during therapy, and (E) DIPSS risk score at enrollment.