Ruxolitinib in cytopenic myelofibrosis: Response, toxicity, drug discontinuation, and outcome

Background: Patients with cytopenic myelofibrosis (MF) have more limited therapeutic options and poorer prognoses compared with patients with the myeloproliferative phenotype. Aims and Methods: Prognostic correlates of cytopenic phenotype were explored in 886 ruxolitinib-treated patients with primary/secondary MF (PMF/SMF) included in the RUX-MF retrospective study. Cytopenia was defined as: leukocyte count <4 × 109/L and/or hemoglobin <11/<10 g/dL (males/females) and/or platelets <100 × 109/L. Results: Overall, 407 (45.9%) patients had a cytopenic MF, including 249 (52.4%) with PMF. In multivariable analysis, high molecular risk mutations (p =.04), intermediate 2/high Dynamic International Prognostic Score System (p <.001) and intermediate 2/high Myelofibrosis Secondary to Polycythemia Vera and Essential Thrombocythemia Prognostic Model (p <.001) remained associated with cytopenic MF in the overall cohort, PMF, and SMF, respectively. Patients with cytopenia received lower average ruxolitinib at the starting (25.2 mg/day vs. 30.2 mg/day, p <.001) and overall doses (23.6 mg/day vs. 26.8 mg/day, p <.001) and achieved lower rates of spleen (26.5% vs. 34.1%, p =.04) and symptom (59.8% vs. 68.8%, p =.008) responses at 6 months compared with patients with the proliferative phenotype. Patients with cytopenia also had higher rates of thrombocytopenia at 3 months (31.1% vs. 18.8%, p <.001) but lower rates of anemia (65.6% vs. 57.7%, p =.02 at 3 months and 56.6% vs. 23.9% at 6 months, p <.001). After competing risk analysis, the cumulative incidence of ruxolitinib discontinuation at 5 years was 57% and 38% in patients with cytopenia and the proliferative phenotype (p <.001), whereas cumulative incidence of leukemic transformation was similar (p =.06). In Cox regression analysis adjusted for Dynamic International Prognostic Score System score, survival was significantly shorter in patients with cytopenia (p <.001). Conclusions: Cytopenic MF has a lower probability of therapeutic success with ruxolitinib as monotherapy and worse outcome. These patients should be considered for alternative therapeutic strategies.