Ruxolitinib Treatment for Myelofibrosis: Efficacy and Tolerability in a Real-World Setting

Introduction: Ruxolitinib has been shown in two randomized clinical trials (RCTs) to be effective in alleviating systemic symptoms and effecting a reduction in spleen size in patients with myelofibrosis (MF). However, JAK2 allele burden is not significantly impacted by this drug and there is no consistent salutary effect on marrow fibrosis or definite improvement in overall survival. Currently, the goals of Ruxolitinib treatment remain palliative. We sought to determine the efficacy and tolerability of Ruxolitinib in a cohort of unselected patients with MF treated in routine clinical practice.

Methods: MF patients treated with Ruxolitinib for at least 3 months in 13 participating centers that are members of the Israel Myeloproliferative Neoplasm (MPN) Working Group were identified. The following demographic and clinical data were analyzed: the form of MF [primary (PMF), post polycythemic myelofibrosis (PPVMF), post essential thrombocytosis myelofibrosis (PETMF)], duration of MPN, indication for treatment, initial dose, dose reduction, hematologic toxicity, response to therapy and withdrawal of treatment.

Results: One hundred and two patients from 13 centers that began Ruxolitinib between January 2012 and April 2014 were identified. Ninety three patients who were treated for more than 3 months were included in the analysis. Median age at diagnosis was 59 years (range 25-84), 57 % were males. PMF was the diagnosis in 44 patients (47.3%), PPVMF in 29 (31.2%) and PETMF in 17 (18.3%). The median duration of disease was 5 years (range 3 months-35 years) for the entire cohort. Median age at Ruxolitinib initiation was 67 years (range 32-84). Seventy two (78.3%) patients received cytoreductive therapies for MF prior to Ruxolitinib. Indications for treatment were constitutional symptoms only in 14 patients (15%), symptomatic splenomegaly only in 6 patients (6%) and both in 71 patients(76%). Two patients received Ruxolitinib for other indications (non-constitutional symptoms and refractory thrombocytosis). The median initial dose of Ruxolitinib was 30 mg per day (range 10-40mg). Median duration of Ruxolitinib therapy was 11 months (range 3-31 months). Eighty two patients (88.2%) responded to therapy, 76 (84.4%) patients had improvement in constitutional symptoms and 60 patients (70.6%) had reduction in spleen length. While on Ruxolitinib, 60 patients (64%) had a nadir hemoglobin level of less than 10g/dL, 43 patients (46%) had a nadir platelet count of less than 100 x 10⁹/µL and in 12 of them (12.9%) a platelet nadir was less than 50 x 10⁹/µL. Twenty one patients (22.6%) needed packed red blood cell (PRBC) transfusion in the 2 months preceding Ruxolitinib initiation and they received a median of 2.5 units (range 1-8), while 27 patients (29.1%) needed PRBC transfusion in the first 2 months after starting treatment and they received a median of 4 units (range 1-8). Thirty five patients required dose reduction of Ruxolitinib and 14 (15.2%) discontinued their therapy. Univariate analysis revealed that response to Ruxolitinib occurred in patients with a lower white blood cell (WBC) count (median 9.7 x 10³/µL vs 21.5 x 10³/µL; P=0.033), a greater degree of splenomegaly (median 12 vs 4 cm below costal margin; P=0.001) and hepatomegaly (median 4 vs 0 cm below costal margin; P=0.011). In multivariate analysis, the degree of splenomegaly was found to be predictive of response to treatment (odds ratio=1.263, p=0.03 and 95% CI=1.08-1.476) while there was a trend to improved response in patients with a lower WBC (p=0.074).

Conclusions: The present analysis of a cohort of MF patients treated with Ruxolitinib in routine clinical practice has demonstrated the efficacy and tolerability of this drug outside of a highly monitored RCT setting. Data of this sort are currently sparse, and emanate mainly from single-center reports. Our study performed in 13 academic and community hospitals provides real-life evaluation of the utility of Ruxolitinib and factors associated with response to treatment.