Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses

Abstract

BackgroundMyelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF.MethodsThis was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24.ResultsA total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146) and 227 to control (n = 154 and n = 73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio [HR], 0.70 [95% CI, 0.54–0.91]; P = 0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR [ruxolitinib vs RPSFT], 0.35 [95% CI, 0.23–0.59]). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR [ruxolitinib vs censored at crossover], 0.53 [95% CI, 0.36–0.78]; P = 0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24.ConclusionsThese findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF.Trial registration ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544.

Adjusting for Treatment Switching in Oncology Trials: A Systematic Review and Recommendations for Reporting

“…The electronic search of PubMed identified 56 articles, of which 13 [27][28][29][30][31][32][33][34][35][36][37][38][39] were included in the review after an assessment of eligibility ( Fig. 1A).…”

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis

“…Ruxolitinib is the first‐in‐class JAK1/JAK2 inhibitor commercially available for the treatment of MF. Ruxolitinib ameliorates inflammation and proliferation, which leads to clinically relevant control of splenomegaly and symptoms in the majority of patients with MF, which may result in prolonged survival . Nonetheless, long‐term studies have demonstrated a lack of response in some patients and loss of response in the majority of patients .…”

“…Ruxolitinib ameliorates inflammation and proliferation, which leads to clinically relevant control of splenomegaly and symptoms in the majority of patients with MF, which may result in prolonged survival. [5][6][7][8] Nonetheless, long-term studies have demonstrated a lack of response in some patients and loss of response in the majority of patients. 9 Some patients may not tolerate ruxolitinib because of therapy-related anemia, thrombocytopenia, or nonhematologic adverse events, in particular, infectious complications.…”

Impact of 2016 WHO diagnosis of early and overt primary myelofibrosis on presentation and outcome of 232 patients treated with ruxolitinib

“…These 2008 WHO‐defined early PMF have always been treated with ET therapies (ie, hydroxyurea, interferons, and anagrelide) that do not include ruxolitinib. Indeed, ruxolitinib is a JAK1/2 inhibitor that was approved for the treatment of primary and post‐Polycythemia Vera/post‐ET myelofibrosis based on the results of two registrative studies that proved its superiority in ameliorating MF‐related splenomegaly and symptoms compared with placebo or best available therapy …”

“…Indeed, ruxolitinib is a JAK1/2 inhibitor that was approved for the treatment of primary and post-Polycythemia Vera/post-ET myelofibrosis based on the results of two registrative studies that proved its superiority in ameliorating MF-related splenomegaly and symptoms compared with placebo or best available therapy. 4,5 In the 2016 WHO criteria, the definition of early PMF was instead reserved to a subgroup of patients that were previously considered as full-fledged PMF. The distinction between early and overt PMF relies mainly on histology criteria, with increased age-adjusted bone marrow cellularity, decreased erythropoiesis, and lower fibrosis (grade 0-1) in early PMF.…”