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Long-Term Treatment with Ruxolitinib Up to 5 Years Is Shown to Prolong Survival in Patients with Myelofibrosis

March 10, 2017-Hong Kong, China — Long-term treatment with ruxolitinib up to 5years has been shown to prolong survival in patients with myelofibrosis compared withbest available treatment or placebo.

This outcome of an exploratory pooled analysis of overall survival in the COntrolledMyeloFibrosis study with ORal JAK inhibitor Therapy (COMFORT) studies at 5 years offollow-up was reported at the 58th Annual Meeting of the American Society ofHematology, from December 3 – 6.

Srdan Verstovsek, MD, PhD, of the University of Texas MD Anderson Cancer Center,Houston, explained that the Janus kinase 1/2 inhibitor ruxolitinib was evaluated forpatients with myelofibrosis in the phase 3 COMFORT studies. In both trials, ruxolitinibprolonged overall survival, reduced splenomegaly, and improved myelofibrosis-relatedsymptoms and quality of life compared with controls.

The double-blind COMFORT-I trial and open-label COMFORT-II trial were randomisedphase 3 evaluations of ruxolitinib in patients with intermediate-2 or high-risk primarymyelofibrosis, post–polycythaemia vera myelofibrosis, or post–essentialthrombocythaemia myelofibrosis. The comparator was placebo in COMFORT-I and bestavailable therapy in COMFORT-II.

The ruxolitinib starting dose was 15 or 20 mg twice daily based on baseline plateletcounts (100 – 200 and >200 x 109/L, respectively. Dose modifications were permitted forsafety and efficacy. Patients were allowed to cross over to ruxolitinib from the controlarm for progressive splenomegaly, defined as a ≥25% increase in spleen volume from baseline (COMFORT-I) or study nadir (COMFORT-II), or select protocol-definedprogression events; crossover was mandatory following treatment unblinding inCOMFORT-I.

Overall survival was a secondary endpoint in both studies and was evaluated in an intent-to-treat analysis using a Cox proportional hazard model that estimated the treatmenteffect stratified by clinical trial and International Prognostic Scoring System risk. Thecrossover-corrected treatment effect was estimated using a rank-preserving structuralfailure time method.

Overall, 528 patients were randomised: 301 to ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 to placebo (n=154) or best available treatment (n=73).All ongoing patients in the control arms had crossed over to ruxolitinib by the 3-yearfollow-up assessment.

Patient populations were similar between the two trials and details were published. In thecombined ruxolitinib group, 162 patients (53.8%) suffered from high-risk myelofibrosisand 139 (46.2%) had intermediate-2 risk myelofibrosis based on International Prognostic Scoring System criteria.

At the 5-year intent-to-treat analysis, 128 patients (42.5%) died in the ruxolitinib groupvs 117 (51.5%) in the control group. Mortality risk was reduced by 30% with ruxolitinibvs control (median overall survival: ruxolitinib 63.5 months; control 45.9 months; hazardratio 0.70; 95% confidence interval 0.54 –0.91; P =.0065).

After correcting for crossover using a rank-preserving structural failure time method, theoverall survival advantage was more pronounced for patients originally randomised toruxolitinib (median overall survival: ruxolitinib 63.5 months; control 27 months; hazardratio 0.35; 95% confidence interval 0.23 –0.59).

An analysis of overall survival censoring patients at the time of crossover alsodemonstrated that ruxolitinib prolonged survival vs control (median overall survival:ruxolitinib 63.5 months; control 28.3 months; hazard ratio 0.53; 95% confidence interval0.36 − 0.78; P = .0013).

Among all patients treated with ruxolitinib, those with lower-risk disease experiencedlonger survival than those with high-risk disease (median overall survival: intermediate-2, not reached [estimated, 102 months]; high-risk, 50 months; hazard ratio 2.86; 95%confidence interval 1.95 – 4.20; P < .0001). In a subgroup analysis, overall survivalfavoured ruxolitinib over placebo for patients with intermediate-2 or high-riskmyelofibrosis (data not shown).

At 5 years, median overall survival appeared to favor patients with intermediate-2 (n=58)or high-risk (n=89) primary myelofibrosis who were originally randomised to ruxolitinibvs historical controls described by Cervantes et al (intermediate-2 primary myelofibrosis,not reached (estimated, 70 vs 48 months; high-risk primary myelofibrosis, 34 vs 27months). Overall survival was longer among patients with intermediate-2 vs high-riskprimary myelofibrosis (P = .0003).

Subgroup analyses showed that ruxolitinib provided an overall survival advantageregardless of age (>65 or ≤65 years), sex, disease type (primary myelofibrosis, post-polycythaemia myelofibrosis, post-essential thrombocythaemia myelofibrosis); risk status(intermediate-2 or high); Janus kinase 2V617F mutation status; baseline spleen volume(>10 or ≤10 cm); anemia; white blood cell count (>25 or ≤25 × 109L); or platelet count(>200 or ≤200 × 109 per liter).

Dr Verstovsek concluded that long-term treatment with ruxolitinib up to 5 yearsprolonged survival in patients with myelofibrosis vs best available treatment or placebo.Corrections for patients who crossed over to ruxolitinib suggested that the separationobserved between ruxolitinib and control in overall survival curves was primarily causedby a delay in ruxolitinib treatment. The results suggest that earlier treatment withruxolitinib may provide a greater survival advantage in patients with myelofibrosis.


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