Response To Ruxolitinib In Patients With Intermediate-1, Intermediate-2 and High-Risk Myelofibrosis: Interim Results Of The UK Robust Trial

Ruxolitinib is a selective small molecule inhibitor of Janus kinase 1 (JAK1) and 2 (JAK2). Ruxolitinib suppresses the activity of the JAK/STAT pathway, and thus targets the underlying pathogenic cause of myelofibrosis (MF). The efficacy and safety of ruxolitinib for the treatment of MF has been demonstrated in two pivotal phase III clinical trials, COMFORT-I and COMFORT-II. Ruxolitinib demonstrated a statistically significant reduction in splenomegaly compared with placebo (in COMFORT-I) and compared with best supportive care (in COMFORT-II) and has been approved for the treatment of patients with primary myelofibrosis (PMF), post polycythaemia myelofibrosis (PPV MF) or post-essential thrombocythaemia myelofibrosis (PET-MF) based on the results of these studies. Both pivotal studies involved patients with intermediate-2 or high-risk disease according to International Prognostic Scoring System criteria. However, a number of myelofibrosis patients with intermediate-1 risk disease have significant constitutional symptoms or pain relating to splenomegaly. The ROBUST trial, a UK open label, multicentre exploratory phase 2 study of ruxolitinib for patients with PMF, PPV MF or PET-MF further investigates the response to ruxolitinib in patients with MF and includes patients with intermediate-1 risk disease in addition to patients with intermediate-2 and high-risk disease.

This open-label multicentre UK study enrolled adult patients diagnosed with PMF, PPV MF or PET-MF (World Health Organization criteria) with or without prior therapy and who had intermediate-1, intermediate-2 or high-risk disease according to the International Working Group for Myelofibrosis Research & Treatment criteria. Patients received ruxolitinib at a dose of 15 or 20 mg twice daily (according to baseline platelet counts) and continued treatment until disease progression, unacceptable toxicity, death, or withdrawal from the study. Spleen size was assessed at baseline and at 4-week intervals by palpation, and symptoms were assessed by patients using the Myelofibrosis Symptom Assessment Form (MF-SAF) at baseline and weeks 4, 12 and 24. This interim analysis presents data at 24 weeks.

A total of 48 patients (risk classification: intermediate-1, n = 20; intermediate-2, n = 11; high, n = 17) were included in the study. Mean ± SD age was 69.1 ± 10.4 years and 43.8% of patients were female. Most patients had an ECOG performance status at baseline of 0 (52.1%) or 1 (35.4%). Mean spleen length at baseline was 13.9 ± 6.9 cm and mean ± SD MF-SAF total symptom score (TSS) was 16.4 ± 11.5. A ≥50% decrease in spleen length from baseline at any time was achieved in 27/48 (56.3%) patients overall, and was similar across all risk groups. At week 24 a decrease in mean spleen length from baseline of 6.4 ± 5.2 was observed overall and was similar across the three risk groups (Table). A mean ± SD improvement in TSS at 24 weeks of 9.1 ± 11.3 was observed overall and improvements were similar in patients with intermediate-1 risk and with high-risk disease (Table).

These results indicate that in patients with MF, ruxolitinib provides marked and sustained reductions in splenomegaly and disease-related symptoms. Symptom and spleen responses were observed across risk categories, including intermediate-1 patients, providing further evidence of the clinical benefit of ruxolitinib in patients with MF. Missing data will be updated prior to the ASH2013 meeting, allowing more robust comparison across risk groups for the different endpoints.

Harrison:S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Shire: Speakers Bureau; Celgene: Honoraria; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Clark:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Chacko:Amgen: Membership on an entity’s Board of Directors or advisory committees; GSK: Membership on an entity’s Board of Directors or advisory committees. Knapper:Novartis: Funding for travel to overseas conference Other, Honoraria. Milojkovic:BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria. Farquharson:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Ali:Novartis: Honoraria. Andrews:Novartis Pharmaceuticals UK Limited: Employment, Equity Ownership. Graham:Novartis Pharmaceuticals UK Limited: Employment. Mead:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.