The Janus kinase (JAK) 1/2 inhibitor ruxolitinib dramatically improves response rates in treating 3 forms of myelofibrosis, according to results from 2 randomized phase 3 clinical trials, known as COMFORT (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment) I and II.
In both COMFORT trials, ruxolitinib was significantly superior to the best available therapy in reducing spleen size and symptom burden and improving quality of life. The studies are the first randomized trials of drug therapy for myelofibrosis.
The findings of significant benefit over currently available therapies should change the standard of care for many patients with myelofibrosis, said COMFORT I study coinvestigator Alessandro Vannucchi, MD, Associate Professor of Hematology, the University of Florence, Italy.
“These patients responded very quickly to ruxolitinib—within 2 to 4 weeks. This therapy has the potential to significantly change the treatment landscape for these patients and could greatly improve their outlook,” Dr Vannucchi said.
The median overall survival (OS) associated with myelofibrosis can exceed 5 years, but high-risk patients live only 2 to 4 years after the diagnosis. Approximately 50% of all patients carry a mutation in the JAK2 gene, although all have an activated JAK signaling pathway. Ruxolitinib is active in these patients regardless of whether patients have a JAK2 mutation.
In the open-label COMFORT II, 219 adults with intermediate- or high-risk primary myelofibrosis (PMF), postpolycythemia vera myelofibrosis (PPV-MF), or postessential thrombocythemia myelofibrosis (PET-MF), were randomized to either ruxolitinib or to best available therapy. After 48 weeks, 28.5% of patients assigned to ruxolitinib achieved a ≥35% reduction in spleen size compared with 0% with best available therapy.
Marked improvement in quality-of-life measures were obtained with ruxolitinib beginning at week 8 and continuing through week 48. In contrast, patients receiving best available therapy showed no change or worsening of symptoms during the study.
Adverse events, including anemia and thrombocytopenia, caused 8.2% of patients assigned to ruxolitinib to stop treatment compared with 5.5% of patients randomized to best available therapy. Grade 3/4 thrombocytopenia occurred in 8% of patients receiving ruxolitinib and in 7% of those receiving best available therapy; grade 3/4 anemia was observed in 42% and 31% of patients, respectively. OS was not an end point in this study but is an end point in ongoing studies.
In COMFORT I, 309 patients with intermediate- or high-risk PMF, PPV-MF, or PET-MF were randomly assigned to twice-daily oral ruxolitinib or placebo. Approximately 25% of patients in the placebo arm crossed over to the ruxolitinib arm as a result of disease progression.
After a median follow-up of 32 weeks, significantly more patients in the ruxolitinib arm attained the primary end point of ≥35% reduction in spleen volume after 24 weeks of therapy (41.9% vs 0.7% with placebo). More ruxolitinib recipients had a ≥50% reduction in symptom burden (including abdominal discomfort, pain under the left ribs, early satiety, night sweats, bone or muscle pain, and inactivity) than placebo recipients.
Ruxolitinib was generally well tolerated. As in COMFORT II, the 2 grade 3/4 adverse events that occurred more often with ruxolitinib than with placebo were thrombocytopenia (12.9% vs 1.3%, respectively) and anemia (45.2% vs 19.2%); both were manageable with dose adjustments.
Only 1 patient in each arm discontinued treatment because of toxicity.