Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis

Abstract

Key Points• Long-term analysis of the COMFORT-II Trial shows that ruxolitinib treatment results in durable reductions in splenomegaly and is well tolerated.• Patients randomized to ruxolitinib showed longer overall survival than those receiving the BAT.Ruxolitinib is a potent Janus kinase (JAK)1/JAK2 inhibitor that has demonstrated rapid reductions in splenomegaly and marked improvement in disease-related symptoms and quality of life in patients with myelofibrosis (MF). The present analysis reports the 3-year follow-up (median, 151 weeks) of the efficacy and safety of Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II (the COMFORT-II Trial), comparing ruxolitinib with the best available therapy (BAT) in 219 patients with intermediate-2 and high-risk MF. In the ruxolitinib arm, with continued therapy, spleen volume reductions of ‡35% by magnetic resonance imaging (equivalent to approximately 50% reduction by palpation) were sustained for at least 144 weeks, with the probability of 50% (95% confidence interval [CI], 36-63) among patients achieving such degree of response. At the time of this analysis, 45% of the patients randomized to ruxolitinib remained on treatment. Ruxolitinib continues to be well tolerated. Anemia and thrombocytopenia were the main toxicities, but they were generally manageable, improved over time, and rarely led to treatment discontinuation (1% and 3.6% of patients, respectively). No single nonhematologic adverse event led to definitive ruxolitinib discontinuation in more than 1 patient. Additionally, patients randomized to ruxolitinib showed longer overall survival than those randomized to BAT (hazard ratio, 0.48; 95% CI, 0.28-0.85; log-rank test, P 5 .009). This trial was registered at clinicaltrials.gov as #NCT00934544. (Blood. 2013;122(25):4047-4053)

Splenomegaly, elevated alkaline phosphatase and mutations in the SRSF2/ASXL1/RUNX1 gene panel are strong adverse prognostic markers in patients with systemic mastocytosis

“…[14][15][16] Splenomegaly is not included in established prognostic scoring systems for MF but data from ruxolitinib-based clinical trials have demonstrated an adverse prognostic impact of the initial spleen volume and the lack of spleen volume reduction on treatment. [17][18][19] In MF, these associations were only established because the spleen volume was accurately measured by volumetry through computer tomography (CT) or MRI.…”

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

“…The long-term outcome of ruxolitinib therapy in MF was recently reported and disclosed a very high treatment discontinuation rate (92% after a median time of 9.2 months) and the occurrence of severe withdrawal symptoms during ruxolitinib treatment discontinuation ("ruxolitinib withdrawal syndrome") characterized by acute relapse of disease symptoms, accelerated splenomegaly, worsening of cytopenias and occasional hemodynamic decompensation, including a septic shock-like syndrome [140]. The 3-year follow-up information on the companysponsored phase 3 study disclosed a 55% drug discontinuation rate and a slight but significant improvement in survival [141]. Furthermore, several reports have now associated ruxolitinib with serious opportunistic infections [122].…”

Safety and efficacy of combination therapy of interferon‐α2 and ruxolitinib in polycythemia vera and myelofibrosis

“…The JAK1‐2 inhibitor ruxolitinib is a potent anti‐inflammatory agent and has shown promising results in the treatment of patients with MF3, 4, 5 and PV6 in regard to reducing splenomegaly, constitutional symptoms, and inflammation‐mediated comorbidities. However, in the large majority of patients, ruxolitinib does not markedly reduce the JAK2 V617F allele burden (%V617F) 5, 6, 7…”

“…However, in the large majority of patients, ruxolitinib does not markedly reduce the JAK2 V617F allele burden (%V617F) 5, 6, 7…”