Results of a randomized study of the JAK inhibitor ruxolitinib (INC424) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential thrombocythemia-myelofibrosis (PET-MF).

Abstract

LBA6501 Background: MF, a myeloproliferative neoplasm characterized by dysregulation of the JAK pathway, is associated with splenomegaly, constitutional symptoms and reduced lifespan. Ruxolitinib is a potent and selective JAK1 and JAK2 inhibitor. Methods: COMFORT-II, a randomized (2:1) phase III study, compared the efficacy and safety of ruxolitinib PO BID with BAT (other agents or no therapy) in adults with intermediate-2 or high-risk (Cervantes et al, Blood 2009) PMF, PPV-MF or PET-MF and palpable splenomegaly. The primary endpoint was the proportion of patients (pts), stratified by baseline risk category, achieving ≥ 35% reduction in spleen volume at week (wk) 48 determined by MRI or CT. The key secondary endpoint was the proportion achieving ≥ 35% reduction in spleen volume at wk 24. Results: 219 pts were randomized: 146 to ruxolitinib and 73 to BAT. Both arms included 49% high- and 51% intermediate-2 risk pts. The wk 48 response rate was 28.5% vs 0% (ruxolitinib vs BAT, P < .0001). The wk 24 response rate was 31.9% vs 0% (ruxolitinib vs BAT, P < .0001). Median duration of response to ruxolitinib was 48 wks. The most common (> 20%) adverse events (AEs) of any grade were (ruxolitinib vs BAT) thrombocytopenia (44.5% vs 9.6%), anemia (40.4% vs 12.3%), diarrhea (24.0% vs 11.0%), and peripheral edema (21.9% vs 26.0%). Grade 3-4 AEs occurring in ≥ 5% of pts in the ruxolitinib arm were: anemia (11%) and thrombocytopenia (7.5%). The most frequent grade 3-4 AEs in the BAT arm were anemia, thrombocytopenia, pneumonia and dyspnea (each 4.1%). Seven deaths occurred on treatment or within 28 days after end of treatment: 4 (2.7%) ruxolitinib and 3 (4.1%) BAT. Disposition of discontinuations were (ruxolitinib vs BAT) 8.2% vs 5.5% due to AEs and 1.4% vs 12.3% due to withdrawn consent. Conclusions: The COMFORT-II study demonstrates that ruxolitinib provides marked and sustained clinical benefit in spleen size and an acceptable safety profile relative to BAT, extends the positive results of COMFORT-I which compared ruxolitinib with placebo, and may result in a new standard of care for a large number of patients with MF.

Serious Adverse Events During Ruxolitinib Treatment Discontinuation in Patients with Myelofibrosis.

“…9 These observations were similar to those seen in the recently completed phase 3 randomized studies of ruxolitinib (COMFORT [Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment] trials) compared to either placebo or best supportive care 13,14 ; the incidence of treatment-induced anemia with ruxolitinib was 31%/40.4% vs 13.9%/12.3% in the placebo/best supportive care groups; the corresponding figures for thrombocytopenia were 34.2%/ 44.5% for ruxolitinib vs 9.3%/9.6% for placebo/best supportive care.…”

JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths

“…Thrombocytopenia (44.5% vs 9.6%) and anemia (40.4% vs 12.3%) were again the most frequent side effects of ruxolitinib; the corresponding frequency comparisons for grade 3 or grade 4 thrombocytopenia and anemia were 7.5% vs 4.1% and 11% vs 4.1%, respectively. 73 There was no difference in survival between the 2 arms (2.7% death rate for ruxolitinib and 4.1% for BAT). A third ruxolitinib phase 3 study is currently ongoing in patients with hydroxyurea-intolerant/resistant PV (ruxolitinib vs best available therapy; www.clinicaltrials.gov).…”

“…72 COMFORT-2 was an open-label study and included 219 patients with IPSS high (49%) or intermediate-2 (51%) risk MF (53% PMF, 31% post-PV MF, and 16% post-ET MF) that were randomized to either best available therapy (BAT; n ϭ 73) or ruxolitinib (n ϭ 146). 73 Eligibility criteria and drug administration schedule were the same as in COMFORT-1. The primary endpoint of the study was achievement of more than or equal to 35% spleen volume reduction by MRI or CT at 48 weeks; response rates were 28.5% for ruxolitinib and 0% for BAT.…”

Comprehensive review of JAK inhibitors in myeloproliferative neoplasms

“…Results of the two randomized, multicenter, double-blind, placebo-controlled phase III trials in the United States and Europe were recently published [Harrison et al 2011Verstovsek et al 2011bVerstovsek et al , 2012 [Harrison et al 2011Verstovsek et al 2011bVerstovsek et al , 2012.…”

“…Thrombocytopenia and anemia occurred more frequently in the patients receiving ruxolitinib than in those receiving BAT. However, these events rarely led to treatment discontinuation (one patient in each group discontinued the study owing to thrombocytopenia) and were generally manageable [Harrison et al 2011. [Tefferi, 2011].…”