SAN DIEGO, CA—Ruxolitinib demonstrated a significant reduction in spleen volume (SV) and improvements in myelofibrosis (MF)-related symptoms in the COMFORT-I study, reported upon at the American Society of Hematology 53rd Annual Meeting and Exposition. Srdan Verstovsek, MD, PhD, from the University of Texas MD Anderson Cancer Center, Houston stated that “approximately 80% of myelofibrosis patients die from the consequences of disease progression such as spleen enlargement, portal hypertension, cardiovascular effects, infections, and bleeding complications; only 20% die from transformation to leukemia. Therefore, we are looking to improve the symptoms and slow the progression of myelofibrosis to improve patients’ quality of life and overall survival.”

Overactive JAK-STAT signaling is considered a key contributor to the pathogenesis of myeloproliferative neoplasms. Dr. Verstovsek and colleagues sought to evaluate the efficacy of ruxolitinib, a selective JAK1 and JAK2 inhibitor, in MF across patient subgroups in the double-blind, placebo-controlled COMFORT-I trial. The subgroups included: MF disease subtype, age, International Prognosis Scoring System (IPSS) risk group, presence/absence of JAK2V617F mutation, baseline hemoglobin, baseline spleen size (palpable spleen length), and baseline total symptom score (TSS). TSS is a measure of combined scores for abdominal discomfort, pain under ribs on left side, early satiety, itching, night sweats, and bone/muscle pain.

The primary endpoint was the proportion of patients achieving ≥35% reduction in SV at Week 24. Key secondary endpoints included the proportion of patients achieving ≥50% reduction in TSS at Week 24 and overall survival (OS).

Depending on baseline platelet count (100–200×109/L or >200×109/L, respectively), a total of 309 patients were randomized to receive ruxolitinib 15mg or 20mg orally twice daily (n=155) or placebo (n=154). Patient demographics were well balanced between the two arms, with the majority of patients having high-risk disease. Median spleen palpitation length was 16cm for both groups. The JAK2 V617F mutation was observed in 73% and 80% of patients in the ruxolitinib and placebo arms, respectively.

Spleen volume change was measured by MRI. Using the modified Myelofibrosis Symptom Assessment Form [MFSAF] v2.0, MF symptoms were assessed daily beginning one week prior to dosing. The percent changes from baseline to Week 24 in SV and MFSAF TSS were compared for ruxolitinib and placebo across the subgroups. Ruxolitinib demonstrated consistent benefit compared with placebo in both SV and TSS across all subgroups evaluated (see Table 1).

The effect of symptom severity on response was evaluated by baseline TSS quartiles (maximum score for TSS=60). Ruxolitinib patients with baseline TSS of <8.5, 8.5–<16.5, 16.5–<25.5 and ≥25.5 had mean percent changes in SV of -28, -31.4, -31.7 and -34.8, and mean percent change in TSS of -40.5, -47.2, -48.1 and -48.2, respectively, vs. +8.1 (SV) and +41.8 (TSS) for all placebo patients combined. These findings suggest that patients with modest to marked symptoms benefit from ruxolitinib therapy in terms of both SV and TSS.

Survival was estimated using the Kaplan-Meier method. Thirteen patients in the ruxolitinib group and 24 patients in the placebo group died during the study or during extended follow-up (median follow-up of 52 and 51 weeks, respectively), representing a hazard ratio of 0.499 (95% CI: 0.254–0.98; P=0.0395) for OS. OS outcomes were not affected by JAK2V617F mutational status, baseline spleen length, or the presence of anemia. (See Table 2). The probability of survival over 48 weeks was 0.98 (95% CI: 0.92–0.99) vs 0.90 (95% CI: 0.81–0.95), for ruxolitinib vs placebo, respectively, for patients with baseline hemoglobin (Hb) ≥10g/dL and 0.84 (95% CI: 0.72–0.91) vs 0.77 (95% CI: 0.63–0.86) for patients with baseline Hb<10g/dL.

There was a low incidence of serious adverse events (SAEs) in the study, with three SAEs documented for each arm. Rates of discontinuation were also similar, 11% for both ruxolitinib and placebo.

It was concluded that patients receiving ruxolitinib had higher response rates than placebo based on reductions in SV and improvements in TSS at Week 24 regardless of baseline subgroup. “The overall survival analysis suggests a benefit with ruxolitinib therapy over placebo,” stated Dr. Verstovsek.