The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo-controlled, Phase III study in patients with myelofibrosis

Abstract

Myelofibrosis (MF) patients can present with a wide spectrum of disease characteristics. We analysed the consistency of ruxolitinib efficacy across patient subgroups in the COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment (COMFORT-I,) a double-blind trial, where patients with intermediate-2 or high-risk MF were randomized to twice-daily oral ruxolitinib (n = 155) or placebo (n = 154). Subgroups analysed included MF subtype (primary, post-polycythaemia vera, post-essential thrombocythaemia), age (≤65, > 65 years), International Prognostic Scoring System risk group, baseline Eastern Cooperative Oncology Group performance status (0, 1, ≥2), JAK2 V617F mutation (positive, negative), baseline haemoglobin level (≥100, <100 g/l), baseline platelet count (100-200 × 10(9)/l, >200 × 10(9)/l), baseline palpable spleen size (≤10, >10 cm), and baseline quartile of spleen volume and Total Symptom Score (TSS; Q1 = lowest, Q4 = highest). Mean percentage change from baseline to week 24 in spleen volume and TSS were calculated for ruxolitinib and placebo in each subgroup. Overall survival was estimated by Kaplan-Meier method according to original randomization group. In ruxolitinib-treated patients, reductions in spleen volume and TSS and evidence of improved survival relative to placebo across subgroups were consistent with those seen in the COMFORT-I population, confirming that ruxolitinib is an effective therapy for the spectrum of MF patients studied in COMFORT-I.

Fig. 1

Percentage change in spleen volume from baseline to week 24 by patient subgroup. Dashed lines represent the mean percentage change from baseline for overall treatment group (Verstovsek et al, 2012). ECOG PS, Eastern Cooperative Oncology Group performance status; Hb, haemoglobin; Int-2, Intermediate-2; IPSS, International Prognostic Scoring System; MF, myelofibrosis; PET, post-essential thrombocythaemia; PMF, primary myelofibrosis; PPV, post-polycythaemia vera; SEM, standard error of the mean.

Fig. 2

Total Symptom Score percentage change from baseline to week 24 by patient subgroup. Dashed lines represent the mean percentage change from baseline for overall treatment group (Verstovsek et al, 2012). ECOG PS, Eastern Cooperative Oncology Group performance status; Hb, haemoglobin; Int-2, Intermediate-2; IPSS, International Prognostic Scoring System; MF, myelofibrosis; PET, post-essential thrombocythaemia; PMF, primary myelofibrosis; PPV, post-polycythaemia vera; SEM, standard error of the mean.

Fig. 3

Change in spleen volume and TSS (baseline to week 24) by (A, B) baseline spleen volume quartile and (C, D) baseline TSS. Patients with missing baseline values for spleen volume or TSS were not included in the analyses for panels B or C, respectively. Q, quartile; SEM, standard error of the mean; TSS, Total Symptom Score.

Fig. 4

Forest plot of survival by patient subgroup. Red line represents the hazard ratio (HR) of the ITT population and the dashed line represents an HR of 1. The squares represent the HR and sample size for each subgroup, where the area of the square is proportional to the subgroup sample size. CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IPSS, International Prognostic Scoring System; ITT, intention-to-treat; PET-MF, post-essential thrombocythaemia myelofibrosis; PMF, primary myelofibrosis; PPV-MF, post-polycythaemia vera myelofibrosis.

Fig. 5

Overall survival by (A, B) JAK2 V617F mutation status, (C, D) baseline IPSS risk category, (E, F) baseline haemoglobin level and (G, H) baseline palpable spleen length. *Patients who received ≥1 unit of RBC transfusions within 12 weeks before baseline were assigned to the haemoglobin <100-g/l subgroup. HR, hazard ratio; IPSS, International Prognostic Scoring System; RBC, red blood cell.