Jason R. Gotlib, MD, MS
Dr. Gotlib receives funding from Incyte for the administration of clinical trials, travel support, and honoraria for serving on an advisory board.
Study Title: Polycythemia Vera Symptom Study Evaluating Ruxolitinib Versus Hydroxyurea in a Randomized, Multicenter, Double-Blind, Double-Dummy, Phase III Efficacy and Safety Study of Patient Reported Outcomes
Clinical Trials.Gov Identifier: NCT01632904
Sponsor: Incyte Corporation
Participating Centers: 61 sites in the Unites States and Europe
Accrual Goal: 110 patients
Study Design: This is a phase III, multicenter, double-blind, placebo-controlled, randomized study. Disease-specific eligibility criteria include the following: 1) patients with symptomatic polycythemia vera (PV) age > 18 years who have received a stable dose of hydroxyurea (HU) for at least 12 weeks; 2) no palpable splenomegaly or no more than one phlebotomy in the prior six months; and 3) the hematocrit has to be controlled within the range of 35 percent to 48 percent before randomization. Subjects are randomized (1:1) to two treatment arms: ruxolitinib and HU-placebo or HU and ruxolitinib-placebo. Subjects in either arm are eligible to transition to open-label ruxolitinib after week 16, and the study ends when the last patient reaches week 48 of treatment. The primary outcome measure is the proportion of patients with a > 50 percent reduction in a cluster of PV-related symptoms at week 16 compared with baseline; secondary outcome measures include the proportion of subjects with a > 50 percent reduction in individual PV-related symptoms (e.g., fatigue, pruritus) at week 16 compared with baseline and the safety of ruxolitinib and hydroxyurea. The validated myeloproliferative neoplasmsymptom assessment form (MPN-SAF) is used to quantify symptom scores.
Rationale: The classic MPNs PV, essential thrombocythemia (ET), and primary myelofibrosis (PMF) can impose a significant burden on the quality of life (QOL) of patients. Among 1,179 MPN patients who completed an Internet-based survey of fatigue and disease-related symptoms, 405 PV patients reported the following prevalence of symptoms: fatigue (85%), itching (65%), night sweats (49%), and bone pain (43%) (Mesa RA et al. Cancer. 2007;109:68-76). Low-dose aspirin and phlebotomy (to maintain the hematocrit below 45%) remain the cornerstones of treatment. Cytoreductive therapy, usually with HU, is employed in older patients (> 60 years) or those with a history of thrombosis, in order to reduce the incidence of thromboembolic complications. Fatigue and impairment of QOL in PV is primarily attributable to disease-related proinflammatory cytokines and, in some cases, drug-related side effects. Treatment with the JAK1/JAK2 inhibitor ruxolitinib demonstrated a statistically significant improvement in total symptom scores compared to placebo in the phase III COMFORT-I trial (Verstovsek S et al. N Engl J Med. 2012;366:799-807) or versus best available therapy (using additional patient-reported outcome [PRO] measures) in the COMFORT-II trial (Harrison C et al; N Engl J Med. 366:787-798). A biologic correlate of these PRO improvements is the reduction of inflammatory cytokine production in patients treated with ruxolitinib, which is felt to be partly related to inhibition of JAK1-related signaling pathways.
Comment: The mitigation of symptoms in higher-risk MF patients with ruxolitinib (and other JAK inhibitors currently under evaluation in clinical trials) justifies the evaluation of these agents in patients with symptomatic PV. Although JAK inhibitors, such as ruxolitinib, show promise in studies with short-term endpoints, such as reduction in number of phlebotomies, control of hematologic parameters, and splenomegaly/symptom reduction (Verstovek S et al. Blood. 2012;120:804), long-term studies are needed to determine whether thrombosis incidence and natural history endpoints such as progression to myelofibrosis or acute leukemia and overall survival are impacted. However, such trials will require several years, if not decades, to generate interpretable results. Because of the relatively low cost of current PV treatments such as aspirin, phlebotomy, and HU, new studies evaluating symptom palliation with targeted therapy are ripe for addressing the dollar-value question: relief at what cost?
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