Management Issues and Controversies in Low-Risk Patients with Essential Thrombocythemia and Polycythemia Vera.
TL;DR: In this paper, the authors discuss the most common management issues specific to the care of low-risk patients, including antiplatelet therapy dosing, pregnancy, and indications for early cytoreduction.
Abstract: Essential thrombocythemia (ET) and polycythemia vera (PV) are the most common myeloproliferative neoplasms (MPNs). Treatment of ET and PV is based on the risk for subsequent thrombosis. High-risk patients, defined as older than 60, JAK2 V617F–positive patients, or patients with a history of prior thrombosis, merit cytoreduction to control blood counts, whereas a watchful waiting paradigm is utilized in low-risk patients. However, low-risk patients have a host of other specific management issues that arise during their disease course. This review will discuss the most common management issues specific to the care of low-risk patients, including anti-platelet therapy dosing, pregnancy, and indications for early cytoreduction. Although low-dose aspirin is well established in PV, its indications and dosing regimens are less clear in ET. Recent evidence has supported twice daily low-dose aspirin in ET and observation alone in very low–risk ET patients. Pregnancy is not contraindicated in MPNs, and we recommend aspirin throughout pregnancy with consideration for prophylactic postpartum anticoagulation. High phlebotomy needs, symptom burden, and extreme thrombocytosis are common reasons for initiation of cytoreduction in low-risk patients, although we typically do not start cytoreduction for an isolated high platelet count alone. Recent data has also demonstrated a potential disease-modifying effect of interferons in MPNs, with some experts now advocating the early use of interferon in low-risk patients, although more mature data is needed before practice guidelines change. We evaluate the literature to inform clinical decision-making regarding these controversies, including most recent data that has challenged the “watchful waiting” paradigm. Our discussion provides guidance on common clinical scenarios seen in low-risk ET and PV patients, who face a myriad of complex management decisions in their care.
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TL;DR: The various complications that patients with PV and ET experience are described, and the evolving understanding of risk stratification in these diseases are detailed, to highlight the available evidence on the management of low-risk PV andET and include a description of novel therapies currently under investigation.
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TL;DR: In this paper , the authors present an updated overview of the diagnosis, prognosis and treatment of primary myelofibrosis and polycythaemia vera (PV) and discuss how their multidisciplinary expert group based across France translates this evidence-based knowledge into routine clinical practice.
Abstract: Primary myelofibrosis (PMF) and polycythaemia vera (PV) are rare BCR-ABL1-negative myeloproliferative neoplasms, associated with an increased risk of thrombosis, haemorrhagic complications and progression to fibrosis or leukaemia or fibrosis for PV. Both diseases are characterised by biological and clinical heterogeneity, leading to great variability in their management in routine clinical practice. In this review, we present an updated overview of the diagnosis, prognosis and treatment of PMF and PV, and we discuss how our multidisciplinary expert group based across France translates this evidence-based knowledge into routine clinical practice.
TL;DR: In this paper , a review of myeloproliferative neoplasms (MPNs) treatment strategies and novel treatment options for clinical development is presented, where the primary objective of ET and PV therapy was to increase survival rates by preventing thrombosis.
Abstract: Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells; these include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPNs are inflammatory cancers, wherein the malignant clone generates cytokines that sustain the inflammatory drive in a self-perpetuating vicious cycle. The course of MPNs follows a biological continuum, that is, from early cancer stages (ET/PV) to advanced myelofibrosis as well as impending leukemic transformation. MPN-related symptoms, e.g., fatigue, general weakness, and itching, are caused by inflammatory cytokines. Thrombosis and bleeding are also exacerbated by inflammatory cytokines in patients with MPN. Until recently, the primary objective of ET and PV therapy was to increase survival rates by preventing thrombosis. However, several medications have recently demonstrated the ability to modify the course of the disease; symptom relief is expected for most patients. In addition, there is increasing interest in the active treatment of patients at low risk with PV and ET. This review focuses on the ET/PV treatment strategies as well as novel treatment options for clinical development.
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University of Texas MD Anderson Cancer Center1, Mayo Clinic2, Stanford University3, Incyte4, University of Toronto5, Washington University in St. Louis6, Monash University7, Oregon Health & Science University8, University of Utah9, Cornell University10, University of Michigan11, Emory University12, Duke University13, University of Pennsylvania14, University of California, Los Angeles15, Columbia University16
TL;DR: Ruxolitinib provided significant clinical benefits in patients with myel ofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival.
Abstract: A B S T R AC T background Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis. methodS In this double-blind trial, we randomly assigned patients with intermediate-2 or highrisk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival. resulTS The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P = 0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group. conclusionS Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.)
1,638 citations
TL;DR: Low-dose aspirin can safely prevent thrombotic complications in patients with polycythemia vera who have no contraindications to such treatment, and reduced the risk of the combined end point of nonf fatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thromBosis, or death from cardiovascular causes.
Abstract: background The use of aspirin for the prevention of thrombotic complications in polycythemia vera is controversial. methods We enrolled 518 patients with polycythemia vera, no clear indication for aspirin treatment, and no contraindication to such treatment in a double-blind, placebo-controlled, randomized trial to assess the safety and efficacy of prophylaxis with low-dose aspirin (100 mg daily). The two primary end points were the cumulative rate of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and the cumulative rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes. The mean duration of follow-up was about three years. results Treatment with aspirin, as compared with placebo, reduced the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (relative risk, 0.41; 95 percent confidence interval, 0.15 to 1.15; P=0.09) and the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (relative risk, 0.40; 95 percent confidence interval, 0.18 to 0.91; P=0.03). Overall mortality and cardiovascular mortality were not reduced significantly. The incidence of major bleeding episodes was not significantly increased in the aspirin group (relative risk, 1.62; 95 percent confidence interval, 0.27 to 9.71). conclusions Low-dose aspirin can safely prevent thrombotic complications in patients with polycythemia vera who have no contraindications to such treatment.
846 citations
TL;DR: Hydroxyurea is effective in preventing thrombosis in high-risk patients with essential throm bocythemia and a high risk of thromboembolic complications.
Abstract: Background Abnormalities in the number and function of platelets may contribute to thromboembolic complications in patients with essential thrombocythemia. We assessed whether maintaining the platelet count below 600,000 per cubic millimeter with hydroxyurea reduces the incidence of thrombosis in patients with essential thrombocythemia and a high risk of thrombosis. Methods A total of 114 patients with essential thrombocythemia (77 women and 37 men; median age, 68 years; range, 40 to 85) and a median platelet count of 788,000 per cubic millimeter (range, 533,000 to 1,240,000 per cubic millimeter) were randomly assigned to receive hydroxyurea (56 patients) or no myelosuppressive therapy (58 patients). Ninety-seven (85 percent) were over 60 years old, and 52 (46 percent) had had thrombosis. The two groups were matched for age, sex, and platelet count at randomization. Antiplatelet prophylaxis with aspirin or ticlopidine was not stopped. Follow-up lasted a median of 27 months in both groups. Results Two pati...
764 citations
TL;DR: In patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera.
Abstract: Background Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. Methods We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging. Results The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two g...
649 citations
Mario Negri Institute for Pharmacological Research1, Catholic University of the Sacred Heart2, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico3, Sapienza University of Rome4, Vita-Salute San Raffaele University5, University of Eastern Piedmont6, University of Messina7, Casa Sollievo della Sofferenza8, University of Padua9, Marche Polytechnic University10, University of Florence11
TL;DR: In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with an intended target of 45 to 50%.
Abstract: A b s t r ac t Background Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been tested in a randomized clinical trial. Methods We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed. Results After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the highhematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P = 0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P = 0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events. Conclusions In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT01645124, and EudraCT number, 2007–006694-91.)
611 citations