Article

Cardiovascular Events and Intensity of Treatment in Polycythemia Vera

The authors' affiliations are listed in the Appendix.
New England Journal of Medicine (Impact Factor: 55.87). 12/2012; 368(1). DOI: 10.1056/NEJMoa1208500
Source: PubMed

ABSTRACT

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 high-hematocrit 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.).

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Available from: Emanuele Angelucci, May 10, 2014
    • "Previous studies have shown that between 10% and 20% of patients with PV treated with HC do not obtain a haematological response to treatment whereas around 20% meet the consensus criteria for resistance/intolerance (Najean & Rain, 1997; Alvarez-Larr an et al, 2012). Of note, patients who did not achieve sustained haematocrit control experienced more frequent thrombosis whereas patients who developed resistance to HC had a lower survival with increased risk of disease transformation (Alvarez-Larr an et al, 2012; Marchioli et al, 2013). However, resistant/intolerant patients may be categorized as such depending on the presence of any of the criteria included in the definition, with this criteria including different situations such as the absence of response despite high doses of HC, the presence of cytopenias at the lowest dose of HC to achieve a response and unacceptable extra-haematological toxicity (Barosi et al, 2010). "
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    ABSTRACT: The clinical significance of resistance/intolerance to hydroxycarbamide (HC) was assessed in a series of 890 patients with polycythaemia vera (PV). Resistance/intolerance to HC was recorded in 137 patients (15·4%), consisting of: need for phlebotomies (3·3%), uncontrolled myeloproliferation (1·6%), failure to reduce massive splenomegaly (0·8%), development of cytopenia at the lowest dose of HC to achieve a response (1·7%) and extra-haematological toxicity (9%). With a median follow-up of 4·6 years, 99 patients died, resulting in a median survival of 19 years. Fulfilling any of the resistance/intolerance criteria had no impact on survival but when the different criteria were individually assessed, an increased risk of death was observed in patients developing cytopenia [Hazard ratio (HR): 3·5, 95% confidence interval (CI): 1·5-8·3, P = 0·003]. Resistance/intolerance had no impact in the rate of thrombosis or bleeding. Risk of myelofibrotic transformation was significantly higher in those patients developing cytopenia (HR: 5·1, 95% CI: 1·9-13·7, P = 0·001) and massive splenomegaly (HR: 9·1, 95% CI: 2·3-35·9, P = 0·002). Cytopenia at the lowest dose required to achieve a response was also an independent risk factor for transformation to acute leukaemia (HR: 20·3, 95% CI: 5·4-76·5, P < 0·001). In conclusion, the unified definition of resistance/intolerance to HC delineates a heterogeneous group of PV patients, with those developing cytopenia being associated with an adverse outcome.
    No preview · Article · Dec 2015 · British Journal of Haematology
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    ABSTRACT: Disease overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms, respectively characterized by erythrocytosis and thrombocytosis. Other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. Diagnosis: PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. Differential diagnosis in ET includes reactive thrombocytosis, chronic myeloid leukemia, and prefibrotic myelofibrosis. Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) mutations occur in approximately 55%, 25%, and 3% of ET patients, respectively. The same molecular markers are also present in prefibrotic myelofibrosis, which needs to be morphologically distinguished from ET. Survival and leukemic/fibrotic transformation: Median survivals are ∼14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Life-expectancy in ET is inferior to the control population. JAK2/CALR mutational status does not affect survival in ET. Risk factors for survival in ET and PV include advanced age, leukocytosis, and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Thrombosis risk stratification: Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis: high-risk is defined by the presence of age >60 years or presence of thrombosis history; low-risk is defined by the absence of both of these two risk factors. Recent data consider JAK2V617F and cardiovascular risk factors as additional risk factors. Presence of extreme thrombocytosis might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. Risk-adapted therapy: The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. In low risk patients, this is accomplished by the use of low-dose aspirin and phlebotomy (hematocrit target <45%) in PV. In high risk (for thrombosis) patients, treatment with hydroxyurea is additionally recommended. Treatment with busulfan or interferon-α is usually effective in hydroxyurea failures and the additional value of JAK inhibitor therapy in such cases is limited. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis.
    Preview · Article · Mar 2012 · American Journal of Hematology
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    ABSTRACT: Marchioli et al.(1) report in the Journal that a hematocrit target of less than 45% for therapeutic phlebotomy reduces the risk of thrombosis in patients with polycythemia vera. In the genomic era, readers may question attention given to a measurement as mundane as the hematocrit, but this study resolves a half-century of debate about the role of phlebotomy in polycythemia vera and has ramifications for diagnosis and management. Polycythemia vera is a unique myeloproliferative disorder in which there is overproduction of morphologically normal erythrocytes, granulocytes, and platelets, a phenotype that is caused by a mutation (V617F) in JAK2, encoding . . .
    No preview · Article · Dec 2012 · New England Journal of Medicine
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