Cardiovascular Events and Intensity of Treatment in Polycythemia Vera

Marchioli, Roberto; Finazzi, Guido; Specchia, Giorgina; Cacciola, Rossella; Cavazzina, Riccardo; Cilloni, Daniela; Stefano, Valerio De; Elli, Elena Maria; Iurlo, Alessandra; Latagliata, Roberto; Lunghi, Francesca; Lunghi, Monia; Marfisi, Rosa Maria; Musto, Pellegrino; Masciulli, Arianna; Musolino, Caterina; Cascavilla, Nicola; Quarta, Giovanni; Randi, Maria Luigia; Rapezzi, Davide; Ruggeri, Marco; Rumi, Elisa; Scortechini, Anna Rita; Santini, Simone; Scarano, Marco; Siragusa, Sergio; Spadea, Antonio; Tieghi, Alessia; Angelucci, Emanuele; Visani, Giuseppe; Vannucchi, Alessandro M.; Barbui, Tiziano

doi:10.1056/nejmoa1208500

Cited by 688 publications

(610 citation statements)

References 21 publications

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“…Median survival in PV before the era of phlebotomy was reportedly <2 years [103] and the current figure of 14 years [35] is clearly an improvement and mostly attributed to aggressive phlebotomy that keeps the hematocrit below 45%; this was confirmed in a controlled study [84]. Therefore, phlebotomy is indicated in all patients with PV.…”

Section: Polycythemia Vera and Essential Thrombocythemiamentioning

confidence: 78%

“…A similar effort was carried out in Europe by Tiziano Barbui (b. 1938), an Italian physician scientist, through the Italian group for hematological diseases in adults (GIMEMA) [83][84][85]. Historically, treatment in MPN was documented more in PV and included skeletal radiation therapy (1917) [86], acetylphenylhydrazine (1918) [87], potassium arsenite (1933) [88], P-32 (1940) [89], lead acetate (1942) [90], nitrogen mustard (1950) [91], triethylene melamine (1952) [92], pyrimethamine (1954) [93], busulfan (1958) [94], 6-mercaptopurine (1962) [95], pipobroman (1962) [96], uracil mustard (1964) [97], chlorambucil (1965) [98], and dapsone (1966) [99].…”

Section: Background Information On Treatment In Myeloproliferative Nementioning

confidence: 87%

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Myeloproliferative neoplasms: A decade of discoveries and treatment advances

2015

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Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR‐ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK‐STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, “driver” mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN. Am. J. Hematol. 91:50–58, 2016. © 2015 Wiley Periodicals, Inc.

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Section: Polycythemia Vera and Essential Thrombocythemiamentioning

confidence: 78%

Section: Background Information On Treatment In Myeloproliferative Nementioning

confidence: 87%

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

2015

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“…Polycythaemia vera is adequately managed with phlebotomy and low‐dose aspirin in some patients (Marchioli et al , 2013), but many require additional therapy to achieve their treatment goals. The most common cytoreductive treatment is hydroxycarbamide (HC, also termed hydroxyurea) (Vannucchi, 2014), which is effective for controlling blood cell counts in some patients (Najean & Rain, 1997; Alvarez‐Larran et al , 2012).…”

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confidence: 99%

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double‐blind, double‐dummy, symptom study (RELIEF)

et al. 2016

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SummaryThe randomized, double‐blind, double‐dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV)‐related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV‐related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID (n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm ‐symptom assessment form total symptom score cytokine symptom cluster (TSS‐C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib‐ and hydroxycarbamide‐treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82–4·04; P = 0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13–16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening‐to‐baseline TSS‐C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P = 0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV‐related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.

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“…The primary endpoint studied was the time until death from a cardiovascular cause or a major thrombotic event. The authors found that those whose hematocrit was maintained below 45% had significantly lower rate of cardiovascular death and major thrombotic events compared to those who had a hematocrit between 45–50% 12 . Additionally, Kunnas et al evaluated the association between hematocrit and coronary heart disease (CHD) in men over 55 13 .…”

mentioning

confidence: 98%

“…For example, an increased number of red blood cells can result in increased blood viscosity and predispose to thrombosis. A recent study by Marchioloi et al analyzed the cardiovascular risks in patients with polycythemia vera 12 . Patients, whose mean age was 64 (62% males), were divided into either a less intensive treatment group in which the target hematocrit was 45–50% or an intensive treatment group in which the target hematocrit was 45–50%.…”

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confidence: 99%

The putative mechanisms underlying testosterone and cardiovascular risk

2014

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The use of testosterone supplementation therapy (TST) is increasing primarily in men with symptomatic hypogonadism. While TST has been shown to have numerous benefits, as its use increases, the role on cardiovascular health must be explored. Previous evidence showed no adverse cardiovascular risks associated with TST use; however, more recent studies suggest that there may be an associated risk. The exact mechanism by which TST may contribute to cardiovascular risk has not been elucidated. Numerous mechanisms have been proposed which include testosterone’s effect on thromboxane A2 receptors, vascular adhesion molecule 1 receptors, erythropoiesis, and obstructive sleep apnea, all of which can ultimately lead to atherogenesis and increased cardiovascular risk.

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Cardiovascular Events and Intensity of Treatment in Polycythemia Vera

Cited by 688 publications

References 21 publications

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double‐blind, double‐dummy, symptom study (RELIEF)

The putative mechanisms underlying testosterone and cardiovascular risk

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