Polycythemia Vera and Essential Thrombocythemia

CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance, as compared to JAK2 mutations [26,27,70–72]. The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations [73]. The presence of the mutation per se does not appear to affect the thrombotic risk [74–76]. Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation [73,77–79].

Venous thromboembolism (VTE) in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems [80]. Risk factors for unusual VTE include younger age [81], female gender (especially with concomitant use of oral contraceptive pills) [82], and splenomegaly/splenectomy [83]. JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic VTE has varied [80]. In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients [84]. Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic VTE. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic VTE is not recommended, as its prevalence in this group is low (< 3%) [85,86].

Risk-Adapted Therapy

Low-Risk PV

All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms [55,87]. Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin [88]. Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In that study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%) [89]. Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis [38].

High-Risk PV

Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Frontline cytoreductive therapies include hydroxyurea or interferon (IFN)-alfa [87]. Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV [90]. In a small trial, hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone [91]. Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients [87]. Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone [92], respectively, although an independent role for hydroxyurea in LT was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study [93]. Approximately 70% of patients will have a sustained response to hydroxyurea [94], while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death [95].

IFN-alfa is a pleiotropic antitumor agent that has found application in many types of malignancies [96] and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases [97,98], albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations [99]. A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN-alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability [100]. Pilot phase 2 trials of PEG-IFN-alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in most patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of 20% to 30% [101–103]. In some patients, JAK2V617F became undetectable over time [104]. Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN-alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN-alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN-alfa in the management of patients with high-risk PV or ET. In two phase 2 studies of PEG-IFN-alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases [105,106]. A new, longer-acting formulation of PEG-IFN-alfa-2a (peg-proline INF-alfa-2b, AOP2014) is also undergoing clinical development [107,108].