Polycythemia Vera and Essential Thrombocythemia: Current Management

Treatment

Cases Continued

Patient A is diagnosed with PV based on the presence of 2 major criteria (elevated hemoglobin and presence of the JAK2V617F mutation) and 1 minor criterion (low erythropoietin level). Given his age, he belongs to the high-risk disease category. He is now seeking advice regarding the management of his newly diagnosed PV.

Patient B presents to the emergency department with right lower extremity swelling and is found to have deep femoral thrombosis extending to the iliac vein. Five days after being discharged from the emergency department, she presents for follow-up. She is taking warfarin compliantly and her INR is within therapeutic range. The patient now has high-risk ET and would like to know more about thrombosis in her condition and how to best manage her risk.

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 the CYTO PV 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. Front-line 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 leukemic transformation was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study.⁹³ About 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 malignancies⁹⁶ 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 the majority of patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of around 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 2 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

The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.