How We Identify and Manage Patients with Inadequately Controlled Polycythemia Vera

Abstract

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) characterized by an overactive Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway through mutations in JAK2 exons 12 or 14 (JAK2 V617F). The dominant clinical characteristics include erythrocytosis (with or without leukocytosis/thrombocytosis), thrombotic events, and symptoms. Increased risk of mortality is mainly caused by thrombotic events and progression to post-polycythemia vera myelofibrosis (PPV-MF) or secondary acute myeloid leukemia (sAML). The most important prognostic factors include age and a history of thrombotic events, although recent evidence has indicated that leukocytosis and additional cytogenetic aberrations may also be of significant prognostic value. First-line therapies include aspirin and phlebotomies, which significantly reduce the incidence of thrombotic events and prolong survival. Cytoreductive treatment with hydroxyurea (approved) and conventional or pegylated interferon-α (effective, but not approved in many countries) is initiated for high-risk or inadequately controlled disease, e.g., uncontrolled hematocrit, leukocytosis, thrombocytosis, thrombotic events, splenomegaly, or symptoms. However, some patients may not receive initial benefit from first-line therapy or may become resistant or intolerant in due course. Although second-line treatment options are limited, clinical trials have shown the efficacy of ruxolitinib toward improving blood counts, enlarged spleen, and symptoms and potentially reducing thrombotic events. Identification of patients with uncontrolled PV is important for clinical care, as such patients have a high risk of complications, and future studies with JAK inhibitors or other agents alone or in combination are needed to test their potential to reduce rates of thrombotic events and transformation to PPV-MF or sAML.

Polycythemia vera: diagnosis, clinical course, and current management

“…Arterial event history and hypertension were the risk factors for arterial events. Although not formally proved in PV and therefore controversial, some authors consider general cardiovascular risk factors in addition to older age and prior thrombosis as important parameters for TE risk prediction (31). The results of the large contemporary PV study just mentioned (30) are in agreement with this approach.…”

From leeches to personalized medicine: evolving concepts in the management of polycythemia vera

“…Therefore, it is urgent to develop a definition of patients with "inadequately controlled disease" who need to be shifted to second-line treatment, including ruxolitinib, a highly effective, but costly, therapy. 104 Patients who continue to have symptoms that are difficult to manage, or who manifest progressive symptomatic splenomegaly or progressive leukocytosis/thrombocytosis, or develop unacceptable toxicities with their current therapy, may obviously belong to that category of patients for whom alternative treatment is required. However, the most important indicator of an inadequately controlled PV in terms of thrombosis and survival is the hematocrit level.…”

Ruxolitinib for the treatment of inadequately controlled polycythemia vera without splenomegaly: 80-week follow-up from the RESPONSE-2 trial

“…However, no effect on the symptom burden was seen in patients, even after the long-term conventional aggressive therapy in CYTO-PV study [9]. It is well known that nearly a quarter of patients discontinue the first-line therapy (HU or interferon) due to the development of resistance or intolerance to treatment [10–12]. …”