Exploring New Perspectives in Diagnosis, Prognosis, and Treatment of PV

The landscape of PV of polycythemia vera (PV) is evolving, with new perspectives in the diagnosis, prognosis, and treatment of the disease. In a recent review appearing in International Journal of Molecular Sciences, researchers outline the latest in PV.

Diagnosis

Since the World Health Organization (WHO) made significant changes to the PV diagnostic criteria in 2016, there have been a higher number of PV diagnoses made among cases that would have previously been diagnosed as myeloproliferative neoplasms (MPN), largely driven by the recognition of the so-called “masked PV,” which is associated with worse outcomes.

A second factor behind the increase was the inclusion of bone marrow (BM) biopsy, for 2 reasons: it can aid in distinguishing between PV and JAK2-positive essential thrombocythemia (ET), and it allows for assessing BM fibrosis as a grade diagnosis allowing for identification of a more aggressive disease.

Among other changes made by WHO in 2016 was the lowering of diagnostic thresholds for hemoglobin and hematocrit (Hct), which were lowered to 16.5 g/dL and 49% for men, and 16 g/dL and 48% for women, respectively. The researchers also highlighted the removal of the endogenous erythroid colony formation “in vitro” as a minor diagnostic criterion.

Prognosis

With thrombotic events being the main cause of morbidity and mortality for patients with PV, the researchers described the emphasis placed on cardiovascular (CV) risk stratification at diagnosis. Currently, patients are typically stratified in 2 categories based on thrombotic risk: a low-risk group of patients aged under 60 years with no previous thromboses and a high-risk group of patients aged older than 60 years and/or with previous thrombotic complications.

It’s been proposed that CV risk factors—hypertension, smoking habits, and leukocytosis—be accounted for in the risk scoring system, as they contribute to the overall risk of thrombosis. Other possible CV risk factors, including red cell distribution width, have also emerged.

Treatment

Historically, management of PV has focused on minimizing the risk of thrombo-hemorrhagic complications, with frontline therapy typically consisting of a combination of phlebotomy to decrease Hct to <45% and low-dose aspirin.

The management of white blood cell (WBC) and platelet counts also represent important treatment goals, as patients with WBC counts ≥ 11 × 109/L versus <7 × 109/L have been shown to have a 4-time greater risk of major thromboses.

With a goal of achieving Hct target levels and normalizing platelet counts, many patients require a cytoreductive treatment, which includes several conventional therapies:

• Hydroxyurea: One of the most commonly used cytoreductive treatments for PV, although some patients may not achieve an adequate benefit with persistent disease-related manifestations or may not tolerate long-term treatment
• Ruxolitinib: Approved in 2014, the treatment is indicated for patients who had an inadequate response to or an unacceptable toxicity from hydroxyurea. Study findings have suggested that the treatment increases the efficacy and tolerability of PEG-IFN alpha-2
• Interferon: Has been used for several decades to control erythrocytosis in most patients with PV. The treatment has also shown similar efficacy in reducing spleen size or relief from pruritus
• Ropeginterferon alpha-2b: Approved by the EMA in 2019 for PV patients with symptomatic splenomegaly, the treatment is characterized by higher tolerability and longer half-life than conventional PEG-IFN alpha. Recently, the treatment has been assessed in patients with low-risk PV

There are also several new drugs under development, including givinostat—a histone daecetylases inhibitor—and idasanutlin—a second-generation oral nutlin.

“While new drugs have recently entered the clinical arena with the promise to improve overall patients’ management, the evidence of a disease-modifying treatment is largely missing,” explained the researchers. “There are several aspects concerning PV, however, that once clarified, might represent significant steps forward for a more adequate and successful treatment strategy, such as a better use of mutational genetics to improve the thrombotic risk stratification of PV patients and a more precise definition of response/safety criteria, which should guide the physician in selecting the most appropriate drug.”

Reference

Iurlo A, Cattaneo D, Bucelli C, Baldini L. New perspectives on polycythemia vera: from diagnosis to therapy. Int J Mol Sci. Published online August 13, 2020. doi:10.3390/ijms21165805.