Despite excellent prognoses in low-risk patients with essential thrombocytopenia (ET) and polycythemia vera (PV), knowledge gaps remain and novel, more tolerable therapies require reevaluation of treatment algorithms.
Treatment of essential thrombocythemia (ET) and polycythemia vera (PV), the most common myeloproliferative neoplasms (MPNs), is based on a patient’s risk of thrombosis. However, there is controversy around the management of low-risk patients, who have distinct disease management issues from high-risk patients. A recent review aimed to provide guidance on common clinical scenarios in low-risk patients with ET and PV.
ET and PV are the most common MPNs, which are clonal stem cell neoplasms characterized by proliferation of mature myeloid lineages. The risk of arterial and venous thrombosis, which occurs in 20% to 30% of patients with ET or PV, is the most notable cause of morbidity and mortality in these diseases. Symptom management is the main goal in MPNs, and there are no treatments that alter the disease course as of yet. Even so, the prognosis for patients with low-risk ET and PV is typically measured in decades.
Risk categories for ET and PV based on the International Prognostic Score of Thrombosis for ET (R-UPSET) are as follows:
In the European Collaboration on Low Dose Aspirin in PV (ECLAP) trial, patients were stratified into 2 risk groups. The guidelines have been adapted since, with low risk defined for patients 60 years or younger with no history of thrombosis, whereas high-risk patients with PV are older than 60 years or have a history of thrombosis.
Treatment for ET or PV generally entails antiplatelet therapy with low-dose (70-100 mg) aspirin. In PV, hematocrit (Hct) should be targeted with phlebotomy and/or cytoreduction with a goal of less than 45%. In high-risk patients, cytoreduction is recommended to reduce the risk of thrombosis, but in low-risk groups, cytoreduction is not indicated solely to prevent thrombosis.
One management issue with low-risk patients—who, by definition, are younger than high-risk patients—is pregnancy in women of child-bearing age. Other clinical scenarios, including extreme thrombocytosis, disease-related symptoms, or excessively high phlebotomy requirements, are not included in treatment guidelines but could be reasons to begin therapy.
“This current paradigm for observation belies many active management decisions that must be addressed in the care of low-risk ET and PV patients,” the authors wrote. “The decision for anti-platelet therapy is less straightforward in a population where thrombosis risk is reduced, and dosing strategies, particularly in ET, are unclear.”
As the treatment landscape expands and more therapies are well tolerated, another discussion creating controversy is whether low-risk patients should be offered early intervention rather than observed.
Treatment and Disease Management Concerns in MPNs
In ET and PV, antiplatelet therapy is the standard of care, and data support the addition of low-dose aspirin for patients with PV. In one trial, patients with no contraindications to aspirin and no prior history of thrombosis were randomized to either low-dose aspirin or placebo, and those on aspirin were 60% less likely to experience nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes vs the placebo. For ET, aspirin use is controversial due to a lack of certainty on dosing and its effects on treatment.
In regard to Hct control, one issue is that aggressive phlebotomy can worsen iron deficiency, which is a common condition in patients with PV at diagnosis. Patients with PV who undergo therapeutic phlebotomy often have iron-deficiency–associated symptoms, but supplementation with iron can be counterproductive when the goal of treatment is to induce iron deficiency so that red blood cell (RBC) production is limited. When phlebotomy requirements increase or RBC mass is consistently elevated in low-risk patients, it is typically an indicator that cytoreduction should begin.
Given that roughly 20% of patients are diagnosed before age 40, pregnancy is another concern related to MPN treatment. Pregnant women typically have excellent outcomes, and aspirin has been shown to improve live birth rates in patients with ET. “We also recommend postpartum prophylactic anticoagulation,” the authors wrote. “In patients who are at higher risk (ie, history of thrombosis, multiple prior pregnancy complications or losses), antepartum anticoagulation or cytoreduction can be considered on an individual basis.”
A platelet count greater than 1000x109/L, known as extreme thrombocytosis, is a clinical scenario more common in younger patients than in the overall ET patient population. The percentage of patients affected jumps from 22% overall to 29% in patients younger than 60 and 44% in patients younger than 40. There are no specific criteria for initiation of cytoreduction and antiplatelet therapy in these patients, and it can be difficult for clinicians to balance the risk of thrombosis with the risk of excessive bleeding due to acquired von Willebrand syndrome (AVWS).
“There is likely an overall relationship between worsening bleeding risk and rising platelet count which is partially mediated by AVWS. However, this bleeding risk is likely affected by other variables including mutation status, medications, and other aspects of disease biology, making it difficult to determine platelet goals in individual patients with the goal of minimizing bleeding,” the authors wrote.
Observation vs Action
Watching and waiting is the current norm in low-risk patients with MPNs, with cytoreduction generally starting arbitrarily at 60 years of age. But as new treatments become available that may affect the course of disease, the discussion around earlier intervention will inevitably be raised. Positive clinical trials of pegylated interferon and ropeginterferon, which led to sustained hematologic remission after therapy discontinuation in some patients, are one example of such treatment.
Considering the data surrounding the management of low-risk patients with ET and PV are generally scarce or conflicting, more research is necessary to close knowledge gaps. And as more therapy options become available, treatment algorithms will need to be reassessed.
“Although low-risk ET and PV patients enjoy an excellent prognosis,” the authors concluded, “their management is far from straightforward, and more research is urgently needed to address remaining clinical uncertainties.”
How J, Hobbs G. Management issues and controversies in low‑risk patients with essential thrombocythemia and polycythemia vera. Curr Hematol Malig Rep. Published online September 23, 2021. doi:10.1007/s11899-021-00649-x