Polycythemia vera (PV) and essential thrombocythemia (ET) are both chronic Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs) characterized by clonal proliferation of myeloid cells.1,2 Compared to PV, ET is more heterogeneous, primarily driven by JAK2, CALR, and MPL mutations, with up to 20% of cases classified as “triple-negative.”1 Additional disease characteristics include splenomegaly, hemorrhage, thrombosis, leukocytosis, microcirculatory symptoms, and risk of fibrotic or leukemic transformation.1

In a review article published in the American Journal of Hematology, Ayalew Tefferi, MD, of the department of medicine at the Mayo Clinic in Minnesota and Tiziano Barbui, MD, of Hospital Papa Giovanni XXIII in Bergamo, Italy, summarized current literature surrounding the diagnosis and risk-stratification of PV and ET. They also reviewed currently available and upcoming therapies in clinical development.

Diagnosis and Risk-Stratification

The diagnosis of PV and ET is established on the basis of suspected clinical signs and symptoms, as well as laboratory findings, with bone marrow morphology as the mainstay of diagnosis. Practically, the detection of the JAK2 V617F mutation in peripheral blood is both sensitive and specific for differentiating PV from other causes of elevated hematocrit. Serum erythropoietin level, which is subnormal in more than 85% of patients with PV, is also measured to eliminate potential false-positive and false-negative mutation test results. Mutational testing for JAK2 exon 12 is needed for patients who lack the JAK2 V617F mutation, but exhibit a subnormal serum erythropoietin level as approximately 3% of PV patients are JAK2 V617F-negative.1


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When assessing thrombocytosis, the discovery of JAK2 V617F, CALR or MPL mutations verifies the presence of an underlying MPN. Conversely, the lack of these mutations does not eliminate the possibility of an MPN since ET can be classified as triple-negative. As a result, bone marrow evaluation is often needed to distinguish ET from other myeloid disorders, including prefibrotic primary myelofibrosis.1

The current risk stratification in PV includes 2 risk categories:

  1. High-risk (age >60 years or presence of thrombosis history)
  2. Low-risk (absence of both factors)

While in ET, risk stratification is divided into 4 categories:

  1. Very low risk (age ≤60 years, no thrombosis history, JAK2 wild-type)
  2. Low risk (age ≤60 years, no thrombosis history, JAK2-mutant)
  3. Intermediate risk (age >60 years, no thrombosis history, JAK2 wild-type)
  4. High risk (thrombosis history or age >60 years, JAK2-mutant)

The risk stratification model for both MPNs is designed to evaluate the probability of recurrent thrombotic complications.

Risk-Adapted Therapy

Table. Selected Treatment Recommendations for PV and ET1

Risk CategorySummary of Recommendations
Low-risk PV or ET, in the absence of extreme thrombocytosis• Low-dose aspirin (81 mg/day; range 40-100 mg/day) has antithrombotic value in PV, among all risk categories
• Evidence supports phlebotomy for all patients with PV
• Low-dose aspirin has been shown to be effective in alleviating vasomotor disturbances associated with ET or PV
• Pruritus can be managed using nondrug measures
Low-risk PV or ET, in the presence of extreme thrombocytosis  • In cases of PV or ET with extreme thrombocytosis, the use of aspirin can lead to bleeding complications
• In the presence of platelets >1000 x 109/L, screening for ristocetin cofactor activity is advised and consideration be given to withhold aspirin therapy if the result shows <20% activity
High-risk PV or ET• In addition to low-dose aspirin and phlebotomy to a hematocrit target of 45%, high-risk patients with PV or ET should receive hydroxyurea (starting dose 500 mg twice daily), as first-line cytoreductive drug of choice, in order to minimize thrombotic risk (the dose of hydroxyurea is titrated to keep platelet count in the normal range)
• PV or ET patients who are either intolerant or resistant to hydroxyurea should be treated with INF-α (started at 45 mcg once weekly; pegylated preparations preferred) or busulfan (started at 2-4 mg/day)
• In PV patients not responding to hydroxyurea, INF-α, or busulfan, and in the presence of intractable pruritus or drug-refractory symptomatic splenomegaly, it is reasonable to treat with JAK2 inhibitor therapy
Abbreviations: ET, essential thrombocythemia; PV, polycythemia vera

To read the comprehensive list of recommendations containing qualifying remarks, readers should refer to the full publication in the American Journal of Hematology.

Expert Perspective: Polycythemia Vera

“The biggest development in PV this past year is the submission for potential approval of ropeginterferon alfa-2b (ropeg) in the US, which was approved in Europe in 2019 for the treatment of PV in patients without symptomatic splenomegaly,” explained Srdan Verstovsek, MD, PhD, of the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston.

“This drug was approved in Europe based on the outcome of the phase 3 PROUD-PV study, but the most important part that led to its approval, however, was continuous observation of patients enrolled in the two arms over the next few years. Superiority of ropeg over control emerged after 2, 3, and 4 years of treatment,” he said in an email interview.

Other Recommendations and Concluding Remarks

The authors noted that the median survival in younger patients may exceed 30 years and is similar for older patients with PV and ET. Consequently, they explained the importance of avoiding nonevidence based treatment strategies that may increase the rate of leukemic or fibrotic transformations, and shorten life-expectancy, which has been previously observed with anagrelide, chlorambucil, pipobroman, and radiophosphorus.1

References

1. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. Published online September 24, 2020. doi:10.1002/ajh.26008

2. Bose P, Verstovsek S. Updates in the management of polycythemia vera and essential thrombocythemia. Ther Adv Hematol. 2019;10:2040620719870052. doi:10.1177/2040620719870052