Back
CME
Interactive Case Challenge: Diagnosing and Managing a Patient With Polycythemia Vera
Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™
Released: April 14, 2026
Expiration: October 13, 2026
Activity
Case Conclusion
The patient begins treatment with ruxolitinib, with a significant reduction in symptoms and no need for phlebotomy after 1 year.
Discussion and Key Research
The case patient in this activity was a 64-year-old man who presented to the ED with chest pain, leading to the diagnosis of myocardial infarction. He had a history of arterial hypertension and deep vein thrombosis. He was referred for exploration of his elevated blood counts (Hgb 20 g/dL, Hct 61.7%, WBC 12.8 x 109/L, and platelets 750 x 109/L).
When approaching elevated platelet counts or elevated red blood cell count, Hgb, or Hct, healthcare professionals often face a wide differential. Secondary causes such as inflammatory conditions, chronic cardiopulmonary disease, or specific drug exposure remain important to consider.
If essential thrombocythemia (ET) or PV is suspected, mutation testing, including assessment for JAK2, CALR, and MPL, forms the cornerstone of diagnostic evaluation.1-3 Virtually all patients with PV carry a JAK2 mutation, whereas patients with ET display a more heterogeneous distribution of mutations across JAK2 (approximately 60%), CALR (approximately 25%), and MPL (approximately 5%-7%).4-6 Identifying the molecular driver supports not only diagnostic clarity but also more informed conversations with patients about prognosis and thrombotic risk.
With regard to PV, major criteria include evidence for increased red blood cell parameters, including an Hgb >16.5 in men and >16 in women, or Hct >49% in men and >48% in women.1-3 Note that the current WHO criteria lowered the Hgb and Hct threshold in formal diagnostic criteria, in recognition that some patients with PV may not have significantly elevated red blood cell parameters.1,7 The full criteria for PV are as follows1-3:
-Major criteria:
- Hgb >16.5 g/dL in men/>16.0 g/dL in women OR Hct >49% in men/>48% in women OR increased red cell mass (ICC only)
- JAK2 mutation
- Bone marrow biopsy showing trilineage proliferation (panmyelosis)
-Minor criterion:
- Subnormal serum EPO level
All 3 major criteria or the first 2 major criteria and the minor criterion must be met for a diagnosis of PV. A bone marrow biopsy is not required for a PV diagnosis if Hgb >18.5 g/dL in men/>16.5 g/dL in women OR Hct >55.5% in men/>49.5% in women.
Although not required for a diagnosis of PV (as with the case patient), in practice, a diagnostic bone marrow biopsy can still help establish a baseline and provide some prognostic information, particularly in younger patients who are at risk of having progression occur in their lifetime.
A subnormal EPO level is a minor criterion for the diagnosis of PV, although it is important to note that up to 20% to 30% of patients with PV will have a normal EPO level, and many can even have increased EPO levels.1-3,8 A normal erythropoietin level does not rule out the diagnosis of PV, but a low EPO level in a patient with erythrocytosis awaiting genetic marker testing is strongly suggestive of PV.
The conventional thrombotic risk stratification for PV was established by Marchioli and colleagues in 2005.9 This model is also utilized in expert consensus guidelines such as those established by the National Comprehensive Cancer Network. Patients are classified into 2 principal risk groups based on 2 clinical factors: age 60 years or older and a history of thrombosis. Patients who are younger than 60 years of age and have no thrombosis history at diagnosis are considered low risk, and those who meet either or both criteria are considered high risk.
In Kaplan–Meier analyses comparing thrombotic outcomes between these 2 conventional risk groups, patients considered high risk demonstrated markedly lower thrombosis‑free survival over time (10.9 cardiovascular events per 100 persons per year in those with a history of thrombosis and age ≥65 years), whereas patients considered low risk had higher rates of cardiovascular event‑free survival (2.5 cardiovascular events per 100 persons per year).
The conventional risk model for PV is used to guide therapy.8,10 Thrombosis remains the most common cause of morbidity and mortality, and patients with PV are at especially high risk for thrombosis. All patients with PV should be treated with aspirin and maintain an Hct <45%. The latter recommendation is based on clinical trial data demonstrating superior thrombotic-free survival in patients who maintained an aggressive (Hct <45%) goal compared to a liberal (Hct 45%-50%) goal.11 For those at low risk (ie, young patients without a history of thrombosis), this could be done through therapeutic phlebotomy. However, in those at high risk, cytoreduction is recommended to keep counts at goal. Cytoreduction provides even more control of Hct than periodic phlebotomy and can also reduce leukocytosis, which has been linked to poorer thrombosis-free survival and thrombocytosis.12,13
The classic guideline management schema for PV utilizes these 2 risk categories. For high-risk patients and some low-risk patients, guidelines recommend cytoreductive therapy with hydroxyurea, peginterferon α-2a, or ropeginterferon α-2b as first-line options and ruxolitinib and first-line recommended therapies as second-line options.8,10
MPD-RC 112 was a randomized phase III study evaluating frontline therapy in 168 high-risk patients with ET or PV who had received no prior cytoreductive treatment.14 Patients were randomized to hydroxyurea or peginterferon α-2a. Hydroxyurea and peginterferon demonstrated comparable complete response rates at 3 years. Peginterferon showed a numerically higher overall response rate, though CR rates were similar.
Results from the PROUD-PV/CONTINUATION-PV trial demonstrated that ropeginterferon α-2b was associated with significant improvements in hematologic and molecular response rates compared with control treatment.15 At 6 years, the control arm primarily included treatment with hydroxyurea because patients in the hydroxyurea group largely continued receiving hydroxyurea in the extension study. Ropeginterferon α-2b is unique in that it has demonstrated efficacy in reducing JAK2 V617F allele burden. Ropeginterferon α-2b was associated with much higher rates of JAK2 V617F allele burden reduction compared with the control group. In addition, longer event-free survival was reported in patients receiving ropeginterferon compared with standard therapy and in patients achieving molecular response compared with those who did not.21,22
The European LeukemiaNet criteria for hydroxyurea resistance or intolerance define resistance as having uncontrolled myeloproliferative neoplasm despite receiving an adequate dose of hydroxyurea. Intolerance is defined as the patient experiencing hematologic or nonhematologic toxicity at the lowest dose required to maintain a clinical hematologic response.16
Two trials examined the use of ruxolitinib in treating PV in patients with resistance or intolerance to hydroxyurea. RESPONSE and RESPONSE-2 were randomized, open-label phase III trials in which patients with PV and resistance or intolerance to hydroxyurea received ruxolitinib or best available treatment (BAT).17,18 In RESPONSE, patients had splenomegaly, whereas RESPONSE-2 excluded patients with splenomegaly. In both trials, the endpoints were similar, and because treatment options are limited, the BAT was primarily hydroxyurea, even though patients had previously experienced treatment failure with hydroxyurea. In both trials, ruxolitinib was superior to BAT for endpoints including Hct control, complete hematologic remission, symptom response, symptom resolution, and spleen response. Ruxolitinib is currently approved for PV in adults who have had an inadequate response to or are intolerant of hydroxyurea.
There are numerous targeted therapies in clinical development for treating PV. Data with 2 notable agents were presented at ASH 2025.
Targeting iron metabolism, including via hepcidin modulation, has emerged as a novel therapeutic strategy in PV. Rusfertide, a hepcidin mimetic, was evaluated in the phase III VERIFY trial, which randomized 293 patients with phlebotomy-dependent PV to rusfertide plus standard of care or placebo plus standard of care.19 Rusfertide significantly improved Hct control and eliminated phlebotomy eligibility in 72.8% of patients vs 21.9% with placebo (P <.0001).
Bomedemstat is an oral LSD1 inhibitor under investigation in PV and ET. LSD1 inhibition increases p53 expression and methylation, enhancing proapoptotic signaling. In a phase II study of 20 patients with PV resistant/intolerant to cytoreductive therapy, 45% achieved sustained 12-week Hct <45% without phlebotomy by Week 36.20 At any time, 90% achieved Hct <45% and platelet counts ≤450 x 10⁹/L; 95% achieved WBC <10 x 10⁹/L. Three phase III trials are ongoing with bomedemstat: Shorespan-007 (ET, treatment-naive; bomedemstat vs hydroxyurea), Shorespan-006 (ET resistant/intolerant to hydroxyurea; bomedemstat vs best available therapy), and Shorespan-017 (long-term extension in ET/PV). Clinical trials should be discussed for all patients with PV and may be considered based on a patient’s goals of therapy.