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Global ET and PV
Global Perspectives on ET and PV Diagnosis and Treatment

Released: May 11, 2026

Ciro Rinaldi
Ciro Rinaldi, MD, PhD
Alessandro M. Vannucchi
Alessandro M. Vannucchi, MD
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Key Takeaways
  • Prioritize accurate diagnosis of ET and PV using a structured approach that includes appropriate molecular testing and the use of bone marrow biopsy.
  • Management of PV and ET focuses on reducing thrombotic and bleeding complications through risk-adapted strategies that include cytoreduction and the growing use of therapies with potential disease-modifying activity.
  • Emerging therapeutics, including LSD1 inhibitors such as bomedemstat, hepcidin mimetics such as rusfertide, and mutant calreticulin–targeted immunotherapies, are shifting the field toward biologically targeted treatment strategies with the potential to alter disease course.

In this commentary, Ciro Rinaldi, MD, PhD, and Alessandro M. Vannucchi, MD, explore contemporary topics in the diagnosis and treatment of essential thrombocythemia (ET) and polycythemia vera (PV).

Key Diagnostic Considerations in ET and PV
Alessandro M. Vannucchi, MD: There are 2 classification systems (from the World Health Organization and International Consensus Classification group) for myeloproliferative neoplasms (MPNs), and it is important to note that the diagnostic criteria for PV and ET are essentially the same in both systems. One of the key aspects emphasized in both classifications is the importance of bone marrow biopsy. Despite the evolution of molecular diagnostics, histopathology remains fundamental to establishing an accurate diagnosis.

Ciro Rinaldi, MD, PhD: I agree. Morphology is still critically important, particularly in ET, because it is the only reliable way to distinguish true ET from prefibrotic myelofibrosis. Patients may present with isolated thrombocytosis and otherwise appear clinically similar, making histologic assessment essential.

The same applies to PV. Many patients present with incidental erythrocytosis or unexplained thrombosis without a clearly elevated hematocrit. In these cases, bone marrow evaluation can clarify the diagnosis, guide prognostication, and ultimately influence follow-up and treatment decisions.

Alessandro M. Vannucchi, MD: Molecular testing has also transformed diagnosis. In PV, approximately 99% of patients harbor a JAK2 mutation, most commonly JAK2 V617F, with a smaller subset carrying exon 12 mutations. This is extremely useful in distinguishing PV from reactive erythrocytosis, even when the mutation burden is very low.

In ET, approximately 60% of patients have JAK2 mutations, 20% harbor CALR mutations, and 5% have MPL mutations, meaning that 85% to 90% of patients with ET have a detectable driver mutation. However, approximately 10% remain “triple negative” for these driver mutations, creating diagnostic challenges. In these cases, healthcare professionals (HCPs) must carefully exclude reactive thrombocytosis, familial thrombocytosis, or inflammatory or malignant conditions. Additional testing for nondriver mutations such as TET2 or ASXL1, or cytogenetic abnormalities, may be required, often in specialized referral centers, with the aim to establish the clonal nature of thrombocytosis.

Ciro Rinaldi, MD, PhD: It is important to have a suspicion of an MPN in patients presenting with thrombotic events. Splanchnic vein thrombosis—including portal, splenic, or mesenteric vein thrombosis—should immediately raise suspicion for an MPN. We know that MPNs, particularly those driven by JAK2 mutations, can cause clots in unusual places. In these cases, HCPs should request JAK2 testing and consider hematology referral.

Similarly, younger patients with unexplained arterial events such as transient ischemic attacks or stroke should be evaluated carefully, especially if persistent thrombocytosis or erythrocytosis is present. Even modest but persistent thrombocytosis above 450 x 10⁹/L warrants investigation for an MPN.

Alessandro M. Vannucchi, MD: Establishing the correct diagnosis is critically important because it directly influences management. For example, patients with splanchnic vein thrombosis associated with an MPN often require lifelong anticoagulation. Accurate diagnosis also informs prognostication and long-term monitoring, particularly because these chronic disorders carry risks of progression to myelofibrosis or, more rarely, acute leukemia.

Contemporary Treatment Approaches in PV
Alessandro M. Vannucchi, MD: The management of PV has historically relied on older therapeutic approaches, but the field is now changing substantially. One of the fundamental principles remains maintaining hematocrit below 45%, which has been shown in a prospective phase III study to significantly reduce thrombosis risk. Low-dose aspirin is another cornerstone of therapy, reducing thrombotic events without significantly increasing bleeding risk.

Patients with PV are traditionally stratified into low-risk and high-risk groups based on age and history of thrombosis. Patients younger than 60 years of age without prior thrombosis are considered low risk and may be managed with phlebotomy and aspirin alone. High-risk patients require cytoreductive therapy, with hydroxyurea remaining the standard frontline agent.

Hydroxyurea is effective, but some patients develop cytopenias, mucocutaneous toxicities, or intolerance that limit the use of this agent. For patients who are refractory or intolerant to hydroxyurea, the JAK inhibitor ruxolitinib has demonstrated efficacy in controlling hematocrit, reducing splenomegaly, and improving symptoms in phase III studies.

We also now have increasing experience with pegylated interferons, particularly ropeginterferon, a long-acting interferon that can maintain hematocrit control without the need for ongoing phlebotomy while also improving symptoms and splenomegaly.

Of importance, our therapeutic goals are evolving beyond thrombosis prevention alone. Increasing evidence suggests that agents such as interferons may exert disease-modifying effects, as demonstrated by reductions in JAK2 variant allele frequency and improved event-free survival. This raises the possibility that therapy may alter the natural history of disease.

Contemporary Treatment Approaches in ET
Ciro Rinaldi, MD, PhD: In ET, treatment has historically focused primarily on reducing thrombotic and bleeding risk rather than altering disease biology. Risk stratification remains central and is still based largely on age, platelet count, thrombotic history, cardiovascular risk factors , and more recently, JAK2 V617F mutation.

Patients with platelet counts above 1500 x 10⁹/L are treated not only because of thrombosis risk but also to reduce bleeding risk. The backbone of therapy remains cytoreduction with hydroxyurea or interferon-based therapy. Hydroxyurea has been used for decades and remains highly effective for thrombosis prevention. Pegylated interferon is also increasingly used and may have disease-modifying potential.

Treatment selection is often individualized according to age and patient preference. In younger patients, particularly those younger than 40 years of age, interferon is generally preferred. In older patients, hydroxyurea remains commonly used, although many HCPs now discuss both options with patients.

Alessandro M. Vannucchi, MD: The middle-aged population, roughly between 40 and 60 years of age, often represents the most nuanced group. Another important consideration is mutational status. Patients with CALR-mutated ET who lack cardiovascular risk factors may not benefit from aspirin. Therefore, management increasingly requires an individualized and comprehensive approach.

Emerging Therapies and Future Directions
Ciro Rinaldi, MD, PhD: We are now seeing a number of investigational therapies that may fundamentally change the treatment landscape. LSD1 inhibitors such as bomedemstat have demonstrated promising activity in ET and PV, not only by reducing thrombocytosis and erythrocytosis but also by potentially exerting disease-modifying effects.

Another novel class in PV includes hepcidin mimetics such as rusfertide, which essentially create a “chemical phlebotomy” by restricting iron utilization in the bone marrow. This allows hematocrit control without inducing iron deficiency associated with repeated phlebotomy.

Alessandro M. Vannucchi, MD: Immunotherapeutic approaches are also emerging. Early studies evaluating monoclonal antibodies directed against mutant calreticulin are particularly exciting. Although calreticulin is normally a cytoplasmic protein, the mutant protein can be expressed on the cell membrane in association with the thrombopoietin receptor, allowing it to become targetable.

These developments may ultimately open the door to highly specific immunotherapies, including potentially CAR T-cell therapy approaches. Although still early, the long-term hope is that these strategies could move beyond disease control toward true eradication or cure.

Ciro Rinaldi, MD, PhD: I agree. For many years, our therapies focused primarily on controlling complications, but the emerging goal is increasingly disease modification and potentially cure, which remains 1 of the greatest unmet needs in ET and PV.

Your Thoughts
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In your current practice, how often do you perform a bone marrow biopsy to confirm a diagnosis of PV in patients who meet hemoglobin/hematocrit and JAK2 mutation criteria?

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