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CME
Interactive Case Challenge: Diagnosing and Managing a Patient With Essential Thrombocythemia
Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™
Released: April 06, 2026
Expiration: October 05, 2026
Activity
Case Conclusion
The patient enrolls in a clinical trial of bomedemstat. She is currently being assessed for hematologic response, symptoms, and other outcomes as part of the trial.
Discussion and Key Research
The case patient in this activity was a 66-year-old woman who presented with fatigue and headaches. Physical examination revealed splenomegaly (1 cm below costal margin), and a CBC demonstrated platelets 650 x 109/L, WBC 6.1 g/L, hemoglobin 13 g/dL, hematocrit 42%, and normal MCV. Further testing revealed normal iron and C-reactive protein, with BCR-ABL1 negativity and JAK2 V617F positivity.
When approaching elevated platelet counts or elevated red blood cell count, hemoglobin, or hematocrit, healthcare professionals often face a wide differential. If 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 ET, major criteria include an increased platelet count, characteristic bone marrow biopsy findings, and a major driver mutation in JAK2, CALR, or MPL. The full criteria for ET are as follows1-3:
-Major criteria:
- Platelets ≥450 x 109/L
- Bone marrow biopsy with predominant proliferation of megakaryocytes
- Not meeting WHO criteria for other MPN subtypes
- JAK2, CALR, or MPL mutation
-Minor criterion:
- Presence of a clonal marker or absence of evidence for reactive thrombocytosis
All 4 major criteria or the first 3 major criteria and 1 minor criterion must be met to confirm a diagnosis of ET. Approximately 10% of patients with ET will be triple negative, or lack a pathogenic driver mutation in JAK2, CALR, or MPL. For this reason, the minor criteria also include a specification that there is either a nondriver pathogenic mutation or no other clear cause of thrombocytosis. Common causes of reactive thrombocytosis that should be ruled out include inflammation, iron deficiency, and splenectomy.
Based on these criteria, this patient was less likely to have PV, as she did not have elevated hematocrit or hemoglobin levels. Three of 4 major criteria for ET were satisfied, with 4 being required (or 3 plus 1 minor criterion, which is also not satisfied). The patient underwent a bone marrow biopsy, which confirmed the diagnosis of ET, showing predominant proliferation of megakaryocytes.
A bone marrow biopsy is required to make a diagnosis of ET, mostly as it is needed to differentiate ET from other MPNs that can also present with isolated thrombocytosis, such as prefibrotic myelofibrosis (MF) or, less commonly, chronic myeloid leukemia. A bone marrow biopsy is also particularly helpful in differentiating reactive thrombocytosis from triple-negative thrombocytosis. There is some practice variation with regard to whether healthcare professionals obtain a bone marrow biopsy to formally diagnose ET, given that practically the bone marrow biopsy infrequently changes management. For instance, in a patient with a JAK2 mutation and thrombocytosis who is found to have pathologic findings that favor prefibrotic MF in the bone marrow, they often clinically behave more like ET and so are treated as ET. However, a diagnostic bone marrow biopsy may be performed as a baseline and can add prognostic information. In frailer or older patients, or those who are strongly against a bone marrow biopsy, it may be more practical to omit. However, if there are concerns for progression, including to overt MF, patients should be counseled that a bone marrow biopsy is more strongly indicated.
The revised International Prognostic Score of Thrombosis for ET (R-IPSET) is a standard risk stratification tool for thrombosis in patients with ET.7 The original version included older age, thrombosis history, JAK2 mutation status, and cardiovascular risk factors.8 Reanalysis of the data used to establish the IPSET found that cardiovascular risk factors added no prognostic value.7 Thus, the revised version includes 4 risk categories based on 3 risk factors: age older than 60 years, history of thrombosis, and presence of a JAK2 mutation. Patients at very low risk are young without a thrombotic history or a JAK2 mutation. This includes, for instance, very young asymptomatic patients with a CALR mutation. Patients at low risk are younger with a JAK2 mutation and no thrombotic history. Patients at intermediate risk are older, without a JAK2 mutation, and no thrombotic history. Finally, patients at high risk are older with a JAK2 mutation or a thrombotic history, regardless of age.
The R-IPSET helps determine how to treat ET to reduce the risk of thrombosis.7,9 All patients are generally treated with aspirin, although some data suggest that in patients at very low risk, aspirin does not significantly reduce thrombotic risk and may increase bleeding; therefore, observation is a reasonable option in this risk category. Cytoreduction is generally recommended in patients who are at high risk for thrombosis and can be omitted in patients who are at low risk. In patients who are at intermediate risk for thrombosis, cytoreduction may be more controversial and should depend on other risk factors present, such as diabetes, hypertension, hyperlipemia, obesity, and smoking status. Although the case patient had no prior history of thrombosis, she is younger than 60 years of age with JAK2-mutated disease, and so would generally be considered in the higher-risk category, indicating cytoreductive therapy as appropriate.
Based on data from the randomized PT1 trial comparing treatment with hydroxyurea vs anagrelide, hydroxyurea is the preferred first-line cytoreductive agent for treating ET, although interferons also may be an option.9-11 Anagrelide may be considered as a second‑line agent in patients with hydroxyurea resistance or intolerance. Ruxolitinib is not generally recommended as first-line therapy for ET, although it may be considered in the second line in specific circumstances.
Looking at ropeginterferon α-2b, SURPASS-ET was a randomized phase III trial in which 174 adults with high-risk ET resistant/intolerant to hydroxyurea (no prior interferon α) were randomized to ropeginterferon α-2b or anagrelide.12 Ropeginterferon α-2b demonstrated a significantly higher response rate vs anagrelide (42.9% vs 6.0%; P = .0001). JAK2 V617 allele burden decreased from 33.7% to 25.3% with ropeginterferon vs 39.7% to 37.3% with anagrelide (baseline to 12 months).
Ruxolitinib is not indicated for treating ET in the US or EU and has not been studied in a randomized, controlled phase III trial. However, it has been investigated in earlier-phase trials, including MAJIC-ET, a randomized phase II trial in patients with ET who were resistant or intolerant to hydroxyurea and who received ruxolitinib or best available therapy (BAT).13 In this trial, ruxolitinib and BAT were associated with similar rates of complete response within 1 year of treatment, which was the primary endpoint. Trial results also demonstrated that ruxolitinib demonstrated superior symptom reduction compared with BAT.
There are numerous targeted therapies in clinical development for treating ET. Clinical trials should be discussed for all patients with PV and may be considered based on a patient’s goals of therapy.
Bomedemstat is an oral LSD1 inhibitor under investigation in PV and ET. LSD1 inhibition increases p53 expression and methylation, enhancing proapoptotic signaling. An open-label phase II study evaluated bomedemstat in patients with ET requiring cytoreduction who had inadequate response/intolerance to ≥1 standard therapy (baseline platelets >450 x 109/L; hemoglobin ≥100 g/L).14 By Week 24, 77% achieved a platelet response (<400 x 109/L) without new thromboembolic events. Durable response (<400 x 109/L for ≥12 weeks) was observed in 72% (n/N = 52/72). Mean platelet counts declined rapidly from approximately 800 x 109/L at baseline to approximately 300-350 x 109/L by Weeks 12-24. Molecular responses were also observed: 85% (39/46) had reductions in variant allele frequency (VAF) at Week 24, including across JAK2, CALR, and MPL mutations; 15% (7/46) showed VAF increases.
Pelabresib, an oral BET inhibitor, was evaluated in the phase II MANIFEST study (arm 4) in 20 patients with high-risk ET (platelets >600 x 109/L, hydroxyurea resistant/intolerant, ≥2 symptoms).15 Complete hematologic response was achieved in 40% (8/20), defined as platelets ≤400 x 109/L and WBC ≤10 x 109/L. Symptom improvement was notable, with total symptom score reduction in 86% (12/14) and a median total symptom score decrease of 31% at Week 12.
Several novel CALR and JAK inhibitors are also being evaluated for managing ET. CALR inhibitors include INCA339891 and JNJ-885499682; JAK inhibitors include AJ1-11095 and INCB160058.