An Update on Current and Emergent Therapies for Essential Thrombocytosis


The therapeutic landscape for myeloproliferative neoplasms is shifting toward a goal of meaningful disease modification.

Streaming blood cells in abstract design | Image Credit: © zketch -

Image Credit: © zketch -

Our understanding of pathophysiology driving Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) has evolved considerably over the past decade. As a result, the therapeutic landscape is shifting toward a goal of meaningful disease modification. For patients with essential thrombocytosis (ET), the immediate goals remain thrombosis risk reduction and symptom control, but newer therapies on the horizon are likely to change our treatment paradigms considerably for this disease.

How do you approach a new patient with ET?
When it comes to the treatment of patients with ET, the main goal of current approved therapy is to mitigate the risk of thrombotic events, as the treatments have minimal impact on disease progression. The choice of treatment is determined by an individual’s specific risk factors for these events. The International Prognostic Score for Thrombosis in ET revised score is used to stratify patients into 4 risk groups: very low risk, low risk, intermediate risk, and high risk. For the majority of low-risk patients, low-dose aspirin is recommended, as it aids in preventing clotting, but patients classified as intermediate or high risk are generally advised to undergo cytoreductive therapy.

What are the standard options for cytoreductive therapy?

The selection of the most suitable cytoreductive agent depends on factors such as the patient’s comorbidities, tolerability of the treatment, future family planning, and individual preferences. Hydroxyurea (HU) and pegylated interferon alfa (peg-IFN) are the primary options for frontline cytoreductive treatment. In the phase 3 study MPD-RC 112 [NCT01259856], which included patients with both ET and polycythemia vera (PV), HU and peg-IFN demonstrated comparable rates of complete response and thrombotic events after 12 months.1 However, over time peg-IFN has shown improved molecular responses in both ET and PV.1-4 Although the clinical implications of these molecular responses aren’t yet entirely clear, these findings are quite exciting to see in this disease that has been so difficult to target. A longer-acting interferon (ropeginterferon alfa-2b-njft; Besremi) is currently in evaluation for patients with ET and has been approved in the United States for patients with PV. In cases where initial treatment approaches do not yield satisfactory results, anagrelide is another option, though its use is often limited by toxicities (eg, headaches, dizziness, palpitations, and fluid retention).

What is on the horizon for treatment of ET?

As we delve deeper into understanding the biologic drivers of ET, promising new therapeutic directions are emerging, including JAK inhibitors, epigenetic agents, and mutation-specific biologic/immunologic therapies.Ruxolitinib (Jakafi), a JAK1/2 inhibitor already widely used for other MPNs, continues to be evaluated in ET. In a randomized study, MAJIC [NCT05057494], ruxolitinib was compared with best available therapy (BAT) for patients with ET who had resistance or intolerance to HU. Both treatments showed similar rates of hematologic response, thrombosis, and hemorrhage. However, ruxolitinib outperformed BAT in improving disease-related symptoms.5 Another ongoing trial called Ruxo-BEAT [NCT02577926] is further exploring the use of ruxolitinib in ET.

When it comes to epigenetic regulators, BET inhibitors and LSD1 inhibitors are emerging as potential therapeutic targets. Both BET inhibitors and LSD1 inhibitors have shown the ability to reduce cytokine production via different mechanisms and impair self-renewal of malignant hematopoietic stem cells, so they may have more significant disease-modifying activity compared with other agents.6,7 The BET inhibitor pelabresib (CPI-0610) is currently being evaluated for ET as well as myelofibrosis. The LSD1 inhibitor bomedemstat is also being studied for both ET and MF, and preliminary reports from the ET study show encouraging ability to control platelets and improve symptoms for many patients.8

Biologic and immunologic approaches are emerging as promising strategies as well. Recently, at the American Society of Hematology annual meeting in 2022, preclinical data were presented on a monoclonal antibody that targets mutant CALR, a key diver for approximately 25% of patients with ET.9 This antibody showed impressive potency in selectively targeting mutant CALR-driven oncogenic mechanisms. There are also other antibody-based therapies showing significant efficacy in preclinical studies, and these strategies are now moving toward the development phases.10 Furthermore, the discovery of T-cell responses against mutant CALR has sparked the development of vaccine-based treatment strategies.11,12 

What are your final thoughts regarding the future of ET?

The development of more targeted agents with the potential to meaningfully disrupt the mechanisms driving MPNs provides a lot of optimism for the future in these diseases. As these therapies move toward “prime time,” we will need to reassess our treatment goals for our patients. Hopefully we will be able to raise the bar for response from simply hematologic control and thrombosis prevention toward the more lofty aims of lengthening survival, improving quality of life, and lowering risk of disease progression.


1. Mascarenhas J, Kosiorek HE, Prchal JT, et al. A randomized phase 3 trial of interferon-alpha vs hydroxyurea in polycythemia vera and essential thrombocythemia. Blood. 2022;139(19):2931-2941. doi:10.1182/blood.2021012743

2. Masarova L, Patel KP, Newberry KJ, et al. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol. 2017;4(4):e165-e175. doi:10.1016/S2352-3026(17)30030-3

3.Quintás-Cardama A, Abdel-Wahab O, Manshouri T, et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood. 2013;122(6):893-901. doi:10.1182/blood-2012-07-442012

4.Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065-3072. doi:10.1182/blood-2008-03-143537

5.Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood. 2017;130(17):1889-1897. doi:10.1182/blood-2017-05-785790

6.Kleppe M, Koche R, Zou L, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33(1):29-43.e27. doi:10.1016/j.ccell.2017.11.009

7.Jutzi JS, Kleppe M, Dias J, et al. LSD1 inhibition prolongs survival in mouse models of MPN by selectively targeting the disease clone. Hemasphere. 2018;2(3):e54. doi:10.1097/HS9.0000000000000054

8.Gill H, Palandri F, Ross DM, et al. A phase 2 study of the LSD1 inhibitor bomedemstat (IMG-7289) for the treatment of essential thrombocythemia (ET). Blood. 2022;140(suppl 1):1784-1787. doi:10.1182/blood-2021-148210

9.Reis E, Buonpane R, Celik H, et al. Discovery of INCA033989, a monoclonal antibody that selectively antagonizes mutant calreticulin oncogenic function in myeloproliferative neoplasms (MPNs). Blood. 2022;140(suppl 1):14-15. doi:10.1182/blood-2022-159435

10.Tvorogov D, Thompson-Peach CAL, Foßelteder J, et al. Targeting human CALR-mutated MPN progenitors with a neoepitope-directed monoclonal antibody. EMBO Rep. 2022;23(4):e52904. doi:10.15252/embr.202152904

11.Holmström MO, Martinenaite E, Ahmad SM, et al. The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy. Leukemia. 2018;32(2):429-437. doi:10.1038/leu.2017.214

12.Holmström MO, Riley CH, Svane IM, Hasselbalch HC, Andersen MH. The CALR exon 9 mutations are shared neoantigens in patients with CALR mutant chronic myeloproliferative neoplasms. Leukemia. 2016;30(12):2413-2416. doi:10.1038/leu.2016.233

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