Category Archives: Essential Thrombocythemia

Tremblay’s Approach to Cytoreduction Across MPNs

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Douglas Tremblay, MD

Douglas Tremblay, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai, discusses the factors which influence the decision to recommend cytoreduction for patients with essential thrombocytopenia (ET) and polycythemia vera (PV).

According to Tremblay, deciding when to start cytoreductive therapy in patients with chronic myeloproliferative neoplasms (MPN) patients like those with PV and ET hinges on accurate risk assessment. While risk stratification tools like the European LeukemiaNet (ELN) classification or the IPSET-Thrombosis score are valuable, Tremblay cautions against oversimplifying things.

He also emphasizes that different factors can indicate which patients are high-risk, including biological age and individual cardiovascular risk factors. Overall, utilizing a personalized approach to risk assessment is key when deciding on cytoreductive therapy for patients with MPN patients. Age should be considered within the context of their overall health and potential for vascular complications. With a personalized approach, experts can ensure that cytoreductive therapy is reserved for those who truly stand to benefit and avoids unnecessary treatment for others.

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Red Blood Cell Contribution to Thrombosis in Polycythemia Vera and Essential Thrombocythemia

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Julien Grenier, Wassim El Nemer, and Maria De Grandis

Abstract

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) characterized by clonal erythrocytosis and thrombocytosis, respectively. The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. Despite a debated notion that red blood cells (RBCs) play a passive and minor role in thrombosis, there has been increasing evidence over the past decades that RBCs may play a biological and clinical role in PV and ET pathophysiology. This review summarizes the main mechanisms that suggest the involvement of PV and ET RBCs in thrombosis, including quantitative and qualitative RBC abnormalities reported in these pathologies. Among these abnormalities, we discuss increased RBC counts and hematocrit, that modulate blood rheology by increasing viscosity, as well as qualitative changes, such as deformability, aggregation, expression of adhesion proteins and phosphatidylserine and release of extracellular microvesicles. While the direct relationship between a high red cell count and thrombosis is well-known, the intrinsic defects of RBCs from PV and ET patients are new contributors that need to be investigated in depth in order to elucidate their role and pave the way for new therapeutical strategies.

Prediction models for essential thrombocythemia from two longitudinal studies involving 2000 patients

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January 23, 2024

Tiziano Barbui and Alessandra Carobbio

Over the past two decades, significant progress has been made in several areas of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs), namely polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). The driver mutations in the JAK2-V617, MPL, calreticulin opened new diagnostic and prognostic possibilities and provided new targets for therapy [1].

ET is currently diagnosed according to the World Health Organization (WHO) [2] and International Consensus Criteria (ICC) [3] criteria, involving a comprehensive evaluation of clinical, laboratory and molecular features, and is defined by clonal thrombocytosis with characteristic bone marrow megakaryocyte morphology, which allows a differentiation from PV and prefibrotic myelofibrosis (pre-PMF); the latter is a distinct entity with a clinical picture often characterized by isolated thrombocytosis mimicking ET. In a multicenter series of 1104 patients previously classified as having ET, the diagnosis was re-evaluated following strict application of the 2008 WHO classification, which includes well-defined histopathological criteria. The diagnosis of ET was confirmed in 891 patients (81%) and revised to pre-PMF in 180 (16%) [4]. A subset of ET patients has a triple-negative (TN) genotype due to the absence of detectable mutations in driver genes and is observed in ~10% of ET cases [1].

Current information on risk factors of the major critical events (thrombosis, evolution to MF, blast phase (BP), and survival) derives from registry and multicenter observational studies while single-center reports conducted at tertiary referral institutions are very limited [5]. Each study design has its strengths and limitations. Observational multicenter studies and registries can capture a large number of cases but may face challenges related to data quality and consistency. Ensuring the accuracy and uniformity of data across multiple centers becomes a critical consideration.

Studies conducted in tertiary centers, exemplified by those presented in this Blood Cancer Journal issue from Florence [6] and Mayo Clinic [7] hospitals, are more robust in nature as they can provide a solid description of natural history of this myeloproliferative neoplasm. These are conducted by specialized teams comprising clinician hematologists, pathologists, geneticists, and other experts with proficiency in MPNs and are equipped with up-to-date technologies including molecular analyses, which are essential in the case of ET where genetic mutations play a significant role in diagnosis and prognosis. Nevertheless, despite providing comprehensive insights into a well-defined cohort of patients, these centers may have a patient referral bias and limited generalizability to the broader population. This may suggest that description of disease presentation and results on prognostic factors may not be universally reproducible, and caution should be exercised when extrapolating the results to consecutive patient groups.

The Mayo and Florence reports each included 1000 ET patients; all 2000 cases met ICC 2022 and WHO diagnostic criteria and were fully annotated for driver mutations; diagnosis required hematopathology review to minimize unintended inclusion of patients with masked PV or pre-PMF. This revision is critical for patients diagnosed with ET prior to the WHO recognition of masked PV and pre-PMF, as the incidence of complications such as thrombosis, myelofibrosis, blast phase, and overall survival differs between these entities compared to “true ET”. All patients in the two studies were annotated for driver mutations, which were found in approximately 90% of cases, with similar proportions in the two series for JAK2 V617F, CALR including CALR type 1/1-like and CALR type 2/2-like, MPL and TN. Interestingly, female sex clustered preferentially with TN and JAK2 vs. CALR/MPL mutations (p < 0.01), and extreme thrombocytosis clustered with CALR (type 2 more than type 1), TN, and MPL, whereas leukocytosis clustered with JAK2 mutation (p < 0.001). It is noteworthy that the two patients’ series from Mayo and Florence showed remarkably similar presentations over the extensive recruitment period of more than 40 years.

In these retrospective cohorts, 20% of patients had a history of vascular complications at diagnosis and a similar percentage of driver mutations clustered in a similar manner. Importantly, these findings are consistent with data observed in other real-world routine clinical practice of recent reviews on ET [8, 9]. This convergence of information on disease presentation between Mayo and Florence highlights that the characteristics of these two retrospective cohorts are unlikely to have been influenced by potential reference bias. Thus, the consistency of these patterns across different settings adds value to the findings of these two studies, reinforcing the reliability of the observed trends and minimizing the impact of referral bias.

Therefore, the Mayo and Florence longitudinal studies offer the unique advantage of capturing the dynamic evolution of ET disease in real-world clinical practice over an extended period of median 8.5 years (range, 0.01–52.7) and 8 years (range, 0.03–42.9), respectively, providing robust estimates of disease-specific outcomes, i.e., arterial and venous thrombosis, progression to overt MF, BP, and survival. This makes the results on risk factors for each of these critical events highly reliable and generalizable. In this context, the confirmation of the prognostic role of increased neutrophil granulocytes and decreased lymphocytes as independent risk factors for survival in 1164 ET patients should be highlighted. This new knowledge opens new avenues for future clinical trials on the role of inflammation in MPN and the associated new targets for therapy [10, 11]. In addition, the large number of cases annotated for driver mutations allowed the identification of risk scores for progression to myelofibrosis and blast phase and confirmed the predictive power of the International Prognostic Score of Thrombosis (IPSET-thrombosis) score. We agree with the authors that these results, obtained in a large series of patients with ET, mutually validated, can constitute a reference standard against which other series of cases fully annotated for driver mutations and followed up for a long time can be compared.

Inspired by the extensive ET series of these two Blood Cancer Journal papers, we reviewed our data on 891 WHO-diagnosed ET patients enrolled from multi-center institutions, in whom we investigated the effect of post-diagnosis intermediate events (thrombosis, MF, and BP) on mortality using multistate models [12]. Using these models, which increase the precision of estimation by correcting for competing risk factors, we found that patients with incident thrombosis had a progressively increased risk of death compared with patients without this event. As expected, the highest risk of death was associated with the occurrence of MF and BP (Fig. 1). Notably, in the time-dependent multivariate analysis, arterial but not venous thrombosis occurrence during follow-up was independently associated with death, together with evolution into MF and BP (Table 1). Therefore, in future analysis of longitudinal studies, we suggest that the conventional baseline prognostic evaluation in MPN should be revised by considering the intermediate events that might integrate the risk of the final outcome of interest in the single patient.

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CALR-Mutated Essential Thrombocythemia Associated With Higher Progression to Myelofibrosis Risk

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CALR mutations in essential thrombocythemia are associated with lower thrombosis risk and higher risk of progression to myelofibrosis (MF) compared with other driver mutations, according to a recent study.

The study was led by Katie Erdos, a Research Program Assistant at Weill Cornell Medicine’s Richard T. Silver, MD Myeloproliferative Neoplasms Center, and presented at the 65th American Society of Hematology Annual Meeting & Exposition.

Erdos and colleagues conducted the study to evaluate the impact of driver mutations on the risks of thromboembolic events, disease progression, and patient mortality.

Of 338 total patients, 216 (64%) were positive for JAK2V617F, 85 (25%) were positive for CALR, 19 (6%) were positive for MPL, and 18 were (5%) triple-negative (TN). Red cell parameters were slightly higher in patients with JAK2V617F mutations (P<0.001), white blood cell count was highest in TN patients (P=0.012), and platelet count did not significantly vary across mutation groups (P=0.064).

The 20-year thrombosis-free survival was 71% for JAK2V617F, 100% for CALR, 90% for MPL, and 83% for TN (P=0.0027). The 20-year MF-free survival was 87% for JAK2V617F, 48% for CALR, 65% for MPL, and 94% for TN (P=0.00053). Meanwhile, the 20-year overall survival was 76% for JAK2V617F, 86% for CALR, 89% for MPL, and 90% for TN (P=0.66).

“Our findings reinforce the need for long-term data to guide therapy for ET based not only on the near-term thrombotic risk, but also on the long-term risk of progression,” wrote Erdos and colleagues.

Reference

Erdos K, Lee N, Lebbe A, et al. Low thrombosis risk CALR mutations confer higher risk of essential thrombocythemia progression. Abstract #1819. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.

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EXCEED-ET Study Evaluates Ropeginterferon alfa-2b-njf in ET

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November 2, 2023

Lucia Masarova, MD

Lucia Masarova, MD, PhD, assistant professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the rationale of the EXCEED-ET study (NCT05482971) of ropeginterferon alfa-2b-njf (Besremi) for patients with essential thrombocytopenia (ET).

Transcription:

0:10 | The EXCEED-ET study is getting the ropeginterferon, which is the novel interferon into the space of ET. It is phase 1/2 study that gets the novel ropeginterferon in patients in North America. The patients are hydroxyurea-refractory or hydroxyurea-naive. Patients that have ET platelets over 450,000 need the therapy with some symptoms, and do not have a contraindication for interferons, which also had to be mentioned that the drugs could not be used in patients that have previous autoimmune disease, psychiatric diseases, or neurological because it could aggravate their symptoms.

0:51 | But those patients, if they would be eligible, they could be getting the full access to the drug. Also, with patients with ET, the escalation is going to be a lot faster to 250 micrograms, every other week, 350, and then 500 is the maximum dose that has been explored. However, I have to say the approval of ropeginterferon for PV had even higher dose, and the maximum-tolerated dose was not reached. This is a perfectly safe dose that we have patients on. We’re going to see how it’s going to do in ET patients.

1:25 | There is a core treatment period, which continues after the 4 weeks of escalation of up to 56 weeks. The patients will be dosed every other week with a tolerable dose. We will be monitoring the primary end points of durability of control, hematologic control, platelets less than 450, white cells less than 10. That will basically sustain 80% of 36 consecutive weeks. Then, the key secondary end points are going to include all important end points in ET patients, such as complete hematologic response, composite hematologic response, that includes control of spleen, control of symptoms, absence of disease progression, and absence of thromboembolic events. Then, it’s going to also have this exciting end point, which is basically a decline or allele burden. We’ll be checking the allo burden, what we call the molecular response, and then bone marrow morphology response.

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Presentation at MPN Congress and ASH Annual Meeting Reinforce Clinical Role of ropeginterferon alfa-2b-njft

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November 2, 2023

BURLINGTON, Mass., November 02, 2023–(BUSINESS WIRE)–PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TPEx:6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology and oncology, today announced that new abstracts on ropeginterferon alfa-2b-njft will be presented during the 15th International Congress on Myeloproliferative Neoplasms (MPN Congress) in Brooklyn, NY on November 2-3, 2023, and during the 65th American Society of Hematology (ASH) Annual Meeting in San Diego, CA on December 9-12, 2023.

Key highlights from the accepted abstracts include:

  • AI-based Discovery: Application of AI technology to identify a potentially important association between myeloproliferative neoplasms (MPNs) and neurodegenerative diseases that may reflect common disease mechanisms and shared targets, including inhibitory immunoreceptors. The analysis suggests that dysregulation of specific immune checkpoints may promote chronic inflammation and thrombosis in MPNs and targeting these pathways may represent a novel approach to restoring immune and vascular homeostasis in these diseases.
  • Patient Survey: A qualitative analysis of responses to a survey distributed to MPN patients in partnership with two MPN advocacy organizations was conducted to help understand the patient experience on ropeginterferon alfa-2b-njft. In the interim analysis, themes that emerged from MPN patient responses ranged from satisfaction of observed outcomes with ropeginterferon alfa-2b-njft, management of safety concerns and comments on the ease of the injection.
  • Clinical Trial in Progress: Study design details of the Phase 2b clinical study EXCEED-ET evaluating ropeginterferon alfa-2b-njft for the investigational treatment of adults with essential thrombocythemia (ET) in the U.S. and Canada will be shared.
  • Medical Chart Review: A description of the study details for a quantitative, retrospective review of medical charts to assess the longitudinal clinical and economic burden of illness in patients with polycythemia vera (PV).
  • Investigator-led Korean study: Interim results from an independent, single-arm, open-label, multicenter study showed that with ropeginterferon alfa-2b-njft therapy and an accelerated dose titration at 12 months, 63% of participants achieved a complete hematological response, 61% achieved molecular response, as well as an overall reduction in JAK2 allele burden. The treatment was well tolerated in evaluated patients with PV.

“PharmaEssentia strives to be an essential partner to the MPN community, and these findings are a testament to the breadth and depth of the current and planned clinical and real-world evidence supporting the safety and efficacy of ropeginterferon alfa-2b-njft as a therapeutic option,” said Raymond Urbanski, M.D., Ph.D., Senior Vice President and U.S. Head of Clinical Development and Medical Affairs at PharmaEssentia. “We believe these encouraging data will help healthcare providers advance important discussions around improving care and outcomes for people living with MPNs who continue to face challenges managing their rare blood cancers.”

MPN Congress Abstract Details

  • Causal AI dissection of RNAseq datasets pinpoints connections between MPNs and neurodegenerative diseases
    • Abstract 127 – Thursday, November 2, 2023, 5:15 – 7 PM ET
  • Sharing the treatment experience of ropeginterferon alfa-2b-njft: A qualitative analysis of patient responses
    • Abstract 141 – Thursday, November 2, 2023, 5:15 – 7 PM ET
  • The clinical and economic burden of illness in patients with polycythemia vera: A retrospective medical chart audit study
    • Abstract 133 – Thursday, November 2, 2023, 5:15 – 7 PM ET
  • EXCEED-ET: A single-arm multicenter study to assess the efficacy, safety, and tolerability of ropeginterferon alfa-2b-njft (P1101) in North American adults with essential thrombocythemia
    • Abstract 137 – Thursday, November 2, 2023, 5:15 – 7 PM ET
  • A single-arm, open-label, multicenter study to assess molecular response of P1101 therapy in patients with polycythemia vera and elevated hematocrit
    • Abstract 116 – Thursday, November 2, 2023, 5:15 – 7 PM ET

ASH Abstract Details

  • A single-arm, open-label, multicenter study to assess molecular response of P1101 therapy in patients with polycythemia vera and elevated hematocrit: results from 12-month core study (New Data)
    • Abstract 4575 – Monday, December 11, 2023, 6 – 8 PM PT

Follow PharmaEssentia USA on Twitter and LinkedIn for news and updates at the meetings.

About Polycythemia Vera (PV)

Polycythemia vera (PV) is a cancer originating from a disease-initiating stem cell in the bone marrow resulting in a chronic increase of red blood cells, white blood cells, and platelets. PV may result in cardiovascular complications such as thrombosis and embolism, and often transforms to secondary myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2.1

About Essential Thrombocythemia (ET)

Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) characterized by an overproduction of platelets in the blood that results from a genetic mutation; data indicates a JAK2 gene mutation is present in approximately half of diagnosed patients. ET is estimated to affect up to 57 per 100,000 people in the U.S. The disease is most commonly diagnosed through routine blood work and is most common in people over the age of 50, with women 1.5 times more likely to be diagnosed than men. As a chronic, progressive disease, ET requires regular monitoring and appropriate treatment. Over time, the disease may progress into more deadly conditions such as myelofibrosis or acute leukemia.2,3

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Statin Use and Outcomes With Polycythemia Vera or Essential Thrombocythemia

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October 19, 2023

Vicki Moore, PhD

In patients with polycythemia vera (PV) or essential thrombocythemia (ET), researchers found that statin therapy was associated with possible benefits related to survival and thrombosis in a new study. The researchers reported their findings in the journal Cancer Medicine.

In this cohort analysis, the researchers evaluated data on statin use and outcomes for 4010 adults with PV or ET who were of age 66 through 99 years at diagnosis and who were identified through the Surveillance, Epidemiology, and End Results-Medicare database.

The researchers analyzed patients in 2 cohorts, based on using either propensity score matching (PSM) or inverse probability of treatment weighting (IPTW), to evaluate possible relationships between statin use and outcomes. Cox proportional hazards analyses were performed to evaluate outcomes related to survival and first incident thrombotic events. The median follow-up time was 3.92 years.

The study included 1809 patients with PV and 2201 patients with ET. Patients had a median age at diagnosis of 77 years in both the PV and ET subgroups. In the first year after being diagnosed with PV or ET, over half (55.8%) of the patients overall had used statins.

For patients with PV, with a median follow-up of 4.00 years, 35.0% of those who used statins had died whereas 43.0% of patients not using statins had died. Among patients with ET, at a median follow-up of 3.84 years, deaths were reported among 35.7% of those who used statins and in 40.9% of those who did not use statins. A sensitivity analysis suggested that survival differences with statin use were significant for patients who had not been receiving statin therapy prior to their PV or ET diagnosis.

Statin use also was associated with a lower risk of thrombosis across the overall study population. In the PSM cohort, the HR was 0.63 (95% CI, 0.51-0.78; P <.01) for this association, and in the IPTW cohort, the HR was 0.57 (95% CI, 0.49-0.66; P <.01). A lower risk of thrombosis with statin use was also observed in PV and ET subgroups.

“Overall, our study demonstrated that statins improved survival and decreased the incidence of thrombotic events in older patients with PV and ET,” the researchers wrote in their report.

Reference

Podoltsev NA, Wang R, Shallis RM, et al. Statin use, survival and incidence of thrombosis among older patients with polycythemia vera and essential thrombocythemia. Cancer Med. Published online September 13, 2023. doi:10.1002/cam4.6528

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Does the Use of Statins Improve Survival in Essential Thrombocythemia, Polycythemia Vera?

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By Patrick Daly – Last Updated: October 16, 2023

In patients with polycythemia vera and essential thrombocythemia, statins improved survival and decreased the risk of thrombosis after being diagnosed with myeloproliferative neoplasms (MPNs), according to a study published in Cancer Medicine.

“We found that among patients with [polycythemia vera] and [essential thrombocythemia], the use of statins improved survival and decreased risk of thrombosis after MPN diagnosis,” wrote the researchers, led by Nikolai Podoltsev, MD, PhD, of Yale University in New Haven, Connecticut

Dr. Podoltsev and colleagues noted that prior studies have suggested statins may improve the survival of patients with various cancers. They performed an analysis to characterize the effects of statins in older patients with polycythemia vera and essential thrombocythemia.

Based on their results, they suggested that this novel finding supports the use of statins “to address hyperlipidemia as one of the modifiable cardiovascular risk factors” in this group of patients. They also suggested that statins could be additionally relevant given the current use of ruxolitinib, which may lead to development or worsening of hypercholesterolemia.

Data Support Statin Use in Polycythemia Vera, Essential Thrombocythemia

Their conclusions were based on analysis of 1809 and 2201 older adults with polycythemia vera and essential thrombocythemia, respectively, in the Surveillance, Epidemiology, and End Results (SEER) database. Analysts used propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) to evaluate the impact of statins on overall survival, and multivariable competing risk models to evaluate associations between statins and thrombosis risk.

Overall, 55.8% of patients used statins within the first year of polycythemia vera and essential thrombocythemia diagnosis. Over a median follow-up of 3.92 years (interquartile range, 2.58-5.75 years), statin use was associated with a 22% reduction in all-cause mortality (PSM hazard ratio [HR], 0.78; 95% CI, 0.63-0.98; P=.03; and IPTW HR, 0.79; 95% CI, 0.64-0.97; P=.03). Statin use was also shown to reduce the risk of thrombosis (PSM HR, 0.63; 95% CI, 0.51-0.78; P<.01; and IPTW HR, 0.57; 95% CI, 0.49-0.66; P<.01).

Noting that a randomized controlled trial of statins in patients with MPNs is unlikely, the investigators suggested that, “based on our results the recommendation can be made for hematologists taking care of patients with [polycythemia vera and essential thrombocythemia] to either be directly involved in or advocate for prescribing statins to these patients who are at a high risk for cardiovascular events.”

 Reference

Podoltsev NA, Wang R, Shallis RM, et al. Statin use, survival and incidence of thrombosis among older patients with polycythemia vera and essential thrombocythemia. Cancer Med. 2023;12(18):18889-18900. doi:10.1002/cam4.6528

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An Update on Current and Emergent Therapies for Essential Thrombocytosis

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Daniel H. Foley, MD
Kristen Pettit, MD

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.

REFERENCES:

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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An Update on Current and Emergent Therapies for Essential Thrombocytosis

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Daniel H. Foley, MD
Kristen Pettit, MD

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

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.

REFERENCES:

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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