Tag Archives: myeloproliferative neoplasms

Study Reveals Prognostic Implications of Pulmonary Hypertension in Myeloproliferative Neoplasms

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January 25, 2024

Lara C. Pullen, PhD

An analysis of patients with myeloproliferative neoplasms (MPN) has revealed that pulmonary hypertension (PH) is associated with an increased risk of hematologic progression and major adverse cardiovascular events (MACE). Orly Leiva, MD, an advanced heart failure and transplantation fellow at the University of Chicago, will present results that shed light on the pathophysiology behind PH and MPN progression, including an association between preserved right ventricular (RV) function and higher MPN progression, during the 66th American Society of Hematology (ASH) Annual Meeting and Exposition.

Dr. Leiva and colleagues designed the retrospective study to examine the connection between cardiology and MPN and determine whether the relatively common transthoracic echocardiographic (TTE) procedure can predict MPN progression. The study included 555 patients, 42.7% of whom had polycythemia vera, 41.1% had essential thrombocythemia, and 16.2% had myelofibrosis at the time of TTE. The cohort was 48.5% male and 86.8% white.

Thirty-five percent of the patients had a diagnosis of PH at the time of their first TTE; PH was defined as a pulmonary artery systolic pressure (PASP) of at least 40 mm Hg. The median time from MPN diagnosis to TTE was 39 months. Patients with PH were a median age of 71 years compared with 66 years for those without PH (p<0.001), and patients with PH were more likely to have myelofibrosis than those without. Patients with PH were also more likely than patients without PH to have a higher variant allele frequency of driver MPN mutation and larger spleen sizes at the time of TTE. They also had a higher rate of prior heart failure, hypertension, and atrial fibrillation than patients without PH.

Dr. Leiva’s team followed the patients for a median of 51 months and noted that composite hematologic outcome and MACE were more common among patients with PH than those without PH. When they performed a multivariable competing-risk regression on the data, the investigators found that PH was associated with an increased risk of hematologic outcome and MACE, such that 23.6% of patients with PH experienced a hematologic outcome. After adjusting for variables that varied significantly between groups, they found that atrial enlargement and valvular regurgitation were associated with decreased risk of hematologic outcome. In contrast, a marker of RV function, tricuspid annular plane systolic excursion, and estimated cardiac output were both associated with an increased risk of hematologic outcome.

“MPNs are a chronic disease,” Dr. Leiva told ASH Clinical News. “Some patients have the potential to live for decades.” Although thrombotic events are a classic cause of mortality in patients with MPN, many die from cardiovascular causes, and the results from this study highlight the non-thrombotic complications of MPN. Dr. Leiva proposed that MPN progression leads to increased catabolic demand and cell turnover, which might lead to increased cardiac output. Such a connection would explain the association between preserved RV function and increased cardiac output among patients with PH and MPN progression.

Dr. Leiva acknowledged that the study was primarily hypothesis-generating, and he called for a prospective study to further investigate the physiology of PH in MPN, characterize PH phenotypes and their associations with outcomes, and assess the utility of TTE screening for PH and surveillance of MPN progression. Until then, he explained that as a cardiologist, when treating a patient with MPN, he looks immediately at the patient’s TTE results. He suggested that all cardiologists and hematologists look for signs of MPN progression if a patient’s PASP exceeds 40 mm Hg or they have other signs of PH on their TTE.

The full study is scheduled to be presented on Saturday, December 7, 2024, at 3:15 p.m. at the 66th ASH Annual Meeting and Exposition in San Diego. This article will be replaced with a summary of the presentation after the session has concluded. Check back later this month for updates!

Any conflicts of interest declared by the authors can be found in the original abstract.

Reference

Leiva O, Soo S, Smilowitz N, et al. Prognostic implications of pulmonary hypertension in myeloproliferative neoplasms and predictors of hematologic progression. Abstract 246. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 7, 2024; San Diego, California.

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Drawing First Blood: How Long Should Patients With a Myeloproliferative Neoplasm Be Anticoagulated?

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December 2024

Leah Lawrence

Patients diagnosed with myeloproliferative neoplasms (MPNs) — including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) — are at a higher risk of both venous and arterial thromboembolism. Management of thrombosis is central to the care of these patients; however, there is a dearth of recommendations specific to MPNs on the duration and selection of anticoagulation for the management of these events.1

In this edition of Drawing First Blood, ASH Clinical News invited Chi-Joan How, MD, clinical chief of hematology at Brigham and Women’s Faulkner Hospital and assistant professor in medicine at Harvard Medical School in Boston, and Brady L. Stein, MD, professor of medicine at Northwestern University’s Feinberg School of Medicine in Chicago, to debate and discuss how long a patient with an MPN should be treated with anticoagulation and other factors to consider when determining the appropriate management of thrombosis. Dr. How was asked to argue for indefinite anticoagulation therapy; Dr. Stein was assigned to argue for limited-duration anticoagulation therapy.’

Chi-Joan How, MD Brady L. Stein, MD

 

 

 

 

 

Chi-Joan How, MD              Brady L. Stein, MD

What are the benefits and risks of indefinite anticoagulant therapy?

Chi-Joan How, MD: Anytime someone is on anticoagulation, we are trying to reduce the risk of thrombosis and balance that against the risk for bleeding. MPNs create a procoagulant state, so patients are at a higher risk of thrombosis. Patients with an MPN who had a prior thrombosis are at an especially high risk for recurrence, up to 10% per year in some patients.

The anticoagulant should be effective for however long someone is on it, but once they stop, there is a risk of thrombotic recurrence. Because patients with an MPN have a higher ongoing risk of subsequent blood clots, staying on the blood thinner can help prevent these events, such as pulmonary embolism (PE), deep vein thrombosis (DVT), or blood clots in the splanchnic venous system.

The risk of indefinite anticoagulant therapy is bleeding. We know that patients with an MPN also have more bleeding issues. We know, for instance, that patients with ET who have a very high platelet count might be predisposed to bleeding rather than thrombosis. A blood thinner would add to this bleeding risk.

Finally, a lot of patients might not want to be on indefinite treatment. Even though it may seem like a small matter, one benefit of a finite duration of anticoagulation is that it is one fewer medication a patient has to take.

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Thrombosis Linked With Second Cancer Risk in MPNs

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Jonathan Goodman, MPhil

Among patients with myeloproliferative neoplasms (MPNs), arterial thrombosis incidence appears to raise the risk of second cancers (SCs) and consequently, mortality, according to an analysis published in Blood Cancer Journal. Inflammatory biomarkers in these diseases suggest a more aggressive disease etiology, the authors added.

In the case of polycythemia vera (PV) or essential thrombocythemia (ET), previous research suggested that thrombosis may heighten the risk of progression to secondary myelofibrosis, which has a high mortality rate. For this retrospective analysis of MPN-patient data, researchers aimed to determine the elements of thrombosis that promote this risk.

Overall, data were evaluated from 1545 patients with PV, 891 patients with ET, 180 patients who were pre-primary myelofibrosis (PMF), and 707 patients with PMF. The median follow-up periods in the PV, ET, pre-PMF, and PMF groups were 5.6 months, 5.6 months, 6.1 months, and 2.92 months, respectively; 19%, 12%, 15%, and 7% of patients had a thrombosis event.

Future therapies should focus on targeting the complex mechanisms involved in both atherogenesis and thrombogenesis…and anti-inflammatory drugs for primary and secondary prevention of thrombosis.

Analysis of the patient data showed that arterial, but not venous or splanchnic, thrombosis was linked with a greater risk of SCs (odds ratio [OR], 2.53; 95% CI, 2.4-5.17). A white blood cell count of at least 11 x 109/L appeared to trend toward a greater risk of SCs, but this link was not significant (OR, 1.27; 95% CI, 0.96-1.67); this was also true of a PMF vs ET diagnosis (OR, 2.54; 95% CI, 0.97-6.61).

“Future therapies should focus on targeting the complex mechanisms involved in both atherogenesis and thrombogenesis, including new cytoreductive drugs targeting the somatic mutations, such as interferon and JAK2 inhibitors, and anti-inflammatory drugs for primary and secondary prevention of thrombosis,” the authors wrote in their report.

Disclosures: This research was supported by FROM-Fondazione per la Ricerca Ospedale di Bergamo-ETS.

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Studies Highlight Prognostic Value of Neutrophil-to-Lymphocyte Ratio in MPNs

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November 14, 2024

Author(s): Mary Caffrey

Two studies published this month are pointing to the value of the neutrophil-to-lymphocyte ratio (NLR) in forecasting either thrombosis or mortality risk in different myeloproliferative neoplasms (MPNs).1,2

Neutrophil | Image: Blausen Medical 2014

This inflammatory biomarker has emerged as an indicator due to the behavior of neutrophils in MPNs; they are known to produce cytokines when activated and to interact with tissue macrophages and dendritic cells, according to authors of a November 6, 2024, study in Blood Cancer Journal that explored NLR as a prognostic indicator of mortality in polycythemia vera (PV).1

These authors, from several institutions in Italy, analyzed the NLR in 1508 patients with PV and concluded that those with an NLR of at least 5 “were generally older, had a longer disease history, and had higher cardiovascular risk factors, more arterial thrombosis, and more aggressive blood counts, indicating a more proliferative disease.”

This was a prospective study based on patients enrolled in the European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) trial, a randomized study to assess the risk/benefit ratio of low-dose aspirin in PV.3

The authors of the new study analyzed data from the 151 deaths (10%) that occurred among the study population, and found an inverse relationship between lymphocyte counts and mortality risk, while also finding that higher lymphocyte counts were associated with a lower risk of death. Their data indicated that a higher NLR correlated with an increased risk of death.1

Thus, these authors concluded that NLR was an accurate predictor of mortality, and those patients with a ratio of at least 5 had worse overall survival with twice the mortality rate of those with a ratio less than 5.1

Previous venous thrombosis was also a strong predictor of death, they wrote.

Findings in Cancer. These findings were consistent with results published November 12, 2024, in Cancer, the official journal of the American Cancer Society, which found a relationship between NLR value at diagnosis and a risk of thrombotic events later on.2 Although this second study was a retrospective study involving fewer patients (473) with essential thrombocythemia (ET), the results also found a predictive value for NLR.

Authors in Cancer, from the University of Milan, reported a total of 78 thrombotic events among the 473 patients, for an incidence rate of 1.8 events per 100 patients/year. This analysis found that an NLR value of at least 4 at diagnosis was associated with a higher cumulative thrombotic risk (HR, 2.05; 95% CI, 1.29-2.28; P = .0001), as well as having diabetes and hypertension.2

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JAK2 Mutations Rarely Found in Patients With MPN Living in High Altitude Areas Who Have Unprovoked Thrombotic Events

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Ryner Lai

JAK2 mutations are rarely found in patients with a myeloproliferative neoplasm (MPN) who have unprovoked thrombotic events — deep vein thrombosis (DVT), pulmonary embolism (PE), or atypical thrombosis — living in high-altitude regions, according to a study published in the International Journal of General Medicine. 

Thrombosis often serves as the initial manifestation of a MPN and is a significant contributor to both morbidity and mortality. JAK2 plays a role in influencing the proliferation of hematopoietic cells and the inflammatory signaling cascade; mutation in JAK2 is notably associated with higher rates of cellular proliferation and differentiation, as well as cytokine release. Patients with MPNs and JAK2 mutations typically have a raised risk of thrombosis when compared with their counterparts who do not have JAK2 mutations.

High-altitude living is associated with alterations in coagulation pathways and blood composition. Studies demonstrate that otherwise healthy individuals with high-altitude hypoxia are at an increased risk of developing idiopathic arterial and venous thrombosis. Scientists suspect that the high altitude can interact with background hereditary/acquired thrombophilia to further exacerbate the risk of initial/recurrent thrombosis.

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New Model Can Assess Blast Phase Progression Risk in Myeloproliferative Neoplasms

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November 12, 2024

Author(s): Alexandra Gerlach, Associate Editor

Researchers from Germany developed a model that utilizes 12 genetic markers to accurately distinguish patients with varying myeloproliferative neoplasms (MPNs) including chronic myeloid leukemia (CML) and BCR::ABL1 negative MPNs polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocythemia (ET). Using the model, clinicians can more precisely characterize their disease and determine their risk of progression to blast phase (BP).

Red blood cells and DNA strand | Image Credit: © GustavsMD – stock.adobe.com

MPNs are clonal disorders of the blood cells and bone marrow characterized by abnormal hematopoietic proliferation, which have been differentiated into 8 subclasses by the World Health Organization. However, the 4 classical types are CML, PV, PMF, and ET, characterized by mutations in the JAK2, CALR, or MPL driver genes.1,2

Diagnosis of a specific MPN is based on their unique morphology; for example, PV is distinguished by a hypercellular bone marrow and elevated hemoglobin level, compared with ET, which is characterized by megakaryocytic proliferation and increased platelet counts. However, this approach fails to acknowledge overlaps, borderline findings, or potential transitions to other MPN subtypes. Patients with PV and patients with ET can progress to post-PV or post-ET myelofibrosis (MF), underscoring the genetic intricacy of these disorders. There is also the risk of progression to BP, also called leukemic transformation, in which the presence of circulating or bone marrow blasts is ≥20%.2-4

In the study, the researchers aimed to use genetic markers to more effectively stratify CML, PV, PMF, and ET, as well as characterize patients with progression to BP. They developed a machine-learning model based on 12 genetic markers observed in routine analysis to accurately classify MPN subtypes and provide useful prognostic information in a user-friendly decision tree format for clinicians. Using data from over 500 patients, they were able to genetically characterize 355 individuals with 1 of the 4 classic MPNs.1

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NCCN Guidelines for MPN Reflect New Drugs, Focus on Clinical Trials

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October 11, 2024

Author(s): Interview by Mary Caffrey

Understanding of myeloproliferative neoplasms (MPNs), a group of blood cancers that occur when a person’s bone marrow makes too many blood cells, has increased since discovery of the JAK2 mutation in 2005.1 Still, the first set of National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPNs, which include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET), did not appear until 2017, and through 2022 there were few updates.

But since then, the NCCN Guidelines for MPNs have had multiple updates per year, with the latest in August 2024,2 a sign of increased activity in the field. In an interview with The American Journal of Managed Care® (AJMC®), Aaron Gerds, MD, MS, who chairs the panel handling the MPN updates, confirms that the more frequent updates reflect new approvals and more options for patients.

Aaron Gerds, MD, MS | Image credit: Cleveland Clinic

“We are regularly looking at the published literature and updates in the field in order to make sure that these guidelines are very nimble, and that they are adjusted to reflect current practice,” said Gerds, who is associate professor of medicine and deputy director for clinical research at the Cleveland Clinic Taussig Cancer Institute. Some guidelines might be updated every 5 to 10 years; but if there’s nothing new, “there’s not a lot of sense in updating things in a large way.”

Conversely, updates often occur when new therapies are approved or become available, Gerds said, as was the case in September 2023 when momelotinib (Ojjaara), the fourth Janus kinase (JAK) inhibitor, became available for the treatment of intermediate or high-risk MF, including primary MF or secondary MF, and post-PV, and post-ET in adults with anemia.3

The most recent update puts a major focus on clinical trials; in many circumstances, they are listed as the preferred option over FDA-approved therapies; in the AJMC interview, Gerds explains how a pair of phase 3 trials involving ruxolitinib combinations will produce results very soon.

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Precipio Expands Bloodhound™ MPN Panel by Adding CALR Mutation Subtyping

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The unique assay enables laboratories to provide clinicians with more informed treatment decisions for their patients

| Source: Precipio, Inc.

NEW HAVEN, Conn., Oct. 08, 2024 (GLOBE NEWSWIRE) — Specialty cancer diagnostics company Precipio, Inc. (NASDAQ: PRPO) announces the launch of a new version of its Bloodhound MPN (Myeloproliferative Neoplasm) panel that is now able to distinguish between CALR type 1 and type 2 mutations. The CALR mutation data plays a critical role in disease prognosis and therapeutic decision-making. This differentiation aligns with the latest National Comprehensive Cancer Network (NCCN) guidelines released in August of this year (Version 2.2024—August 8, 2024).

This is the only quantitative PCR-based panel of its kind on the market that distinguishes between CALR Type 1 and Type 2 alongside the other genes relevant to the molecular evaluation of MPN.

“As science and discovery constantly evolve the diagnostic world, Precipio is committed to maintaining its competitive advantage and being at the forefront of our industry,” said Ilan Danieli, Precipio CEO. “Our customers and their patients will continue to benefit from access to cutting-edge technologies combined with the highest clinical value, enhancing patient care.”

Clinical Significance of CALR Subtyping in MPN Management
The inclusion of CALR mutation subtyping is a direct response to the evolving landscape of MPN patient care where understanding the specific type of CALR mutation can influence treatment strategies and outcomes.

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HTR1B Expression and Thrombosis in Patients With Myeloproliferative Neoplasms

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Vicki Moore, PhD

In this retrospective study, the researchers evaluated expression levels of HTR1B based on messenger RNA from peripheral blood mononuclear cells obtained from patients with newly diagnosed MPN, in addition to conducting other analyses. The researchers had a goal of evaluating possible differences in expression of this gene across MPN subtypes.

There were 85 patients with newly diagnosed MPN included in the analysis, with a median age of 57 years (range, 23-80). Among these patients, 28 had polycythemia vera (PV), 25 had essential thrombocythemia (ET), and 32 had primary myelofibrosis (PMF). Additionally, comparisons of HTR1B expression included 6 healthy volunteers.

Across MPN subtypes and control individuals, the expression of HTR1B did not significantly differ (P =.3089). However, there was large variation observed in expression levels. The researchers further examined expression levels in the context of other patient factors, including based on whether patients had a thrombotic or non-thrombotic history.

A total of 32 patients were considered to have thrombotic MPNs and 53 patients were considered to have nonthrombotic MPN, with median ages of 57 years in each group. Levels of HTR1B expression were significantly different when analyzed across groups organized by thrombotic MPN, nonthrombotic MPN, or status as control individuals.

The level of HTR1B expression appeared highest among patients with thrombotic MPNs, while levels appeared to not be significantly different between patients with nonthrombotic MPNs and control individuals. Among patients with thrombotic MPNs, there was no statistically significant difference observed in the level of fold-change in HTR1B expression by MPN subtype.

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Researchers Identify INCA033989 as a Potential Treatment for Myeloproliferative Neoplasms

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By Alexandra Gerlach, Associate Editor

Data from a study published in Blood demonstrates the therapeutic potential of INCA033989 as the first targeted therapy for myeloproliferative neoplasms (MPNs) that does not interfere with normal blood cell production. Existing therapeutic options for MPNs are effective at symptom management but have high discontinuation rates due to resistance and inadequate drug tolerability. The development of INCA033989 opens pathways to more effective, targeted options with disease-modifying potential without any negative impact on surrounding blood cells.1

The development of INCA033989 has positive implications for the evolving treatment landscape of patients with MPNs. Image Credit: © Anna – stock.adobe.com

MPNs are a group of malignancies characterized by the overproduction of red and white blood cells and is an umbrella for 6 different disease types: myelofibrosis (MF), essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, chronic neutrophilic leukemia, and chronic eosinophilic leukemia. Calreticulin (CALR) mutations are responsible for disease development in 20% to 30% of patients with MPNs, which can be either insertions or deletions in exon 9 of CALR. The mutated CALRprotein (mutCALR) is responsible for the stable interaction with thrombopoietin receptors (TPO-R), which are crucial for controlling blood cell production.2,3

Janus kinase (JAK) inhibitors, such as ruxolitinib (Jakafi; Incyte Corp), are the recommended treatment options for patients with MF or other MPNs; however, they are associated with adverse effects (AEs), namely grade 3 or 4 anemia. INCA033989 is a high affinity, fully human immunoglobulin G1 selective monoclonal antibody targeting mutCALR-driven oncogenesis to suppress TPO-R signaling, thereby preventing the proliferation and progression of disease. According to data from the original study announcing the development of this agent, there was an observed synergism between INCA033989 and ruxolitinib which resulted in the inhibition of cell proliferation and indicated the ability of INCA033989 to enhance the efficacy of ruxolitinib.3,4

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