Tag Archives: myeloproliferative neoplasms

Ruxolitinib Combinations in MPNs: Updates From ASH

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January 8, 2025

Author(s): Mary Caffrey

Following its approval in 2011 for myelofibrosis (MF), ruxolitinib (Jakafi, Incyte) became the backbone of treatment for MF and later for polycythemia vera (PV), 2 of the 3 common myeloproliferative neoplasms (MPNs).

But although ruxolitinib improves survival outcomes and quality of life, some patients may not respond to therapy, while others may stop due to genetic mutations, disease progression, or other factors. For years now, investigators have been studying the Janus kinase (JAK) inhibitor in combination with other drugs, both in first-line treatment and refractory disease. Abstracts and oral presentations at the recent 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7-10, 2024, in San Diego, California, offered updates on several combinations in the pipeline:

MANIFEST-2. Previous results from this phase 3 study (NCT04603495) of pelabresib, a selective bromodoman and extraterminal domain (BET) inhibitor, with ruxolitinib show it met its primary end point; in patients with MF not treated with a JAK inhibitor, a statistically significant higher proportion showed at least 35% reduction in spleen volume from baseline at week 24 with the combination vs ruxolitinib and placebo. Results presented at ASH showed those results were maintained after a median follow-up of 72 weeks, with a 48-week response rate of 57.0% for the combination vs 37.5% for ruxolitinib and placebo. An improvement in the Myelofibrosis Symptom Assessment Form total symptom score (TSS) by at least 50% was seen in 45.3% of patients receiving the combination vs 39.4% in the placebo group.1

Bomedemstat. An abstract at ASH reported on an ongoing phase 2 study (NCT05569538) involving bomedemstat combined with ruxolitinib in patients with advanced MF.2 Bomedemstat is an irreversible inhibitor of lysine-specific demethylase 1 (LSD1), which plays a role in gene regulation; blocking this enzyme alters cell differentiation and growth. In August 2024, Merck announced the second phase 3 trial of bomedemastat in another MPN, essential thrombocythemia (ET).

The abstract authors noted that about 50% of patients with MF stop ruxolitinib after 3 years, mostly due to disease progression or cytopenia; median OS after discontinuation is 14 months.2 LSD1, they write, is “critical for self-renewal” of cancerous stem cells, and has shown promise as a single agent. This study reported on 2 cohorts: Cohort A had a suboptimal response to ruxolitinib, and cohort B patients had MF and were treatment naive. Patients in cohort A remained on the entry dose of ruxolitinib while cohort B started 10 mg twice per day; all patients received a starting dose of 0.4 mg/kg/day of bomedemstat. Dose adjustments were permitted every 4 weeks to achieve an optimal platelet count; downward titrations were done at any time for safety reasons. After a median of 61.7 weeks, in 40 evaluable patients, at week 24, 11 patients had at least a 50% improvement in TSS, with 25.9% in cohort A and 30.7% in cohort B; 17.5% had at least 35% spleen volume reduction, with 7.4% in cohort A and 38.5% in cohort B; and 50% of patients had stable or improved hemoglobin (51.9% in cohort A and 46.3% in cohort B). There were no safety signals or deaths related to the drug, the authors said.2

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Baseline Basophilia Associated With Aggressive MPN and Poor Outcomes

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Andrea S. Blevins Primeau, PhD, MBA
Publish Date

A more aggressive disease phenotype and poorer clinical outcomes were associated with higher baseline basophil levels among patients with myeloproliferative neoplasms (MPNs), according to the results of a retrospective study published in the American Journal of Hematology.

In the study, researchers analyzed data from 195 patients who were diagnosed with an MPN between 2008 and 2019 at a single center. Cases of chronic myeloid leukemia, chronic eosinophilic leukemia, and chronic neutrophilic leukemia were excluded. Basophilia was defined as a relative or absolute increase in peripheral blood or bone marrow aspirate within 6 months of the patient’s first diagnostic biopsy.

Of the 195 patients, 40.5% had essential thrombocythemia (ET), 23.1% had overt fibrotic phase primary myelofibrosis (PMF), 10.8% had post-ET myelofibrosis (MF), 8.2% had pre-fibrotic PMF, 8.2% had MPN-unclassifiable (MPN-U), 7.2% had polycythemia vera (PV), and 2.1% had post-PV MF.

Basophilia were present among 22% of patients. The lowest level of basophilia was present among patients with ET and PV at 8% compared with 35% among patients with pre-PMF, F-PMF, post-ET MF, post-PV MF, or MPN-U (P <.0001). There were 9% of patients who demonstrated basophilia in the bone marrow, but not the blood.

Of the patients without basophilia at baseline, researchers found that 12% developed basophilia within a median of 19.6 months after diagnosis. Older age (P <.001), higher white blood cell count (P <.001), higher reticulin grade (P =.0007), lower hemoglobin levels (P =.01), and lower platelet counts (P <.001) were significantly associated with basophilia.

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Options for MPN Treatment Are Expanding Rapidly With More on the Horizon

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December 24, 2024

Author(s): Laura Joszt, MA, Luke Halpern

The past few years have been an exciting time in myeloproliferative neoplasms (MPNs) with new treatments providing new options for patients and additional products in the pipeline that explore new mechanisms of action, explained Firas El Chaer, MD, associate professor of medicine, University of Virginia School of Medicine. At the American Society of Hematology annual meeting, El Chaer had presented research and been a coauthor on abstracts related to treatment for myeloproliferative neoplasms.

He discussed how MPNs are diagnosed, the current treatment landscape, and promising new therapies in the pipeline. When diagnosing for MPNs, particularly for myelofibrosis, a bone marrow biopsy is needed, but the challenge is that this can be “patchy,” he explained, and the amount of fibrosis present in the particular part of the bone marrow that is biopsied is what is relied upon to make the diagnosis.

The good news is that the approval of many new Janus kinase inhibitors has changed the treatment landscape of myelofibrosis dramatically in the last few years, El Chaer said, which has provided patients with additional options for treatment. In addition, there are new mechanisms of action that can improve anemia in this patient population.

“I’m very excited that currently we’re thinking about combination therapies,” he said, to improve anemia or that potentially have a disease-modifying capability. “Our field is expanding very quickly.”

He highlighted some of the new mechanisms of action being studied in myeloproliferative neoplasms, such as bromodomain molecules and TGF-β agonists, which can potentially be helpful for anemia and this patient population. He had presented phase 1/2 data on nuvisertib, or TP-3654, which is a highly selective PIM1 kinase inhibitor that has reduced spleen size and bone marrow fibrosis either alone or in combination with ruxolitinib. Nuvisertib has minimal cytopenia side effect and can be combined with other molecules for treatment. Currently, enrollment is ongoing in 3 arms of the study (NCT04176198) to continue to evaluate nuvisertib as a monotherapy and in combination with ruxolitinib and momelotinib.

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HMGA2 overexpression with specific chromosomal abnormalities predominate in CALR and ASXL1 mutated myelofibrosis

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Shivani Handa, Christoph Schaniel, Joseph Tripodi, Daiva Ahire, Md. Babu Mia, Sophie Klingborg, Douglas Tremblay, Bridget K. Marcellino, Ronald Hoffman & Vesna Najfeld

December 23, 2024

Abstract

Although multiple genetic events are thought to play a role in promoting progression of the myeloproliferative neoplasms (MPN), the individual events that are associated with the development of more aggressive disease phenotypes remain poorly defined. Here, we report that novel genomic deletions at chromosome 12q14.3, as detected by a high-resolution array comparative genomic hybridization plus single nucleotide polymorphisms platform, occur in 11% of MPN patients with myelofibrosis (MF) and MPN-accelerated/blast phase (AP/BP) but was not detected in patients with polycythemia vera or essential thrombocythemia. These 12q14.3 deletions resulted in the loss of most of the non-coding region of exon 5 and MIRLET7 binding sites in the 3’UTR of the high mobility group AT hook 2 (HMGA2), which negatively regulate HMGA2 expression. These acquired 12q14.3 deletions were predominately detected in MF patients with CALR and ASXL1 co-mutations and led to a greater degree of HMGA2 transcript overexpression, independent of the presence of an ASXL1 mutation. Patients with 12q structural abnormalities involving HMGA2 exhibited a more aggressive clinical course, with a higher frequency of MPN-AP/BP evolution. These findings indicate that HMGA2 overexpression associated with genomic deletion of its 3’UTR region is a newly recognized genetic event that contributes to MPN progression.

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Transforming Care With Collaboration, Individualized Treatment, and Novel Therapies

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Author(s): Laura Joszt, MA

December 20, 2024

Patients with chronic hematologic malignancies are living for decades, especially with new treatments, making it an important time to shape value-based treatments being offered to these patients, said Jennifer Vaughn, MD, during a fireside chat at the Cleveland Regional Institute of Value-Based Medicine (IVBM) event hosted by The American Journal of Managed Care.

Vaughn, a hematology specialist specializing in myelodysplastic syndromes at The Ohio State University, was joined by Akriti Jain, MD, a hematologist at Cleveland Clinic, to discuss quality care initiatives in rare hematological disorders.

With myelofibrosis, for example, the disease can be very high risk or very low risk, and there have been recently approved Janus kinase (JAK) inhibitors to treat the disease, with more coming. There are 4 approved JAK inhibitors1: ruxolitinib (Jakafi), fedratinib (Inrebic), pacritinib (Vonjo), and momelotinib (Ojjaara). With multiple treatments available, it’s important to understand the individual patient’s symptoms to choose the most effective therapy.

“One of the main things that we talk about these days is individualizing care, right? Not every patient is the same,” Jain said. “So, when I see a patient with myelofibrosis in clinic, the first question is: What are they presenting with?” If a patient has the typical symptoms of myeloproliferative neoplasms (MPNs), a JAK inhibitor is probably the right way to go, she said. If they don’t have those symptoms but they have anemia or thrombocytopenia, then a little more investigation is needed.In the polycythemia vera space, there are also a number of agents now available that can lead to a reduced risk of progression in the future. Vaughn explained that when she sees a younger patient, they now have the opportunity to take aspirin and go to the doctor for routine phlebotomies and labs or a treatment that they can manage and can limit time away from work and their kids.

“That’s been, now, a really interesting discussion in that patient population for me, because there are many of my patients who have actually opted to go on therapy,” she said. “We all think of phlebotomy as this very low-risk, easy [procedure] to undergo, but phlebotomy is just a real…pain for them. They can’t spend the time away.”

She added that “time toxicity” is being considered more and more, which is a way to evaluate how much time patients spend having to engage in their health care treatments.

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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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