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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Thrombosis and Inflammation Drive Mortality and Cancer Risk in Myeloproliferative Disorders

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November 15, 2024

Lisa Kuhns, PhD, MD

Despite the advancements in treatment, thrombosis remains a significant challenge for patients with myeloproliferative neoplasms (MPNs), contributing to increased mortality and the development of secondary cancers, according to an article published in Blood Cancer Journal.

“These risks arise from disease-related clonal hematopoiesis and subsequent chronic systemic inflammation, leading to thrombosis and genetic instability,” explained Tiziano Barbui, FROM, Fondazione per la Ricerca Ospedale di Bergamo ETS, Bergamo, Italy, and coauthors. “In our large databases of patients with MPN, we investigated the incidence and risk factors of thrombosis that may explain this association, culminating in an increased risk of mortality.”

Recent research has highlighted the persistent risk of thrombotic events in patients with classic MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These disorders are characterized by a high incidence of both arterial and venous thrombosis, which complicates patient management and contributes to disease progression. Notably, studies indicate that approximately 20% of MPN diagnoses are heralded by thrombotic events, with ongoing risks observed over time.

A large-scale study involving more than 9000 patients with MPN revealed significantly elevated hazard ratios for thrombotic events compared with matched controls. Specifically, arterial thrombosis hazard ratios were 3.0 at 3 months and 2.0 at 1 year postdiagnosis. Venous thrombosis rates were even more alarming, with hazard ratios of 9.7 at 3 months and 4.7 at 1 year. While conventional treatments such as hydroxyurea have demonstrated efficacy in reducing arterial thrombosis, their impact on venous events is less pronounced.

The implications of these findings extend beyond immediate health risks and suggest a potential link between thrombosis and progression to more severe forms of MPNs, such as myelofibrosis and acute leukemia. In particular, arterial thrombosis has been identified as an independent predictor of increased mortality in patients with ET and PV. For instance, a multistate model analysis indicated that patients experiencing arterial thrombosis had a 25% increase in mortality risk compared with those without such events.

Emerging evidence also suggests that thrombosis may be associated with an increased risk of developing secondary cancers in patients with MPN. A nested case-control study found that the occurrence of arterial thrombosis was independently linked to a higher incidence of secondary cancers, particularly among younger patients with MPNs. This correlation underscores the complex interplay between chronic inflammation induced by MPNs and the risk factors for both cardiovascular disease and cancer.

“We believe that arterial, and possibly venous thrombosis occurring during follow-up should be considered in the context of long-term occurring outcomes, including an increased incidence of solid tumors,” concluded the study authors.

Continued research is essential to unravel the underlying mechanisms linking thrombosis with disease progression and secondary malignancies, ultimately improving patient outcomes in this vulnerable population.

Reference

Barbui T, Ghirardi A, Carobbio A, et al. Thrombosis in myeloproliferative neoplasms: a viewpoint on its impact on myelofibrosis, mortality, and solid tumors. Blood Cancer J. 2024;14(1):188. doi:10.1038/s41408-024-01169-6

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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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Ropeginterferon Alfa-2b Demonstrates Similar Pharmacokinetics Across Ethnic Groups With PV

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Andrea S. Blevins Primeau, PhD, MBA

The pharmacokinetic (PK) profile of ropeginterferon alfa-2b (Ropeg) was consistent between Chinese and Caucasian populations with polycythemia vera (PV), according to a modeling study published in Frontiers in Pharmacology.

These results confirm “its efficacy and safety in the global treatment of PV” and “support the broader application of Ropeg in diverse patient populations,” the researchers wrote in their report.

The researchers used data from studies of Ropeg in subjects without myeloproliferative neoplasms (MPN) and among patients with PV to perform modeling analyses for PK parameters, efficacy, and safety in Chinese and Caucasian populations.

PK was assessed using a population PK model using data from phase 1 studies of Chinese and Caucasian volunteers without MPN. There was no significant difference in Ropeg clearance, volume of distribution, or absorption rate between the groups.

In an exposure-response analysis, data from phase 2 clinical trials were used to inform the model. A higher complete hematologic response (CHR) rate was observed in the study of Chinese patients due to a higher starting dose. The CHR was 63% among Chinse patients and 35% among Caucasian patients at 24 weeks. The CHR rates reported from the trials were similar at 61.2% and 27%, respectively.

Our results support the use of Ropeg as an effective and tolerable first-line treatment for PV regardless of ethnic variations.

This “indicates that there is a similar exposure-response relationship between Chinese and Caucasian populations,” the researchers explained.

Phase 2 data were also used to inform the exposure-safety analysis. In the Chinese group, the high dose level of Ropeg was associated with asymptomatic higher liver transaminase levels. There was no association between exposure and gamma-glutamyl transferase, white blood cell count, or neutrophil count.

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Ojjaara (momelotinib) approved in Canada for the treatment of myelofibrosis in adults who have moderate to severe anemia

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  • Ojjaara (momelotinib) is the only approved treatment for newly diagnosed and previously treated myelofibrosis patientsi who have moderate to severe anemia and other key manifestations associated with the disease.ii
  • This approval underscores GSK’s commitment to help drive progress for people living with complex blood cancers.

MISSISSAUGA, ON, Nov. 12, 2024 /CNW/ – GSK announced today that Health Canada has approved Ojjaara (momelotinib) for the treatment of splenomegaly and/or disease-related symptoms, in adult patients with intermediate or high-risk primary myelofibrosis (MF), post polycythemia vera MF or post essential thrombocythemia MF who have moderate to severe anemia.iii Ojjaara is the first and only approved medication globally, and now in Canada, that treats both the anemia and other key manifestations of myelofibrosis (newly diagnosed and previously treated).iv

“Treatment options for myelofibrosis-related anemia have been limited. We are proud to offer this treatment alternative for Canadian patients to address this critical unmet need and other myelofibrosis symptoms. With most myelofibrosis patients becoming anemic over time, Ojjaara’s approval represents a significant milestone to improve the outcomes of these patients while also highlighting GSK’s commitment to making an impact in Canada’s hematology oncology space through innovative new treatments,” said Michelle Horn, Interim Country Medical Director, GSK Canada.

Myelofibrosis is a rare blood cancer part of the broader myeloproliferative neoplasms (MPNs) diseases. MPNs have an incidence rate of 2.05 new cases per 100,000 Canadians.v Currently there are between 1,400-2,177 estimated people living with this type of disease in Canada.vi Anemia is a common symptom of myelofibrosis and a major unmet needvii, but awareness among Canadians is low. A 2024 survey shows that 90% of Canadians have heard of anemia but almost 50 per cent do not know about blood cancer related anemia.viii Canadians also have low knowledge of anemia with over 40 per cent of the same respondents saying they know little to nothing about this condition.ix

“Anemia and related transfusions significantly affect the quality of life, prognosis and survival for anemic myelofibrosis patients,” said Cheryl Petruk, CEO of HEAL Canada. “We are excited to witness progress in this rare disease space and to see Ojjaara approved in Canada. This new treatment has the potential to help improve the lives of patients while addressing the disease’s main challenges, namely anemia and other major symptoms.”

Ojjaara is the only once-a-day, oral JAK1/JAK2 and activin A receptor type 1 (ACVR1) inhibitor.x The approval of Ojjaara by Health Canada is supported by data from the pivotal MOMENTUM Phase III trial, which demonstrated significant improvements in Total Symptom Score (TSS), Transfusion Independence, and Splenic Response Rate.xi Additional support came from a subset of patients in the SIMPLIFY-1 Phase III trial, reinforcing Ojjaara’s efficacy in treating moderate to severe anemia and related symptoms in myelofibrosis patients.xii

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Dr DeAngelo on the Integration of JAK Inhibitors in Myelofibrosis Management

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November 11, 2024

Author(s): Daniel J. DeAngelo, MD, PhD

Daniel DeAngelo, MD, PhD, professor, medicine, Harvard Medical School, chief, Division of Leukemia, institute physician, Dana-Farber Cancer Institute, discusses the integration of JAK inhibitors into clinical practice for patients with myelofibrosis. Lower third needs to be updated

When incorporating JAK inhibitors, such as ruxolitinib (Rituxan), into clinical practice, it is essential to understand both their benefits and the challenges they present, particularly regarding anemia, DeAngelo begins. The phase 3 COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) trials, which initially sought to address symptom control and spleen reduction, demonstrated a notable survival advantage with ruxolitinib over placebo in patients with intermediate-2 or high-risk myelofibrosis, or intermediate-1 disease with symptomatic splenomegaly, he reports. These results led to ruxolitinib becoming the standard of care for high-risk or symptomatic patients, especially as allogeneic transplantation remains limited to select candidates, DeAngelo shares.

A primary consideration with ruxolitinib is its tendency to induce a hemoglobin level drop of approximately 2 points during the first 2 months of treatment due to on-target JAK2 inhibition, which affects erythropoiesis, he continues. Although newer agents are now approved by the FDA specifically for patients with baseline anemia, clinicians using ruxolitinib should anticipate this hemoglobin level decline, he states. Importantly, the initial drop in hemoglobin level does not indicate treatment failure but is a manageable effect that is often misunderstood, leading some oncologists to discontinue or reduce dosing with the drug prematurely, DeAngelo notes.

He goes on to state that his advice for integrating JAK inhibitors into myelofibrosis management plans is to proactively address these expected effects with patients. Patients can be supported through transfusions, growth factors, or alternative JAK inhibitors if needed, according to DeAngelo. In most cases, hemoglobin levels tend to stabilize and improve after the first few months, typically between months 3 and 4, he notes. Setting clear treatment expectations helps ensure patient adherence to therapy and optimizes outcomes when using JAK inhibitors in clinical practice, DeAngelo concludes.

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Frequent Testing for Driver Mutations Critical in Myelofibrosis

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Nov 12, 2024

Researchers from the Munich Leukemia Laboratory in Germany have developed a model that uses 12 genetic markers to accurately stratify patients with myeloproliferative neoplasms (MPNs), according to a study published online ahead of print in Leukemia.

The WHO categorizes classical MPNs—using cytomorphology, bone marrow biopsy, grading of fibrosis, blood counts, and a handful of molecular markers—into four individual entities: chronic myeloid leukemia (CML) and the BCR::ABL1 negative MPNs polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocythemia (ET).

“However, overlaps, borderline findings, or transitions between MPN subtypes occur, and incomplete clinical data often complicates diagnosis,” Manja Meggendorfer, PhD, and the study coauthors wrote.

The researchers analyzed 355 patients with MPN to use the results to stratify MPN entities and provide prognostic information. The investigation revealed the presence of genetically distinct subgroups with different cytogenetic abnormalities, mutations, and JAK2 allele statuses.

“Notably, differences in JAK2 allele status (heterozygous/homozygous) correlated with diverse EFS [event-free survival] and OS [overall survival] outcomes, potentially due to additional prognostic mutations,” the researchers reported. “In contrast, groups with cytogenetic aberrations and additional mutations generally had shorter EFS and poorer OS regardless of the diagnosed entity, aligning with studies on the impact of karyotype and mutation count on survival.”

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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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Lower Pharmacy Costs Give Ruxolitinib Edge for Patients With MF and Anemia

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November 9, 2024

Author(s): Mary Caffrey

The clinical benefits and lower transfusion costs of momelotinib (Ojjaara) are not enough to offset its higher pharmacy costs compared with an older therapy for patients with myelofibrosis (MF) and anemia who rely on transfusions, according to a recent cost-effectiveness analysis.

The results were presented in a poster at the 16th International Congress on Myeloproliferative Neoplasms, held in Brooklyn, New York, October 24-25, 2024.1

Aaron T. Gerds, MD, MS | Image Credit: Cleveland Clinic

Led by Aaron T. Gerds, MD, MS, assistant professor of Medicine, Cleveland Clinic Taussig Cancer Institute, the authors presented data based on a predictive model that computed per-patient total cost of care for 6-month, 1-year, and 2-year periods, comparing the Janus kinase (JAK) inhibitors ruxolitinib (Jakafi), and momelotinib (Ojjaara). Both inhibit the JAK/STAT pathway, with momelotinib additionally targeting a pathway that can result in improved iron-restricted anemia.

As the poster authors stated, ruxolitinib is indicated for patients with intermediate- or high-risk MF, including those with primary MF, post-polycythemia vera MF, post–essential thrombocythemia MF. Momelotinib is indicated for patients with intermediate- or high-risk MF, including those with primary MF, post-polycythemia vera MF, and post–essential thrombocythemia MF in in adult patients with anemia.1

The SIMPLIFY-2 study showed that patients switching from ruxolitinib to momelotinib took less time to achieve transfusion in dependence.2

This analysis presented in Brooklyn was based on the SIMPLIFY-1 study, which compared ruxolitinib and momelotinib in patients who had not previously received a JAK inhibitor.3 The authors, many of whom worked SIMPLIFY-1, found that the difference in pharmacy costs is $11,095 per month, with momelotinib being more expensive. Although transfusion costs for ruxolitinib were projected to cost an additional $10,854 over a 6-month period, the total cost of care still favored ruxolitinib, Results were as follows:

  • At the 6-month mark, the total cost of care favored ruxolitinib by$46,388.
  • At the 1-year mark, the total cost of care favored ruxolitinib by $84,239.
  • At the 2-year mark, the total cost of care favored ruxolitinib by $144,539.

Assumptions in the model. Authors wrote that the model assumed patients remained on therapy for the entire duration of the study or until death. It was limited to pharmacy- and transfusion-related costs, “to isolate costs associated with reductions in transfusion; other costs of care were assumed similar between ruxolitinib and momelotinib.”

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