Category Archives: Blood Cancer

Prognostic Implications of Pulmonary Hypertension in Myeloproliferative Neoplasms and Predictors of Hematologic Progression

Posted on by

Orly Leiva, MD, Steve Soo, MD, Nathanial Smilowitz, Harmony Reynolds, Binita Shah, Samuel Bernard, Michelle Hyunju Lee, MD, Chi-Joan How, MD, and Gabriela S. Hobbs, MD

Introduction:
Myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are a group of disorders of clonal hematopoiesis associated with increased risk of cardiovascular disease (CVD), including pulmonary hypertension (PH). In a prior study of patients with MPN and established CVD, PH was associated with increased risk of hematologic progression to secondary MF or acute leukemia and major adverse cardiovascular events (MACE). However, the prognostic implication of PH among patients with MPN regardless of prior CVD status is unclear. Furthermore, transthoracic echocardiographic (TTE) characterization of risk of hematologic progression among those with PH has not been well studied.
Methods:
This was a multicenter retrospective cohort study of MPN patients with ≥ 1 TTE after diagnosis of MPN at New York University Langone Health and Massachusetts General Hospital from 2010 to 2023. PH was defined as estimated pulmonary artery systolic pressure (PASP) ≥ 40 mmHg on first TTE after MPN diagnosis. The primary outcome was a composite hematologic outcome of progression to secondary MF, acute leukemia, or death from MPN. Secondary outcome was MACE, a composite of arterial or venous thrombosis, heart failure (HF) hospitalization, or CV death. Given the competing risk of death, multivariable Fine-Gray competing-risk regression was used to estimate subhazard ratio (SHR) of the primary and secondary outcomes, and were adjusted for age at first TTE, MPN type, driver mutation, any non-driver mutation status, time from MPN to TTE, hemoglobin and WBC concentration, and spleen size. The association between PH and MACE was further adjusted for treatment for the MPN, left ventricular ejection fraction (LVEF), prior CVD, indication/setting of TTE, diastolic dysfunction, anti-thrombotic use, statin use, and creatinine. Hemodynamic predictors of the composite hematologic outcome among patients with PH was assessed using univariate competing-risk regression. Variables that were significantly different between groups (p < 0.05) were adjusted for age, time from MPN to TTE, driver and non-driver mutations, and spleen size.
Results:
Of the 555 patients included, 42.7% had PV, 41.1% ET, and 16.2% had MF at time of TTE, 48.5% were male and 86.8% were White race. PH was diagnosed in 195 patients (35.1%). The median time from MPN diagnosis to TTE was 39 months. Patients with PH were older (median age 71 vs 66 years, p <0.001), more likely to have MF (25.6% vs 11.1%, p <0.001), and higher VAF of driver MPN mutation (median 50% vs 40%, p = 0.002) and larger spleen sizes at time of TTE (median 13.7 vs 12.0 cm, p <0.001). Patients with PH had a higher rate of prior HF (15.4% vs 3.3%, p <0.001), hypertension (69.7% vs 56.7%, p= 0.003), and AF (29.7% vs 15.6%, p <0.001). After a median follow-up of 51 months, the composite hematologic outcome (23.6% vs 10.3%, p <0.001) and MACE (41.5% vs 19.2%, p <0.001) were more common among patients with PH. After multivariable competing-risk regression, PH was associated with increased risk of hematologic outcome (aSHR 1.79, 95% CI 1.10-2.92) and MACE (aSHR 1.67, 95% CI 1.10-2.56). Among patients with PH, 46 (23.6%) had hematologic outcome. After adjustment, atrial enlargement (aSHR 0.42, 95% CI 0.20-0.90) and valvular regurgitation (aSHR 0.30, 95% CI 0.16-0.57) were associated with decreased risk of hematologic outcome. Tricuspid annular plane systolic excursion (TAPSE, aSHR 2.44, 95% CI 1.27-4.69), a marker of right ventricular (RV) function, and estimated cardiac output (CO, aSHR 1.33, 95% CI 1.40-1.70) were associated with increased risk of hematologic outcome.
Conclusions:
Among patients with MPN, PH was associated with increased risk of hematologic progression and MACE. Our study also sheds some light on the pathophysiology behind PH and MPN progression given the association between preserved RV function and higher CO and MPN progression. MPN progression may lead to increased catabolic demand and cell turnover that may increase CO and may in part explain the association of preserved RV function and increased CO among patients with PH and MPN progression. However, further studies are needed to better understand the physiology of PH in MPN, characterize PH phenotypes and their associations with outcomes, and to assess the utility of TTE for screening for PH and surveillance of MPN progression.

 

Drug Offers New Option for Patients With Rare Blood Disorders in ‘No Man’s Land’

Posted on by

By Sara Bondell – 

Myelodysplastic/myeloproliferative neoplasms are a group of diseases that occur when bone marrow produces too many blood cells while also demonstrating evidence of dysfunctional blood cell production, thereby having characteristics of both myelodysplastic syndromes and myeloproliferative neoplasms. Consensus for treating patients with these diseases is lacking, and patients are often excluded from clinical trials.

This puts patients with myelodysplastic/myeloproliferative neoplasms in a “no man’s land,” says Andrew Kuykendall, MD, a hematologist at Moffitt Cancer Center.

Since the syndromes can present with symptoms similar to those seen in myelofibrosis, a rare type of bone marrow cancer, Kuykendall decided to investigate if a myelofibrosis treatment could be effective in myelodysplastic/myeloproliferative neoplasms.

A phase 2 trial presented at the American Society of Hematology annual meeting assessed the efficacy of a JAK inhibitor called fedratinib in patients with myelodysplastic/myeloproliferative neoplasms or chronic neutrophilic leukemia. A JAK inhibitor is a type of medication that treats inflammation driven by malignant or inflammatory disorders by blocking the body’s production of cytokines, or proteins that cause inflammation.

Andrew Kuykendall, MD

Andrew Kuykendall, MD

“Fedratinib, interestingly, is also caught in ‘no man’s land’ within the treatment paradigm of myelofibrosis despite demonstrating significant potency. It was the second of four approved JAK inhibitors but has failed to establish a clear niche,” Kuykendall said.

Twenty-four patients on the trial received fedratinib daily. After 24 weeks, 53% of patients responded to the treatment. Half of patients had a symptom response, and 37.5% had a spleen response.

“This is a very high-risk group of patients who frequently harbor clinical characteristics that would suggest less likelihood of responding to treatment, so it is encouraging that fedratinib was able to achieve response rates of this magnitude,” Kuykendall said. “This data suggests that this is a very reasonable treatment option for these patients.”

Kuykendall says that while the results are promising, fedratinib does not replace allogeneic stem cell transplants, which should be the goal for eligible patients with these diseases. The drug, however, can be used to bridge patients to transplant.

“I also think one of the biggest takeaways from this study for me is that you can enroll a trial with a very rare disease,” Kuykendall said. “One of the reasons people don’t necessarily put resources behind these rare diseases is because they fear they can’t enroll, and I think we proved that’s not the case.”

Read more

Thrombosis Linked With Second Cancer Risk in MPNs

Posted on by
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.

Read more

Age, Race, Insurance Status Can Predict CV Mortality for Those With MPNs

Posted on by

November 2, 2024

Author(s): Mary Caffrey

Among those diagnosed with myeloproliferative neoplasms (MPNs), age, race, marital status, and insurance status can help predict cardiovascular mortality (CVM), based on an analysis of more than 24,000 US patient records.1

A new study finds that clinical factors and social determinants of health can predict cardiovascular mortality among patients with myeloproliferative neoplasms.

| Image Credit: yodiyim – stock.adobe.com

The study, appearing this week in Therapeutic Advances in Hematology,1 aimed to identify prognostic factors that can guide clinicians in treating patients with MPNs, which are a group of hematopoietic stem cell disorders that are generally diagnosed in individuals after age 40; according to the Leukemia & Lymphoma Society, most patients are diagnosed in their 60s or 70s.

The team from Sun Yat-sen University in China culled records for more than 48,000 patients diagnosed with MPNs between 2000 and 2018 from the Surveillance, Epidemiology, and End Results (SEER) database, but narrowed their analysis to those records for patients that lived at least a year and included other essential clinical information. That left a database of 24,277 patient records.

Among the demographic findings:

  • The database included 10,409 patients (42.9%) with polycythemia vera (PV), 3229 (13.3%) with myelofibrosis (MF) and 10,639 (43.8%) with essential thrombocythemia (ET).
  • Prevalence of the condition was higher among White males in PV and MF compared with females in ET.
  • At diagnosis, only 8.0% were younger than 40 years old; 29.0% were 40-59 years old, 47.0% were 60-79 years old; and 16% were older than 80 years of age.

The analysis took a snapshot of patients at 200 months of follow-up (16 years, 8 months) and found that the cumulative mortality was the following CVD (17.9%), other noncancer (22.1%), MPN (18.8%), and other cancers (6.1%). However, investigators found that more than 50% of patients initially diagnosed with MF died from their primary disease during this period, which may be due to conversion of their disease to acute myeloid leukemia.

Read more

Exploring Possibilities in Disease Modification in MPNs

Posted on by

October 25, 2024

Author(s): Mary Caffrey

Treatment of myeloproliferative neoplasms (MPNs) has historically focused on delaying or avoiding transformation to acute myeloid leukemia (AML) as well as symptom relief and improving quality of life; strategies addressed thrombosis or enlarged spleen both with therapy and with nonpharmacological strategies such as smoking cessation or encouraging patients to lose weight.

Although these strategies were associated with improving life expectancy, they did not measure disease modification through molecular responses that signal survival benefits, in the way that trials do with AML and chronic myeloid leukemia (CML).

Claire N. Harrison, MD, FRCP, FRCPath | Image credit: Guy’s and St Thomas

Now, in an essay appearing in HemaSphere, a publication of the European Hematology Association (EHA), investigator Claire N. Harrison, MD, FRCP, FRCPath, of the Department of Haematology, Guy’s and St Thomas NHS Foundation Trust, asks whether the study and treatment of MPNs is ready for a new era with new end points, with data that show how survival benefits are biologically linked to changes in the spleen, reduction in fibrosis, or other responses.

The challenge, Harrison writes, is that the requirements will be different from today’s standards. “These data should hopefully influence a paradigm shift for the regulatory agencies and the field toward a focus instead of disease modification, but this will certainly require data extending beyond the recent standard of 24 weeks,” she writes.

In the perspective piece, “Are we ready for disease modification in myeloproliferative neoplasms?” Harrison notes that a dramatic shift that came with arrival of Janus kinase (JAK) inhibitor–based therapy for patients with myelofibrosis (MF) who could not receive a stem cell transplant. Therapy shows the capacity to reduce spleen size and symptoms. “Both of these facets of MF do probably reflect underlying pathophysiology and, furthermore, spleen size reduction has been shown to correlate with overall survival advantage.”

Read more

Recognizing Symptoms of Myeloproliferative Neoplasms and Clinical Trial Challenges

Posted on by

October 24, 2024

Author(s): Mary Caffrey, Laura Joszt, MA

The symptoms of myeloproliferative neoplasms can be variable and common, which can make it difficult to diagnose if you aren’t looking for the right thing, said Ruben Mesa, MD, FACP, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center and president of Atrium Health Levine Cancer.

He also discusses the challenges with getting patients enrolled in clinical trials, such as the limited availability of them and patient factors that make it difficult to participate.

Read more

Thrombosis in myeloproliferative neoplasms: a viewpoint on its impact on myelofibrosis, mortality, and solid tumors

Posted on by

October 25, 2024

Tiziano Barbui, Arianna Ghirardi, Alessandra Carobbio, Valerio De Stefano, Alessandro Rambaldi, Ayalew Tefferi & Alessandro M. Vannucchi

Abstract

This viewpoint summarizes findings from analyses of large personal patient databases of myeloproliferative neoplasms (MPNs) to assess the impact of thrombosis on mortality, disease progression, and second cancers (SC). Despite advances, the current incidence of arterial and venous thrombosis remains a challenge. These events appear to signal a more aggressive disease course, as evidenced by their association with myelofibrosis progression and mortality using multistate models and time-dependent multivariable analysis. Inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), are associated with the aggressiveness of polycythemia vera (PV) and essential thrombocythemia (ET), linking thrombosis to SC risk. This suggests a common inflammatory pathway likely influencing cardiovascular disease and cancer incidence. Notably, this is observed more frequently in younger patients, likely due to prolonged exposure to MPN and environmental inflammatory triggers. These data underscore the need for new studies to validate these associations, delineate the sequence of events, and identify therapeutic targets to mitigate thrombotic events and potentially improve overall patient outcomes in MPN.

Read more

 

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

Posted on by

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.

Read more

Education on MPN Symptoms, Treatments Leads to Greater Involvement in Care

Posted on by

October 3, 2024

Author(s): Darlene Dobkowski, MA

Fact checked by: Alex Biese

Learning more about the different symptoms and treatment goals of myeloproliferative neoplasms (MPNs) can help patients be more involved in management decisions throughout the disease trajectory, an expert said.

“It’s not just the doctor and the nurses; it’s the person who has the disease [that] is the main person, so their involvement is very important,” said Dr. Swati Goel at the recent CURE® Educated Patient® Updates in MPNs at Montefiore Medical Center in the Bronx, New York.

Goel is the Leader of the Myeloproliferative Disorder Clinic, assistant director of the hematology-oncology fellowship program and associate professor in the department of oncology and medicine at Montefiore Einstein in New York, New York.

Throughout the event, Goel discussed that there are three types of MPNs: polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis.

Read more

MPN Word of the Month: Platelets

Posted on by

As we know, myeloproliferative neoplasms (MPNs) are a group of blood cancers that involve the overproduction of blood cells in the bone marrow. These conditions primarily include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). One of the primary features of certain MPNs, particularly essential thrombocythemia, is the abnormal production and function of platelets, that help with blood clotting and maintaining vascular integrity. Understanding the relationship between platelets and MPNs is crucial for diagnosing,
monitoring, and managing these disorders.

What Are Platelets?

Platelets, also known as thrombocytes, are small, disc-shaped cell fragments in the blood. Produced in the bone marrow by megakaryocytes, platelets are essential for hemostasis—the process that prevents excessive bleeding when blood vessels are injured. When a blood vessel is
damaged, platelets adhere to the site of injury, coagulate to form a plug, and interact with clotting factors to stabilize the clot, preventing further blood loss.

How Do Platelets Work In MPNs?

In MPNs, the bone marrow exhibits uncontrolled proliferation of hematopoietic stem cells, leading to the overproduction of various blood cells, including platelets. This dysregulation can significantly impact platelet function and count, resulting in both hemorrhagic and thrombotic complications.

Platelets in Essential Thrombocythemia (ET)
Essential thrombocythemia is characterized by an excessive production of platelets due to  mutations in genes such as JAK2, CALR, or MPL. In ET:

● High Platelet Counts: Patients often present with elevated platelet counts, sometimes exceeding one million platelets per microliter of blood. Despite the abundance of platelets, they may not function normally, leading to an increased risk of clotting (thrombosis) and bleeding (hemorrhage).
● Thrombotic Risk: Abnormally high platelet counts increase the likelihood of clot formation within blood vessels, potentially leading to complications such as stroke, heart attack, deep vein thrombosis (DVT), and pulmonary embolism.
● Bleeding Risk: Interestingly, patients with extremely high platelet counts can also experience bleeding issues. This is because the overproduction of platelets can lead to a depletion of von Willebrand factor (vWF), which is necessary for platelet adhesion,

Platelets in Polycythemia Vera (PV)
In PV, there is an overproduction of red blood cells, often accompanied by increased platelets and white blood cells:

● Platelet Dysfunction: Although the platelet count in PV is usually elevated, platelet function can be abnormal. This dysfunction can result in an increased risk of thrombosis even though there is a high platelet count.
● Thrombotic Events: Similar to ET, patients with PV have a higher risk of blood clots because the not only is there an increase in blood viscosity (from elevated red blood cell mass) there is also altered platelet function.

Platelets in Myelofibrosis (MF)
Myelofibrosis is marked by the replacement of bone marrow with fibrous tissue, impairing normal blood cell production:

● Variable Platelet Counts: Patients with MF may have either low (thrombocytopenia) or high (thrombocytosis) platelet counts, depending on disease progression and bone marrow function.
● Abnormal Platelet Function: Regardless of the platelet count, platelet function is often compromised, which leads to a higher risk of both bleeding and clotting events.

Platelets in Diagnosis and Management
The evaluation of platelet count and function is an important part of diagnosing and managing MPNs. Laboratory tests commonly used include:

● Complete Blood Count (CBC): To assess platelet count, red blood cell mass, and white blood cell count.
● Bone Marrow Biopsy: To examine marrow architecture and megakaryocyte proliferation, providing insight into the degree of myeloproliferation.
● Genetic Testing: To identify mutations in JAK2, CALR, and MPL genes, which are associated with different MPNs.
● Platelet Function Tests: In some cases, platelet aggregation studies may be used to evaluate platelet function, especially if bleeding complications are present.

The primary goal in managing MPNs is to minimize the risk of thrombotic and hemorrhagic events. Several treatment strategies are used to address abnormal platelets such as cytoreductive therapies, antiplatelet agents, JAK2 inhibitors, and close monitoring of blood counts.

Platelets play a central role in the diagnosis, progression, and care of myeloproliferative neoplasms. Understanding the complex interactions between platelets and MPNs is crucial for effective diagnosis, risk assessment, and management of these disorders. With appropriate
monitoring and individualized treatment strategies, the risks associated with abnormal platelet activity in MPNs can be managed, improving patient outcomes. For more information about MPNs visit our website at www.mpnadvocacy.com.