Understanding Thrombocytosis in MPN Patients: What You Need to Know

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For patients living with myeloproliferative neoplasms (MPNs), the term “thrombocytosis” often arises. While thrombocytosis—an elevated platelet count—is a hallmark of some MPNs like essential thrombocythemia (ET), it can also appear in other forms of MPNs or even due to unrelated secondary causes. Understanding the different contexts in which thrombocytosis occurs is key to effective management and improving quality of life.

Thrombocytosis in MPNs: A Common Feature

1. Essential Thrombocythemia (ET)

  • Primary Cause of Thrombocytosis: In ET, the overproduction of platelets is driven by genetic mutations such as JAK2, CALR, or MPL in the stem cells of the bone marrow.
  • Platelet Levels: Platelet counts in ET are persistently elevated, often exceeding 450,000/μL, and can reach over 1,000,000/μL.
  • Risk of Complications: ET-associated thrombocytosis increases the risk of blood clots (thrombosis) and bleeding due to dysfunctional platelets.

2. Polycythemia Vera (PV)

  • Secondary Thrombocytosis: PV primarily involves elevated red blood cell counts, but platelet counts are often high as well. This occurs because of the overactivity of the bone marrow, commonly linked to the JAK2 mutation.
  • Complications: In PV, elevated platelets further amplify the risk of clotting, especially when combined with high red blood cell counts.

3. Myelofibrosis (MF)

  • Variable Platelet Counts: In early stages of MF, thrombocytosis may occur due to hyperactive bone marrow. However, as the disease progresses and fibrosis (scarring) of the bone marrow develops, platelet counts often drop (thrombocytopenia).
  • Implications: Elevated platelets in early MF contribute to the overall risk of thrombosis but are usually less prominent than in ET or PV.

Thrombocytosis in MPNs vs. Reactive Thrombocytosis

MPN patients may also develop reactive thrombocytosis, where platelet levels rise due to an external trigger rather than the disease itself. This is important to differentiate, as the treatment approach varies.

Causes of Reactive Thrombocytosis in MPN Patients:

  • Infection: Common colds, bacterial infections, or systemic inflammation.
  • Iron Deficiency: Iron depletion, often seen in PV due to phlebotomy or blood loss, can elevate platelet counts.
  • Surgery or Trauma: Any significant physical stress can temporarily increase platelet production.
  • Inflammatory Conditions: Co-existing autoimmune diseases or inflammatory processes.

Managing Thrombocytosis in MPN Patients

For MPN patients, managing thrombocytosis involves addressing both the underlying condition and associated risks:

1. Medications to Control Platelet Levels

  • Low-Dose Aspirin: Reduces the risk of clotting in patients with high platelet counts and cardiovascular risks.
  • Cytoreductive Therapy: Drugs like hydroxyurea or anagrelide may be prescribed to reduce platelet counts in high-risk patients.
  • JAK Inhibitors: For conditions like PV or MF with thrombocytosis, drugs like ruxolitinib target the underlying JAK2 pathway.

2. Monitoring and Prevention

  • Regular Blood Tests: Monitoring platelet counts and clotting markers is crucial.
  • Lifestyle Modifications: Staying active, avoiding smoking, and maintaining a healthy weight can help reduce clotting risks.
  • Avoiding Triggers: Identifying and managing secondary causes like iron deficiency or inflammation can prevent exacerbation.

3. Managing Complications

  • Clotting Risks: Thrombocytosis in MPNs increases the risk of strokes, heart attacks, and deep vein thrombosis (DVT). Prompt treatment of symptoms like chest pain, shortness of breath, or limb swelling is essential.
  • Bleeding Risks: Paradoxically, MPN patients with thrombocytosis may experience bleeding due to abnormal platelet function, such as nosebleeds, gum bleeding, or gastrointestinal bleeding. Report unusual bleeding to your healthcare provider immediately.

Living with Thrombocytosis as an MPN Patient

Thrombocytosis in the context of MPNs requires long-term management, but there are steps you can take to improve your quality of life:

  • Stay Informed: Learn about your specific MPN and its implications for thrombocytosis.
  • Build a Support Network: MPNs are rare conditions. Connecting with support groups or online communities can provide emotional support and practical advice.
  • Communicate with Your Care Team: Keep an open dialogue with your hematologist, and don’t hesitate to ask about treatment options, clinical trials, or lifestyle recommendations.

Thrombocytosis in MPN patients is more than just a high platelet count—it’s a complex condition with significant implications for your health. Understanding the nuances of your condition is essential for effective management, whether it’s caused by essential thrombocythemia, polycythemia vera, or reactive triggers. By working closely with your healthcare team and staying proactive in your care, you can navigate the challenges of thrombocytosis and live a fuller, healthier life.

A Commitment to New Therapies for MPN Despite Scientific Challenges

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January 2, 2025

Author(s): Darlene Dobkowski, MA

Fact checked by: Alex Biese

A researcher discussed the evolving understanding of myeloproliferative neoplasms (MPNs), from their initial classification to their potential for progression, and emphasized the scientific community’s commitment to developing new therapies despite the inherent challenges of research.

John Crispino, director of the division of experimental hematology at St. Jude Children’s Research Hospital in Memphis, Tennessee, was recognized at the CURE MPN Heroes event for his dedication to the community both through his scientific breakthroughs and his advisory role for the MPN Research Foundation.

CURE also spoke with Crispino about what he has learned about patients with MPNs and the research around the condition over his years in the field. One of the things he mentioned was the disease’s transition from a myeloproliferative disorder to a myeloproliferative neoplasm. In particular, the World Health Organization (WHO) changed the classification of these conditions to MPNs to reflect the understanding that these conditions are a type of cancer.

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Q&A: Transforming MPN Care by Aligning Research With Patient-Centered Outcomes

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December 26, 2024

Physician’s Weekly (PW) met with John O. Mascarenhas, MD, and Kapila Viges to learn how the latest research impacts care for patients with myeloproliferative neoplasms (MPN).

PW: What do you see as the most beneficial of all the combinations that are being explored right now?

Ms. Viges: It’s important to remember that options matter for patients. In myelofibrosis and MPN, more broadly, these chronic diseases, patients live for decades in relatively stable health. But knowing that there are options over time if something either stops working or their disease progresses, knowing that they can sequence through a few more options and maybe even some newer combinations that are interesting, brings a lot of hope and promise for patients and gives them some comfort as they navigate their journey through their disease.

Dr. Mascarenhas: The key to treating myelofibrosis is that you need options to tailor the therapy. It’s not one treatment fits all. So, whether it’s a monotherapy, a combination, or when to switch, each agent to pick is individualized for the patient. The more options we have as physicians, the more likely we can tailor and optimize a treatment for an individual.

Ms. Viges: That’s our motto—options matter. We at MPN Research Foundation recently surveyed 676 patients to learn their treatment goals. Of these, 50% said improved quality of life. More specifically, 40% said relief from symptoms is their primary goal. Patients value the options coming online, the combinations, and how we measure and manage symptoms.

Dr. Mascarenhas: Symptoms are complex and sometimes hard to measure. It’s hard to measure the actual or absolute benefit of a given therapy or combinations with symptoms. So, it’s been an area in our field for drug development where we’re trying to figure out the best way to capture that benefit for any individual patient because some patients may benefit to greater degrees than others, and not all therapies are ideal for any given patient. It is a complex world that we’re living in in terms of trying to navigate this. But, patients are symptomatic, and they want to feel better. Physicians want to make patients feel better, but we also want to extend survival with good symptomatology. So it’s a mixed picture. For some patients, the symptoms may be systemic or cytokine symptoms.

Do you think trials will continue considering additional endpoints or exploring more markers?

Dr. Mascarenhas: One of the fundamental deficiencies in our field is that we currently measure spleen and symptom reduction as our primary endpoints for clinical trials because we started the field with JAK inhibitors. They don’t do it for everyone perfectly and don’t always maintain it indefinitely for every patient. So that’s some of the nuances, but we are moving into an area where we’re looking now at therapeutics that might be able to change the natural disease history. The problem with the trials we design often is that we don’t follow patients because you need a lot of patients; you need a lot of power to do it.

Statistically, we don’t always follow them to the point where we can confirm survival. So we are in a desperate search for surrogate markers that you can look at earlier on, whether it’s spleen reduction or symptom burden even, or bone marrow fibrosis reduction, driver mutation reduction, cytokine reductions, things that you can measure maybe at a six month period that may correlate and associate down the line with a survival benefit. It’s key for us as investigators and the research foundation to figure out how we do that as a group so that we’re not at the stumbling block where we’re trying to understand what we are achieving.

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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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Bromodomain and BET Inhibitor INCB057643 Shows Benefit for Patients With Myelofibrosis

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12/19/24

Emily Estrada

According to research presented by Justin Watts, MD, Sylvester Cancer Center Institute, University of Miami, Miami, Florida at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California, INCB057643 may improve patient outcomes in the treatment of hematologic malignancies, including myelofibrosis (MF).

A small-molecular bromodomain and extra-terminal BET protein inhibitor, INCB057643, has shown safety and tolerability as monotherapy and combination with Janus kinase (JAK) 1 and 2 inhibitors among patients with MF in previous phases of the ongoing phase 1/2 clinical trial. In this dose-escalation and expansion portion of the trial, the dose of INCB057643 in patients with MF receiving monotherapy was increased from 4mg to 12mg and for patients with MF who had an inadequate response to ruxolitinib, combination therapy dosage was increased from 4mg to total maximum dosage.

The primary end points were safety and tolerability, as well as dose-limiting toxicities of INCB057643 at 24 weeks. The secondary end points included spleen volume reduction greater than 35% from baseline (SVR35), symptom reduction by greater than 50% from baseline via MPN-Symptom Assessment Form (TSS50), and anemia response of a hemoglobin increase at least 1.5 g/dL from baseline in patients that were not receiving transfusions or transfusion-free for at least 12 weeks for patients dependent on transfusions at baseline.

Patients with relapsed/refractory MF (84.1%%), essential thrombocythemia ([ET]; 4.5%), myelodysplastic syndromes (MDS), or myeloproliferative neoplasm (MPN) syndromes (11.4%). were included in the study. In total, 18 patients were treated with a monotherapy dose escalation and 10 patients received dose expansion. Combination therapy dose escalation was received by 16 patients whose median age was 71 years and whose median ruxolitinib dose was 22.4mg per day. The median duration of INCB057643 exposure was 195.5 days for patients in the monotherapy dose-escalation cohort and 139.0 days for patients in the dose-expansion cohort. As for patients who were in the combination therapy dose-escalation cohort, median INCB057643 exposure was 194.0  days.

At 24 weeks, 3 out of 16 patients who received monotherapy achieved SVR35 and 5 out of 14 achieved TSS50 with any dose of INCB057643, of which 3 received a dose of at least 10 mg. During any time of treatment, improvements in spleen volume and TSS50 best response were demonstrated by 13/19 and 12/15 patients, respectively. Among patients who received combination therapy of INCB057643 and ruxolitinib, 3 out of 12 patients achieved SVR35 and 6 out of 11 achieved TSS50 at any combo dose. Improvements were seen at any time during treatment for both SVR35 and TSS50 in 13 out of 16 and 10 out of 15 patients, respectively. Of patients not dependent on blood transfusions, an anemia response was demonstrated by 3 patients in both the monotherapy and the combination group. Additionally, of 6 patients who were blood transfusion dependent at BL, 2 achieved transfusion independence.

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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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Combination of PXS-5505 With Standard Ruxolitinib Therapy Shows Potential Benefit for Patients With Myelofibrosis

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12/16/2024

According to data from an ongoing multicenter, open-label phase 1/2a trial, the addition of the pan-lysyl oxidase inhibitor PXS-5505 to standard Janus kinase (JAK) inhibitor therapy demonstrated safety and potential efficacy for patients with intermediate or high-risk myelofibrosis (MF).

Peter T Tan, MBSS, One Clinical Research Pty Ltd, Nedlands, Australia presented these findings at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California.

Previous dose escalation and cohort expansion of PXS-5505 trial phases have established safety and tolerability of a monotherapy dose of 200 mg BID over 24 weeks in patients with MF. Researchers evaluated the safety and efficacy of a 200 mg BID dose of PXS-5505 as an add-on to standard JAK2 inhibitor, ruxolitinib (RUX), therapy among patients with MF.

Enrolled in the study were patients with MF with a Dynamic International Prognostic Scoring System (DIPPS) score of intermediate-2/high risk disease. Before initial PXS-5505 administration, patients had been under current RUX treatment for 12 or more weeks, with a stable dose for at least 8 weeks.  A bone marrow biopsy was completed within 3 months of start date for all patients. Patients received PXS-5505 for 52 weeks or until progressive disease, dose limiting toxicity, or unacceptable toxicity. Dosage of PXS-5505 remained consistent at 200 mg BID, however patients were entitled to change RUX dose or discontinue RUX therapy while continuing to receive PXS-5505.

In this add-on phase of the trial, 15 patients were included, of which 6 had primary MF, 2 had post-ET MF, 7 patients had post-PV MF, 3 patients were considered high risk, and all other patients were Int-2. Among patients, the median duration of RUX treatment was 26 months (range, 3.5-74) and a median of 58 months (range 6.5-120) since time of MF diagnosis. The median myeloproliferative neoplasms symptom asssessment form total symptom score (PMN-SAF TSS) was 22.5. The median baseline spleen volume was 1353 cm3 (n=14) and medial baseline hemoglobin was 94 g/dL.

Additionally, 11 patients had hemoglobin levels over 100 g/dL at baseline and almost half had platelet levels below 100×109/L, 2 of which were transfusion-dependent at the start of the study. Baseline mutation profiles for 11 patients revealed a JAK2 V617F mutation among 7 patients and 6 patients with more than 1 high risk mutation.

“The results from this trial using a novel combination of PXS-5505 and RUX will add to the existing safety profile of PXS-5505 and provide preliminary indicators of efficacy to help inform future investigations of PXS-5505 in patients with MF,” the researchers concluded.

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Patient-Reported Outcomes Drive Effective MPN Treatment

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December 16, 2o24

Author(s): Laura Joszt, MA

With patients with myeloproliferative neoplasms (MPNs) having long life expectancies, it’s important that treatments optimize quality of life and patient-reported outcomes, said Jennifer Vaughn, MD, hematologist-oncologist and assistant professor in the Division of Hematology at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute.

This transcript has been lightly edited for clarity.

Transcript

How are patient-reported outcomes currently being used and incorporated into clinical practice to inform treatment for rare hematological conditions?

I think myeloproliferative neoplasms are an important area where patient-reported outcomes are so important. The drug ruxolitinib or Jakafi, which is a JAK [Janus kinase] inhibitor used in both polycythemia vera and myelofibrosis, was actually originally approved in myelofibrosis because of the improvement it led to in patient quality of life.

First of all, it was able to objectively reduce spleen volume, which led to improvement in patient symptoms, and it led to reductions in symptom scores on the MPN symptom assessment form, which is sort of the standard form we use now to assess how a patient is feeling over time. While there have been some data later on that suggests there may be an overall survival benefit in certain subsets of myelofibrosis, we really do decide to put patients on that treatment because of what they’re telling us about, how they feel. This was really one of the first models of using patient-reported outcomes in looking at whether or not a drug is valuable to society and to patients themselves.

Patients with MPNs become very symptomatic, and many of them will live [long] or have very excellent prognosis in terms of expected lifespan, but their quality of life is quite impeded by the symptoms of the disease. So, it’s really important for clinicians to be kind of reevaluating that on a regular, routine basis.

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Thrombosis Linked With Second Cancer Risk in MPNs

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Jonathan Goodman, MPhil
Publish Date

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).

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