Tag Archives: mpn

New Trial Will Assess Safety and Efficacy of MF Drug

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Leonardo Jaimes, MD

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A clinical trial aiming to determine the efficacy, safety, and pharmacokinetics of the experimental drug WJ01024 combined with ruxolitinib in patients with myelofibrosis (MF) is set to begin soon.

“Although the clinical efficacy of ruxolitinib tablets has been confirmed, only about half of MF patients can achieve the ideal therapeutic effect (≥35% reduction in spleen volume and ≥50% improvement in disease symptoms at 24 weeks),” the authors wrote. “Therefore, there is an urgent need for innovative drugs that can be combined with ruxolitinib tablets to enhance therapeutic efficacy and meet clinical needs,” they added.

WJ01024 aims to enhance the therapeutic efficacy of ruxolitinib through  XPO-1 inhibition. Previous in vitro studies have confirmed that the drug enhances ruxolitinib anti-cell proliferation activity, the researchers noted. Furthermore, preliminary studies on humans suggest that WJ01024 is effective as monotherapy for relapsing patients and those intolerant to JAK inhibitors, they added.

The trial will consist of a dose escalation and a dose extension phase (phase 1a and phase 2). Phase 1b will divide patients into three groups receiving 40 mg, 60 mg, and 80 mg of WJ01024, respectively. Phase 2 will be an open-label evaluation of the efficacy and safety of the recommended dose in combination with ruxolitinib.

The study will only include patients diagnosed with MF and with the international prognostic scoring system risk category of intermediate-1, intermediate-2, or high-risk. Patients in the accelerated blast phase or previous treatment with either JAK or XPO-1 inhibitors are not eligible for participation.

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Rusfertide Cuts Phlebotomy Need in Polycythemia Vera: Andrew Kuykendall, MD

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April 10, 2025

Author(s): Maggie L. Shaw, Andrew Kuykendall, MD

With an expected completion date sometime in June, the phase 3 VERIFY trial (NCT05210790) will soon conclude its investigation of rusfertide (Takeda) as add-on therapy to a patient’s current course of treatment for their polycythemia vera. The investigative agent has already received breakthrough therapy, orphan drug, and fast track designations from the FDA.

In this fourth part of a discussion with The American Journal of Managed Care®, Andrew Kuykendall, MD, clinical researcher at Moffitt Cancer Center and VERIFY investigator, speaks to the impressive patient-reported outcomes seen thus far.

This transcript has been lightly edited for clarity; captions were auto-generated.

Transcript

Can you summarize the key findings seen so far in the phase 3 VERIFY study?

Super exciting results that we saw. The study design, a lot of this was really built on a phase 2 study that was published in The New England Journal of Medicine that took patients with polycythemia vera who were requiring phlebotomies on a regular basis. That study basically put everyone on rusfertide and assessed over time their need for phlebotomy. There are a couple of different nuances to that study, but I would say the take home point of what we saw is that rusfertide very effectively eliminated the need for these patients that were regularly needing phlebotomies to need any phlebotomies at all—really rapidly reduced that and so certainly paved the way for designing a phase 3 clinical trial that could show that in comparison to standard therapy.

This trial took patients that had polycythemia vera that were requiring regular phlebotomy—so at least 3 over the preceding 28 weeks or 5 over the course of the prior year—and it randomized them to either stay on their standard therapy and add rusfertide or stay on their standard therapy and add a placebo. Everyone was treated in kind of the standard way, even if you were randomized to the “placebo arm”; that was just the standard therapy. If you were on cytoreductive therapy like hydroxyurea or interferon or ruxolitinib—these are agents we use to treat the disease as well—you stayed on those agents and you continued to get phlebotomies, as you would if you if you were kind of in routine clinical care. Then the other group did the same thing, but they added on rusfertide as a weekly subcutaneous injection. For 20 weeks, there was a a dose-finding period where rusfertide, the doses were increased based on hematocrit level and various different control of the disease.

The primary end point, at least in the US, was looking at the number of patients that were “phlebotomy eligible,” meaning that they needed a phlebotomy to control their disease—and that was being looked at between weeks 20 and 32. What we found is significantly more patients in the placebo group, so in the patients that were not receiving rusfertide, were “phlebotomy eligible” during that period of time. Another way to say that is, more patients in the rusfertide group did not need a phlebotomy during that that critical time period. Just another way of showing the control that rusfertide has, and that was the primary end point. Based on the phase 2 data, we certainly were optimistic that this was going to be reached.

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Exploring the interplay between myeloproliferative disorders and atherosclerosis

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Published April 3, 2025

Maham Khan, Sandipta Banerjee, Rekha Kumari, Shubhayu Roy Chowdhury, Nada Madkour, Ikponmwosa Jude Ogieuhi, Chinonyelum Emmanuel Agbo, Victor Oluwatomiwa Ajekiigbe, Olanipekun Lanny Ntukidem, Folajimi Josiah Atunde & Chukwuemelie Darlington Okeke

Abstract

The relationship between hematologic malignancies and atherosclerosis is vital in clinical conditions due to common risk factors. These two diseases may negatively affect cardiovascular health, so understanding their complex dynamics is essential for detecting disease mechanisms and establishing effective patient care. This review aims to focus on the involvement of hematologic malignancies in the onset and progression of atherosclerosis at a biological level. Furthermore, it looks at the case for heightened cardiovascular risk in patients with hematological cancers and the chances of management and treatment against it. A comprehensive literature review was performed, and studies that revealed the link between hematologic malignancies and atherosclerosis were preferred. Inclusion and exclusion criteria guided the selection of studies for consideration. The biological pathways between hematologic malignancies and atherosclerosis have been elucidated, including the inflammatory pathways and the shared risk factors. Clinical evidence reveals that cardiovascular diseases are more likely to occur in patients with hematologic cancers, thus showing the necessity of targeted preemptive measures to lower this risk. The findings reveal that it is essential to consider cardiovascular health when handling hematologic malignancies. Future research should focus on creating holistic treatment procedures that jointly deal with both conditions, which will be necessary to enhance patients’ lives and well-being.

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Navigating the peginterferon Alfa-2a shortage: practical guidance on transitioning patients to ropeginterferon alfa-2b

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Published April 3, 2025

Ruben Mesa, Abdulraheem Yacoub, Tsewang Tashi, Wanxing Chai-Ho, Chang Ho Yoon & John Mascarenhas

Dear Editor,

We write to highlight the critical shortage of peginterferon alfa-2a (peg-IFN), as confirmed by the FDA [1], which has impacted many patients with myeloproliferative neoplasms (MPNs). Those relying on peg-IFN for long-term disease control in polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) face supply disruptions that can compromise disease stability and overall health.

Ropeginterferon alfa-2b (ropeg-IFN) is a viable alternative. It is the only FDA-approved interferon for PV and is considered first-line therapy as per the January 2025 NCCN Guidelines [2]. Though not yet approved for ET or MF, off-label use may be justified in situations where no other options exist. Our group has accumulated experience in transitioning patients from peg-IFN to ropeg-IFN due to historic insurance issues and clinical trial participation, allowing us to propose practical strategies for safe conversion.

A best-practice approach to dose equivalence, based on collective experience and real-world data, is pragmatic given that no formal head-to-head dosing trials exist.[3,4,5] For patients previously on peg-IFN 135–180 µg weekly, we typically initiate ropeg-IFN at 250–350 µg every two weeks, adjusting for hematologic response and tolerability. Those on lower peg-IFN doses (45–90 µg/week) may begin on 200–250 µg every two weeks. If disease control proves challenging, starting at, e.g., 350 µg with possible escalation to 500 µg every two weeks can be considered. Whichever starting dose is chosen, close monitoring and dose adjustments are essential to maintain efficacy while minimizing toxicity.

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Global, regional, and national burden of myelodysplastic syndromes and myeloproliferative neoplasms, 1990-2021: an analysis from the global burden of disease study 2021

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Xinyue Gou 1, Zhuo Chen 2,*, Yudi Shangguan 3

Abstract

Objective

To analyze the trends and cross-country inequalities in the burden of Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) over the past 30 years and forecast potential changes through 2045.

Methods

Estimates and 95% uncertainty intervals (UIs) for incidence, deaths, and disability-adjusted life-years (DALYs) associated with MDS/MPN were obtained from the Global Burden of Diseases (GBD) 2021 database. We described the epidemiology of MDS/MPN at global, regional, and national levels, analyzed trends in the burden of MDS/MPN from 1990 to 2021 through overall, local, and multidimensional perspectives, decomposed the burden based on population size, age structure, and epidemiological changes, quantified cross-country inequalities in MDS/MPN burden using standard health equity methods recommended by the WHO, and predicted changes of MDS/MPN burden to 2045.

Results

The global incidence of MDS/MPN has shown a marked increase, escalating from 171,132 cases in 1990 to 341,017 cases in 2021. Additionally, the burden was found to be significantly greater in men compared to women. The overall global burden of MDS/MPN exhibited a consistent increase from 1990 to 2021, although the growth rate showed a noticeable slowdown between 2018 and 2021. Decomposition analysis identified population growth as a key factor influencing the variations in the burden of MDS/MPN. An inequality analysis across countries indicated that high Socio-demographic Index (SDI) countries bore a disproportionate share of the MDS/MPN burden, with significant SDI-related disparities remaining evident. Interestingly, while the incidence and deaths of MDS/MPN, along with the age-standardized rate (ASR) for DALYs, are projected to decline annually from 2020 to 2045, the absolute number of cases for these indicators is expected to continue rising. By 2045, the projected numbers are estimated to reach 457,320 cases for incidence, 82,047 cases for deaths, and 1,689,518 cases for DALYs.

Conclusions

As a major public health issue, the global burden of MDS/MPN showed an overall increasing trend from 1990 to 2021, which was primarily driven by population growth and aging. The largest share of the MDS/MPN burden was seen primarily in men, with older demographics. Countries with elevated SDI experienced a significantly higher burden of MDS/MPN. While the burden of MDS/MPN was most pronounced in high SDI quintile, the fastest growth was observed in the low-middle SDI quintile, especially in tropical Latin America. This study highlighted great challenges in the control and management of MDS/MPN, including both growing case number and distributive inequalities worldwide. These findings provide valuable insights for developing more effective public health policies and optimizing the allocation of medical resources.

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JAK Inhibitors Associated With Less Thromboembolic Events in MF

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Leonardo Jaimes, MD
Publish Date:

Janus kinase inhibitors (JAKi) therapy could prevent thromboembolic events in patients with myeloproliferative neoplasms (MPNs) such as myelofibrosis (MF), according to a recently published meta-analysis in the Journal of the British Society of Hematology.

Despite the well-documented clinical improvement associated with JAKi therapy in patients with MPNs, adverse effects such as weight gain and cholesterol increase have raised concerns about increased cardiovascular risk. Furthermore, the ORAL surveillance trial demonstrated that JAKi was associated with an increase in the rate of major adverse cardiovascular events (MACEs).

As the effects of JAKi therapy on thrombotic risk are still poorly understood, the authors aimed to compare the rates of MACEs, thrombosis, and hypertension in patients with MPN taking JAKis through a meta-analysis.

The meta-analysis included prospective and retrospective studies involving patients taking JAKi and a JAKi-naive control group. The initial search yielded over 1500 studies, of which 23 met the inclusion criteria.

Nine studies, including over 1800 patients, assessed thromboembolic risk. The pooled analysis with a confidence interval of 95% revealed that the rate of thromboembolic events was 48% lower in patients receiving JAKi therapy. The pooled analysis of the 16  studies analyzing MACE or hypertension, on the other hand, revealed no significant difference between groups.

The authors remarked that the findings correspond with evidence presented by Samuelson et al., which demonstrated that ruxolitinib was associated with lower rates of hemolysis. Furthermore, recent posthoc analysis of the ORAL surveillance trial found that the apparent increased frequency of MACE in patients receiving JAKi therapy was observed in patients with preexisting atherosclerotic disease.

“JAKi treatment was not associated with an increased risk of MACE or hypertension, adding to the existing body of evidence demonstrating the safety of JAKi in the treatment of MPNs,” the authors wrote.

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Mutations With Diagnostic Potential for MF Identified

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Leonardo Jaimes, MD
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Next-generation sequencing (NGS) identified 14 gene mutations with diagnostic and prognostic potential in patients with myelofibrosis (MF), according to a recently published study in the Journal of Applied Genetics.

“The incredible progress that has been made over the last 10 years in the field of genetic diagnostics has prompted the identification of additional genetic abnormalities linked to MPN,” the authors wrote.

Driver mutations in the CALR, JAK2, and MPL genes have a high diagnostic and prognostic value in patients with myeloproliferative neoplasms, like MF. the researchers noted. However, other mutations are also involved in the pathophysiology of these conditions, and many of them are associated with treatment resistance and poorer prognosis, they added.

Therefore, the authors aimed to use an NGS of 40 genes to retrospectively study a cohort of 42 CALR-positive patients with either essential thrombocytosis (ET) or MF and determine the impact of gene mutations in disease progression.

Patients with ET (n=28) and MF (MF) were further divided according to the type of CARL mutation. Among patients with MF, the type 1 CARL mutation represented 92% of the population.

NGS revealed 44 potentially pathogenic variants. The most frequently mutated genes were associated with epigenetic regulatory mechanisms, namely ASXL1, TET2, and DNMT3A. Approximately 48% of patients had additional mutations, 33% had more than one additional mutation, and 23% had high molecular risk mutations.

The presence of additional mutations correlated with disease transformation, as five out of seven patients who progressed from ET to MF had additional mutations. Furthermore, the two patients that progressed to acute myeloid leukemia had additional mutations.

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Reducing Polycythemia Vera–Associated Thrombotic Risk Through Iron Regulation

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April 1, 2025

Author(s): Maggie L. Shaw, Andrew Kuykendall, MD

The investigational rusfertide (Takeda), is currently being evaluated in the phase 3 VERIFY trial (NCT05210790) as an injectable therapeutic to treat polycythemia vera (PV) through achieving and sustaining hematocrit control. This agent has already breakthrough therapy, orphan drug, and fast track designations from the FDA.

In part 3 of a discussion, Andrew Kuykendall, MD, clinical researcher at Moffitt Cancer Center and VERIFY investigator, talks of rusfertide’s ability to free patients from being tethered to the need for regular phlebotomies and live a more viable life.

Part 1 and part 2 of this interview are also available to learn more about this potential novel PV treatment.

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Symptom burden in myeloproliferative neoplasms: clinical correlates, dynamics, and survival impact—a study of 784 patients from the Quebec MPN research group

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April 1, 2025

Alisa Poullet, Lambert Busque, Shireen Sirhan, Robert Delage, Ghislain Cournoyer, Ines Chamakhi, Danielle Talbot, Luigina Mollica, Daniele Marceau, Vincent Ethier, Pierre Desjardins, Harold J. Olney, Michaël Harnois & Natasha Szuber

Classic BCR::ABL1-negative myeloproliferative neoplasms (MPN) include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). While patients may benefit from extended survival, they also endure lifelong symptoms, ranging from mild to incapacitating [1]. These include physical manifestations related to hyperviscosity, bone pain, pruritus, constitutional symptoms, and consequences of splenomegaly, among others, as well as psychological symptoms (e.g., depression, anxiety) [2, 3]. Ultimately, symptom burden impairs quality of life (QoL) [4], an independent predictor of mortality [5]. Addressing symptom burden in MPN patients is crucial in guiding and individualizing therapy; however, several important challenges remain, including obscure mechanistic underpinnings and scarcity of robust data to inform practice. While the current patient-reported symptom assessment tool was conceived as a universal instrument for the collective MPN population—facilitating its clinical application, distinct profiles across subtypes may not be captured. Cut-off values determining ‘significant’ scores may also warrant further evaluation. Furthermore, kinetics of symptom profiles over time and correlations with biological variables have not fully been explored. The objectives of the current study were to comprehensively characterize symptom burden in a large MPN cohort, determining: i) age/sex-associated differences; ii) longitudinal dynamics and treatment effects; iii) biologic correlatives; and iv) impact on overall survival (OS) in a real-world population-based setting.

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A Patient Story: Are MPNs Hereditary?

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Our story started when I was heavily pregnant with our first child in July 2022. My husband and I were not aware that he had an MPN. One morning, before he went to the doctor before work where they told him to go to the hospital for potential internal bleeding. He went in and was admitted and spent 2 long weeks where he had numerous CT scans, endoscopies, blood test, and other various medical drips. My husband was released but we still didn’t have answers to what had caused him to have internal bleeding. We were just told they needed to do further tests; however, they were pointing towards something to do with his liver which we were very much confused by.

Time went by and we had our baby girl! We were so busy with the joy of our new arrival we had almost forgotten about the hospital. 4 weeks later we were ablet to finally see a liver specialist with our new baby and were told that he had a blood disorder that caused him to have varices in his throat that burst, causing the internal bleeding. We left the appointment with a sense of relief to finally have an answer.

A few weeks later we had an appointment with the hematologist and were told that he had a JAK2 mutation myeloproliferative neoplasm, a blood cancer. We were devastated by this news. At the age of 31, this was not something we understood or had ever heard of. The only words we heard were “blood cancer” and, even though his hematologist is very knowledgeable and reassuring, we left feeling like our world had been turned upside with a 6-week-old baby girl.

After being told that his MPN diagnosis was not hereditary, we spent numerous hours researching the condition to better understand what we were dealing with. We moved on, so to say, and made the most of every day.

Just before our daughter turned one, we took her into the doctor’s office because she had a cough, and I was worried that she might have enlarged lymph nodes. The doctor didn’t seem too concerned but referred her for some blood tests just to be on the safe side considering my husband’s recent diagnosis. Her test results showed high platelets, and we were told to have the tests repeated as the rise in platelets could have been due to iron deficiency or an infection.

The second blood test once again showed that her platelets were unusually high. The hematologist referred us to genetic testing and another full blood count. Her results came back stating she also had a JAK2 mutation, the same one as my husband’s (JAK2 V617I). After this diagnosis, we sent off nail clipping to confirm that he has a germline mutation.

When our daughter was 6 months old, we became pregnant with our second child. We learned that my mother-in-law also has the JAK2 mutation but hers was never activated. My husband has now been officially diagnosed with polycythemia vera (PV) and is being checked every 6 months with stable blood work. We are now focused on living a positive, happy life despite all the challenges we were presented and remain grateful for our family every day.