Ten years of experience with ruxolitinib since approval for polycythemia vera: A review of clinical efficacy and safety

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Lucia Masarova MD1 | John Mascarenhas MD, MS2 | Raajit Rampal MD, PhD3 | Wilson Hu MD4 | Robert A. Livingston MD, MPH4 | Naveen Pemmaraju MD1

Abstract
The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was approved by the US Food and Drug Administration in 2014 for the treatment of patients with polycythemia vera (PV) who have an inadequate response to or intolerance of hydroxyurea (HU). PV is a chronic myeloproliferative neoplasm defined by primary absolute erythrocytosis, bone marrow hypercellularity, and JAK mutations such as JAK2V617F. Patients with PV experience burdensome symptoms and are at risk of thromboembolic events, in particular those with resistance to or intolerance of initial treatments such as HU. Other risks for patients with PV include progression of disease to more aggressive forms with worse prognoses, such as myelofibrosis or blast‐phase myeloproliferative neoplasms. This review summarizes the efficacy and safety of ruxolitinib from key phase 2 and 3 trials (MAJIC‐PV, RESPONSE, RESPONSE‐2, RELIEF, and Ruxo‐BEAT), large real‐world studies, and a decade of postmarketing surveillance safety data. The authors focus on improved blood count control, rates of thromboembolic events, symptom improvement, and markers of disease modification such as reduction of JAK2V617F allele burden in patients treated with ruxolitinib. They also discuss the well‐characterized safety profile of ruxolitinib regarding hematologic and other adverse events of interest. In the 10 years since its approval, ruxolitinib remains a safe and effective standard‐of‐care treatment for PV. As the treatment landscape for PV continues to evolve in the coming years, the efficacy and safety profiles of ruxolitinib suggest it will remain a
preferred treatment as monotherapy and as a potential backbone of future combination regimens.

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

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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.”

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Authors Identify Monoclonal Antibody to Selectively Target CALR Mutations in MPNs

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November 29, 2024

Author(s): Mary Caffrey

A monoclonal antibody that selectively targets mutations in calreticulin (CALR), the second most common driver of myeloproliferative neoplasms (MPNs), showed promising results in tests with engineered cell lines and in a mouse model, according to findings published yesterday in Blood.1

A decade after the discovery of CALR, the results are the first for a possible therapy for CALR-mutated MPNs to reach the clinic, according to an accompanying commentary,2 which described the discovery of CALR mutations as the activator in most cases of JAK2V617F-negative essential thrombocythemia (ET) and myelofibrosis (MF) cases “as a surprise, because a major role for CALR had not been previously described.”2

Incyte logo | Image: Incyte

The monoclonal antibody, INCA033989, being developed by investigators from Incyte with collaborators from the University of York and hospitals in France, was described by study authors as having “antagonized mutated CALR-driven signaling and proliferation in engineered cell lines and primary CD34+ cells from patients with MPN. ”At the same time, the novel antibody showed no binding activity with other cells.

Finally, in an experiment with mouse model of mutated CALR-driven MPN, treatment with an antibody surrogate designed for the mouse model “effectively prevented the development of thrombocytosis and accumulation of megakaryocytes in the bone marrow.”

The investigational antibody reduced replication of disease-initiating cells in both primary and secondary transplantations, the authors said, “illustrating its disease-modifying potential.”

There are 3 main types of MPN disorders, with most driven by mutations in Janus kinase (JAK2); this mutation accounts for 90% of patients with polycythemia vera (PV), 60% of patients with ET, and 55% of patients with MF. Next, CALR mutations are found in 25% of patients with ET and 35% of patients with MF. Mutations in CALR are not responsible for PV, the authors state.

They note that the mutant CALR protein is oncogenic; patients with ET and MF show clonal proliferation of hematopoietic stem cells. Patients with ET in particular are at risk of thrombosis and hemorrhage while those with MF may develop anemia or leukopenia, splenomegaly, bone marrow fibrosis, or see their disease transform into leukemia. A 2021 study appearing in Blood found that the 10-year mortality risk for patients younger than age 60 was 13% for those with ET, 18% for PV, and 49% for MF, compared with 6% for a control group.3

The investigators note that there has been great progress understanding mutated CALR in the 10 years after its discovery, including how it interacts with the thrombopoietin receptor (TPOR) and the resulting behavior of the mutated CALR protein with TPOR on the cell surface.

“Such findings fueled interest in targeted therapeutics,” they wrote, with both vaccines and antibodies being pursued.1 The cell surface of mutated CALR makes it an obvious target for antibodies, and the authors outlined results from earlier preclinical studies involving the mechanisms that contributed to development of the investigational antibody.

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Study Reveals Prognostic Implications of Pulmonary Hypertension in Myeloproliferative Neoplasms

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January 25, 2024

Lara C. Pullen, PhD

An analysis of patients with myeloproliferative neoplasms (MPN) has revealed that pulmonary hypertension (PH) is associated with an increased risk of hematologic progression and major adverse cardiovascular events (MACE). Orly Leiva, MD, an advanced heart failure and transplantation fellow at the University of Chicago, will present results that shed light on the pathophysiology behind PH and MPN progression, including an association between preserved right ventricular (RV) function and higher MPN progression, during the 66th American Society of Hematology (ASH) Annual Meeting and Exposition.

Dr. Leiva and colleagues designed the retrospective study to examine the connection between cardiology and MPN and determine whether the relatively common transthoracic echocardiographic (TTE) procedure can predict MPN progression. The study included 555 patients, 42.7% of whom had polycythemia vera, 41.1% had essential thrombocythemia, and 16.2% had myelofibrosis at the time of TTE. The cohort was 48.5% male and 86.8% white.

Thirty-five percent of the patients had a diagnosis of PH at the time of their first TTE; PH was defined as a pulmonary artery systolic pressure (PASP) of at least 40 mm Hg. The median time from MPN diagnosis to TTE was 39 months. Patients with PH were a median age of 71 years compared with 66 years for those without PH (p<0.001), and patients with PH were more likely to have myelofibrosis than those without. Patients with PH were also more likely than patients without PH to have a higher variant allele frequency of driver MPN mutation and larger spleen sizes at the time of TTE. They also had a higher rate of prior heart failure, hypertension, and atrial fibrillation than patients without PH.

Dr. Leiva’s team followed the patients for a median of 51 months and noted that composite hematologic outcome and MACE were more common among patients with PH than those without PH. When they performed a multivariable competing-risk regression on the data, the investigators found that PH was associated with an increased risk of hematologic outcome and MACE, such that 23.6% of patients with PH experienced a hematologic outcome. After adjusting for variables that varied significantly between groups, they found that atrial enlargement and valvular regurgitation were associated with decreased risk of hematologic outcome. In contrast, a marker of RV function, tricuspid annular plane systolic excursion, and estimated cardiac output were both associated with an increased risk of hematologic outcome.

“MPNs are a chronic disease,” Dr. Leiva told ASH Clinical News. “Some patients have the potential to live for decades.” Although thrombotic events are a classic cause of mortality in patients with MPN, many die from cardiovascular causes, and the results from this study highlight the non-thrombotic complications of MPN. Dr. Leiva proposed that MPN progression leads to increased catabolic demand and cell turnover, which might lead to increased cardiac output. Such a connection would explain the association between preserved RV function and increased cardiac output among patients with PH and MPN progression.

Dr. Leiva acknowledged that the study was primarily hypothesis-generating, and he called for a prospective study to further investigate the physiology of PH in MPN, characterize PH phenotypes and their associations with outcomes, and assess the utility of TTE screening for PH and surveillance of MPN progression. Until then, he explained that as a cardiologist, when treating a patient with MPN, he looks immediately at the patient’s TTE results. He suggested that all cardiologists and hematologists look for signs of MPN progression if a patient’s PASP exceeds 40 mm Hg or they have other signs of PH on their TTE.

The full study is scheduled to be presented on Saturday, December 7, 2024, at 3:15 p.m. at the 66th ASH Annual Meeting and Exposition in San Diego. This article will be replaced with a summary of the presentation after the session has concluded. Check back later this month for updates!

Any conflicts of interest declared by the authors can be found in the original abstract.

Reference

Leiva O, Soo S, Smilowitz N, et al. Prognostic implications of pulmonary hypertension in myeloproliferative neoplasms and predictors of hematologic progression. Abstract 246. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 7, 2024; San Diego, California.

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Myelofibrosis symptom assessment form total symptom score version 4.0: measurement properties from the MOMENTUM phase 3 study

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November 25, 2024

Christina Daskalopoulou, Boris Gorsh, Gerasimos Dumi, Samineh Deheshi, Chad Gwaltney, Jean Paty, Catherine Ellis, Jun Kawashima & Ruben Mesa

Abstract

Purpose

The Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) comprises 7 common MF symptom items (fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, bone pain) and is the first patient-reported outcome (PRO) instrument designed to assess MF symptom burden. Given that information on the psychometric properties of this instrument has been limited, we sought to evaluate its measurement properties and validate its use in the phase 3 MOMENTUM trial.

Methods

Data were pooled to assess MFSAF item distribution, structural validity, reliability (test-retest and internal consistency), construct validity (convergent, divergent, and known-groups), and sensitivity to change. Other PRO measures included Patient Global Impression of Severity/Change (PGIS/PGIC), EORTC QLQ-C30, PROMIS Physical Function Short Form 10b, and ECOG performance status.

Results

Participants (N = 195) showed high completion rates (> 93%) across 24 weeks. Moderate to strong Spearman correlation coefficients among items were mostly observed at baseline (range, 0.289–0.772) and week 24 (range, 0.391–0.829), which supported combining items into a multi-item scale and total score. Internal consistency (Cronbach’s α, 0.877 at baseline and 0.903 at week 24) and test-retest reliability (intraclass correlation coefficient, > 0.829) were satisfactory across selected time intervals. Reliability was also supported by McDonald’s omega (ω) coefficient (> 0.875). MFSAF moderately correlated with PRO measures of similar content, differentiated between PGIS and ECOG groups (P < .001), and was able to detect change over time.

Conclusions

The MFSAF v4.0 is a valid tool to assess MF symptom burden, supporting its use in future trials in similar populations.

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A robust tool for complex time-to-event data analysis in the context of myeloproliferative neoplasms

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November 25, 2024

by Gunilla Sonnebring, Karolinska Institutet

A new thesis from Karolinska Institutet shows the effectiveness of flexible parametric survival models in modeling multiple time-scales, providing a robust tool for complex time-to-event data analysis. The models were tested in the context of myeloproliferative neoplasms, a group of chronic hematologic malignancies in which the bone marrow makes too many red blood cells, white blood cells, or platelets.

This overproduction can lead to various complications, including blood clots (thrombosis), bleeding problems, transformation to acute myeloid leukemia and myelodysplastic syndromes.

In her thesis, doctoral student Nurgul Batyrbekova at the Department of Medical Epidemiology and Biostatistics, describes a novel method to modeling multiple time-scales in time-to-event analysis by using flexible parametric survival models (FPM) that can seamlessly incorporate multiple time-scales without requiring data splitting. She also explores whether traditional survival models that rely on a single time-scale lead to bias and inaccuracies in certain scenarios.

In two of her studies, using the novel method, Nürgul investigates clinically relevant questions for MPN, specifically, how the rate of thrombosis and the rate of transformation to AML/MDS are affected by age and duration of MPN disease.

Overall, her thesis could show that the new way to use multiple time-scales in survival models was better and provides answers to clinically relevant research questions in the field of MPN.

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Drawing First Blood: How Long Should Patients With a Myeloproliferative Neoplasm Be Anticoagulated?

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December 2024

Leah Lawrence

Patients diagnosed with myeloproliferative neoplasms (MPNs) — including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) — are at a higher risk of both venous and arterial thromboembolism. Management of thrombosis is central to the care of these patients; however, there is a dearth of recommendations specific to MPNs on the duration and selection of anticoagulation for the management of these events.1

In this edition of Drawing First Blood, ASH Clinical News invited Chi-Joan How, MD, clinical chief of hematology at Brigham and Women’s Faulkner Hospital and assistant professor in medicine at Harvard Medical School in Boston, and Brady L. Stein, MD, professor of medicine at Northwestern University’s Feinberg School of Medicine in Chicago, to debate and discuss how long a patient with an MPN should be treated with anticoagulation and other factors to consider when determining the appropriate management of thrombosis. Dr. How was asked to argue for indefinite anticoagulation therapy; Dr. Stein was assigned to argue for limited-duration anticoagulation therapy.’

Chi-Joan How, MD Brady L. Stein, MD

 

 

 

 

 

Chi-Joan How, MD              Brady L. Stein, MD

What are the benefits and risks of indefinite anticoagulant therapy?

Chi-Joan How, MD: Anytime someone is on anticoagulation, we are trying to reduce the risk of thrombosis and balance that against the risk for bleeding. MPNs create a procoagulant state, so patients are at a higher risk of thrombosis. Patients with an MPN who had a prior thrombosis are at an especially high risk for recurrence, up to 10% per year in some patients.

The anticoagulant should be effective for however long someone is on it, but once they stop, there is a risk of thrombotic recurrence. Because patients with an MPN have a higher ongoing risk of subsequent blood clots, staying on the blood thinner can help prevent these events, such as pulmonary embolism (PE), deep vein thrombosis (DVT), or blood clots in the splanchnic venous system.

The risk of indefinite anticoagulant therapy is bleeding. We know that patients with an MPN also have more bleeding issues. We know, for instance, that patients with ET who have a very high platelet count might be predisposed to bleeding rather than thrombosis. A blood thinner would add to this bleeding risk.

Finally, a lot of patients might not want to be on indefinite treatment. Even though it may seem like a small matter, one benefit of a finite duration of anticoagulation is that it is one fewer medication a patient has to take.

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Rusfertide Reduces Phlebotomy Need, Improves Symptom Control in Polycythemia Vera

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November 21, 2024

Author(s): Alexandra Gerlach, Associate Editor

Rusfertide (Takeda; Protagonist Therapeutics Inc) controlled erythrocytosis, maintained a hematocrit of less than 45% and reduced or eliminated the use of phlebotomy in patients with polycythemia vera (PV), according to data from the REVIVE trial (NCT04057040). Published in The New England Journal of Medicine, the results suggest the agent could become an additional therapeutic tool to reduce disease-related symptoms and the need for phlebotomy.1,2

Blood cells | Image Credit: © Ifti Digital – stock.adobe.com

PV is a rare type of blood cancer characterized by the overproduction of red blood cells in the bone marrow, contributing to blood clots, as well as the development of other blood disorders, such as myelofibrosis (MF). Both PV and MF are types of BCR‐ABL1‐negative myeloproliferative neoplasms with shared mutations and are associated with risk of thrombosis, hemorrhagic complications, and progression to acute myeloid leukemia. Approximately 1 in 4 patients with PV will develop MF, which is referred to as post–polycythemia vera myelofibrosis.3-5

Standard-of-care treatment for PV focuses on symptom reduction including treatments for to reduce itching or control blood cell counts, using agents such as hydroxyurea (Droxia; Bristol Myers Squibb) or ruxolitinib (Jakafi; Incyte Corp). The most common treatment for PV is frequent blood withdrawals to decrease blood volume, which is done via phlebotomy.5

Rusfertideis is an injectable, peptide mimetic of hepcidin. Hepcidin, produced in the liver, is a master regulator of iron trafficking. Some preclinical models suggest that increasing hepcidin could help control red blood cell production in patients with PV. In the phase 2 REVIVE trial, rusfertide demonstrated favorable safety and efficacy, with the potential to greatly decrease or eliminate the need for phlebotomy.2

The international, phase 2 REVIVE trial is divided into 2 parts. In part 1, patients were enrolled in a 28-week dose-finding assessment of rusfertide. In part 2, a double-blind, randomized withdrawal period, patients were assigned 1:1 ratio to receive either rusfertide (n = 30) or placebo (n = 29) for 12 weeks. The primary end point was response, which was defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Outcomes were reported by patients and were assessed using the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF).2

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Thrombosis Linked With Second Cancer Risk in MPNs

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Jonathan Goodman, MPhil

Among patients with myeloproliferative neoplasms (MPNs), arterial thrombosis incidence appears to raise the risk of second cancers (SCs) and consequently, mortality, according to an analysis published in Blood Cancer Journal. Inflammatory biomarkers in these diseases suggest a more aggressive disease etiology, the authors added.

In the case of polycythemia vera (PV) or essential thrombocythemia (ET), previous research suggested that thrombosis may heighten the risk of progression to secondary myelofibrosis, which has a high mortality rate. For this retrospective analysis of MPN-patient data, researchers aimed to determine the elements of thrombosis that promote this risk.

Overall, data were evaluated from 1545 patients with PV, 891 patients with ET, 180 patients who were pre-primary myelofibrosis (PMF), and 707 patients with PMF. The median follow-up periods in the PV, ET, pre-PMF, and PMF groups were 5.6 months, 5.6 months, 6.1 months, and 2.92 months, respectively; 19%, 12%, 15%, and 7% of patients had a thrombosis event.

Future therapies should focus on targeting the complex mechanisms involved in both atherogenesis and thrombogenesis…and anti-inflammatory drugs for primary and secondary prevention of thrombosis.

Analysis of the patient data showed that arterial, but not venous or splanchnic, thrombosis was linked with a greater risk of SCs (odds ratio [OR], 2.53; 95% CI, 2.4-5.17). A white blood cell count of at least 11 x 109/L appeared to trend toward a greater risk of SCs, but this link was not significant (OR, 1.27; 95% CI, 0.96-1.67); this was also true of a PMF vs ET diagnosis (OR, 2.54; 95% CI, 0.97-6.61).

“Future therapies should focus on targeting the complex mechanisms involved in both atherogenesis and thrombogenesis, including new cytoreductive drugs targeting the somatic mutations, such as interferon and JAK2 inhibitors, and anti-inflammatory drugs for primary and secondary prevention of thrombosis,” the authors wrote in their report.

Disclosures: This research was supported by FROM-Fondazione per la Ricerca Ospedale di Bergamo-ETS.

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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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