Category Archives: Myelofibrosis

Ruxolitinib Plus SOC Prophylaxis Is Associated With Lower Rates of GVHD in Myelofibrosis

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February 14, 2025

Author(s): Dylann Cohn-Emery

Fact checked by: Jonah Feldman

Treatment with the combination of ruxolitinib (Jakafi) and standard-of-care graft-vs-host disease (GVHD) prophylaxis led to a reduction in the rates of acute and chronic GVHD without compromising survival rates in patients with myelofibrosis undergoing hematopoietic stem cell transplantation (HCT), according to data from a phase 2 prospective study (NCT04384692) presented at the 2025 Transplantation and Cellular Therapy Meetings.1

The study conducted at Fred Hutchinson Cancer Center showed grade II to IV acute GVHD occurred in 32% of patients receiving peri-transplant ruxolitinib, whereas it occurred in 71% in a pre-transplant ruxolitinib group of a similar preliminary study. The percentage of patients with chronic GVHD at 1 year with peri-transplant ruxolitinib 12%, whereas it was 25% with pre-transplant ruxolitinib. These rates of GVHD also coincided with high overall survival (OS) rates at year 1 and 2 of 100% and 87%, respectively, in the peri-transplant ruxolitinib trial.

“The incidence of acute and chronic GVHD was markedly reduced without the expense of non-relapse mortality, relapse, or survival. It doesn’t appear that infections or transfusion needs were increased,” Rachel B. Salit, MD, associate professor at Fred Hutchinson Cancer Center, said in her presentation.

Janus kinase (JAK) inhibitors prevent activation of the JAK domain by binding to the kinase, in turn preventing STAT phosphorylation and translocation of the nucleus. This process reduces the production of pro-inflammatory cytokines. GVHD pathogenesis has shown to be affected by the JAK-STAT pathway, and JAK signaling is key in the process leading to tissue damage and inflammation.

In previous trials of ruxolitinib, such as COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544), this JAK inhibition showed significantly better results in reducing symptoms and splenomegaly compared with best available therapy in patients with myelofibrosis. Additionally, the REACH1 (NCT02953678), REACH2 (NCT02913261), and REACH3 (NCT03112603) trials demonstrated significantly improved response with ruxolitinib vs best available therapy when treating patients with acute and chronic GVHD.

The preliminary study (NCT02251821) of ruxolitinib pre-transplant showed improved survival in this patient population. With a median time of 7 months on ruxolitinib, 38% of patients had more than a 10% decrease in spleen size and 36% were stable. In patients with symptoms prior to ruxolitinib, 55% had stable or improved symptoms by the time of HCT.

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Patients With Cytopenic Primary Myelofibrosis Face Unique Therapeutic Challenges, Poor Prognosis

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February 12, 2025

Author(s): Luke Halpern, Assistant Editor

Patients with primary myelofibrosis (PMF) harboring the cytopenic phenotype called cytopenic (CyP) PMF face greater unmet needs and worsened prognosis compared with other myeloproliferative neoplasms (MPNs), including polycythemia vera (PV) and essential thrombocytopenia (ET), according to an analysis of data from the European multicenter collaborative ERNEST registry.1

Myelofibrosis that advances to blast phase worsens outcomes for patients affected. | Image Credit: © tonaquatic – stock.adobe.com

Disease behavior of MF can vary widely based on clinical phenotype. Two distinct subgroups comprise MF: proliferative MF and cytopenic MF, which is also called myelodepletive MF. For patients with cytopenic MF, disease presentation can encompass lower blood counts—specifically thrombocytopenia and anemia—additional somatic mutations, and a worse prognosis compared with proliferative MF.2

Additionally, approved Janus kinase (JAK) inhibitors that can improve constitutional symptoms of MF carry risks of worsening anemia and thrombocytopenia in CyP MF, making treatment uniquely challenging for patients. Severe anemia is known to further worsen patient prognosis, and measures to relieve disease burden, such as transfusions, can lead to disease progression into blast phase (BP) MF. Given the poor outcomes MF patients with CyP face, describing the clinical characteristics and outcomes of this population is critical.1,3

The current investigators analyzed data gathered from the European multicenter collaborative ERNEST registry, with a focus on the clinical outcomes and characteristics of MF patients with CyP. In total, 559 patients comprised the study population; a CyP was defined by the presence of at least 1 cytopenia at diagnosis, including sex-adjusted anemia, thrombocytopenia, or leukopenia. Patients who showed none of these characteristics were considered MyP.1

Median follow-up was 5.4 years. A CyP was identified in 275 patients (49.2%); these patients were more likely to be older, less frequently JAK2V617F-mutated, and included in higher risk categories. In total, 392 patients (70.1%) died, including 59.9% of MyP patients and 80.7% of CyP patients, and the incidence rate of death among patients with both anemia and thrombocytopenia was the highest among the subgroups analyzed.1

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Allogeneic Hematopoietic Stem Cell Transplantation May Resolve Osteosclerosis in MF

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Özge Özkaya, MSc, PhD
Publish Date

Allogeneic hematopoietic stem cell transplantation leads to extensive skeletal homeostasis reconstruction and subsequent resolution of osteosclerosis in patients with myelofibrosis (MF), according to a new study published in the peer-reviewed journal Nature Communications.

For the study, a team of German researchers outlined the skeletal characteristics of patients with MF before and after allogeneic hematopoietic stem cell transplantation using clinical high-resolution imaging, laboratory analyses, and bone marrow biopsy studies.

The team reported that even though the bone microarchitecture was not impaired at peripheral skeletal sites, there was a marked increase in bone mineral density at the lumbar spine and proximal femur.

This, the researchers said, is histologically related to severe bone marrow fibrosis and osteosclerosis.

Following allogeneic hematopoietic stem cell transplantation, the bone marrow fibrosis was fully normalized.

The team also reported that the regression of fibrosis was accompanied by vanishing osteosclerosis together with restored osteoclastic resorption activity and whole-body calcium homeostasis.

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Lactate is a Key Regulator of Immune Escape, Bone Marrow Fibrosis in Myelofibrosis

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February 11, 2025

Author(s):

Luke Halpern, Assistant Editor

New study results published in the Journal of Translational Medicine reveal that circulating lactate is a key regulator of immune escape and bone marrow (BM) fibrotic transformation in patients with myelofibrosis (MF), with a marked increase in lactate concentration and lactate import channel monocarboxylate transporter 1 (MCT1) expression in the site of blood cell production. The investigators suggest that MCT1 blocking could be used as a novel antifibrotic strategy in patients with MF.1

An enlarged image of fibrous scar tissue, dense collagen network
Myelofibrosis can cause fibrosis in bone marrow. | Image Credit: © Jasmine – stock.adobe.com

According to the study authors, the pathophysiology of MF is significantly influenced by alterations in the BM microenvironment, and these changes are often associated with the metabolic reprogramming of cancer cells in patients. Glycolysis is a hallmark aspect of the changes that occur in cancer cells; prior evidence from investigational models strongly suggests that lactate production is associated with tumor microenvironment (TME) progression in patients with certain types of cancer.1-3

Prior observations also indicate that increases in lactate dehydrogenase A (LDHA) have a central role in glycolysis, with high LDHA levels typically found in the sera of patients with MF, predicting shorter overall and leukemia-free survival. Within this context, excess lactate that is secreted by cancer cells can promote immune suppression and angiogenesis while also possibly playing a role in increasing the number of cancer-affiliated phenotypes (CAF), which promote fibrotic tumor formation, the investigators wrote.1,4

These authors sought to fill a gap in knowledge within the characterization of TME metabolic composition in patients with MF. Through their analysis, they demonstrated that the amount of circulating lactate increases in patients with MF, which eventually leads to the expansion of immunosuppressive subsets and the development of fibrosis. Furthermore, they observed that the expression of lactate export channel monocarboxylate transporter 4 (MCT4) in the TME becomes deeply remodeled during fibrotic transformation, “suggesting a link between lactate trafficking and pro-fibrotic establishment.”1

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Reevaluating Available Options for Anemia in Myelofibrosis

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February 6, 2025

By Targeted Oncology Staff
Fact checked by Jonah Feldman

DISCUSSION QUESTIONS

  • How do you monitor and manage anemia in patients with primary myelofibrosis prior to starting Janus kinase (JAK) inhibitor therapy?​
  • While receiving a JAK inhibitor therapy?

Andrew Kuykendall, MD: How do you monitor and manage anemia in patients with myelofibrosis even prior to starting a JAK inhibitor? If you’re initially evaluating someone, they come in with hemoglobin of 7 or 8 g/dL or something like that, how does that impact your thinking, and how do you work that up?

Lazaros Lekakis, MD: The first thing is to make sure that they don’t have something easily fixable [such as] iron, B12, or folate deficiency. Theoretically, if you don’t have any nutritional cause or any immune causes, you could use erythropoietin analogs, but they are very tricky because they don’t help with the spleen, at least in my experience, and they may increase the risk of clots. I try to avoid them if possible. If I have to start a JAK inhibitor, if they have symptoms, either I go away from ruxolitinib [Jakafi] or I start a low dose of ruxolitinib. Sometimes I use anabolic steroids and prednisone. We have the thalidomide/prednisone [regimen] that now is kind of forgotten about.

Kuykendall: Erythropoietin-stimulating agents [ESAs] are limited in what they do, and certainly not helping other aspects of the disease. You did mention one of my favorite regimens, thalidomide/prednisone, which is looked over a bit nowadays, but has quite a potential for efficacy in terms of improving hemoglobin. But it’s probably something that’s gone by the wayside in many practices.

Luis Sumoza, MD: As Dr Lekakis says, there are some other options that you can use. Danazol is sometimes something you can use perfectly in this patient population. From the JAK inhibitors, there is momelotinib [Ojjaara]. But a priority for me is to refer a patient for a stem cell transplant; when I was a fellow, we did the first allogeneic bone marrow transplant at the University of Illinois, Chicago, and it was a very nice experience.

Kuykendall: [Dr Lekakis] also mentioned steroids, [and we are] thinking about things like danazol, androgen derivatives. We saw from the MOMENTUM study [NCT04173494] looking at momelotinib that danazol is an active agent.1 It was a large, randomized trial, one of the first randomized trials with danazol. The focus there was on momelotinib, but there’s also a lot to learn about what danazol could do as well from that study.

Sumoza: You’re mainly talking about anemia here, and [if], the patient is not a candidate for a transplant or a clinical trial [there are] the data about navitoclax/ruxolitinib, which basically double the response and reduction of the spleen.2

Kuykendall: Yes, these emerging therapies to some degree may change how we approach this disease. But I think that with some of these older therapies, especially when you’re when you’re first talking about someone who’s coming in with anemia, you need to think about ESA, danazol, and thalidomide/prednisone.

I think that ESA is probably the most prominently used. How many of you are checking serum erythropoietin levels in these patients to assess their candidacy for ESAs, is that a common practice?

Mukesh Kumar, MD: Yes, I’m checking on all of my patients.

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Second-Line Fedratinib Produces Early Platelet Count Improvements in Myelofibrosis

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February 5, 2025

Author(s): Jax DiEugenio

Fact checked by: Chris Ryan

Patients with myelofibrosis who received second-line fedratinib (Inrebic) experienced early increases in platelet count compared with those given best available therapy (BAT), and a higher magnitude of benefit was observed in patients with a low platelet count at baseline, according to findings from the phase 3 FREEDOM2 trial (NCT03952039) presented at the 2024 ASH Annual Meeting.

Findings showed that in the overall safety population, fedratinib generated improvements in mean platelet count and mean change from baseline platelet count, most noticeably in early treatment cycles.

In patients with a low platelet count at baseline, defined as at least 50 to less than 100 x 109/L, patients treated with fedratinib (n = 34) experienced a mean increase in platelet count of 45% on day 15 of cycle 1 compared with 11% for those given BAT (n = 21). Among patients with a high platelet count at baseline of at least 100 x 109/L, these rates were 27% for fedratinib (n = 85) and –6% for BAT (n = 39).

During a presentation of the data, lead study author Haifa Kathrin Al-Ali, MD, explained that increased platelet count was not correlated with changes in spleen size, pointing to a potential benefit for fedratinib on thrombopoiesis.

“These data suggest a platelet-sparing effect of second-line fedratinib vs BAT, and support fedratinib as a promising second-line treatment option for patient with myelofibrosis with low or high baseline platelet count,” said Al-Ali, who is a professor of translational oncology and head of the Krukenberg Cancer Center at the University Hospital of Halle (Saale) in Germany.

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Calreticulin Mutations Can Worsen Survival Outcomes in Ruxolitinib-Treated Patients With Myelofibrosis

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January 31, 2025

Author(s): Luke Halpern, Assistant Editor

Patients with myelofibrosis (MF) who harbor calreticulin (CALR) mutations begin treatment with ruxolitinib presenting severe disease with a longer median time from diagnosis, with inferior spleen responses and lower rates of symptom responses observed at 6-months, according to study results published in Annals of Hematology.1

3D illustration Virus DNA molecule, structure. Concept destroyed code human genome. Damage DNA molecule. Helix consisting particle, dots. DNA destruction due to gene mutation or experiment
CALR mutations in patients with myelofibrosis being treated with ruxolitinib can lead to worsened outcomes. | Image Credit: © rost9 | stock.adobe.com

CALR mutations can be found in around 20% of patients with primary and post-essential thrombocythemia (ET) MF. Patients who harbor CALR mutations often present with distinct clinical features compared with Janus kinase (JAK)2-mutated patients. Typically, they feature lower levels of hemoglobin and white blood cells, present at younger age, and are associated with better survival rates.1,2

Ruxolitinib (Jakfafi; Incyte) is a targeted therapeutic option for patients with MF that has shown efficacy regardless of the driver mutation in patients. However, new therapies continue to be developed that specifically target CALR, necessitating further research on therapies that are currently standard in CALR-positive patients, according to the investigators.1,3

The study authors reported the outcomes of a sub-analysis of the RUX-MF clinical trial, documenting 135 patients with CALR mutation who received ruxolitinib in a real-world setting. The analysis was performed with major considerations, including that the younger age of CALR-mutated patients compared with JAK2-mutated patients may influence survival outcomes, and that younger patients are eligible for allogeneic stem cell transplantation, which the investigators noted could meaningfully impact the treatment algorithm.1

In total, 786 patients from the RUX-MF trial were JAK2-mutated, while 135 had a CALR mutation. Only 78 CALR-mutated patients were evaluable, in which their mutation was type 1-like in 66.7% of the population, while 30.8% had type 2-like mutation. At the beginning of ruxolitinib initiation, CALR-mutated patients were younger, had higher percentages of peripheral blasts, and lower median hemoglobin levels compared with JAK2-mutated patients.1

Responses to ruxolitinib and patient outcomes according to mutation type were reported at 6 months. There were no major differences in spleen responses (CALR: 21.4%; JAK2: 25.7%), and there were comparable rates of treatment-emergent anemia (CALR: 35.7%; JAK2: 30.4%) and both overall and treatment-emergent thrombocytopenia. However, symptoms response was significantly lower in CALR-mutated patients (56.1% vs 66.7%), and overall anemia rates (60.3% vs 50.3%) were higher in this population compared with JAK2-mutated participants.1

Across the 135 patients with CALR mutation, there were no factors associated with spleen or symptom response. Notably, factors correlated with worse survival included hemoglobin below 10 g/dL and a high burden of symptoms. In the subgroup of 72 CALR-mutated patients who began ruxolitinib over 2 years following diagnosis, anemia (HR: 1.92; 95% CI, 1.02-3.79) and the use of a reduced ruxolitinib initiation dose (HR: 2.29; 95% CI, 1.15-4.56) were associated with poor overall survival.1

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Real-world treatment patterns and health outcomes for patients with myelofibrosis treated with fedratinib

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January 14, 2025

Francesco Passamonti Shalon Jones e , a,b , Siddhi Korgaonkar c Dorothy Zissler e , , Keith L Davis Rohan C Parikh c c , Manoj Chevli d , and Samantha Slaff

ABSTRACT

Aim: Assess real-world fedratinib (FEDR) treatment patterns and clinical outcomes in patients with primary or secondary myelofibrosis following discontinuation of ruxolitinib (RUX). Patients & Methods: This study was a retrospective, noninterventional medical record review of patients in Canada, Germany, and the United Kingdom (UK). A total of 70 physicians (primarily hematologist-oncologists [78.6%]) provided data for 196 eligible patients.

Results: Patients were mostly male (62.8%) with primary myelofibrosis (76.5%) and initiated FEDR at a mean age of 67.7 years. Median treatment duration was 11.5 months (median follow-up, 13.8 months), and nearly half (49.5%) of patients initiated FEDR at the label-indicated dose of 400 mg daily. Six months post-initiation, 77.7% and 66.8% of patients experienced symptom and spleen response, respectively. Kaplan-Meier estimates of median progression-free and overall survival from initiation were 23.8 months (95% CI, 21.1–27.6) and 29.8 months (95% CI, 23.9-NE), respectively.

Conclusion: These findings demonstrate real-world FEDR effectiveness among patients with myelofibrosis who discontinued RUX.

PLAIN LANGUAGE SUMMARY

What is this summary about?

Myelofibrosis (MF) is a rare blood cancer that can cause unhealthy spleen growth and symptoms, such as feeling tired, loss of appetite, bone pain, and fever. This is a summary of an article that reviewed medical records of patients with MF from treatment centers in Canada, Germany, and the United Kingdom (UK). The study looked at people who had been taking a medication called fedratinib (FEDR) for their MF after they had stopped taking a different medication called ruxolitinib (RUX). Many of the people stopped taking RUX because their MF got worse within a few years. The study wanted to see if taking FEDR reduced symptoms and spleen size for people with MF after they stopped taking RUX.

What were the results?

After at least 6 months of taking FEDR, 77.7% of the people in the study had fewer symptoms, and 66.8% of people in the study had a decrease in spleen size or no spleen growth. Additionally, most people taking FEDR after discontinuing RUX went nearly 2 years without their MF symptoms or illness getting worse.

What do the results mean?

These results suggest that FEDR is an effective treatment for people with MF who have stopped taking RUX.

Cardiovascular Risk Factors Increase Thrombosis, Mortality in Patients With Myelofibrosis, Other MPNs

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January 27, 2025

Author(s): Luke Halpern, Assistant Editor

 

Cardiovascular risk factors (CVRFs) that increase thrombosis and overall mortality are more prevalent in patients with myeloproliferative neoplasms (MPNs), and especially those with myelofibrosis (MF), who have increased rates of hyperlipidemia and hypertension compared with patients with essential thrombocythemia (ET) or polycythemia vera (PV), according to study results published in Blood: Vessels, Thrombosis, and Hemostasis.1

Thrombosis is a potentially serious complication of myelofibrosis. | Image Credit: © Artur | stock.adobe.com

Managing thrombosis risk in patients with MF are pillars of optimal treatment, along with controlling bleeding. Studies have indicated that thrombosis is common across a variety of MPNs, including MF, ET, and PV, and more common in those patients when compared with the general population. CVRFs such as hypertension, hyperlipidemia, type 2 diabetes, and obesity have known effects on thrombosis in the general population, but data is unclear on the impact of CVRFs on patients with MF or other MPNs.2,3

For patients with MF, it is critical for pharmacists and treatment providers to recognize the prevalence of thrombosis and its potential risk factors, including CVRFs. In this current study, the investigators conducted a retrospective cohort analysis of 1005 patients with MPNs to evaluate the impact of CVRFs on real-world patient outcomes. Additionally, study authors investigated the likelihood of MPN transition to conditions such as MF or acute leukemia.1,2,3

Across the study sample, 215 patients had MF, 28 had pre-MF, 415 had ET, and 313 had PV. Patients with MF were found to be more likely to harbor at least 1 CVRF compared with those with ET, PV, and the general patient population (46% vs 34% in the general MPN population), according to the investigators. The most common CVRFs observed in the overall patient population were hypertension (21%), hyperlipidemia (16%), and having a body mass index (BMI) greater than or equal to 30 (12%). For patients with MF, these incidences were 31%, 22%, and 11% respectively.1

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Fedratinib for the treatment of myelofibrosis: a critical appraisal of clinical trial and “real-world” data

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January 14, 2025

Adrian Duek, Ilona Leviatan, Osnat Jarchowsky Dolberg & Martin H. Ellis

Abstract

Fedratinib is a predominantly JAK2 inhibitor that has shown efficacy in untreated and ruxolitinib-exposed patients with myelofibrosis (MF). Based on randomized clinical trial data, it is approved for use in patients with International Prognostic Scoring System (IPSS) or Dynamic International Prognostic Scoring System (DIPSS) intermediate-2 or high-risk disease and is distinguished from ruxolitinib in that it can be administered without dose reduction in patients with thrombocytopenia, to a platelet count above 50,000/µL. In these trials, fedratinib achieved significant spleen volume reduction in ~30–45% of patients and improvement in total symptom scores in 35–40% with good tolerability. In contrast, recently published real-world data suggest that these responses may not be as robust outside clinical trials. In the context of routine clinical practice spleen responses are documented in only 13–68%, with varying degrees of symptom improvement. This may be due to the lack of a uniform definition of ruxolitinib failure, which may influence the timing of initiating fedratinib as a second-line treatment and result in a more prolonged exposure to ruxolitinib prior to intitaing fedratinib treatment. We suggest that given the growing number of drugs available for use in MF, recognizing the failure of first-line (and potentially subsequent) treatments is critical to allow timely transition to potentially more active agents, as highlighted by the data pertaining to fedratinib.

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