February 25, 2025
by Thita Chiasakul and Ross I. Baker
February 25, 2025
by Thita Chiasakul and Ross I. Baker
February 21, 2025
Fedratinib (Inrebic) as a maintenance therapy following allogeneic hematopoietic cell transplant given at a 400 mg daily dose was determined to be safe and established as the maximum tolerated dose (MTD) for patients with myeloproliferative neoplasms (MPNs).1
Findings come from a recent phase 1 trial where experts explored the potential of fedratinib, a JAK2 inhibitor already approved for pre-transplant myelofibrosis, as a post-transplant maintenance therapy to reduce relapse risk and mitigate graft-vs-host disease (GVHD).
In an interview with Targeted OncologyTM, Hany Elmariah, MD, associate member at the Moffitt Cancer Center in the department of bone marrow transplant and cellular immunotherapy, discussed the trial’s findings, the safety profile of fedratinib, and its evolving role in the post-transplant setting.
Targeted Oncology: Could you discuss the background of this study and what motivated the research?
Elmariah: One of my areas of research is transplant for myelofibrosis and myeloproliferative neoplasms. While transplant can be curative, the cure rate, depending on the study, is generally in the 40% to 60% range. The main reason patients are not cured by transplant is largely the risk of relapse, which [occurs when] the cancer returns after the transplant. For those who do not relapse, there is also the risk of toxicity, such as GVHD, where the transplant attacks the patient’s own body. There are many strategies in development, both for myelofibrosis and other cancers, to reduce the risks of relapse and GVHD.
February 20, 2025
Markus Hoffmann & Lothar Hennighausen
The JAK-STAT pathway is central to cytokine signaling and controls normal physiology and disease. Aberrant activation via mutations that change amino acids in proteins of the pathway can result in diseases. While disease-centric databases like COSMIC catalog mutations in cancer, their prevalence in healthy populations remains underexplored. We systematically studied such mutations in the JAK-STAT genes by comparing COSMIC and the population-focused All of Us database. Our analysis revealed frequent mutations in all JAK and STAT domains, particularly among white females. We further identified three categories: Mutations uniquely found in All of Us that were associated with cancer in the literature but could not be found in COSMIC, underscoring COSMIC’s limitations. Mutations unique to COSMIC underline their potential as drivers of cancer due to their absence in the general population. Mutations present in both databases, e.g., JAK2Val617Phe/V617F – widely recognized as a cancer driver in hematopoietic cells, but without disease associations in All of Us, raising the possibility that combinatorial SNPs might be responsible for disease development. These findings illustrate the complementarity of both databases for understanding mutation impacts and underscore the need for multi-mutation analyses to uncover genetic factors underlying complex diseases and advance personalized medicine.
Alexander Coltoff (Medical University of South Carolina, United States) John Mascarenhas (Icahn School of Medicine at Mount Sinai, United States)
Dysregulated JAK/STAT signaling underlies the pathogenesis of myelofibrosis, a myeloproliferative neoplasm characterized by cytopenias, splenomegaly and constitutional symptoms. JAK inhibitors, such as fedratinib, are the primary therapeutic option for patients with high-risk or symptomatic myelofibrosis. Fedratinib has characteristics that distinguish it from the other commercially available JAK inhibitors, such as its preferential inhibition of JAK2 and its inhibitory effects on kinases such as FLT3 and BRD4. Fedratinib is most often used in the second-line setting after intolerance or resistance to other JAK inhibitors, but there is substantial evidence that it is an effective first-line option in the appropriate patient population. Prevention and early treatment of fedratinib-related gastrointestinal toxicity is key to maintaining adequate drug exposure, and clinicians must remain vigilant for Wernicke encephalopathy during treatment. Fedratinib’s JAK2 selectivity and kinome profile make it an appealing agent for alternative indications, such as myelodysplastic/myeloproliferative neoplasms and maintenance after bone marrow transplantation, which are under active investigation.
Symptoms such as fatigue, itchy skin, and mental health issues can make it difficult to function, but they can be managed. “This is a chronic condition that people can live with,” says Jacqueline S. Garcia, MD, a medical oncologist at Dana-Farber Cancer Institute in Boston.
Here are some common challenges of living with PV and ways to cope, so you can stay healthy and live well as you manage this condition.
The degree of fatigue can vary from one person to another and depend on age, menopausal status, other health conditions — such as cardiovascular disease or diabetes — and more factors, says Garcia.
Maintaining healthy lifestyle habits may help you feel more energized every day. For instance, Garcia recommends exercising in moderation, as long as you have your doctor’s okay and don’t push yourself if you feel faint.
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.
February 2025
Kathrine GotfredsenAndreas Abou-TahaCharlotte LiisborgMarie Krogh NielsenMorten Kranker LarsenVibe SkovLasse KjærHans Karl HasselbalchTorben Lykke Sørensen
Purpose: Previous findings indicate that patients with myeloproliferative neoplasms (MPN) exhibit elevated levels of inflammatory biomarkers and have a high prevalence of AMD. In this study, we aim to determine whether drusen and systemic inflammation in patients with MPN affect macular sensitivity in the same manner as in patients with AMD.
Methods: The study was conducted as a prospective cross-sectional study. A total of 139 study eyes of 71 patients were included in this study. We measured macular sensitivity using microperimetry and extracted blood samples to evaluate systemic inflammation markers.
Results: Multilevel linear mixed-effect analysis did not show any difference in macular sensitivity when comparing eyes of MPN patients with AMD to those without drusen (β = −0.254, P = 0.657). However, higher levels of the complement system fragment C5a were significantly correlated with decreased total macular sensitivity (β = −0.561, P = 0.027), irrespective of the presence of drusen.
Conclusions: We found that high levels of the systemic inflammation marker C5a are associated with reduced macular sensitivity, regardless of the presence of visible degenerative changes in the macular area. These findings suggest an early contribution of the complement system to macular sensitivity.
February 2025 Vol 11 No 1
Dr. Lucia Masarova
Polycythemia vera was first recognized by French physician Louis H. Vaquez in 1892 and was known then as maladie de Vaquez.1 The name poly-cyt-[h]emia originates from the Greek and Latin, and literally means many-cells-in the blood. In 1951, Dr. William Dameshek included polycythemia vera in the category of classic Philadelphia chromosome–negative myeloproliferative disorders (now classified as myeloproliferative neoplasms, MPNs; myelo refers to the bone marrow, proliferative refers to rapid growth of blood cells, and neoplasm describes abnormal and excessive growth). It is the only one among the 3 classic MPNs that exhibits erythrocytosis, the increased production of red blood cells. Polycythemia vera is a condition associated with overproduction of all blood cells, including white cells and platelets.
Polycythemia vera is a chronic, incurable disease of the hematopoietic stem cells, the primary cells that can develop into different types of blood cells and are responsible for the production of blood cells during a human’s entire life. It is a clonal disease, meaning it occurs when a mutated hematopoietic stem cell starts making clones—cells with the same genetic mutation. Most affected patients can live a relatively normal and long life.
A breakthrough discovery of a genetic “driver” of polycythemia vera was made in 2005—a mutation in the JAK2 gene was found in 95% of cases, typically JAK2V617F, a mutation that leads to the constitutive activation of the JAK-STAT protein pathway causing unregulated overproduction of hematopoietic cells. This discovery led to improved understanding of the biology, pathogenesis, and long-term behavior of the disease and initiated numerous efforts to develop novel therapies focused on the inhibition of the JAK-STAT pathway.
The abnormal function of the immune system and the subsequent increased inflammation, powerfully driven by the JAK-STAT pathway as the major regulator of inflammatory signaling, contribute to disease progression and an impaired quality of life. Despite the relatively slow progression of the disease course in most patients, the disease possesses its challenges and risks, including a lifetime risk of developing thrombosis (blood clots); the evolution into myelofibrosis, a chronic type of leukemia; or development into acute leukemia. Both blood clots and leukemia are consequences that can shorten life expectancy significantly.
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
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
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.