Tag Archives: mpn

Scientists team up with York Hospital to study DNA mutations behind blood cancers

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Posted on 23 May 2024

Scientists from the University of York are working with doctors and patients at York Hospital to understand the DNA mutations linked to a group of chronic blood cancers, and investigate why, in some cases, they can suddenly become more aggressive.

The researchers, from the newly formed Centre for Blood Research at the University of York, are recruiting participants from York Hospital with myeloproliferative neoplasms (MPNs), a group of blood cancers characterised by the overproduction of red blood cells and/or platelets.

There are around 4,000 cases of MPNs in the UK each year and they most commonly affect people over 60. Often, they remain stable and progress slowly, which means people can live with them for a long time without being very unwell.

However, in a few rare cases, they can transform into more aggressive cancers which need urgent treatment, such as acute myeloid leukaemia (AML), where faulty myeloid cells – which include red blood cells and platelets – build up in the body and stop the blood and immune system from functioning normally.

Valuable insights

Dr Katherine Bridge, from the Department of Biology and Centre for Blood Research at the University of York, said: “We want to better understand the DNA mutations that cause these cancers, and to see whether there are additional factors that cause them to suddenly transform and become more aggressive.

“MPNs behave like the early stages of other blood cancers, offering valuable insights into their progression. Often, these crucial initial stages occur too quickly in other cancers for us to be able to track them effectively. By focusing on MPNs, we have a unique opportunity to scrutinise these early events, potentially uncovering strategies to halt the advancement of more aggressive malignancies.”

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JAK Inhibitor–Based Combinations Could Represent the Next Frontier in Myelofibrosis

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Ryan Scott

In an interview with OncLive® following the Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium, Ashwin Kishtagari, MD, discussed advancements in the treatment of patients with intermediate-risk to high-risk myelofibrosis and highlighted recent data from the 2023 ASH Annual Meeting for combination therapies using JAK inhibitors.

Studies presented at the meeting included the phase 3 TRANSFORM-1 clinical trial (NCT04472598)evaluating navitoclax plus ruxolitinib (Jakafi), as well as the phase 3 MANIFEST-2 trial (NCT04603495) investigating pelabresib (CPI-0610) in combination with ruxolitinib.1,2

Kishtagari, who serves as an assistant professor of medicine in the Department of Hematology and Oncology at Vanderbilt University Medical Center, as well as a clinical research fellow in Bick Lab at Vanderbilt University School of Medicine in Nashville, Tennessee, provided further updates on JAK inhibitors for the treatment of patients with myelofibrosis in another interview with OncLive.

OncLive: How do you see the treatment paradigm for myelofibrosis evolving in the future?

Kishtagari: We have 4 JAK inhibitors which are FDA approved for the treatment of [patients with] myelofibrosis, with the first being ruxolitinib. Fedratinib [Inrebic] was the second agent approved in 2019. Pacritinib [Vonjo] was approved by the FDA in 2022, and momelotinib [Ojjaara]was approved in 2023.

We are moving toward combination therapies because our goal is to have a more significant improvement in splenomegaly response and symptom improvement. The whole field of myelofibrosis is moving toward combination therapy, especially for patients with higher- or intermediate-risk myelofibrosis.

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Metformin May Help Reduce the Risk of Developing Myeloproliferative Neoplasms

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By The ASCO Post Staff

Posted: 5/21/2024 9:31:00 AM
Last Updated: 5/21/2024 12:27:21 PM

 

Treatment with metformin may be associated with a lower risk of developing myeloproliferative neoplasms over time, according to a recent study published by Kristensen et al in Blood Advances.

Background

Myeloproliferative neoplasms are a group of diseases that develop over long periods of time and affect how bone marrow produces blood cells, resulting in an overproduction of red blood cells, white blood cells, or platelets that can lead to bleeding problems, a greater risk of stroke or heart attack, and organ damage.

Metformin—a therapy used to treat high blood sugar in patients with type 2 diabetes—works by increasing the effect of insulin, reducing how much glucose is released from the liver, and increasing the body’s glucose absorption.

Previous analyses have demonstrated that the therapy may reduce the risk of gastrointestinal cancer, breast cancer, urologic cancer, as well as other solid tumors and hematologic malignancies.

“Our team was interested in understanding what other effects we see with commonly prescribed treatments like metformin,” explained senior study author Anne Stidsholt Roug, MD, PhD, Clinical Associate Professor at Aalborg University Hospital and Chief Physician at Aarhus University Hospital in Denmark. “The anti-inflammatory effect of metformin interested us, as [myeloproliferative neoplasms] are very inflammatory diseases,” she added.

Study Methods and Results

In the recent study, investigators examined metformin use among 3,816 patients diagnosed with myeloproliferative neoplasms and 19,080 matched controls from the Danish general population between 2010 and 2018.

The investigators found that 7.0% (n = 268) of the patients with myeloproliferative neoplasms and 8.2% (n = 1,573) controls received metformin. Just 1.1% of the patients with myeloproliferative neoplasms had received the therapy for over 5 years vs 2.0% of controls. After adjusting for potential confounders, the investigators noted that the protective effect of metformin was observed in all subtypes of myeloproliferative neoplasms.

Conclusions

“We were surprised by the magnitude of the association we saw in the data,” emphasized lead study author Daniel Tuyet Kristensen, MD, a PhD student at Aalborg University Hospital. “We saw the strongest effect in [patients] who had taken metformin for more than 5 years as compared [with] those who had taken the treatment for less than 1 year,” he added.

The investigators revealed that the study was limited by its registry-based retrospective design and an inability to account for lifestyle factors influencing cancer risk such as smoking, obesity, and dietary habits. They hope to conduct additional studies to better understand the mechanisms behind the therapy’s protective effects against the development of myeloproliferative neoplasms. The investigators further plan to identify any similar trends with myelodysplastic syndromes and acute myeloid leukemia in population-level data in future studies.

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Ajax Therapeutics Announces FDA Clearance of IND Application for AJ1-11095, a First-in-Class Type II JAK2 inhibitor, for the Treatment of Myelofibrosis

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– AJ1-11095 is the first Type II JAK2 Inhibitor to ever enter the clinic –

– Phase 1 dose escalation study expected to begin in 2H 2024 –

NEW YORK & CAMBRIDGE, Mass.–(BUSINESS WIRE)–Ajax Therapeutics, Inc., a biopharmaceutical company developing next generation JAK inhibitors for patients with myeloproliferative neoplasms (MPNs), today announced that it has received clearance for its Investigational New Drug (IND) application from the U.S. Food and Drug Administration (FDA) to initiate a Phase 1clinical study of AJ1‑11095, a first-in-class Type II JAK2 inhibitor, for the treatment of patients with myelofibrosis.

“This is an important milestone for our company and our first program to enter the clinic and the first clinical study to ever evaluate a Type II JAK2 inhibitor in patients.”

“We are thrilled to obtain clearance to advance AJ1-11095 into the clinic and excited to bring this innovative new medicine to patients with myelofibrosis,” said Martin Vogelbaum, co-founder and CEO of Ajax Therapeutics. “This is an important milestone for our company and our first program to enter the clinic and the first clinical study to ever evaluate a Type II JAK2 inhibitor in patients.”

“We look forward to the clinical development of AJ1-11095 in myelofibrosis and to initiating our Phase 1 dose escalation study, AJX-101, later this year,” said David Steensma, MD, FACP, Chief Medical Officer at Ajax. “As a first-in-class therapy with a unique mechanism as a Type II inhibitor of JAK2, AJ1-11095 was developed to provide a much-needed new treatment for patients with myelofibrosis by offering the potential for improved efficacy with disease modifying effects compared to existing therapies.”

About AJ1-11095

AJ1-11095 was designed by Ajax, through our collaboration with Schrödinger, to be a next generation JAK2 inhibitor by using structure-based drug design and computational methods at scale to selectively bind the Type II conformation of the JAK2 kinase and to provide greater efficacy with disease modification compared to all currently approved JAK2 inhibitors which bind the Type I conformation of JAK2. Additionally, AJ1-11095 has been shown in preclinical studies to reverse marrow fibrosis, reduce mutant allele burden and maintain efficacy against MPN cells that become resistant to chronic Type I JAK2 inhibition.

About Myelofibrosis

Myelofibrosis (MF) is a rare blood cancer that affects approximately 20,000 patients in the United States. The disease is characterized by spleen enlargement, scarring (fibrosis) in the bone marrow, progressive anemia, and debilitating symptoms, such as fatigue, night sweats, itching, and abdominal discomfort, which can impair a patient’s’ quality of life. The most widely used treatment for MF patients are Type I JAK2 inhibitors which can reduce spleen size and provide symptomatic improvement but have little effect on the underlying cause of disease. Over time, most MF patients stop Type I JAK2 inhibitor therapy. The most common causes for treatment discontinuation include a lack of benefit or loss of response, adverse events, and disease progression, leaving significant unmet treatment needs for these patients.

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Novel Targets Beyond the JAK-STAT Pathway Aim to Push Myelofibrosis Treatment Forward

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Jax DiEugenio

Ongoing research in myelofibrosis continues to focus on agents directed at novel targets with the hope of expanding treatment options beyond the host of JAK inhibitors used in this treatment paradigm, according to Anthony M. Hunter, MD.

“[There are] a lot of novel agents on the horizon [that could] work in combination with JAK inhibitors to hopefully continue to move that bar forward for patients [with myelofibrosis,” said Hunter, who is an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and the medical director of the Immediate Care Center at Winship Cancer Institute of Emory University in Atlanta, Georgia.

In an interview with OncLive®, Hunter explained the evolving understanding of the biology of myelofibrosis, detailed the growth of JAK inhibitors being used for the treatment of these patients, and expanded on novel targets and agents currently being tested in clinical trials.

OncLive: How has our understanding of the pathology of myelofibrosis evolved in recent years as more research studies have been conducted?

Hunter: What has been well documented for years now is that the key biologic pathway or cell-signaling pathway actually involved in myeloproliferative neoplasms [MPN] or myelofibrosis is the JAK-STAT pathway. That [understanding] was advanced in 2005 when we found out about the JAK2 mutation in a large percentage of these patients, [and we] subsequently [found out about] the MPL and CALR mutations, as well. We find that in all patients with MPN or myelofibrosis, irrespective of those mutations, we see activation of this JAK-STAT signaling pathway, which has a lot of different effects and we can break those up into effects on hematopoiesis, or how they affect sort of blood cell production.

Then we also see increases in inflammatory cytokine signaling. The JAK/STAT pathway signals through a lot of cytokine and inflammatory receptors, so we see a lot of inflammatory signaling increase in a number of different cytokine levels and in myelofibrosis, which impacts the disease and the symptoms that we see. That has been key to [understanding] the biology [of myelofibrosis] and has led to the development of JAK inhibitors.

We’ve started to move beyond [the JAK-STAT] pathway a little bit, as well. A lot of the research now and new agents that are being explored in clinical trials are largely looking at non–JAK inhibitor agents, combining other pathways such as BET inhibitors, various other signaling molecules, and anti-fibrotic type compounds. All of those have additional roles, along with the JAK-STAT pathway in myelofibrosis.

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Pooled Analysis Shows Cytoreduction to Be Safe, Tolerable in Younger Patients With PV

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Ashling Wahner

Cytoreductive therapy with interferon alfa (rIFNα) or hydroxyurea is safe and well tolerated in patients with polycythemia vera (PV) under the age of 60 years and induces annualized discontinuation rates comparable to those reported with these agents in older patients with PV, for whom cytoreductive therapy is routinely used, according to findings from a meta-analysis that were published in Blood Advances.1

Across the 14 studies included in this analysis, rIFNα discontinuation rates ranged from 4.6% to 37% over median durations of 0.4 to 6.3 years. Hydroxyurea discontinuation rates ranged from 2.6% to 17% over median durations of 0.5 to 14 years.

Although the use of cytoreductive agents, such as rIFNα and hydroxyurea, is associated with reduced thrombosis risk in PV, these agents are not routinely recommended by the European LeukemiaNet (ELN) or the National Comprehensive Cancer Network (NCCN) for patients with PV under the age of 60 years. The ELN recommends cytoreductive therapy for patients with PV who are younger than 60 years of age and have not had prior thrombotic events provided that they have strictly defined phlebotomy intolerance, symptomatic progressive splenomegaly, persistent or progressive leukocytosis, extreme thrombocytosis, persistently high cardiovascular risk, inadequate hematocrit control requiring phlebotomies, and/or persistently high symptom burden.2 The NCCN does not recommend cytoreductive therapy as initial treatment for patients with low-risk disease.3

“Unfortunately, effective and potentially life-prolonging cytoreductive therapy is often deferred in younger patients who are considered ‘low-risk’ because of their age and lack of thrombosis history,” senior study author Ghaith Abu-Zeinah, MD, an instructor in medicine at Weill Cornell Medical College and an assistant attending physician at the NewYork Presbyterian Hospital in New York, New York, and coauthors, wrote in the paper.1 “The rationale for withholding cytoreductive therapy is data-sparse and driven by theoretical concerns for toxicity and unknown benefits from early treatment. Yet, there is some evidence that early treatment is both well tolerated and potentially useful.”

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Momelotinib Improves Anemia in JAK Inhibitor-Naive Myelofibrosis

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Sabrina Serani

Treatment with momelotinib (Ojjaara) delivered benefits to anemia among patients with myelofibrosis who were naive to JAK inhibitors, regardless of their baseline hemoglobin level. Further, momelotinib provided significant anemia benefits compared with ruxoltinib (Jakafi), according to an analysis from the phase 3 SIMPLIFY-1 study (NCT01969838).

SIMPLIFY-3 randomized 432 patients with myelofibrosis who had not received JAK inhibitors toreceive momelotinib or ruxolitinib.In patients who were anemic and received momelotinib, mean hemoglobin levels increased by weeks 2 to 4 of treatment, and hemoglobin levels remained stable among patients who were not anemic.

Comparatively, patients who were anemic and nonanemictreated with ruxolitinib experienced an initial decrease in mean hemoglobin. This decrease stabilized after weeks 4 to 6 as patients received red blood cell transfusions. Patients receiving ruxolitinib were permitted to cross over to the momelotinib group, and mean hemoglobin levels increased after this change.

The study also evaluated patients at different levels of anemia. Among patient who were mildly anemic, with ahemoglobin levelbetween 10 and 12 g/dL, 90.4% of patients were transfusion-free at baseline, 93.9% of these patients remained transfusion-free while receiving momelotinib. Four patients who were not transfusion-free at baseline became transfusion-free while on treatment. In contrast, patients who were mildly anemic in the ruxolitinib arm became more dependent on transfusion; 50% of patients who were transfusion-free at baseline required a transfusion while on ruxolitinib.

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Serum Albumin Levels May Predict Survival Among Patients With Myelofibrosis Treated With Ruxolitinib

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Jonathan Goodman, MPhil

Serum albumin may function as a dynamic surrogate marker for clinical outcomes among patients with myelofibrosis treated with ruxolitinib, according to research published in JCO Precision Oncology. The utility of this surrogate measure may, however, vary by a given patient’s treatment status.

Previous work has established ruxolitinib, a JAK inhibitor, as a standard of care among patients with myelofibrosis. Yet although this treatment may help to reduce spleen size and symptom burden, it is unclear whether it improves overall survival (OS) rates.

New models, such as the RR6 model, have aimed to provide a prognostic surrogate measure for OS, though whether these models effectively distinguish high-risk disease from cases where there is no response to treatment is unclear. For this study, researchers aimed to evaluate whether serum albumin — which is linked with an anti-inflammatory response to treatment — is an effective surrogate marker for OS among patients with myelofibrosis.

Overall, data from 396 patients were included. In the cohort, among evaluable patients, 91 had received ruxolitinib while 305 were naïve to treatment, 58% of patients were male sex, and 72% of patients had primary myelofibrosis.

Analysis suggested that serum albumin levels frequently dropped among all patients, though this was less pronounced among patients treated with ruxolitinib. Relatedly, patients with a high serum albumin level at baseline had improved median OS periods (53.5 months) compared to patients with low levels (29.8 months; odds ratio, 1.95; P <.001).

The link between serum albumin levels and OS was independent of variables included in the dynamic international prognostic scoring system, though only among patients who were naïve to ruxolitinib.

Future efforts to incorporate serum albumin with other inflammatory markers into an inflammatory index and assess its relevance in the context of other JAK inhibitors and combinations are ongoing.

Furthermore, among patients treated with ruxolitinib, changes in serum albumin levels predicted OS. Among patients with stable levels or an increase, median OS was 82.7 months, compared with 64.1 months among patients with a decrease (P =.04).

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Genetics and Genetic Testing to Inform Myelofibrosis Clinical Management

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by Charles Bankhead, Senior Editor, MedPage Today May 1, 2024

The history of primary myelofibrosis dates back to 1951 and the description of four distinct clinicopathologic entitiesopens in a new tab or window that came to be known as myeloproliferative neoplasms (MPNs): chronic myeloid leukemia (CML), polycythemia vera, essential thrombocythemia, and myelofibrosis.

Discovery of the Philadelphia (Ph) chromosome in 1960opens in a new tab or window paved the way to identification of BCR/ABL as the principal genetic driver of CML. Another 45 years passed before the discovery of a first genetic driver of non-Ph MPNs, a mutation in the Janus kinase 2 (JAK2) gene,opens in a new tab or window which occurs in 50-60% of myelofibrosis cases.

“The identification of that particular pathway was foundational, and it has changed the face of how we treat patients,” said James Rossetti, DO, of the University of Pittsburgh. “The JAK2 mutation is not present in everyone with myelofibrosis, and there are other mutations as well.”

Researchers identified a third key driver in 2013opens in a new tab or window: calreticulin gene (CALR). The mutation is associated with about 25% of myelofibrosis cases.

Most studies have shown that JAK2, MPL, and CALR are mutually exclusiveopens in a new tab or window and do not occur together. However, a few studies have shown co-occurrence of the three key mutations. Even though JAK2, MPL, and CALR usually do not occur together, numerous other mutations have been identified in association with the three primary mutations. As many as 80% of patients with myelofibrosisopens in a new tab or window have one or more other mutations.

Historically, myelofibrosis treatment was palliative in nature, aimed at relieving specific symptoms. The discovery of the JAK2 driver mutation has transformed treatment. Since 2011 four JAK2 inhibitors have received FDA approval: ruxolitinib (Jakafi)opens in a new tab or window, fedratinibopens in a new tab or window (Inrebic), pacritinibopens in a new tab or window (Vonjo), and momelotinibopens in a new tab or window (Ojjaara). All four drugs demonstrated ability to reduce splenomegaly, a major clinical manifestation of myelofibrosis, as well as symptoms.

Some of the co-occurring mutations are targetable, creating interest in combination therapies that simultaneously target different signaling pathways, said Aaron Gerds, MD, of the Cleveland Clinic. One such combination was evaluated in a clinical trial that paired a JAK2 inhibitor with an IDH2 inhibitor.

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Direct and indirect costs for patients with myeloproliferative neoplasms

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Jingbo Yu, James Nelson, Taylor Marlin, Evan Braunstein, & Michelle Jerry

Abstract

Myeloproliferative neoplasms (MPNs) are associated with substantial healthcare resource use and productivity loss. This retrospective cohort analysis used disability leave and medical claims data to measure direct and indirect healthcare costs associated with MPNs. The analysis included 173 patients with myelofibrosis (MF), 4477 with polycythemia vera (PV), 6061 with essential thrombocythemia (ET), and matched controls (n = 519, n = 13,431, and n = 18,183, respectively). Total healthcare costs were significantly higher for cases versus controls in each cohort (mean cost difference: MF, $67,456; PV, $10,970; ET, $22,279). Cases were more likely than controls to take disability leave and incurred higher disability-related costs. Among subgroups with thrombotic events, direct and indirect costs were higher for cases versus controls. Thrombotic events substantially increased direct costs and disability leave for patients with PV or ET compared with the full PV or ET cohorts. These findings demonstrate increased economic burden for patients with MPNs.

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