Tag Archives: myeloproliferative neoplasms

Ambitious £4 million project to develop clinical platform for blood cancer prevention

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4th Feb 2024 – Edward Pinches

Professor George Vassiliou from the Wellcome-MRC Cambridge Stem Cell Institute (CSCI), University of Cambridge will spearhead the project, which focuses on myeloid blood cancers, a group of blood cancers that accounts for more than 11,000 deaths each year in the UK.

The blood cancers, which affect both the bone marrow and blood, include acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and rarer cancers like chronic myelomonocytic leukaemia (CMML).

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Truong on the Rationale for Investigating ERK2 Substrate Binding Modalities in MPNs

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Billy Truong, PhD candidate, Fox Chase Cancer Center, discusses the rationale for investigating the functions of ERK2 substrate binding modalities in myeloproliferative neoplasms (MPNs).

Truong and colleagues are conducting research investigating cell signaling programs that are altered in MPNs. Specifically, treatment resistance often arises from the activation of the MAPK pathway, Truong says. Approximately 85% of cancers have genetic modifications in proteins, especially in the RAS protein, which ultimately drive uncontrolled tumor cell proliferation, Truong explains.

Downstream of the MAPK pathway is the ERK2 protein, which is a common target of cancer therapies, Truong notes. However, drugs that target the kinase function of ERK2 are traditionally designed to be nonspecific and are therefore toxic to healthy cells expressing ERK2, Truong emphasizes. Accordingly, drug specificity remains an unmet need for patients with MPNs.

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Exploring the Molecular Aspects of Myeloproliferative Neoplasms Associated with Unusual Site Vein Thrombosis: Review of the Literature and Latest Insights

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by Erika Morsia1,2,*, Elena Torre1, Francesco Martini 2,3, Sonia Morè 1,2, Antonella Poloni 1,2, Attilio Olivieri 1,2 and Serena Rupoli 1

Abstract

Myeloproliferative neoplasms (MPNs) are the leading causes of unusual site thrombosis, affecting nearly 40% of individuals with conditions like Budd–Chiari syndrome or portal vein thrombosis. Diagnosing MPNs in these cases is challenging because common indicators, such as spleen enlargement and elevated blood cell counts, can be obscured by portal hypertension or bleeding issues. Recent advancements in diagnostic tools have enhanced the accuracy of MPN diagnosis and classification. While bone marrow biopsies remain significant diagnostic criteria, molecular markers now play a pivotal role in both diagnosis and prognosis assessment. Hence, it is essential to initiate the diagnostic process for splanchnic vein thrombosis with a JAK2 V617F mutation screening, but a comprehensive approach is necessary. A multidisciplinary strategy is vital to accurately determine the specific subtype of MPNs, recommend additional tests, and propose the most effective treatment plan. Establishing specialized care pathways for patients with splanchnic vein thrombosis and underlying MPNs is crucial to tailor management approaches that reduce the risk of hematological outcomes and hepatic complications.

Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements

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by Tanvi Verma 1, Nikolaos Papadantonakis2, Deniz Peker Barclift1 and Linsheng Zhang

Simple Summary

Myelofibrosis refers to fibrosis in the bone marrow associated with certain bone marrow cancers. It is a characteristic of primary myelofibrosis and may develop later in other bone marrow cancers with overproduction of blood cells, such as polycythemia vera and essential thrombocythemia. It has been confirmed that mutations in three key genes, Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia oncogene (MPL), can increase the activity of blood-producing cells, make them grow more actively, and are associated with the development of myelofibrosis. Approximately 80% of myelofibrosis cases carry additional mutations that often involve proteins that control how genes are turned on and off. The presence of mutations provides evidence of a cancerous process. The order in which these mutations occur can influence how the disease manifests. Studies have shown that fibrosis is secondary to the cancerous process and is closely linked to abnormal cell growth driven by mutations. Sophisticated scoring systems have been developed to guide treatment decisions. Specific mutations and genetic changes significantly affect the scores and survival of individual patients. Currently, common treatment involves JAK inhibitors, which can help improve clinical symptoms; however, only a small number of patients show significant alleviation in the biology of the malignant process. New treatments being explored in clinical trials include drugs that target the regulation of genes and substances that modulate the immune system or inflammatory processes. Combining these with JAK inhibitors shows promising results, especially in patients with complex genetic profiles. In the future, by studying more genes, it is expected that researchers will uncover the reasons behind cases where mutations are not found in the three key genes and understand how genetic changes are connected to variable disease presentations, ultimately guiding personalized treatment plans for better outcomes with a chance for cures.

Abstract

Myelofibrosis (MF) is an essential element of primary myelofibrosis, whereas secondary MF may develop in the advanced stages of other myeloid neoplasms, especially polycythemia vera and essential thrombocythemia. Over the last two decades, advances in molecular diagnostic techniques, particularly the integration of next-generation sequencing in clinical laboratories, have revolutionized the diagnosis, classification, and clinical decision making of myelofibrosis. Driver mutations involving JAK2, CALR, and MPL induce hyperactivity in the JAK-STAT signaling pathway, which plays a central role in cell survival and proliferation. Approximately 80% of myelofibrosis cases harbor additional mutations, frequently in the genes responsible for epigenetic regulation and RNA splicing. Detecting these mutations is crucial for diagnosing myeloproliferative neoplasms (MPNs), especially in cases where no mutations are present in the three driver genes (triple-negative MPNs). While fibrosis in the bone marrow results from the disturbance of inflammatory cytokines, it is fundamentally associated with mutation-driven hematopoiesis. The mutation profile and order of acquiring diverse mutations influence the MPN phenotype. Mutation profiling reveals clonal diversity in MF, offering insights into the clonal evolution of neoplastic progression. Prognostic prediction plays a pivotal role in guiding the treatment of myelofibrosis. Mutation profiles and cytogenetic abnormalities have been integrated into advanced prognostic scoring systems and personalized risk stratification for MF. Presently, JAK inhibitors are part of the standard of care for MF, with newer generations developed for enhanced efficacy and reduced adverse effects. However, only a minority of patients have achieved a significant molecular-level response. Clinical trials exploring innovative approaches, such as combining hypomethylation agents that target epigenetic regulators, drugs proven effective in myelodysplastic syndrome, or immune and inflammatory modulators with JAK inhibitors, have demonstrated promising results. These combinations may be more effective in patients with high-risk mutations and complex mutation profiles. Expanding mutation profiling studies with more sensitive and specific molecular methods, as well as sequencing a broader spectrum of genes in clinical patients, may reveal molecular mechanisms in cases currently lacking detectable driver mutations, provide a better understanding of the association between genetic alterations and clinical phenotypes, and offer valuable information to advance personalized treatment protocols to improve long-term survival and eradicate mutant clones with the hope of curing MF.

Dr Vincelette on MYC Expression in Myelofibrosis

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Nicole D. Vincelette, PhD

Nicole D. Vincelette, PhD, postdoctoral fellow, Moffitt Cancer Center, discusses findings from a study investigating the role of MYC expression and S100A9-mediated inflammation in a subgroup of triple-negative myeloproliferative neoplasms (MPNs).

To determine how MYC expression drives MPNs, such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis, Vincelette and colleagues conducted a study in which they generated a mouse model that overexpresses MYC in the stem cell compartment. This analysis demonstrated that MYC overexpression was associated with the mice developing a myelofibrosis-like phenotype, which included anemia, atypical megakaryocytes, splenomegaly, bone marrow fibrosis, liver fibrosis, spleen fibrosis. The mice also experienced adverse clinical outcomes, such as reduced overall survival (OS), compared with wild-type mice, Vincelette says.

Since the MYC-overexpressed mice developed myelofibrosis, the next step of this research was to investigate how MYC drives myelofibrosis, Vincelette explains. Investigators performed single-cell RNA sequencing to compare the bone marrow cells from MYC-overexpressed and wild-type mice. MYC overexpression correlated with upregulation of the S100A9 protein, which contributes to inflammation and innate immunity, according to Vincelette. Therefore, MYC drives the development of myelofibrosis through S100A9-mediated chronic inflammation. To validate the role of S100A9 downstream of MYC in myelofibrosis, investigators created a mouse model with S100A9 knockout in the presence of MYC overexpression, Vincelette notes. The S100A9 knockout protected against the development of myelofibrosis phenotype in that mouse model, Vincelette emphasizes.

By generating a mouse model that overexpresses S100A9, investigators also determined that S100A9 overexpression alone contributes to the development of myelofibrosis phenotypes, Vincelette says. When investigators treated the MYC-overexpressing mice with the S100A9 inhibitor tasquinimod (ABR-215050), the agent only partially abrogated the myelofibrosis phenotype, meaning the mice had reduced atypical megakaryocytes and splenomegaly. Additionally, the mice developed anemia and no OS difference occurred between tasquinimod and vehicle treatment, potentially because of off-target drug effects, Vincelette concludes.

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Three Key Relationships Bring New Drugs to the MPN Community

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 Byline:  Ann Brazeau, CEO & Founder

MPN Advocacy and Education International prides itself on bringing the experts to the MPN Community to ensure they are receiving accurate and updated information about clinical trials, treatment options, quality of life issues, and everything that could affect them medically.  It also brings biopharmaceutical companies together with the researchers/clinicians at all of their programs in an effort to inform both physician and patient who is doing what in the laboratories around the world that could bring a new drug to commercialization for their use.

These three relationships are critical to new drug development.  Our Industry Partners’ research and development teams work tirelessly in their labs to find answers to perplexing questions myeloproliferative neoplasms present.  The MPN specialists who give so much of their time to speak at our programs, spend hours in their labs and also see patients throughout each day to understand the complexities of MPNs and how to best treat each patient, and many participate in heading trials at their academic and medical institutions.  Patients participate and commit to lengthy clinical trials to help discover what works and what doesn’t.  Without them, drugs would not be developed or approved. Drugs have to be tested for safety and efficacy in patients.  There is no way around this fact.  Hats off to those who volunteer to participate in clinical trials in hopes that the drug may one day benefit others who have the same condition as theirs.  Participation in a clinical trial is a major contribution to our society.

Learn more about MPN clinical trials

This intricate connection is the key to so many discoveries that have saved lives, cured the common headache, stopped seizures, and cured some cancers.  While preclinical research answers basic questions about a drug’s safety, it is not a substitute for studies of ways the drug will interact with the human body.  People living with a chronic disease, like an MPN, benefit enormously from the pipeline of medications brought to market by hard-working clinical researchers who design and carry out clinical trials that show promise after testing in animals.

Education is critical to the success of clinical trials and participation.  If physicians that treat you are not aware of the numerous trials currently underway, is it your responsibility to share what you know? We would say yes.  Our programs for physicians that treat MPN patients always includes updates about current trials to be sure they are made aware of every single trial in the MPN space.  This information coupled with site locations and trial criteria are essential to connecting the patient to a specific trial.

In this era of individualized treatment protocols and combination therapies, which will eventually be widespread in not only MPNs but other disease areas, it would be a shame to miss opportunities where potentially good therapies might fall off the grid for lack of trial participants and trial sites due to already strained programs.  With the robust activity in MPNs currently, the challenges accompany the gains.  Thus, the relationships among the three groups is even more important.

MPN Advocacy and Education International understands the challenges experienced by all three entities.  Each plays an integral role in bringing new drugs to the shelves and ultimately to patients.  Researchers who participate in trials and see patients can be overwhelmed.  Patients may have financial issues that prohibit a commitment to a trial even if they want to participate.  There are social and cultural factors that have historically left many trials with one demographic of participants, namely white, insured, and often retired.

The good news is organizations and our partners want to understand the challenges and want to help in all ways.  In the seventeen years I’ve been working in MPNs, I am seeing the fruits of our advocating and educational efforts not only for patients, but in our relationships with biopharmaceutical companies and the hundreds of physicians who are not necessarily MPN specialists that see MPN patients.  Our engagement and desire to grow a deeper understanding of the many challenges patients face has created a real interest in finding ways to close the gaps in areas of access, participation, education, and support.

Without collaboration and communication, the momentum needed for new drug development would quickly lose steam.  MPN Advocacy and Education International remains committed to providing a platform for the dialogue necessary to keep the wheels in motion.

View our MPN Clinical Trials 101 Webinar

 

 

MPN Specialists Videos

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MPN Advocacy & Education International partnered with MPN specialists to offer insights on patient concerns and updates on drug treatments during this pandemic. The videos are now available on our YouTube channel, click here to subscribe.

These videos are made possible by a grant from Bristol Myers Squibb

Naveen Pemmaraju, MD-MD Anderson Cancer Center

 

Mark Heaney, MD, PhD-Columbia University Medical Center

 

Ellen Ritchie, MD-Weill Cornell Medicine

 Linda Smith-Resar, MD-Johns Hopkins

Dr. Resar’s presentation will be posted as soon as it is available.

One Patient’s Point of View on “Living” with Myelofibrosis

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David told his story at the Cleveland MPN Patient Program in November

On a beautiful fall day in late August 2013, I received a call that changed the course of my life. The voice on the other end told me that they had reviewed my blood counts and determined that I had some sort of leukemia. They had pre-admitted me to the local hospital to meet an oncologist and have the necessary tests. After about two weeks I received my diagnosis of Primary Myelofibrosis, Intermediate 1. I was told that treatment options were limited and the only true cure was allogeneic bone marrow transplan

It is tempting to focus all our energies on our hope in medical interventions. But diagnosis brings fear, denial, anger, & depression. These impact your relationships and can throw you into a downward spiral. Being diagnosed with a life-threatening disease like an MPN is an existential challenge. It raises all the questions: Why are we here? What is life about? What lies beyond this life? How you answer these questions will affect how you deal with your disease and its physical effects.

We are all tempted to be sad and maybe even angry. But you do not have to give in to the negative. You can choose to respond with a positive attitude.

 

My diagnosis has changed the course of my life – but for the better. Because of myelofibrosis, I realized that I was spending far too much of my time and energy focused on some sort of future achievement. I was super-busy every day and the days passed in a blur. But myelofibrosis woke me up to the truth that life is not about some future achievement. Life is about today. Since my diagnosis, I have come to have a heightened enjoyment of the simple pleasures of daily living.

These last six years have been wonderful and I have enjoyed them more because of my disease. My son and his wife have been kind enough to give us two new grandchildren in the past four years – and I am making the most of that. I’ve made many good friends in the MPN community.  I took up motorcycle riding.  The more aware I am of my mortality – the more I savor every experience of life.

Your life only comes one day at a time. Today is the day you have – make it into something good. Refuse to let an uncertain future rob you of today’s joys.

David shared his story in the MPN Community Connection Newsletter click here to view

 

David is the support group coordinator for the northern Pennsylvania/Ohio area, if you are interested in participating you can contact us for more information. Click here to contact us.