MPN Word of the Month: Cytokines

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MPN Word of the Month:

Cytokines

Recently, I heard someone describe cytokines as ingredients that make up a recipe. The recipe is a response to a specific event. Like, when we make chicken soup when someone we love has a cold. Each person with an MPN has their own special ingredients that come together in  response  to different events that happen inside and outside of the body. 

So what are cytokines, really? Cytokines are tiny proteins secreted by cells to communicate with one another.  What do they say? Basically, they say to activate (go from doing nothing to doing something), proliferate (make more cells), or differentiate (become more specialized, like becoming an eye cell or a liver cell).

Cytokines can send messages to increase inflammation (pro-inflammatory), or stop inflammation (anti-inflammatory). Inflammatory cytokines play a role in the development and progression of myeloproliferative neoplasms. 

Some research suggests that there are certain cytokines commonly associated with MPNs. For example, IL-1β (Interleukin-1beta), TNF-α (Tumor Necrosis Factor-alpha) , IL-6 (Interleukin-6), IL-8 (Interleukin-8), VEGF (Vascular Endothelial Growth Factor), PDGF (Platelet Derived Growth Factor), TGF-β (Transforming Growth Factor-beta), and IFNs (Interferons). These cytokines are expressed in different ways that may contribute to the various MPN subtypes. 

For example, a recipe may call for tomatoes, but there are different kinds of tomatoes based on their individual genetic makeup…Roma tomatoes, San Marzano tomatoes, Cherry tomatoes. This recipe (cytokine expression) can be seen in different subtypes. For example, people with polycythemia vera (PV) have been known to have elevated levels of IL-12, IL-4 and GM-CSF when compared to people with essential thrombocythemia (ET). Some cytokines, such as BLC, Eotaxin-2, M-CSF, and TIMP-1, may one day help diagnose and predict the progression of fibrosis in MPN subtypes. 

While it is not completely clear how your cytokine “recipe” can be affected by lifestyle, conventional wisdom tells us that healthy lifestyle changes can’t hurt. Reducing additional inflammation that may occur through lifestyle choices could help to support your body in ways that impact your experience of your symptoms at the least. A healthy diet, exercise, and stress reduction have all been associated with lowering inflammation in the body. 

A Patient’s Story: Perseverance and Advocacy

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Julie describes her PV journey as one that was initially filled with confusion, anxiety and an unclear path. In 1997, just 6 months after her father passed away from Non-Hodgkin’s lymphoma, abnormal lab results and her recent family history prompted her doctor to perform a bone marrow biopsy. At just 26 years old, she didn’t think twice when the biopsy was all clear and she was given a clean bill of health. 

Years later, an athlete and competitive mountain biker, Julie’s body suddenly refused to cooperate. After a noticeable change in her performance, she went to the doctor again. This time the doctor ordered a series of tests…and then an ultrasound…and then a heart catheterization. Her healthcare team had assured her, she was young, she was thin, she was in shape, she had no family history of heart problems, she was probably fine. Boy, were they wrong! Julie  had a 90 % blockage in her left anterior descending artery. Now, in her 30’s, she was told she would need a stent. What, no way?! she was on her way to Miami Beach with her friends, she had a bikini all picked out,  she was not doing surgeries and stents and hospitals. But that is exactly what she did. And afterwards, she felt amazing. 

This is where we have to stop and ask ourselves, why would a young woman with no family history of heart problems, who was thin, fit and otherwise well have this kind of episode? Well, the doctors didn’t know, so they labeled it coronary artery disease, told her to cut back on salt and sent her on her way. 

In 2008, Julie was racing motorcycles and working 60 hours a week. She was in charge of a large software roll out at the company she worked for…but something was off. In one week, her stomach was swollen, she lost her appetite, and when she did eat she was full almost immediately. By day four, she was so uncomfortable she couldn’t sleep, that’s when she headed to the ER. A percussion test revealed that her abdomen was filled with fluid (ascites) and they drained 2.2 liters that night. After being poked and prodded, they admitted her to the hospital and though perplexed, felt she may have ovarian cancer. The next six weeks were filled with various bouts of internal bleeding affecting multiple organs and bouncing in and out of the hospital, mostly in. It turns out, she had a serious clot in the hepatic vein that runs from the liver to the heart. Her liver was being strangled and “sweating like a quart of milk.” Not only was Julie unwell, but she was out of work during a pivotal moment for her company and her career. She felt as though was letting a lot of people down by being sick. 

At this point, she had a team of doctors who reviewed her medical records for the last 15 years. Enter the young, vibrant (and I would like to imagine) attractive doctor with a brand new Jak2 genetic blood test. The results? Julie was positive, and so were her doctors.  After a decade-long medical odyssey,  Julie was formally diagnosed with Polycythemia Vera. Another member from her medical team  told her, “Your life as you know it is over. You ride motorcycles, forget that, you’re not doing that. You’re 38, well you won’t have kids because you’ll have  a high-risk pregnancy. You are going to be on blood thinners for the rest of your life..” And the list went on. 

“You have to be feeling down, and then notice that if you start feeling more down, it takes twice the work to get back up again. And that’s what PV has taught me, so it’s not avoidance [of getting down] it’s more about where I am going to look? I learned that from motorcycling, wherever you look, that’s where you go.” Once stabilized, she walked out of the hospital, and looked up at the moon for the first time in 6 weeks. She felt lucky that she was even able to walk out of the hospital, some people were not. 

She said she has learned to sit with the fear, anxiety, and frustration when they creep up instead of running from them. But she doesn’t stay there, “you can go cry in your room, but you can’t just stay there and die.” Julie remembers that people usually die with PV, but not from it and that she is living with cancer. 

How did she cope? She started keeping track of how she felt each day. She was forced to get better at listening to her body. After a while, she saw patterns emerging and associations between her feelings and her lab work. For example, when her hematocrit spikes her scalp gets itchy and her fingertips get red. When this happens she knows it’s time for a phlebotomy. The more she knew about herself, the more she felt she was able to take care of herself, and that confidence reduced her anxiety. From there, she was able to start talking to the people around her about what she was experiencing and what she needed. She was even able to begin to direct her medical team, sharing with them important associations and symptoms that they could use to make better decisions about her treatment together. 

Four years after her diagnosis, Julie and her husband welcomed their son into the world. Pregnancy suited her, and her PV. Not only did she become a mom, she also became a mentor to MPN patients. She said that what she went through, and what she still goes through is more purposeful if she can share it to help someone else feel less afraid, less isolated, and less confused. 

Julie emphasized that PV has been and continues to be a journey, she hasn’t arrived, the journey is still in process. She said, “PV is the gift I didn’t want because it made me more grateful for the life I have, more aware of the people around me, more open to the world and its beauty…and it didn’t start out that way.”

If you want to learn more about Julie’s journey you can see her talk about her story on Facebook or read more about her at Woman’s Day. She also did a quick video about itching and is available to connect with other patients at  pvmamawarrior@gmail.com.

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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Sobi to present new myelofibrosis data at the ASCO 2024 Annual Meeting

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WALTHAM, Mass., May 24, 2024 (GLOBE NEWSWIRE) — Sobi North America, the North American affiliate of Swedish Orphan Biovitrum AB (Sobi®), today announced the presentation of three abstracts that highlights data from its myelofibrosis treatment option at the American Society of Clinical Oncology (ASCO) Annual Meeting taking place in Chicago from May 31 – June 4, 2024.

Sobi’s commitment to delivering innovative treatments for people living with hematological diseases is seen in global studies spanning multiple rare disorders, including myelofibrosis.

A retrospective analysis will be presented that demonstrates the efficacy of pacritinib in spleen volume reduction, symptom benefit and red blood cell transfusion response, compared with best available therapy, in patients with myelofibrosis who have both thrombocytopenia and anemia.

An additional retrospective analysis will be presented that shows the substantial symptom benefit pacritinib provides compared with best available therapy or low-dose ruxolitinib, specifically in patients who required red blood cell transfusion at the time of pacritinib initiation. The number of patients experiencing treatment emergent Grade 3 anaemia was similar between pacritinib and BAT groups.

New real-world data will be presented that demonstrates treatment with pacritinib provides stability or improvement in thrombocytopenia and/or anemia in patients with myelofibrosis, regardless of baseline counts, and has favorable overall survival similar to other JAK inhibitor historical controls.

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Metformin Use Linked to Lower Odds of Myeloproliferative Neoplasms

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By: Elana Gotkine

Medically Reviewed By: Mark Arredondo, M.D.

THURSDAY, May 23, 2024 (HealthDay News) — Metformin use, including long-term use, is associated with significantly lower odds of myeloproliferative neoplasm (MPN) diagnosis, according to a study published online May 17 in Blood Advances.

Daniel Tuyet Kristensen, M.D., from Aalborg University Hospital in Denmark, and colleagues conducted a population-based case-control study using Danish registers to examine the association between metformin use and the risk for MPN. Cases with MPN diagnosed between 2010 and 2018 were identified, and metformin use prior to MPN diagnosis was ascertained. Metformin use was compared among cases with MPN and an age- and sex-matched control group from the Danish general population (3,816 cases and 19,080 controls).

The researchers found that 7.0 and 8.2 percent of cases and controls were categorized as ever-users of metformin, respectively (odds ratio [OR] for MPN, 0.84; adjusted OR for MPN, 0.70). Long-term metformin use (at least five years) was more infrequent and occurred in 1.1 and 2.0 percent of cases and controls, respectively (OR, 0.57; adjusted OR, 0.45). When cumulative duration of treatment was analyzed, there was a dose-response relationship observed; in stratified analyses of sex, age, and MPN subtypes, this was consistent.

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.

Read more

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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