MPN Word of the Month: Genetic Mutations

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Understanding Genetic Mutations in Myeloproliferative Neoplasms (MPNs)

A Quick Recap: What Are MPNs?

MPNs are a group of blood cancers that cause your bone marrow to produce too many blood cells. The three most common types are:

1. Polycythemia vera (PV) – where the body makes too many red blood cells.
2. Essential thrombocythemia (ET) – where the body produces too many platelets.
3. Primary myelofibrosis (PMF) – characterized by scarring of the bone marrow, which can lead to anemia, fatigue, and other complications.
A key driver of these conditions is genetic mutations, which affect how your blood cells grow and develop.

What Are Genetic Mutations?
A genetic mutation is a change in the DNA sequence. DNA is the instruction manual that tells our cells how to function, grow, and repair themselves. When a mutation occurs, it can disrupt these instructions and cause cells to behave abnormally—such as producing too many blood cells, which happens in MPNs.

Somatic Mutations and MPNs
Most of the genetic mutations associated with MPNs are somatic mutations. But what exactly does that mean?

● Somatic mutations are genetic changes that occur after birth, rather than being inherited from a parent. These mutations happen in specific cells, such as blood cells, and are not passed on to children.
● In the case of MPNs, somatic mutations occur in the hematopoietic stem cells—the cells in your bone marrow responsible for producing blood cells. When these stem cells acquire mutations, they can start producing too many blood cells, leading to the development of an MPN.

Understanding that MPNs are driven by somatic mutations is important because it helps explain why people develop these conditions later in life and why the mutations only affect blood cell production rather than all cells in the body.

Key Genetic Mutations in MPNs

There are several genetic mutations commonly associated with MPNs. The three most important ones to understand are JAK2, CALR, and MPL. Let’s take a closer look at each:

1. JAK2 Mutation (Janus Kinase 2)

○ What it is: JAK2 mutations are the most common genetic changes seen in MPNs, particularly in PV, where it’s found in about 95% of patients. It’s also present in approximately 50-60% of people with ET or PMF.
○ What it does: The JAK2 gene plays a key role in regulating blood cell production. When mutated, it sends constant signals to produce blood cells—even when your body doesn’t need them. This can lead to the overproduction of red blood cells, platelets, or other blood cells, depending on the type of MPN.
○ What it means for you: If you have a JAK2 mutation, your treatment plan may include JAK inhibitors, a type of medication that can reduce the activity of the mutated gene and help control your blood cell counts.

2. CALR Mutation (Calreticulin)

○ What it is: CALR mutations are found in about 20-25% of patients with ET and PMF, but not in PV. This mutation is the second most common genetic change in MPNs.
○ What it does: CALR mutations lead to overproduction of platelets or scarring of the bone marrow, depending on your specific condition. However, patients with CALR mutations tend to have a more favorable prognosis compared to those with JAK2 mutations, particularly in PMF.
○ What it means for you: Knowing that you have a CALR mutation can help guide your treatment options and give insight into your likely disease course. People with this mutation tend to have lower risks of blood clots compared to those with JAK2 mutations.

3. MPL Mutation (Myeloproliferative Leukemia Virus Oncogene)

○ What it is: MPL mutations are found in about 5-10% of patients with ET or PMF, but are not usually associated with PV.
○ What it does: MPL mutations cause abnormal signaling in blood cell production, similar to JAK2. This results in an overproduction of platelets and can contribute to bone marrow scarring in PMF.
○ What it means for you: MPL mutations are less common, but knowing you have this mutation can help your healthcare provider tailor your treatment and monitoring strategy, particularly when managing PMF.

Other Less Common Mutations
In addition to these key mutations, there are other genetic changes that can occur in MPNs, including ASXL1, TET2, and EZH2. These mutations are often referred to as “high-risk mutations” because they can affect the severity of the disease and the likelihood of progression to more serious conditions, such as acute myeloid leukemia (AML).

If you have one or more of these additional mutations, your doctor may recommend more aggressive monitoring or treatment to prevent complications.

Why Do Genetic Mutations Matter in MPNs?
Understanding your genetic mutation can give you important insights into your condition. Here’s why it matters:

● Prognosis: Some mutations are associated with a more aggressive disease course, while others may indicate a more stable condition. For example, patients with CALR mutations often have a better prognosis than those with JAK2 or MPL mutations.
● Treatment Options: Certain treatments may be more effective depending on your mutation. For instance, JAK inhibitors are often used to manage patients with a JAK2 mutation, while other therapies might be considered for patients with CALR or MPL
mutations.
● Risk of Complications: The type of mutation you have may affect your risk of developing complications like blood clots, bone marrow scarring, or progression to leukemia.

How Are Genetic Mutations Detected?

Your healthcare provider can determine if you have a specific genetic mutation through a bone marrow biopsy or a blood test. Genetic testing is an important part of diagnosing and managing MPNs, as it helps to confirm the type of MPN you have and guides treatment decisions.
Moving Forward: How to Manage Your MPN Based on Your Mutation If you’ve been diagnosed with an MPN and your genetic mutation has been identified, here are a few things to keep in mind:

1. Ask Questions: Don’t hesitate to ask your doctor about your specific mutation and what it means for your condition. Understanding your mutation can help you make informed decisions about your care.
2. Personalized Treatment: Treatments are becoming more targeted based on the specific mutations driving your disease. Work with your healthcare team to find the best approach for your mutation.
3. Regular Monitoring: MPNs can change over time, so regular check-ups and blood tests are essential. This allows your healthcare team to adjust your treatment as needed based on any new developments.

4. Support: Dealing with an MPN can feel overwhelming, but remember you’re not alone. Joining support groups or seeking counseling can help you cope with the emotional aspects of your diagnosis.

Genetic mutations, especially somatic mutations, are the driving force behind MPNs,influencing how the disease behaves and how it can be treated. By understanding the role of mutations like JAK2, CALR, and MPL, you can take an active role in managing your condition.
Genetic testing provides a clearer picture of your specific type of MPN, allowing your healthcare team to personalize your treatment and monitor your disease effectively.

In the Trenches: Dr. Anthony Hunter

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1. Why did you choose hematology as a specialty, specifically MPNs?

There was no singular moment that I knew this would be my career path. I have always been fascinated by the biology and genetics of blood cancers. As I was exposed to clinical care throughout my medical training, I continually found myself drawn to patients with hematologic malignancies. I find MPNs in particular to be such unique diseases, and have observed the significant unmet clinical need within the field. Most importantly, I greatly enjoy the ability to develop a long-term relationship with my MPN patients and to hopefully have a positive impact on their lives.

2. Can you share your approach to MPN patient care?

If I can summarize this in four words, I would describe my approach as 1) informative, 2) patient-centered, 3) individualized, and 4) proactive. I find that many patients who arrive at my clinic do not have a sufficient understanding of their disease, even those who have been dealing with their disease for many years. With all of my patients, I try to educate and provide a thorough understanding of their disease. Particularly at initial consultations, I spend a great detail of time discussing their disease, including the biology of MPNs, how we diagnose them, the potential complications, as well as the available potential treatment options. I find that providing this thorough overview helps patients to feel empowered and more in control of their disease, and provides a good framework for further discussions moving forward. As we develop diagnostic, treatment, and monitoring plans, I feel strongly that there is no “one-size-fits-all” approach. Every patient is unique, and I try to discuss all reasonable paths forward with my patients taking into account their health, personal goals, and concerns, as well as their unique disease characteristics. I feel that shared decision-making is vital to determining a treatment plan that works for all involved parties. Lastly, the clinical care of MPNs has historically taken a more passive approach. I feel that a proactive approach is more appropriate given our current understanding of MPNs and the available treatments, and seek to employ this in my practice. Despite many advances in the past decade, we have a long way to go in improving and extending the lives of patients with MPNs. I remain actively involved in cutting-edge MPN research, integrating this into the clinical care of my patients as appropriate.

3. What advice would you impart to MPN patients?

I’m going to cheat here and give two because I think that they are both important. The first is that “knowledge is power”; cliché, I know! However, it is vital to learn about your disease and understand the potential complications that could arise, what treatments are available to you, and what you should be watching out for. Along those same lines, it is important to recognize that you will always be your own strongest advocate. It’s critical to actively participate in your care journey and speak up if you have concerns. There are many great physicians out there, but we are human; it is important to express your fears and concerns and to seek out the care team that best fits you.

Jakafi, Pegasys Combination Beneficial in Newly Diagnosed Polycythemia Vera

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November 4, 2024

Author(s): Alex Biese

Fact checked by: Spencer Feldman

Among patients with who were newly diagnosed polycythemia vera (PV), treatment with Jakafi (ruxolitinib) and low-dose Pegasys (pegylated interferon alfa-2a) was found to be beneficial, resulting in high rates of hematologic and molecular response, research has shown.

Findings from the two-year end-of-study results of the phase 2 COMBI II clinical trial, published in Blood Advances, showed that the combination treatment was associated with improvements to patients’ cell counts with what researchers described as acceptable toxicity.

Researchers utilized the participation of 25 patients with PV, with a median age of 70 years. According to the study, 14 patients (56% of participants) achieved remission at 24 months, with three (12%) attaining complete remission and 11 (44%) reaching partial remission. Researchers reported what they observed as significant reductions to abdominal discomfort, night sweats, itching and bone pain, while the median JAK2V617F VAF was decreased from 47% to 7% and 60% of patients achieved molecular remission.

One of the 25 patients dropped out of the study within two years, while one patient discontinued both drugs while two patients each discontinued Jakafi and Pegasys and continued stand-alone therapy with the other drug.

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Age, Race, Insurance Status Can Predict CV Mortality for Those With MPNs

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November 2, 2024

Author(s): Mary Caffrey

Among those diagnosed with myeloproliferative neoplasms (MPNs), age, race, marital status, and insurance status can help predict cardiovascular mortality (CVM), based on an analysis of more than 24,000 US patient records.1

A new study finds that clinical factors and social determinants of health can predict cardiovascular mortality among patients with myeloproliferative neoplasms.

| Image Credit: yodiyim – stock.adobe.com

The study, appearing this week in Therapeutic Advances in Hematology,1 aimed to identify prognostic factors that can guide clinicians in treating patients with MPNs, which are a group of hematopoietic stem cell disorders that are generally diagnosed in individuals after age 40; according to the Leukemia & Lymphoma Society, most patients are diagnosed in their 60s or 70s.

The team from Sun Yat-sen University in China culled records for more than 48,000 patients diagnosed with MPNs between 2000 and 2018 from the Surveillance, Epidemiology, and End Results (SEER) database, but narrowed their analysis to those records for patients that lived at least a year and included other essential clinical information. That left a database of 24,277 patient records.

Among the demographic findings:

  • The database included 10,409 patients (42.9%) with polycythemia vera (PV), 3229 (13.3%) with myelofibrosis (MF) and 10,639 (43.8%) with essential thrombocythemia (ET).
  • Prevalence of the condition was higher among White males in PV and MF compared with females in ET.
  • At diagnosis, only 8.0% were younger than 40 years old; 29.0% were 40-59 years old, 47.0% were 60-79 years old; and 16% were older than 80 years of age.

The analysis took a snapshot of patients at 200 months of follow-up (16 years, 8 months) and found that the cumulative mortality was the following CVD (17.9%), other noncancer (22.1%), MPN (18.8%), and other cancers (6.1%). However, investigators found that more than 50% of patients initially diagnosed with MF died from their primary disease during this period, which may be due to conversion of their disease to acute myeloid leukemia.

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Ruxolitinib Plus Pegylated Interferon Alfa-2a Show Promise in Newly Diagnosed Polycythemia Vera

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November 1, 2024

Author(s): Alexandra Gerlach, Associate Editor

Ruxolitinib (Jakafi; Incyte Corp) in combination with pegylated interferon alfa-2a demonstrated efficacy and tolerability in patients with newly diagnosed polycythemia vera (PV). According to the 2-year end-of-study results from the phase 2 COMBI 2 clinical trial (EudraCT2018-004150-13), the treatment improved cell counts, bone marrow cellularity, and fibrosis in patients with PV.1

In the phase 2 COMBI 2 trial, researchers evaluated the safety and efficacy of ruxolitinib and low-dose peg-IFN-α2a in patients with newly diagnosed PV.

Image Credit: © MdBabul – stock.adobe.com

PV is a chronic, progressive myeloproliferative neoplasm characterized by the overproduction of red blood cells. The excess cells thicken the blood, slowing its flow and contributing to serious complications, such as blood clots. Almost all patients with PV have the JAK2V617F mutations, and the JAK2V617F variant allele frequency (VAF) is key for determining outcomes, including thrombosis and progression to myelofibrosis.2-4

Ruxolitinib is a Janus kinase inhibitor approved by the FDA in 2011 and is indicated for the treatment of patients with high-risk MF with reduced abnormal expression of PF4, which can lead to decreased fibrosis. It is additionally indicated as a second-line treatment of PV for patients who have an inadequate response to or cannot tolerate hydroxyurea. In the COMBI 2 trial, researchers assessed the efficacy of ruxolitinib in combination with pegylated interferon alfa-2a (peg-IFN-α2a) (Pegasys ProClick; Genentech), an injection commonly used to treat hepatitis B and C infections. According to data from prior studies, peg-IFN-α2a has been shown to induce durable hematologic and molecular remissions in patients with PV. However, approximately 20% to 40% of patients are intolerant or show limited response to peg-IFN-α2a.5-8

In the phase 2 COMBI 2 trial, researchers evaluated the safety and efficacy of ruxolitinib and low-dose peg-IFN-α2a in patients with newly diagnosed PV in an effort to counterbalance intolerance to peg-IFN-α2a. The primary end point was safety, with secondary end points including efficacy, based on hematologic parameters, quality-of-life measurements, and JAK2V617F variant allele frequency (VAF).8

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FORUS Therapeutics Inc. and PharmaEssentia Corporation Have Entered Into an Exclusive Licensing Agreement for The Registration and Distribution of BESREMi(R) (ropeginterferon alfa-2b) for The Treatment of polycythemia vera (PV), in Canada

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October 31, 2024 8:30 AM EDT | Source: FORUS Therapeutics Inc.

  • Under the terms of the agreement, FORUS is licensing BESREMi from PharmaEssentia for PV in Canada, with potential expansion to other investigational myeloproliferative neoplasms (MPN) indications.
  • FORUS will oversee the drug registration and commercialization of BESREMi in Canada, including securing approval of BESREMi in PV and meeting certain milestones.

Oakville, Ontario–(Newsfile Corp. – October 31, 2024) – FORUS Therapeutics Inc (“FORUS”) and PharmaEssentia Corporation (“PharmaEssentia”) have entered into an exclusive licensing agreement for the registration and distribution of BESREMi® (ropeginterferon alfa-2b) for the treatment of polycythemia vera (PV), in Canada.

“On behalf of the FORUS Therapeutics team, I am truly excited to announce this licensing agreement with PharmaEssentia and to commence the process of commercializing BESREMi in Canada. BESREMi represents the second novel therapeutic in the FORUS hematology-oncology pipeline and is another important step in fulfilling the organization’s mission and vision. We are committed to rapidly advancing BESREMi through the regulatory and reimbursement pathways to ensure that PV patients in Canada have broad access to this novel medication,” said Kevin Leshuk, President and CEO of FORUS. “We are making this announcement today to support the momentum created by the September 12th, Annual MPN Awareness Day and the International Congress on Myeloproliferative Neoplasms, recently held in Brooklyn, New York. We believe that continuing to elevate awareness with the goal of meeting the unmet needs of the MPN community is critical to making a difference in the lives of patients.”

“BESREMi is an important and significant development for clinicians who treat patients with PV. BESREMi as a potential future treatment option is particularly critical for Canada, where treatment options are notably limited for these patients,” says Dr. Shireen Sirhan, a founding member and the current President of the Canadian MPN group, and Vice-President for research in MPNs of the Groupe Québécois de recherche en LMC-NMP. “Canadian physicians have played a significant role in the clinical development program for BESREMi and we look forward to having this important treatment available in the clinic for our patients in need.”

“This is very exciting news for the PV community across Canada,” says Doug Chisholm and Patricia Saluk, the former and current Chair, Board of Directors of the Canadian MPN Network Patient Advocacy group. “Polycythemia vera is a rare blood cancer and the future commercialization of BESREMi in Canada offers highly anticipated new hope for patients, families, and their support networks. We hope the Canadian regulatory and payor systems will work as quickly as possible to ensure our patient community has access to this much needed new treatment regimen.”

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Inrebic May Reduce Spleen Volume in Myelofibrosis

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October 31, 2024

Author(s): Alex Biese

Fact checked by: Spencer Feldman

Among patients with myelofibrosis who have been previously treated with Jakafi (ruxolitinib), treatment with Inrebic (fedratinib) was beneficial, particularly regarding spleen volume reduction (SVR) when compared to treatment with otherwise best-available therapy (BAT), researchers have found.

Findings from the phase 3 FREEDOM2 trial were published in The Lancet Hematology.

“In the FREEDOM2 trial, patients with myelofibrosis previously treated with [Jakafi] showed superior SVR and symptom response when treated with [Inrebic] compared with BAT (predominantly [Jakafi]),” researchers concluded in the study. “The safety profile of [Inrebic] was consistent with previous trials, and mitigation measures effectively managed known adverse events. Overall, the results indicate that [Inrebic] is a promising option for second-line JAK inhibitor treatment of myelofibrosis.”

Inrebic, a type of tyrosine kinase inhibitor, works by blocking JAK2 and other proteins — which, as defined by the National Cancer Institute, may help keep abnormal blood cells or cancer cells from growing. It was approved by the Food and Drug Administration for the treatment of patients with myelofibrosis in 2019.

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Karyopharm to Host Investor Event with Leading Myelofibrosis KOLs and Provide a Favorable Study Design Update on October 31, 2024

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NEWTON, Mass., Oct. 30, 2024 /PRNewswire/ — Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today announced it will host a conference call and audio webcast at 8:00 a.m. ET on Thursday, October 31, 2024 to provide a favorable study design update on the Company’s pivotal Phase 3 SENTRY study in JAKi naive myelofibrosis.

The call will feature leading myelofibrosis key opinion leaders Dr. Raajit Rampal, Director of the Center for Hematologic Malignancies and Director of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center and Dr. John Mascarenhas, principal investigator of the Phase 3 SENTRY trial, Professor of Medicine at the Icahn School of Medicine at Mount Sinai and Director of the Center of Excellence for Blood Cancers and Myeloid Disorders.

To access the conference call, please dial (800) 836-8184 (local) or (646) 357-8785 (international) at least 10 minutes prior to the start time and ask to be joined into the Karyopharm Therapeutics call. A live audio webcast of the call, along with accompanying slides, will be available under “Events & Presentations” in the Investor section of the Company’s website, http://investors.karyopharm.com/events-presentations. An archived webcast will be available on the Company’s website approximately two hours after the event.

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Ajax Therapeutics Announces First Patient Dosed in Phase 1 Clinical Trial Evaluating AJ1-11095, a First-in-Class Type II JAK2 inhibitor, for the Treatment of Myelofibrosis

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October 30, 2024

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

– Preclinically, AJ1-11095 has demonstrated superior efficacy to Type I JAK2 inhibitors, such as ruxolitinib, with disease modifying effects on mutant allele burden and fibrosis –

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 the first patient has been dosed in its Phase 1 clinical trial evaluating AJ1‑11095, a first-in-class Type II JAK2 inhibitor, for the treatment of patients with myelofibrosis.

“We’re excited to announce dosing of the first patient enrolled in our first-in-human study with AJ1-11095” said David Steensma, MD, FACP, Chief Medical Officer at Ajax. “As a first-in-class therapy with a unique mechanism of action as a Type II inhibitor of JAK2, AJ1-11095 was developed to provide a much-needed new treatment for patients with myeloproliferative neoplasms by offering the potential for improved efficacy compared to existing therapies.”

AJ1-11095 is the first JAK2 inhibitor to enter the clinic that binds the Type II conformation of the JAK2 kinase as opposed to all the other approved JAK2 inhibitors, including ruxolitinib, that bind the Type I conformation. The advancement of AJ1-11095 into this Phase 1 clinical trial was based on preclinical studies in which AJ1-11095 showed superior efficacy when compared to Type I JAK2 inhibitors with significant disease modifying effects on mutant allele burden and fibrosis, two of the main hallmarks of myelofibrosis.

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Treatment Differences for Younger vs Older Patients With MPNs

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October 30, 2024

Author(s): Laura Joszt, MA, Mary Caffrey

The age distribution of people affected by myeloproliferative neoplasms (MPNs) is broad, explained Ruben Mesa, MD, FACP, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, president of Atrium Health Levine Cancer.

With younger patients, it’s important to understand the increased risk of their disease progressing given how long they’ll live with their illness, and the impact therapies may have on fertility.

This transcript was lightly edited for clarity.

Transcript

About 20% of patients with myeloproliferative neoplasms are in the adolescent to young adult population. Are there characteristics that differentiate this younger population from older ones or treatment considerations that differ among the age groups?

I would say that the median age is in the 60s. However, I would say that the distribution is broad. As opposed to it being a median in the 60s and there being a high concentration only in individuals that are older, it is a broader distribution. In particular the earlier phases of MPN, ET [essential thrombocythemia], and PV [polycythemia vera}, are not uncommon in those that are 30s, 40s and 50s years old. Teenagers and those in their 20s—that AYA [adolescent and young adult] population—certainly is less common, but it is more common than, I think, had been appreciated, that there’s a broader distribution affecting these individuals.

Clearly, with younger individuals, we’re mindful of several things. One, the length of time that they have the illness does increase our concern that they have a higher risk of the disease progressing to a more advanced myeloid neoplasm the longer they have the disease. Particularly individuals with 10 years or more of the disease have increasing risk from ET and PV progressing to myelofibrosis. Overall, we think myelofibrosis can be a life-threatening disease, where ET and PV usually can be managed without a decrease in survival. So, that progression is really a negative, and the younger you are, the more exposure you really have to that. Additionally, they have a higher risk of progressing to acute leukemia because of this increased length of time.

Additionally, there are issues as it relates to both the preservation of fertility and the selection of medical therapy. Historically, in ET and PV, there had been a lot of use of the medication hydroxyurea, that is counter indicated in pregnancy, and that has implications in terms of therapy selected, so that medications like interferons or long-acting interferons tend to be preferred in this group of patients, both for that reason, as well as there is the data suggesting that interferons may help to slow the progression of the disease. And again, in younger individuals, that makes it a more relevant therapy for these individuals.

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