Ojjaara (momelotinib) approved in Canada for the treatment of myelofibrosis in adults who have moderate to severe anemia

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  • Ojjaara (momelotinib) is the only approved treatment for newly diagnosed and previously treated myelofibrosis patientsi who have moderate to severe anemia and other key manifestations associated with the disease.ii
  • This approval underscores GSK’s commitment to help drive progress for people living with complex blood cancers.

MISSISSAUGA, ON, Nov. 12, 2024 /CNW/ – GSK announced today that Health Canada has approved Ojjaara (momelotinib) for the treatment of splenomegaly and/or disease-related symptoms, in adult patients with intermediate or high-risk primary myelofibrosis (MF), post polycythemia vera MF or post essential thrombocythemia MF who have moderate to severe anemia.iii Ojjaara is the first and only approved medication globally, and now in Canada, that treats both the anemia and other key manifestations of myelofibrosis (newly diagnosed and previously treated).iv

“Treatment options for myelofibrosis-related anemia have been limited. We are proud to offer this treatment alternative for Canadian patients to address this critical unmet need and other myelofibrosis symptoms. With most myelofibrosis patients becoming anemic over time, Ojjaara’s approval represents a significant milestone to improve the outcomes of these patients while also highlighting GSK’s commitment to making an impact in Canada’s hematology oncology space through innovative new treatments,” said Michelle Horn, Interim Country Medical Director, GSK Canada.

Myelofibrosis is a rare blood cancer part of the broader myeloproliferative neoplasms (MPNs) diseases. MPNs have an incidence rate of 2.05 new cases per 100,000 Canadians.v Currently there are between 1,400-2,177 estimated people living with this type of disease in Canada.vi Anemia is a common symptom of myelofibrosis and a major unmet needvii, but awareness among Canadians is low. A 2024 survey shows that 90% of Canadians have heard of anemia but almost 50 per cent do not know about blood cancer related anemia.viii Canadians also have low knowledge of anemia with over 40 per cent of the same respondents saying they know little to nothing about this condition.ix

“Anemia and related transfusions significantly affect the quality of life, prognosis and survival for anemic myelofibrosis patients,” said Cheryl Petruk, CEO of HEAL Canada. “We are excited to witness progress in this rare disease space and to see Ojjaara approved in Canada. This new treatment has the potential to help improve the lives of patients while addressing the disease’s main challenges, namely anemia and other major symptoms.”

Ojjaara is the only once-a-day, oral JAK1/JAK2 and activin A receptor type 1 (ACVR1) inhibitor.x The approval of Ojjaara by Health Canada is supported by data from the pivotal MOMENTUM Phase III trial, which demonstrated significant improvements in Total Symptom Score (TSS), Transfusion Independence, and Splenic Response Rate.xi Additional support came from a subset of patients in the SIMPLIFY-1 Phase III trial, reinforcing Ojjaara’s efficacy in treating moderate to severe anemia and related symptoms in myelofibrosis patients.xii

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Dr DeAngelo on the Integration of JAK Inhibitors in Myelofibrosis Management

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November 11, 2024

Author(s): Daniel J. DeAngelo, MD, PhD

Daniel DeAngelo, MD, PhD, professor, medicine, Harvard Medical School, chief, Division of Leukemia, institute physician, Dana-Farber Cancer Institute, discusses the integration of JAK inhibitors into clinical practice for patients with myelofibrosis. Lower third needs to be updated

When incorporating JAK inhibitors, such as ruxolitinib (Rituxan), into clinical practice, it is essential to understand both their benefits and the challenges they present, particularly regarding anemia, DeAngelo begins. The phase 3 COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) trials, which initially sought to address symptom control and spleen reduction, demonstrated a notable survival advantage with ruxolitinib over placebo in patients with intermediate-2 or high-risk myelofibrosis, or intermediate-1 disease with symptomatic splenomegaly, he reports. These results led to ruxolitinib becoming the standard of care for high-risk or symptomatic patients, especially as allogeneic transplantation remains limited to select candidates, DeAngelo shares.

A primary consideration with ruxolitinib is its tendency to induce a hemoglobin level drop of approximately 2 points during the first 2 months of treatment due to on-target JAK2 inhibition, which affects erythropoiesis, he continues. Although newer agents are now approved by the FDA specifically for patients with baseline anemia, clinicians using ruxolitinib should anticipate this hemoglobin level decline, he states. Importantly, the initial drop in hemoglobin level does not indicate treatment failure but is a manageable effect that is often misunderstood, leading some oncologists to discontinue or reduce dosing with the drug prematurely, DeAngelo notes.

He goes on to state that his advice for integrating JAK inhibitors into myelofibrosis management plans is to proactively address these expected effects with patients. Patients can be supported through transfusions, growth factors, or alternative JAK inhibitors if needed, according to DeAngelo. In most cases, hemoglobin levels tend to stabilize and improve after the first few months, typically between months 3 and 4, he notes. Setting clear treatment expectations helps ensure patient adherence to therapy and optimizes outcomes when using JAK inhibitors in clinical practice, DeAngelo concludes.

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Frequent Testing for Driver Mutations Critical in Myelofibrosis

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Nov 12, 2024

Researchers from the Munich Leukemia Laboratory in Germany have developed a model that uses 12 genetic markers to accurately stratify patients with myeloproliferative neoplasms (MPNs), according to a study published online ahead of print in Leukemia.

The WHO categorizes classical MPNs—using cytomorphology, bone marrow biopsy, grading of fibrosis, blood counts, and a handful of molecular markers—into four individual entities: chronic myeloid leukemia (CML) and the BCR::ABL1 negative MPNs polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocythemia (ET).

“However, overlaps, borderline findings, or transitions between MPN subtypes occur, and incomplete clinical data often complicates diagnosis,” Manja Meggendorfer, PhD, and the study coauthors wrote.

The researchers analyzed 355 patients with MPN to use the results to stratify MPN entities and provide prognostic information. The investigation revealed the presence of genetically distinct subgroups with different cytogenetic abnormalities, mutations, and JAK2 allele statuses.

“Notably, differences in JAK2 allele status (heterozygous/homozygous) correlated with diverse EFS [event-free survival] and OS [overall survival] outcomes, potentially due to additional prognostic mutations,” the researchers reported. “In contrast, groups with cytogenetic aberrations and additional mutations generally had shorter EFS and poorer OS regardless of the diagnosed entity, aligning with studies on the impact of karyotype and mutation count on survival.”

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JAK2 Mutations Rarely Found in Patients With MPN Living in High Altitude Areas Who Have Unprovoked Thrombotic Events

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Ryner Lai

JAK2 mutations are rarely found in patients with a myeloproliferative neoplasm (MPN) who have unprovoked thrombotic events — deep vein thrombosis (DVT), pulmonary embolism (PE), or atypical thrombosis — living in high-altitude regions, according to a study published in the International Journal of General Medicine. 

Thrombosis often serves as the initial manifestation of a MPN and is a significant contributor to both morbidity and mortality. JAK2 plays a role in influencing the proliferation of hematopoietic cells and the inflammatory signaling cascade; mutation in JAK2 is notably associated with higher rates of cellular proliferation and differentiation, as well as cytokine release. Patients with MPNs and JAK2 mutations typically have a raised risk of thrombosis when compared with their counterparts who do not have JAK2 mutations.

High-altitude living is associated with alterations in coagulation pathways and blood composition. Studies demonstrate that otherwise healthy individuals with high-altitude hypoxia are at an increased risk of developing idiopathic arterial and venous thrombosis. Scientists suspect that the high altitude can interact with background hereditary/acquired thrombophilia to further exacerbate the risk of initial/recurrent thrombosis.

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New Model Can Assess Blast Phase Progression Risk in Myeloproliferative Neoplasms

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November 12, 2024

Author(s): Alexandra Gerlach, Associate Editor

Researchers from Germany developed a model that utilizes 12 genetic markers to accurately distinguish patients with varying myeloproliferative neoplasms (MPNs) including chronic myeloid leukemia (CML) and BCR::ABL1 negative MPNs polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocythemia (ET). Using the model, clinicians can more precisely characterize their disease and determine their risk of progression to blast phase (BP).

Red blood cells and DNA strand | Image Credit: © GustavsMD – stock.adobe.com

MPNs are clonal disorders of the blood cells and bone marrow characterized by abnormal hematopoietic proliferation, which have been differentiated into 8 subclasses by the World Health Organization. However, the 4 classical types are CML, PV, PMF, and ET, characterized by mutations in the JAK2, CALR, or MPL driver genes.1,2

Diagnosis of a specific MPN is based on their unique morphology; for example, PV is distinguished by a hypercellular bone marrow and elevated hemoglobin level, compared with ET, which is characterized by megakaryocytic proliferation and increased platelet counts. However, this approach fails to acknowledge overlaps, borderline findings, or potential transitions to other MPN subtypes. Patients with PV and patients with ET can progress to post-PV or post-ET myelofibrosis (MF), underscoring the genetic intricacy of these disorders. There is also the risk of progression to BP, also called leukemic transformation, in which the presence of circulating or bone marrow blasts is ≥20%.2-4

In the study, the researchers aimed to use genetic markers to more effectively stratify CML, PV, PMF, and ET, as well as characterize patients with progression to BP. They developed a machine-learning model based on 12 genetic markers observed in routine analysis to accurately classify MPN subtypes and provide useful prognostic information in a user-friendly decision tree format for clinicians. Using data from over 500 patients, they were able to genetically characterize 355 individuals with 1 of the 4 classic MPNs.1

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Lower Pharmacy Costs Give Ruxolitinib Edge for Patients With MF and Anemia

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November 9, 2024

Author(s): Mary Caffrey

The clinical benefits and lower transfusion costs of momelotinib (Ojjaara) are not enough to offset its higher pharmacy costs compared with an older therapy for patients with myelofibrosis (MF) and anemia who rely on transfusions, according to a recent cost-effectiveness analysis.

The results were presented in a poster at the 16th International Congress on Myeloproliferative Neoplasms, held in Brooklyn, New York, October 24-25, 2024.1

Aaron T. Gerds, MD, MS | Image Credit: Cleveland Clinic

Led by Aaron T. Gerds, MD, MS, assistant professor of Medicine, Cleveland Clinic Taussig Cancer Institute, the authors presented data based on a predictive model that computed per-patient total cost of care for 6-month, 1-year, and 2-year periods, comparing the Janus kinase (JAK) inhibitors ruxolitinib (Jakafi), and momelotinib (Ojjaara). Both inhibit the JAK/STAT pathway, with momelotinib additionally targeting a pathway that can result in improved iron-restricted anemia.

As the poster authors stated, ruxolitinib is indicated for patients with intermediate- or high-risk MF, including those with primary MF, post-polycythemia vera MF, post–essential thrombocythemia MF. Momelotinib is indicated for patients with intermediate- or high-risk MF, including those with primary MF, post-polycythemia vera MF, and post–essential thrombocythemia MF in in adult patients with anemia.1

The SIMPLIFY-2 study showed that patients switching from ruxolitinib to momelotinib took less time to achieve transfusion in dependence.2

This analysis presented in Brooklyn was based on the SIMPLIFY-1 study, which compared ruxolitinib and momelotinib in patients who had not previously received a JAK inhibitor.3 The authors, many of whom worked SIMPLIFY-1, found that the difference in pharmacy costs is $11,095 per month, with momelotinib being more expensive. Although transfusion costs for ruxolitinib were projected to cost an additional $10,854 over a 6-month period, the total cost of care still favored ruxolitinib, Results were as follows:

  • At the 6-month mark, the total cost of care favored ruxolitinib by$46,388.
  • At the 1-year mark, the total cost of care favored ruxolitinib by $84,239.
  • At the 2-year mark, the total cost of care favored ruxolitinib by $144,539.

Assumptions in the model. Authors wrote that the model assumed patients remained on therapy for the entire duration of the study or until death. It was limited to pharmacy- and transfusion-related costs, “to isolate costs associated with reductions in transfusion; other costs of care were assumed similar between ruxolitinib and momelotinib.”

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Ruxolitinib Provides Better Efficacy Than Best Available Therapy in Polycythemia Vera

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Andrea S. Blevins Primeau, PhD, MBA
According to the results of a systematic review and meta-analysis published in the journal APMIS, patients with polycythemia vera (PV) achieved greater hematocrit control and improved symptoms with ruxolitinib compared with best available therapy (BAT). Ruxolitinib was also associated with higher rates of nonmelanoma skin cancer, anemia, and certain infections.

Researchers identified 6 studies, including 4 randomized controlled trials and 2 observational studies, comprising 1061 patients with PV during the systematic review of reports published through 2023. The meta-analyses used a risk ratio (RR) to estimate effect size.

All patients received treatment with ruxolitinib or BAT, which included hydroxyurea, interferon, pegylated interferon, pipobroman, or anagrelide. The primary outcomes were hematocrit control and complete hematologic response (CHR).

In the cohort, the median age was 66.4 years and 72.8% of patients were male. There were 41.6% of patients were treated with ruxolitinib, 34% were hydroxyurea resistant, and 60% were hydroxyurea intolerant.

Higher rates of hematocrit control were observed in the ruxolitinib group compared with the BAT group (RR, 1.907; 95% CI, 1.135-3.205; P =.015). Ruxolitinib was also associated CHR compared with BAT (RR, 1.965; 95% CI, 1.025-3.768; P =.042).

Among patients with hydroxyurea-resistant or intolerant PV, higher rates of CHR (RR, 2.28; 95% CI, 1.36-3.84; P <.01), at least a 50% reduction in the MPN-SAF score (RR, 3.19; 95% CI, 1.21-8.46; P =.02), and PGIC score (RR, 6.86; 95% CI, 3.45-13.63; P <.01).

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Neutrophil-to-lymphocyte ratio as a prognostic indicator of mortality in Polycythemia Vera: insights from a prospective cohort analysis

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Tiziano Barbui, Alessandra Carobbio, Arianna Ghirardi, Francesca Fenili, Maria Chiara Finazzi, Marta Castelli, Alessandro M. Vannucchi, Paola Guglielmelli, Alessandro Rambaldi, Naseema Gangat & Ayalew Tefferi

Abstract

We analyzed the neutrophil-to-lymphocyte ratio (NLR) in 1508 patients with PV and found that those with an NLR ≥ 5 were generally older, had a longer disease history, and had higher cardiovascular risk factors, more arterial thrombosis, and more aggressive blood counts, indicating a more proliferative disease. NLR was an accurate predictor of mortality, with patients with NLR ≥ 5 having significantly worse overall survival and more than twice the mortality rate compared to those with NLR < 5. Multivariable models confirmed that increasing age, previous venous thrombosis and NLR ≥ 5 were strong predictors of death, further influenced by cardiovascular risk factors. We examined the interaction between NLR and the number of cardiovascular risk factors and found a progressive trend of increased mortality risk for NLR values ≥ 5 in addition to the presence of more than one risk factor. In conclusion, patients with NLR ≥ 5 require careful monitoring and management of cardiovascular risk factors because they increase mortality when associated with progressive levels of NLR.

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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.