Myelofibrosis: Bringing Hope with New Treatments

Myelofibrosis (MF) is a rare blood cancer that causes scarred bone marrow tissue. Excessive scar tissue makes it difficult for MF patients to produce healthy and abundant blood cells, which leads to severe tiredness, low red blood cell counts (anemia), an enlarged spleen, weight loss, and related complications.

While there is a possible cure for MF, most patients are ineligible, making symptom management with medication their best option. Although current treatments are effective in easing symptoms for many patients, they can also be problematic for some of the population due to treatment resistance, disease progression, and intolerance. Thankfully, recent advances in treatment have aimed to address these issues so that a wider range of patients can live fulfilling lives with the disease.

Signaling Pathways and Myelofibrosis Treatment Today

The underlying cause for the abnormal blood cell count seen in MF patients is often due to an overactive JAK-STAT Signaling Pathway (Janus Kinase–Signal Transducer and Activator of Transcription). This overactivation can lead to abnormally high blood cell counts (early-stage MF) or abnormally low blood cell counts (late-stage MF). To control this hyperactivity, JAK inhibitors are commonly used because of their ability to reduce activity of this pathway. Reduced JAK-STAT activity decreases inflammation and stabilizes blood cell production, improving symptoms of MF.

One of the most used JAK inhibitors for MF treatment is ruxolitinib because of its effectiveness in shrinking spleen size and reducing night sweats and fatigue (Tefferi et al., 2012). Managing symptoms like these is essential in MF to improve quality of life and well-being. As an illness with little chance for cure, drug treatment effectiveness for MF symptoms is critical, and finding treatments that produce minimal side effects is imperative.

While ruxolitinib has provided relief to many MF patients, others have been resistant or intolerant to the medication. Those who are treatment resistant may find that its benefits diminish over time, while those who are intolerant may experience side effects that make it hard to tolerate ruxolitinib. Ruxolitinib can also worsen anemia by lowering red blood cell and platelet counts, which limits how long a person can safely stay on the medication. Because of these challenges, researchers have been working to find alternative treatment options for people with MF.

Emerging JAK Inhibitors

1. Fedratinib

One JAK inhibitor that works similarly to ruxolitinib but is designed for people who haven’t responded well to the drug is fedratinib. Fedratinib has demonstrated effectiveness in reducing spleen size and associated symptoms in ruxolitinib-resistant patients in clinical trials, making it an effective second line of treatment for MF (Verstovsek et al., 2015).

Despite these benefits however, there is some concern that fedratinib may cause Wernicke’s encephalopathy (a serious brain condition linked to low levels of vitamin B1). Fortunately, this risk can usually be managed with regular monitoring and vitamin B1 (thiamine) supplementation. 

2. Pacritinib

Since ruxolitinib and fedratinib can both worsen platelet count, pacritinib can be a safer alternative for those with very low platelet counts (Pardanani et al., 2015). Unlike ruxolitinib and fedratinib, pacritinib can be given to patients with platelet counts below 50,000/ µL, which is a population that has often been excluded from MF treatments (Mascarenhas et al., 2022). Pacritinib also does not significantly worsen anemia in most patients, which is a major advantage over many other JAK inhibitors like ruxolitinib (Mascarenhas et al., 2022).

3. Momelotinib

Another JAK inhibitor that helps to address the issue of anemia, while also reducing spleen size and associated symptoms, is momelotinib. Momelotinib has been shown to reduce the number of blood transfusions needed for MF patients, which could improve quality of life, while reducing healthcare costs (Talpaz et al., 2023).

Promising New Therapies Beyond JAK Inhibitors

Scientists are also exploring alternatives to JAK inhibitors that specifically help those with low platelet or red blood cell counts.  

1. Pelabresib

Investigational drugs called BET inhibitors (bromodomain and extraterminal domain inhibitors) work by altering gene expression (how genes are turned on and off) to reduce inflammation and to slow down scar tissue buildup in bone marrow. The BET inhibitor pelabresib has been shown to effectively reduce spleen size and symptoms, particularly in combination with ruxolitinib (Pardanani et al., 2023). The combination pelabresib + ruxolitinib has shown to be more effective than ruxolitinib alone.

2. Luspatercept

Luspatercept is a type of drug that helps the body produce more red blood cells so that MF patients with anemia may need fewer blood transfusions. In combination with ruxolitinib, this drug could effectively improve energy levels and reduce the burden and risks that come with getting frequent blood transfusions, while addressing additional MF symptoms (Kantarjian et al., 2020).

Stem Cell Transplants for MF: A Possible Cure?

Right now, the only known cure for MF is a stem cell transplant (also called a bone marrow transplant). This involves replacing the damaged bone marrow with healthy stem cells from a donor. People who are over 60 are not eligible for stem cell transplants since they are very intense and can cause serious side effects. Unfortunately, MF is most often diagnosed in people over 60 and stem cell transplants are usually only offered to younger, healthier patients with aggressive or high-risk disease (Tefferi et al., 2012). This means that currently, there is no cure for most MF patients.

Personalized Treatment

MF severity can now be assessed using advanced tools alongside factors like age, overall health, blood counts, spleen size, and genetic mutations. Specialized prognostic scoring systems like the Dynamic International Prognostic Scoring System (DIPSS) and the Mutation-Enhanced International Prognostic Scoring System (MIPSS) can be used to guide decision-making for MF.

·      DIPSS –This tool helps estimate disease risk based on clinical features such as age, hemoglobin level, white blood cell count, and the presence of symptoms like fever or weight loss. It is “dynamic” because it can be applied at any point during the disease, not just at diagnosis.

·      MIPSS –This score builds on DIPSS by adding information about specific genetic mutations (e.g., JAK2, CALR, MPL, ASXL1), offering a more personalized risk assessment based on the biology of the disease.

Using these scoring systems allows doctors to categorize patients into low-, intermediate-, or high-risk groups, which helps tailor treatment plans to suit individual prognoses and overall health goals (Tefferi et al., 2012).

What’s Next?

The future of MF treatment is full of promise. Scientists are testing new combinations of medications and working on ways to catch and treat the disease earlier. New drugs like pelabresib and momelotinib may soon become part of everyday treatment hope.

Thanks to research, people with MF today have more options and more hope than ever before.

References

Kantarjian, H., Al-Kali, A., & Jabbour, E. (2020). Luspatercept in myelofibrosis with anemia. The New England Journal of Medicine, 382(15), 1466–1476. https://doi.org/10.1056/NEJMoa1916355

Mascarenhas, J., Vannucchi, A. M., & Verstovsek, S. (2022). Pacritinib versus physician's choice in patients with myelofibrosis and thrombocytopenia: A randomized, phase 3 trial (PERSIST-2). The Lancet Haematology, 9(1), e13–e24. https://doi.org/10.1016/S2352-3026(21)00261-4 

Pardanani, A., Tefferi, A., & Mesa, R. (2015). Pacritinib for patients with myelofibrosis and severe thrombocytopenia. The New England Journal of Medicine, 373(9), 808–819. https://doi.org/10.1056/NEJMoa1505743

Pardanani, A., Palandri, F., & Tefferi, A. (2023). Pelabresib in myelofibrosis. The New England Journal of Medicine, 388(1), 1–11. https://doi.org/10.1056/NEJMoa2205555

Talpaz, M., Kantarjian, H., & Garcia-Manero, G. (2023). Momelotinib in myelofibrosis. The New England Journal of Medicine, 388(15), 1402–1411. https://doi.org/10.1056/NEJMoa2300035

Tefferi, A., Pardanani, A., & Mesa, R. (2012). Ruxolitinib therapy in myelofibrosis: COMFORT studies update. American Journal of Hematology, 87(3), 272–274. https://doi.org/10.1002/ajh.22231 

Verstovsek, S., Mesa, R. A., & Gotlib, J. (2015). A double-blind, placebo-controlled trial of fedratinib in primary and secondary myelofibrosis. The Lancet Haematology, 2(7), e317–e326. https://doi.org/10.1016/S2352-3026(15)00124-2

Assessed and Endorsed by the MedReport Medical Review Board