Optimizing the Management of Myelofibrosis

In this Managed Healthcare Executive K-Cast video series, Zahra Mahmoudjafari, Pharm.D., MBA, discussed the epidemiology of myelofibrosis and its symptoms, treatment and management. Mahmoudjafari is the clinical pharmacy manager of the Division of Hematological Malignancies and Cellular Therapeutics at the University of Kansas Health System. Click here to see the video series.

Incidence and prevalence

Myelofibrosis is a rare and chronic bone marrow disease included in the broader category of myeloproliferative neoplasms (MPNs), Mahmoudjafari explained. The annual incidence is approximately 0.3 to 0.5 cases per 100,000 people per year, which translates into between approximately 13,000 and 18,000 individuals in the U.S. with the disease at any given time.

The other MPNs include polycythemia vera and essential thrombocythemia. Myelofibrosis has the poorest prognosis of the MPNs, said Mahmoudjafari. It is characterized by bone marrow fibrosis, which can lead to cytopenia. Myelofibrosis can progress to acute myeloid leukemia, and management and treatment of the disease is aimed at preventing that from happening, she said. Polycythemia vera is characterized by increased red blood cell production and essential thrombocythemia by excessive platelet production. Importantly, both are less likely to progress to acute myeloid leukemia.

Myelofibrosis can occur at any age, said Mahmoudjafari, but it’s most commonly diagnosed in older individuals and has a median age of diagnosis of between approximately 65 to 70 years. Men are disproportionately affected.

Symptoms and treatment goals

Many of the symptoms of myelofibrosis stem from the cytopenia it causes. Among the most common are fatigue, weight loss and night sweats. The symptoms tend to be more severe and debilitating than those experienced by patients with polycythemia vera or essential thrombocythemia. The polycythemia vera symptoms are related to blood viscosity, the essential thrombocythemia symptoms to thrombosis due to abnormal platelet function.

A large proportion of patients develop splenomegaly [an enlarged spleen], which can cause discomfort, pain, early satiety and abdominal fullness. Those can lead to complications such as portal hypertension, which can lead to ascites and varices, Mahmoudjafari said.

Fatigue, a result of ineffective hematopoiesis, can significantly impair a patient’s ability to carry out their daily tasks and reduce their quality of life, she noted. Patients can experience significant emotional and psychological effects from the fatigue and the other systemic effects, such as night sweats, and they can, in turn, lead to anxiety, depression and social isolation. Bone pain from the bone marrow fibrosis is another aspect of myelofibrosis that requires ongoing management, according to Mahmoudjafari.

One of the primary goals of treatment is to slow down any potential disease progression to acute myeloid leukemia, Mahmoudjafari said. Another is control of symptoms, which she said can be achieved with medications, blood transfusion and other supportive therapies. Complications, such as infections and bleeding, must also be managed.

JAK inhibitors

The treatment of choice for high-risk patients who are not candidates for a stem cell transplant is one of the Janus kinase (JAK) inhibitors, said Mahmoudjafari. Dosing frequency is an issue when deciding among them, she said. Ruxolitinib (sold under the brand name Jakafi) is administered twice a day and needs adjustment depending on platelet counts whereas fedratinib (sold under the brand name Inrebic) is administered once a day with no additional dose adjustment for cytopenia. For patients with platelet counts less than 50,000 per microliter, pacritinib (sold under the brand name Vonjo) might be considered before the other JAK inhibitors. Mahmoudjafari said it might be best to hold off on using momelotinib (sold under the brand name Ojjaara) upfront.

When weighing whether to change a patient’s treatment from one JAK inhibitor to another, clinicians need to consider how long the patient has been on the JAK inhibitor. “Is that really lack of response or is it a loss of response either because the disease has evolved or additional mutations have occurred?” she said. Mahmoudjafari said one of the questions she is often asked is about sequencing to another JAK inhibitor after ruxolitinib. Stopping ruxolitinib can cause withdrawal systems, so that needs to be taken into consideration when transitioning from ruxolitinib to another JAK inhibitor.

Comorbidities and drug-to-drug interactions need to be considered when prescribing JAK inhibitors, Mahmoudjafari said, noting that pacritinib and momelotinib are associated with an increased risk of cardiac events.

Monitoring

Current recommendations are for physical examination, symptom assessments and complete blood counts, which should be done every three to six months. Bone marrow biopsies to assess changes in the bone marrow fibrosis, the bone marrow cellularity and the general morphology of the bone marrow tissue should be done on an annual or a biannual schedule.

“If we are monitoring appropriately, we are looking for a lack of improvement in our patients’ symptoms, such as splenomegaly-related discomfort, fatigue, night sweats and bone pain. We’re looking for evidence of disease progression and treatment-related adverse events,” Mahmoudjafari said. A close relationship with patients is important in the treatment of myelofibrosis, she added. “We want to make sure that we meet their treatment goals, their preferences, really ensuring that we are in alignment with their expectations,” said Mahmoudjafari.

Cost burden

Patients with myelofibrosis are treated for extended periods, and the drugs they are treated with have high prices. That combination means the cost burden on patients can be heavy, especially for those with high-deductible health insurance coverage. Drugs with lower wholesale acquisition cost (WAC) prices may help by evening out the out-of-pocket expenses until the deductible amount is reached, Mahmoudjafari said. A lower WAC price can also help reduce the burden of coinsurance because the coinsurance is based on the cost of the medication. She noted that some health plans have programs (called copay accumulators) that do not count the value of the manufacturer’s copay assistance program toward the deductible, which can add to the financial burden on patients.

Areas of research

One of the main areas of focus is combining JAK inhibitors with other agents in other classes of drugs, such as the PI3K (phosphoinositide 3-kinase) inhibitors, the mTOR (mammalian target of rapamycin) inhibitors and the BCL2 (B-cell lymphoma 2) inhibitors, Mahmoudjafari said.

Among the new agents under investigation are BET (bromodomain and extraterminal domain) inhibitors that target proteins involved in gene expression and inflammation.

Researchers reported encouraging results for the combination of navitoclax, an investigational BCL2 inhibitor, and ruxolitinib, at the 2023 annual meeting of the American Society of Hematology (ASH), Mahmoudjafari said. Researchers also presented positive results for imetelstat (sold under the brand name Rytelo), a telomerase inhibitor, as a treatment for myelofibrosis at the ASH meeting, she said.

Piqray (alpelisib), a PI3K inhibitor, is being studied as a treatment for patients who have suboptimal outcomes or resistance to JAK inhibitors, Mahmoudjafari noted. And there is ongoing research into agents that can inhibit the expression of mutated CALR genes that play a causative role in myelofibrosis. “There is a lot going on in the setting of myelofibrosis, and it’s important to make sure we keep up as the treatment paradigm continues to involve,” she said.