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MF Treatment
Pharmacists Discuss Practical Considerations and Novel Treatment Options for Patients With Myelofibrosis

Released: July 31, 2023

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Key Takeaways
  • JAK inhibitors reduce symptoms and improve quality of life and are key first-line treatment options for  myelofibrosis.
  • Pharmacists can contribute to care of patients with myelofibrosis by providing patient education on therapeutic expectations and frequently monitoring disease- or drug-related symptoms.
  • Disease- or treatment-related anemia can worsen prognosis in myelofibrosis, emphasizing the need for therapies with multiple mechanisms of action.

Best practices in treating myelofibrosis (MF) continue to evolve with drug approvals and ongoing late-phase clinical trials. In this commentary, Justin Arnall, PharmD, BCOP, and Victoria R. Nachar, PharmD, BCOP, discuss recent developments and key concepts for pharmacists in managing patients with MF.

Best Practices for Pharmacists in Treating MF

Justin Arnall, PharmD, BCOP:
With approximately 3000 new cases reported annually in the United States, MF is a rare hematologic malignancy typically associated with older patients. The majority of patients experience symptoms as a consequence of cytopenia, including anemia, both from the disease and from therapy. Splenomegaly, B symptoms, pruritus, and bone pain are other symptoms in this population that should be followed and addressed across the course of disease management. The main goals of treatment on a more immediate basis are reduction in the degree of splenomegaly and improvement in symptoms and quality of life. On a longer-term basis, the goal is to improve survival.

Victoria R. Nachar, PharmD, BCOP:
Because the JAK inhibitors for MF have not been directly compared, it is not clear whether one front-line therapy is superior. Ruxolitinib is used most frequently as front-line therapy, and we have the most clinical experience with this drug. There is potential for improved survival with ruxolitinib if it is well tolerated, and dose escalation can occur quickly without thrombocytopenia. We personally have used ruxolitinib in the setting of thrombocytopenia. Before alternatives were available, we became comfortable using ruxolitinib regardless of platelet count. Now, with the availability of pacritinib and fedratinib, the first-line choice in higher-risk MF is healthcare professional specific.

Justin Arnall, PharmD, BCOP:
With MF, the symptom burden contributes to a decreased quality of life, so the supportive care element is an essential part of management. The JAK inhibitors have been demonstrated to reduce symptoms, so monitoring for improvement is part of optimizing care. However, the use of JAK inhibitors is not indicated in all symptomatic patients. Therefore, the presence of symptoms requires a focused approach to care. Pharmacists can support patients with MF by reviewing the appropriate dosing of medication, providing education on therapeutic expectations, and monitoring disease- or drug-related symptoms. It is important to assess symptoms such as pruritus, bone pain, headaches, tinnitus, and symptomatic anemia frequently. Our specialty pharmacy team created and reported on the implementation of a referral service whereby our specialty pharmacists regularly perform these assessments along with ongoing risk stratification assessments before clinic visits. This service operates in a standardized manner across our healthcare system, irrespective of whether we were filling a prescription. The success of this service has encouraged us to develop several other patient-care initiatives in and around MF and other myeloproliferative neoplasms.

Transitioning to Second-line Therapy 

Victoria R. Nachar, PharmD, BCOP:
Ultimately, most patients with MF eventually will progress and need a next-line therapy. Data with ruxolitinib showed that 50% of patients will discontinue treatment within the first 3 years. Although the reasons for ruxolitinib discontinuation within the first 3 years vary, outcomes are poor once patients stop a first-line JAK inhibitor.

Definitions of suboptimal response or refractoriness are also variable, which makes interpreting trial results difficult. In the real world, failure is a big bucket. Some patients may be primary refractory or just do not respond at all. Others have relapse or loss of initial response, either on a suboptimal dose or at a stable appropriate dose. It is hard to know whether to increase the dose or change therapies. We have patients who are just completely intolerant to first-line JAK inhibitors or who experienced adverse events and others who have accelerating disease or leukemic transformation. The reason for first-line JAK inhibitor discontinuation helps determine what to do in the second line. Nonetheless, if a patient does not respond to one JAK inhibitor or has disease progression, the next options are a clinical trial or another JAK inhibitor.

Both fedratinib and pacritinib have been evaluated as second-line therapy. With fedratinib, the single-arm phase II JAKARTA-2 study evaluated patients resistant or intolerant to ruxolitinib. Approximately 55% of patients demonstrated spleen volume reduction, and approximately one quarter of patients had a symptom score reduction. The PERSIST-2 trial with pacritinib in patients with prior JAK inhibitors and platelets ≤100 x 109/L showed that fewer than 20% had a reduction in spleen volume. It is difficult to compare this data and choose one agent over another because the definitions of ruxolitinib failure were different in these studies. When it comes to sequencing JAK inhibitors, choosing the next-line therapy really comes down to patient-specific factors such as age, comorbidities, current medications, and adverse event profiles with these agents. It may be believed that the best JAK inhibitor is the one the patient can obtain and afford, but nobody really knows how to pick the next line of treatment.

Current and Emerging Treatment Options for MF-Associated Anemia: What to Know Now? 

Victoria R. Nachar, PharmD, BCOP:
In MF, JAK inhibitors often contribute to anemia, but the disease itself can be causative. The presence of anemia with MF is associated with a worse prognosis. There are treatment modalities to target anemia, but response rates are low, and options are limited. The JAK inhibitor momelotinib is in the pipeline and may be approved by the FDA soon. It inhibits JAK1 and JAK2 and has potent inhibitory activity against ACVR1, which is believed to be responsible for anemia improvements. Momelotinib was evaluated in the SIMPLIFY trials, and although it did not meet noninferiority endpoints for symptom control vs ruxolitinib, investigators saw improvement in anemia, hemoglobin, and transfusion requirements, pivoting its focus to anemia treatment. The phase III MOMENTUM trial compared momelotinib with danazol in patients with high-risk MF and anemia who already had received a JAK inhibitor. Momelotinib improved spleen volume reduction and total symptom score compared with danazol. Of importance, there was a noninferior improvement in transfusion independence, and the hemoglobin response to momelotinib occurred within the first 4 weeks. In addition, patients who crossed over from danazol to momelotinib gained an improvement in hemoglobin.

The adverse event profile of momelotinib appears to be similar to other JAK inhibitors. We are looking forward to having momelotinib in our armamentaria for treatment.

The other agent of interest for anemia is luspatercept, which is a fusion protein that allows erythropoiesis to start again. It is currently approved for anemias with other conditions but not in MF. The ongoing phase III INDEPENDENCE trial compares luspatercept with placebo in patients receiving a JAK inhibitor who still require red blood cell transfusions for anemia.

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