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First-line MF Treatment
Expert Insights on Personalizing First-line Medication Therapy for Myelofibrosis

Released: June 23, 2023

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Key Takeaways
  • Prognostic risk scoring and symptom burden assessment are used to tailor myelofibrosis treatment.
  • Three FDA-approved oral JAK inhibitors are available for the treatment of high-risk symptomatic myelofibrosis: ruxolitinib, fedratinib, and pacritinib.
  • Selecting among the JAK inhibitors for first-line therapy requires an assessment of how the unique features of each option best align with the individual patient’s clinical scenario.

The primary goals of treatment for myelofibrosis (MF) are to reduce splenomegaly, improve symptoms and quality of life, and improve survival. These goals overlap in that reduction in spleen size may reflect reduced marrow fibrosis, allowing improved bone marrow hematopoiesis and less burden on the spleen. Similarly, reduced symptoms and spleen size likely reflect overall reduction in disease burden, which can contribute to longer survival. For this reason, spleen size and symptom score often are used as surrogate markers of treatment efficacy in clinical trials. Symptom burden and quality of life are quantified using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF-TSS), which includes hallmark symptoms of bone marrow fibrosis and splenomegaly such as fatigue, early satiety, and night sweats. This scoring system has been validated in MF and demonstrated to strongly correlate with patient-reported quality of life.

When it comes to personalizing treatment for MF, prognostic scoring tools such as the Dynamic International Prognostic Scoring System (DIPSS) Plus and the Mutation-Enhanced International Prognostic Scoring System 70 (MIPSS70) are used to determine risk category. Risk category is considered in conjunction with symptom burden assessed by the MPN-SAF-TSS to tailor treatment strategies. Patients who are asymptomatic and considered low or very low risk by prognostic scoring generally are managed by observation only, with monitoring to allow intervention once symptoms present. Patients who are symptomatic in the very low‒/low-risk category may receive supportive care specifically addressing symptoms (eg, anemia) as needed. Although JAK inhibitors have not been prospectively studied in low-risk MF, some healthcare professionals may consider their potential benefit, for example, in patients who are more heavily symptomatic who still fall in the low-risk prognostic category.

For people who have higher-risk prognostic scores, healthcare professionals must first determine if they are a candidate for allogeneic stem cell transplantation. Allogeneic stem cell transplantation is the only curative option for patients with MF. However, because many patients with MF are advanced in age and have other comorbidities associated with high morbidity and mortality in the transplant setting, this is not an option in most cases. For patients in the high-risk prognostic category who are not transplantation candidates and who have symptoms other than anemia, 3 FDA-approved oral JAK inhibitors are effective: ruxolitinib, fedratinib, and pacritinib.

 

Ruxolitinib

Ruxolitinib was the first JAK inhibitor to be approved by the FDA for the treatment of MF and thus also carries the most extensive clinical experience. Ruxolitinib is indicated for first-line treatment of intermediate- or high-risk MF in patients with platelet counts ≥50 x 109/L. In the randomized phase III COMFORT-1 trial, ruxolitinib was superior to placebo for the primary endpoint of ≥35% spleen volume reduction (SVR) at Week 24 in patients with intermediate-2 or high-risk MF and platelet counts ≥100 x 109/L. In addition, a significantly higher percentage of patients achieved ≥50% reduction in total symptom score with ruxolitinib vs placebo. Ruxolitinib also demonstrated superiority vs best available therapy in a similar patient population enrolled in the randomized phase III COMFORT-II trial. The primary endpoint for COMFORT-II was ≥35% SVR at Week 48.

 

Notable adverse events reported in ruxolitinib clinical trials include grade 3/4 anemia and thrombocytopenia. In COMFORT-I, platelet counts declined during the first 8-12 weeks of treatment and then remained stable through continued treatment. Hemoglobin levels likewise declined during the first 8-12 weeks but then began to increase gradually over time with continued therapy. One challenge with these 2 adverse events is determining if they are occurring because of disease progression or the medication itself, which may be providing therapeutic benefit. It is important to recognize that these adverse events are common, that patients generally can be supported through the declines to obtain clinical benefit, and that early discontinuation in the absence of other signs of clinical failure may not be the best course of action. Dose adjustments or interruptions often are effective for severe cases.

 

Ruxolitinib is dosed twice daily, and the starting dose is based on platelet count: 20 mg twice daily for platelet counts >200 x 109/L, 15 mg twice daily for platelet counts 100-200 x 109/L, and 5 mg twice daily for platelet counts 50 to <100 x 109/L. However, it is important to note that an analysis of the COMFORT-I trial and additional real-world data have demonstrated only limited changes from baseline in spleen volume and total symptom score with ruxolitinib doses <10 mg twice daily. Therefore, if a lower initial dose is needed, it is important to maintain the goal of safely escalating the dose as tolerated and with extensive support as needed in those first few months to improve the likelihood that patients will experience a clinical response to treatment.

 

Additional adverse events and warnings to keep in mind when supporting patients receiving ruxolitinib are the potential for increased lipid levels, infections, nonmelanoma skin cancer, thrombosis, secondary malignancy, and cardiovascular events. These considerations warrant risk and drug‒drug interaction assessments at the start of therapy and monitoring throughout treatment.

 

Fedratinib

Similar to ruxolitinib, fedratinib is an oral JAK inhibitor indicated for first-line treatment of intermediate-2 or high-risk MF in patients with platelet counts ≥50 x 109/L. In the randomized phase III JAKARTA trial, fedratinib 400 mg or 500 mg once daily was compared with placebo in patients with intermediate-2 or high-risk MF and platelet counts ≥50 x 109/L. Both doses of fedratinib demonstrated significantly higher rates of achieving the primary endpoint of ≥35% SVR at Week 24 vs placebo and were comparable. In addition, Week 24 symptom response rates were significantly higher with fedratinib vs placebo.

 

Also similar to ruxolitinib, rates of anemia and thrombocytopenia are high with fedratinib, including grade 3/4. In JAKARTA, rates of grade 3/4 anemia and thrombocytopenia were higher with fedratinib 500 mg once daily vs fedratinib 400 mg once daily. Thus, the approved dose is 400 mg once daily, making fedratinib the only once-daily oral JAK inhibitor approved for MF treatment.

 

Fedratinib was associated with a high incidence of low-grade diarrhea, nausea, and vomiting, which can occur rapidly upon treatment initiation (eg, within 1 day) and generally improves over time. Patients can be advised that taking fedratinib with a high-fat meal may decrease the risk of gastrointestinal events, and good supportive care at the onset of therapy can aid patients in staying on therapy, including provision of a prophylactic antidiarrheal and antiemetic. Fedratinib also carries a black box warning for Wernicke encephalopathy (ataxia, altered mental status, ophthalmoplegia), which occurred in 8 of 608 (1.3%) patients receiving fedratinib in clinical trials. Thiamine levels and nutrition status should be assessed at baseline and periodically throughout fedratinib treatment, with thiamine supplementation as needed, and fedratinib should not be administered if the patient has thiamine deficiency. It is also important to educate all members of the healthcare team—as well as patients and their caregivers—about Wernicke encephalopathy symptoms, including mental status changes, and the importance of prompt care if symptoms present.

 

Additional adverse events and warnings to keep in mind when supporting patients receiving fedratinib are the potential for increased liver or pancreatic enzymes, thrombosis, secondary malignancy, and cardiovascular events. These considerations warrant risk and drug‒drug interaction assessments at the start of therapy and monitoring throughout treatment.

 

Pacritinib

Pacritinib is the third oral JAK inhibitor to receive FDA approval for MF treatment. It is dosed at 200 mg twice daily and is indicated for first-line treatment of intermediate or high-risk MF in patients with platelet counts <50 x 109/L, distinguishing it from ruxolitinib and fedratinib. Pacritinib was assessed in 2 randomized phase III clinical trials enrolling patients with intermediate-1, intermediate-2, and high-risk MF: PERSIST-1 and PERSIST-2. In PERSIST-1, patients needed to have a platelet count of ≥25 x 109/L at baseline, with randomization to receive pacritinib 400 mg once daily vs best available therapy, excluding JAK inhibitors. In PERSIST-2, patients were required to have platelet counts ≤100 x 109/L at baseline (minimum 25 x 109/L), with randomization to receive pacritinib 400 mg once daily, pacritinib 200 mg twice daily, or best available therapy, including ruxolitinib. The primary endpoints of both trials included SVR ≥35% at Week 24. PERSIST-2 also included ≥50% reduction in total symptom score at Week 24 as a coprimary endpoint. In addition, 48% of patients enrolled in PERSIST-2 had received previous ruxolitinib treatment. In both trials, patients who received pacritinib experienced significantly higher rates of SVR ≥35% at Week 24 vs best available therapy. Relative to best available therapy, after 24 weeks of treatment, pacritinib also was associated with greater hemoglobin increases in patients with anemia at baseline and reduced transfusion burden in patients who were transfusion dependent at baseline. This outcome reflects the off-target inhibition of ACVR1 with pacritinib. Inhibition of ACVR1 results in hepcidin suppression, allowing release of sequestered iron and restoration of iron homeostasis.

 

The adverse event profile of pacritinib is similar to fedratinib, with considerable rates of grade 3/4 anemia and thrombocytopenia, as well as gastrointestinal events (diarrhea, nausea, and vomiting) that occur early but improve over time and warrant good supportive care (eg, providing as-needed antiemetic and antidiarrheal medication, counseling on increasing oral hydration). Of note, the safety outcomes with pacritinib were similar among patients with baseline platelet counts <50 x 109/L and 50-100 x 109/L, leading to the FDA indication for lower platelet count levels. It also was demonstrated that pacritinib 200 mg twice daily maximized spleen response while minimizing toxicity vs pacritinib 400 mg once daily.

 

Additional adverse events and warnings to keep in mind when supporting patients receiving pacritinib are the potential for hemorrhage and/or thrombocytopenia (particularly because of the indication for patients with low baseline platelet counts), prolonged QT interval, thrombosis, secondary malignancy, infection risk, and cardiovascular events. These considerations warrant risk and drug‒drug interaction assessments at the start of therapy and monitoring throughout treatment.

 

Selecting Among JAK Inhibitors

When selecting the most appropriate first-line JAK inhibitor for patients with intermediate- or high-risk symptomatic MF, it is important to consider the unique characteristics of each option alongside individual patient characteristics and clinical scenarios. In our clinics, we use ruxolitinib for first-line treatment in most patients given the totality of available clinical data, the lack of data on ruxolitinib in subsequent lines of therapy (thus preserving fedratinib and pacritinib for those settings), and the assumption that the patient can initiate or quickly escalate to an effective dose of 10-20 mg twice daily. However, ruxolitinib may not be the best first-line option in certain situations. For example, in a patient with strong adherence concerns, fedratinib as the only once-daily JAK inhibitor for MF treatment may be a better choice. As another example, pacritinib would be a better option in a patient with a baseline platelet count <50 x 109/L who is deemed unlikely to tolerate higher ruxolitinib doses or who is at high risk of bleed with thrombocytopenia where close monitoring may not be possible.

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