Is Fedratinib Safe for Myelofibrosis Patients with Low Platelets?

Is the JAK2 inhibitor fedratinib (Inrebic, BMS) a safe second treatment for myelofibrosis patients with low platelet levels?

Understanding Myelofibrosis and Platelets

In the early stages of myelofibrosis, before significant bone marrow scarring develops, patients may have an abnormally high platelet count. This occurs because myelofibrosis triggers an overproduction of megakaryocytes—the cells responsible for platelet production—leading to an excess release of platelets into the bloodstream. However, these platelets may not always function properly.

As the cancer progresses and bone marrow scarring worsens, platelet production is disrupted, often resulting in low platelet counts (thrombocytopenia).

A key concern with certain treatments, like the JAK1/2 inhibitor ruxolitinib (Jakafi, Incyte), is that although it helps reduce spleen size, fatigue, and bone marrow scarring, it also lowers platelet levels. This raises questions about the safety of certain myelofibrosis treatments for patients already at risk of bleeding/bruising due to low platelets. 

Insights from Dr. Haifa Kathrin Al-Ali

Dr. Haifa Kathrin Al-Ali from the University Hospital of Halle, Germany, presented a sub-analysis of the FREEDOM2 trial at the 2024 ASH conference. She and her team focused on whether intermediate-2 or high-risk patients with low platelet counts (between 50 and 99 x 109/L) who relapsed or were refractory to ruxolitinib could benefit from fedratinib as their second treatment.

"We know that a low platelet count is not a good thing for patients with myelofibrosis and has a negative impact on survival," Dr. Al-Ali explained. "This sub-analysis examined patients based on their platelet levels to assess the drug’s safety and efficacy. All patients included in the study were refractory to a first-line JAK inhibitor, usually ruxolitinib, and needed a second-line treatment."

Watch her interview or read the study summary below to learn about the findings.

Fedratinib’s Impact on Myelofibrosis Patients with Low Platelet Levels 

Patients were divided into two groups: one group received fedratinib, while the other received the best available therapy. Researchers tracked how patients responded, focusing on spleen size reduction, platelet levels, and overall safety. 

One of the key findings of the study was that patients who received fedratinib generally saw an increase in their platelet levels over time. This was especially noticeable in patients who started with lower platelet counts.

By day 15 of the first treatment cycle, 43% of patients in the low platelet group who received fedratinib saw an increase in platelets, compared to just 11% of patients in the best available therapy group. 

Additionally, fedratinib was more effective at reducing spleen size, a common problem in myelofibrosis. About 47% of patients with low platelet counts saw their spleen shrink by at least 35% after six treatment cycles, compared to 0% of patients who received the best available therapy. Patients in the high platelet group also saw spleen reductions, though the effect was slightly lower.

Dr. Al-Ali noted that "no matter how high or low the platelets were before the start of the trial, all patients could benefit from a full dose of the drug—400 mg once daily—without reducing effectiveness. Interestingly, patients with low platelet counts showed even better responses compared to those with higher platelet counts. Nearly half of the patients had improvements in spleen size and symptoms."

Were There Side Effects? 

While fedratinib showed benefits in platelet levels and spleen size reduction, it also came with risks. Some patients experienced worsening thrombocytopenia and anemia. These side effects were more common in patients who started with lower platelet counts. 

Dr. Al-Ali acknowledged these risks but pointed out that:

"Only one patient had to stop treatment due to low platelet levels. Most patients continued with adjusted dosing when necessary. Gastrointestinal side effects were also present, but giving the medication in the evening after meals helped improve tolerability."

Conclusion

For myelofibrosis patients with low platelet counts, fedratinib offers a potential treatment option that may help stabilize platelet levels while also reducing spleen size. 

However, it is important for patients and their doctors to weigh the benefits against the possible side effects. Regular blood monitoring and careful dose management may help minimize risks while maximizing the benefits of the treatment.

Dr. Al-Ali emphasized that "patients with moderate thrombocytopenia—those with platelet counts between 50 and 99—can still benefit from fedratinib because of its platelet-sparing effect. The findings are consistent with earlier studies that led to the drug’s approval. Even though second-line treatments are often more challenging, these results are encouraging for those needing another option."

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Sources: 

• Efficacy and Safety of Fedratinib in Patients with Myelofibrosis and Low Baseline Platelet Counts in the Phase 3 Randomized FREEDOM2 Trial
• 634. Myeloproliferative Syndromes: Clinical and Epidemiological: JAK Inhibitors in MPDs, Novel Insights and Next-Gen Agents