A review on the effects of Janus kinase (JAK) inhibitors for the treatment of myelofibrosis, including the first approved, ruxolitinib, and others currently in development.
The available treatment options for patients with myelofibrosis (MF) are expanding as 1 Janus kinase inhibitor (JAK-i) was recently approved and 2 more are in development.
Approximately 20,000 US citizens have MF, which is a chronic myeloid neoplasm characterized by primary MF or secondary MF following thrombocythemia or polycythemia vera. It can cause serious anemia and splenomegaly, which prior to JAK-i treatments required patients to receive splenectomies to remedy.
Ruxolitinib was the first JAK-i and was approved for the treatment of MF in 2011. In clinical trials, ruxolitinib showed a 35% spleen volume reduction (SVR) in 41.9% of patients and was maintained for 48 weeks in 67% of those patients compared to patients receiving placebos. Reduction of MF symptom burden was observed in 45.9% of patients, with a mean improvement of 41.8% for all patients.
Although the drug likely improves survival of MF, allowing progressing patients to attain a median survival of 14 months, it does not cure the disease and the median time of response is only 3.2 years.
All of the current JAK-i vary in degrees of success and alternatives to ruxolitinib show promise in mitigating drug side effects that cause patients to discontinue treatment or become drug resistant.
“Once the other JAK-i are available, there will be an array of treatment options available to patients....There will also be excellent alternatives for patients who do not tolerate 1 of the JAK-i due to side effects,” said investigators.
Fedratinib is the first JAK-i alternative to ruxolitinib and was approved for marketing in 2019. The drug has shown a beneficial impact on the spleen, reducing the volume in 39% of patients after 6 months and 47% of patients after 12 months. Symptom burden was found to be reduced as well, with 75% of patients experiencing improvement after 1 month and 50% having complete resolution.
In clinical trials, the most common hematologic toxicity was anemia, which had an onset between 12 to 16 weeks. Fortunately, 79% of the patients who became transfusion dependent experienced an improvement in hemoglobin, allowing them to become transfusion independent.
However, encephalopathy was found in some patients, leading to the discontinuation of a clinical trial as researchers worried that the drug could lead to Wernike’s encephalopathy (WE), an acute neuropsychiatric disorder caused by an overproduction of thiamine.
Another study concluded that fedratinib did not increase the risk of WE development, but the drug does have a black box warning for physicians to check thiamine levels in patients prior to initiating therapy.
There are 2 other JAK-i in development: momelotinib and pacritinib. Both have completed phase 3 clinical trials and are completing additional steps to seek FDA approval. Momelotinib may be attractive for patients with anemia and pacritinib may be geared more to patients with low platelet counts.
In clinical trials comparing momelotinib to the best available treatment (BAT), no significant differences were found in the SVR. A 50% reduction in symptoms burden occurred in 26% of patients administered momelotinib compared with 6% receiving BAT. In the study, 89% of patients in the BAT arm were taking ruxolitinib.
Momelotinib was not approved based on the low number of patients that saw a significant reduction in symptom burden in clinical trials. In SIMPLIFY-1, momelotinib had an inferior improvement in myeloproliferative neoplasm total symptom score compared with ruxolitinib. However, another phase 3 trial is underway looking at the effects of momelotinib in combination with danazol.
Pacritinib has been shown to reduce spleen size in patients with anemia and thrombocytopenia but has also had multiple clinical trials stopped due to unexpected poor outcomes.
In February 2016, there was a clinical hold placed on pacritinib due to reports of deaths from bleeding and cardiac events in trial participants. However, extensive evaluation concluded that this was likely related to the underlying disease and not the medication, the authors noted. Reevaluations have shown a 35% SVR and a 50% reduction in symptom burden observed in patients across treatment arms.
Previous studies evaluating the effects in patients with platelet counts lower than 100 showed a reduction in SVR in 18% of patients compared with 3% of taking the BAT (50% exposed to ruxolitinib). A superior response was also observed in the treatment arm receiving pacritinib 200 mg twice daily.
Palmer J, Mesa R. The role of fedratinib for the treatment of patients with primary or secondary myelofibrosis. Ther Adv Hematol. 2020;11:1-7. doi:10.1177/2040620720925201