Jakafi Reintroduced to Patients with Myelofibrosis After Discontinuation May Extend Survival

Most patients with myelofibrosis who were reintroduced to treatment with Jakafi (ruxolitinib) after not tolerating it at first had clinical improvements and a potential survival advantage, according to data published in Cancer.

Researchers also found a substantial rate of permanent discontinuation of treatment with Jakafi.

“In the absence of alternative treatment strategies, (Jakafi) rechallenge may, therefore, be considered in virtually all patients with active disease,” the study authors wrote. “However, the duration of (Jakafi) rechallenge was quite short. … This observation may suggest strict clinical follow-up of patients during the rechallenge and the rapid implementation of alternative therapeutic strategies when required.”

Previously, discontinuation of Jakafi often left patients with myelofibrosis with a poor outcome and not many therapeutic possibilities, the study authors wrote. Jakafi is the first JAK1/JAK2inhibitor approved for treatment of splenomegaly (or enlarged spleen) and symptoms for patients with myelofibrosis. Although it demonstrates efficacy and improvement in quality of life and overall survival, many patients cannot tolerate it and cannot achieve a response over time.

Researchers sought to discover the frequency and reintroduction of Jakafi, its therapeutic effects and the impact on overall survival in 219 patients with myelofibrosis who discontinued treatment with Jakafi for at least 14 days and survived for at least 30 days.

Jakafi was reintroduced in 60 patients after at least 14 days of discontinuation and 159 patients discontinued the treatment permanently. The median duration of Jakafi before the first or only discontinuation was 16.5 months in patients who restarted treatment and 12.3 months in those who permanently stopped treatment. Median follow-up with the reinitiation group was 18.8 months compared with 15.5 months in the permanent discontinuation group.

During the reintroduction period, respectively, 44.6% of patients had spleen improvement and 48.3% experienced symptom improvement. In addition, there was a significant increase in the number of patients with a reduction in Total Symptom Score which indicates symptom severity. The use of Jakafi at a twice-daily dose of greater than 10 milligrams predicted patients who had better spleen and symptom improvements. Despite this, the reasons for and the duration of discontinuation with Jakafi, and the use of other therapies before reinitiating Jakafi was not linked with the efficacy of therapy reinitiation.

Of the patients who reinitiated treatment with Jakafi, 33.3% permanently discontinued the therapy at one year and 48.3% permanently discontinued it at two years. Median overall survival (the time since treatment that patients are still alive) was 27.9 months, which was significantly longer for patients who reinitiated treatment with Jakafi, the study authors note.

In the 60 patients who reinitiated therapy with Jakafi, therapy was temporarily discontinued at first due to toxicity (70%), which included severe or life-threatening low blood platelet count (38.1%), anemia (26.2%), infections (21.4%) and other types of side effects (14.3%). Ten patients discontinued treatment due to lack of response and eight patients for loss of response.

After reintroduction, 31 patients discontinued permanently. Some of these causes included death (32.3%), lack of response (29%), blood-related toxicity (19.3%), disease progression (6.5%), infection (3.2%) and bleeding (3.2%). In addition, 6.5% of patients discontinued to undergo allogeneic stem cell transplantation despite having a good response to treatment with Jakafi.

Among the 159 patients who never reinitiated treatment with Jakafi, 75 (47.2%) discontinued because of inadequate spleen response (56 to lack of response and 19 to loss of response), and 15 stopped to undergo autologous stem cell transplantation. Side effects that caused discontinuation in this group included serious or life-threatening anemia (40.6%), thrombocytopenia (27.5%), infections (18.8%) and other reasons such as second primary malignancies and blood clots (13.1%).

“Overall, these findings provide important real-life evidence that (Jakafi reintroduction) may be effective after initial (Jakafi) failure, with clinical improvements achieved in a not negligible portion of patients,” the study authors wrote. “However, (Jakafi) rechallenge was used mainly in intolerant patients and was associated with a high rate of permanent drug discontinuation.”

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