Editorial theme | The management of relapsed/refractory myelofibrosis: Part 2 – novel JAK inhibitors

As part of the new editorial theme on the management of relapsed or refractory myelofibrosis (R/R MF), we are now looking at the emerging therapeutic approaches in treating this hard-to-treat patient population. In this second Editorial Theme Article, we will focus on new Janus kinase inhibitors (JAKi); and in our third article, on other options beyond JAK inhibition including allogeneic hematopoietic stem cell transplantation (allo-HSCT).

In case you have missed it, here is the link to our first editorial article summarizing challenges of treating patients whose disease failed to respond to ruxolitinib.

Fedratinib

Fedratinib is a pyrimidine-based JAK2 inhibitor approved by the U.S. Food and Drug Administration (FDA) back in 2019¹, and very recently, the European Medicines Agency (EMA) granted approval for the treatment of adults with primary or secondary MF who are treatment naïve or have received prior ruxolitinib therapy. It provides an oral therapeutic option given once daily.

The approvals were based on favorable results from the phase III JAKARTA trial (conducted in JAKi-naïve patients) and JAKARTA2 trial (conducted in patients who previously received ruxolitinib). Fedratinib was associated with ≥35% spleen volume reduction in about 30% of patients, and ≥50% reduction in MF-related symptom score in 27% of patients.

However, early study results with fedratinib raised questions due to neurological symptoms indicative of the thiamine-deficiency condition of Wernicke encephalopathy (WE), and a clinical hold by the FDA followed. There were also concerns about gastrointestinal (GI) toxicity. Reassessment of the JAKARTA trials indicated that WE events were not associated with fedratinib therapy.  If you would like to know more on the long approval journey of fedratinib, read the article here. Two phase III trials, FREEDOM and FREEDOM2, are currently investigating the efficacy and safety of fedratinib in patients with intermediate/high-risk MF as frontline or second line treatment. WE and GI toxicities are events of special interest and closely being monitored. The results of both trials are still expected.

Pacritinib

Pacritinib is a JAK2 and interleukin-1 receptor-associated kinase 1 (IRAK1) inhibitor that was associated with better outcomes compared with best available therapy, in patients with primary MF and thrombocytopenia who did not receive a JAK inhibitor previously in the phase III PERSIST-1 and PERSIST-2 trials.

The phase III PACIFICA trial (NCT03165734) is currently assessing pacritinib in patients who have had no or limited exposure to any JAK2 inhibitor with severe thrombocytopenia; the phase II results from the JAK2-exposed cohort, PAC203, were recently presented. A pacritinib dose of 200 mg given twice daily resulted in

• clinically meaningful spleen volume reduction
• a reduction in total symptom score
• only a few high-grade cardiac and hemorrhagic treatment-emergent adverse events (TEAEs)

These preliminary findings have suggested that pacritinib may provide a new therapeutic option for patients who were intolerant to ruxolitinib or did no longer respond to ruxolitinib. In addition, pacritinib seems to induce less thrombocytopenia compared with other JAKi. The key results of the PAC203 trial were summarized on the MPN Hub, here.

In September 2020, the FDA agreed to a new drug application (NDA) submission for an accelerated approval based on PERSIST-1, PERSIST-2, and phase II PAC203 trials. The submission is expected to be completed in early 2021.

Momelotinib

Momelotinib is another JAK1/2 inhibitor and activin A receptor, type I (ACVR1) activator that has the potential to improve anemia in MF, which was under investigation in the phase III SIMPLIFY-1 and SIMPLIFY-2 trials in patients who were JAKi-naïve or with suboptimal response to ruxolitinib, respectively. Patients were randomized to ruxolitinib or momelotinib followed by momelotinib. Both trials demonstrated promising outcomes in OS:

• In the SIMPLIFY-1 trial, median OS was 53.1 months with ruxolitinib followed by momelotinib, while it was not reached with momelotinib in JAKi-naïve patients (p = 0.97)
• In the SIMPLIFY-2 trial, median OS was 37.5 months with ruxolitinib followed by momelotinib, and 34.3 months with momelotinib in ruxolitinib-exposed patients

In both trials, momelotinib was associated with spleen response at any time and transfusion independence in JAKi-naïve patients. Balanced hemoglobin and platelet counts while on momelotinib allowed for full dose intensity compared with dose reductions with ruxolitinib. Myelosuppression was mild and no cumulative toxicity was reported.

The MPN Hub previously summarized the updated results and long-term safety analyses of the SIMPLIFY-1 and -2 trials.

The phase III MOMENTUM trial (NCT04173494) is currently comparing momelotinib and danazol in symptomatic and anemic patients with MF who were previously treated with a JAKi.

Challenges of treating patients after ruxolitinib

• Failure of treatment with ruxolitinib leads to a shorter OS in patients
• Switching therapies from one JAK inhibitor to another needs careful consideration due to a possible risk of developing an inflammatory response (for more information on switching between JAKi, click here)
• The management of ruxolitinib-induced thrombocytopenia represents an unmet need (for more information, read this MPN Hub article)

Conclusion

There is an unmet clinical need for treating patients with R/R MF, and there is a continuous effort to improve outcomes and modify disease progression in several studies. Promising results have been obtained with the new JAKi fedratinib, momelotinib, and pacritinib, both in JAKi-naïve and JAKi-exposed patients. It seems that some of these newer agents come with less hematologic side effects such as anemia and thrombocytopenia.

In the next article, the MPN Hub will cover novel treatment approaches with different modes of action that are under evaluation in clinical trials.