Status Update: What Is the Current Data on JAK Inhibitors for Myelofibrosis?

At the Fourth Annual National General Medical Oncology Summit, Andrew Kuykendall, MD, an assistant member of the Department of Malignant Hematology at Moffit Cancer Center, Tampa, Florida, presented on the status of myelofibrosis (MF) treatment in the era of 4 approved Janus kinase (JAK) inhibitors: ruxolitinib, fedratinib, pacritinib, and momelotinib.

“The approval of JAK inhibitors has not transformed the field, but it’s allowed us to extend the percentage of patients who are able to benefit from JAK inhibition,” Dr. Kuykendall said during the presentation.

Ruxolitinib

First, Dr. Kuykendall gave an overview of data supporting the use of ruxolitinib for patients with intermediate- and high-risk MF. The JAK inhibitor reduced spleen volume, rapidly improved symptoms, and was associated with a survival benefit in the COMFORT study.¹ At 24 weeks, 41.9% of patients in the ruxolitinib group achieved a spleen volume reduction (SVR) of 35% or more, compared with 0.7% of patients in the placebo group.²

“This is something that sometimes gets overlooked because ruxolitinib isn’t getting rid of the disease, but it’s something that could meaningfully impact a patient’s experience with the disease,” Dr. Kuykendall shared during his presentation.

However, ruxolitinib is associated with myelosuppression, anemia, and thrombocytopenia, which limits dosing. Due to high rates of grade 3 and 4 anemia and thrombocytopenia, most patients In the COMFORT study reduced their dose from 20 mg twice daily to 15 mg twice daily.¹ “This is going to impact response rates, and we know it factors into overall survival expectations,” Dr. Kuykendall noted. Patients who require transfusions, don’t have substantial SVR, or receive doses lower than 20 mg twice daily are predicted to have worse overall survival according to the RR6 [Response to Ruxolitinib after 6 months] prognostic model.¹

Fedratinib

Next, Dr. Kuykendall shared efficacy and safety data on fedratinib for patients with newly diagnosed MF and those resistant or intolerant to ruxolitinib. In the JAKARTA-2 and FREEDOM-2 trials, 400 mg of daily fedratinib improved splenomegaly and symptoms in the second-line setting. “Ruxolitinib is preferred in the frontline setting in the vast majority of patients, but fedratinib may have a role here as a second-line agent after ruxolitinib failure or intolerance,” he explained in the presentation.

Pacritinib

Pacritinib, the third approved JAK inhibitor, showed superiority in terms of spleen and symptom responses compared with best available therapy in patients with MF and thrombocytopenia, according to the PERSIST-2 trial. SVR of at least 35% was achieved in 18.4% of patients in the pacritinib group, compared with 3% in the best available therapy group (P=0.001).³

In a reanalysis of PERSIST-2, pacritinib was also associated with anemia benefits, such as a reduction in transfusions, compared with best available therapy. The rate of transfusion independence was 37% in the pacritinib group, compared with 7% in the best available therapy group.¹

Momelotinib

In SIMPLIFY-1, a head-to-head trial of momelotinib versus ruxolitinib, momelotinib was noninferior to ruxolitinib in terms of spleen volume responses but was not noninferior in terms of symptom improvement. “Ruxolitinib is the best symptom drug in terms of patients feeling better,” Dr. Kuykendall explained.¹

Momelotinib was not superior to best available therapy (including rituximab) in the SIMPLIFY-2 trial of patients who received prior ruxolitinib. Seven percent of patients in the momelotinib group achieved SVR of at least 35% after 24 weeks, compared with 6% in the best available therapy group.⁴

“This study failed in the sense that the primary end point was looking at spleen volume responses, which were rarely seen on either arm in this study,” Dr. Kuykendall noted.¹

These 2 trials led to the phase 3 MOMENTUM study, in which symptomatic patients with MF and anemia with prior ruxolitinib treatment were randomized to receive either momelotinib or danazol. Momelotinib was superior to danazol in terms of both symptom improvement (25% vs 9%, respectively) and SVR of at least 35% (22% vs 3%, respectively).¹

“Where we really want to use momelotinib is in patients who have anemia,” Dr. Kuykendall said. “Here, it was quite encouraging. Momelotinib had better anemia responses in this patient population as well.”¹

Unmet Needs

To conclude, Dr. Kuykendall highlighted the unmet needs in myelofibrosis, such as improving hematopoiesis and altering the natural history of the disease by using combination therapies or targeting core driver mutations. Ongoing trials are evaluating luspatercept, elritercept, and DISC-0974, as well as pelabresib, selinexor, navtemadlin, and imetelstat combinations.¹

References

1. Kuykendall A. State of the art treatment of myelofibrosis. Presented at: Fourth Annual National General Medical Oncology Summit; February 28-March 2, 2025; Miami, FL.
2. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/NEJMoa1110557
3. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818
4. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018;5(2):e73-e81. doi:10.1016/S2352-3026(17)30237-5