SIMPLIFY Trials: JAK Inhibitor Yields Long-Term Survival Benefit and Transfusion Independence in Myelofibrosis

Get Permission

Treatment with the novel JAK inhibitor momelotinib led to long-term overall survival and sustained transfusion independence in patients with intermediate- or high-risk myelofibrosis, according to updates from the SIMPLIFY-1 and SIMPLIFY-2 trials presented at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition.1 Overall survival was “robust” both in patients with no prior JAK inhibitor exposure and in those previously treated with ruxolitinib, said Srdan Verstovsek, MD, PhD, Chief of the Section for Myeloproliferative Neoplasms at The University of Texas MD Anderson Cancer Center, Houston.

“The ability to achieve or maintain transfusion independence represents a substantive clinical benefit in light of the progressive myelosuppression associated with myelofibrosis.”
— Srdan Verstovsek, MD, PhD

Tweet this quote

Myelofibrosis results from dysregulated JAK-STAT signaling. Momelotinib is a selective and orally bioavailable inhibitor of JAK1, JAK2, and ACVR1, a tyrosine kinase important for iron homeostasis. Unlike other JAK inhibitors, momelotinib is not myelosuppressive, so dose reductions are not necessary.

“Momelotinib’s unique mechanism of action—targeting JAK1, JAK2, and ACVR1—is translating to durability of activity and survival data consistent with its clinical and biologic profile,” Dr. Verstovsek said. The drug offers the antiproliferative effects and anti-inflammatory effects of JAK inhibition and the influence of ACVR1 inhibition on anemia, he explained. “The findings demonstrate momelotinib’s potential ability to durably address the unmet needs of patients with myelofibrosis.”


The results reported at the 2020 ASH meeting were based on findings from 558 patients in whom momelotinib was compared with ruxolitinib or best available therapy. The double-blind -SIMPLIFY-1 first-line trial involved 432 JAK inhibitor–naive patients treated with momelotinib (200 mg daily) or ruxolitinib (20 mg twice daily) for 24 weeks. The open-label SIMPLIFY-2 second-line trial involved 156 ruxolitinib-exposed patients with anemia or thrombocytopenia treated with momelotinib or best available therapy for 24 weeks. In both studies, crossover to extended momelotinib was allowed after the 24-week randomization period. The splenic response rate was the primary endpoint in both studies.

‘Robust’ Overall Survival in Both Trials

Overall survival was “robust” in the final analyses of this endpoint, according to Dr. Verstovsek. In JAK inhibitor–naive patients randomly assigned to momelotinib in SIMPLIFY-1, median overall survival was not reached at 4.5 years. In patients randomly assigned to ruxolitinib who crossed over to momelotinib, median overall survival was 53.1 months (hazard ratio [HR] = 0.99; P = .97).

In SIMPLIFY-2, patients who had prior ruxolitinib treatment had a median overall survival of 34.3 months with randomization to momelotinib and 37.5 months after receiving best available therapy (predominantly ruxolitinib) and crossing over to momelotinib (HR = 0.96; P = .86).

“The durable survival reflects momelotinib’s benefit, as patients in both treatment arms could receive extended treatment with it after week 24,” Dr. Verstovsek commented. “These overall survival results are among the best survival reported in patients who have been previously treated with ruxolitinib.”

Splenic Response and Transfusion Independence

Splenic response, defined as a reduction in spleen volume of at least 35% from baseline at week 24, was achieved by 40% of patients receiving momelotinib in SIMPLIFY-1. The median duration of splenic response was not reached whether patients were initially assigned to momelotinib or crossed over at 24 weeks to receive the drug.

“This splenic response was durable, with a median time to loss of response not reached for subjects, regardless of whether they were initially randomly assigned to momelotinib or ruxolitinib and then crossed over,” noted Dr. Verstovsek.

Momelotinib was associated with high rates of transfusion independence in both studies. In SIMPLIFY-1, at 24 weeks, 67% of the momelotinib arm were transfusion-independent compared with 49% of the control arm (P < .001). Furthermore, the median duration of transfusion independence has not been reached after more than 3 years of follow-up. In SIMPLIFY-2, transfusion independence at week 24 was 43% in the momelotinib arm and 21% in the control arm (P = .001), Dr. Verstovsek reported.

“The ability to achieve or maintain transfusion independence represents a substantive clinical benefit in light of the progressive myelosuppression associated with myelofibrosis,” he added.

Mechanism of Action Responsible for Multiple Benefits

Patients randomly assigned to momelotinib had levels of hemoglobin and platelets that were sustained across the treatment period. In contrast, patients randomly assigned to ruxolitinib experienced rapid decreases in hemoglobin levels and platelet counts, which increased over baseline and were sustained after crossover to momelotinib.


  • Momelotinib, an inhibitor of JAK1, JAK2, and ACVRI, improved overall survival in patients with JAK inhibitor–naive myelofibrosis and in those previously treated with ruxolitinib in the SIMPLIFY trials.
  • In patients with prior JAK inhibitor therapy, median overall survival was 37.5 months for patients receiving best supportive care for 24 weeks, then crossing over to momelotinib, and 34.3 months for patients originally randomly assigned to momelotinib.
  • In JAK inhibitor–naive patients, median overall survival was 53.1 months for patients on ruxolitinib crossing over to momelotinib and was not reached for those originally assigned to momelotinib.
  • High rates of splenic response and transfusion independence were also achieved with momelotinib.

“Rapid and sustained increases in hemoglobin levels seen over the dosing period are consistent with the compound’s inhibition of ACVR1, resulting in decreased hepcidin and increased iron that is available for erythropoiesis,” Dr. Verstovsek said. “Since momelotinib is not myelosuppressive, patients’ red blood cell counts and platelets rebound once they cross over.”

In addition, momelotinib’s differentiated hematologic profile allows for high-dose intensity. In the studies, the drug was initiated at full-dose intensity, which was sustained throughout treatment. In contrast, ruxolitinib’s dose intensity was lower at initiation and diminished throughout.

Safety Profile

Safety results from SIMPLIFY-2 were published in 2018.2 For momelotinib vs controls, the most common grade ≥ 3 adverse events were anemia (14% vs 14%), thrombocytopenia (7% vs 6%), and abdominal pain (1% vs 6%). Peripheral neuropathy occurred in 11% of patients receiving momelotinib, only one of which was grade 3, and in no patients on best available therapy. Serious adverse events were observed in 35% of the momelotinib arm and 23% of the control arm.

The global, randomized, double-blind phase III MOMENTUM trial ( identifier NCT04173494) will enroll an estimated 180 patients with myelofibrosis who are symptomatic, anemic, and have been previously treated with a JAK inhibitor. Patients will be randomly assigned to momelotinib or danazol; after 24 weeks of treatment, patients on the danazol arm will be permitted to cross over to receive momelotinib. The primary endpoint is total symptom score. Data are expected early in 2022. 

DISCLOSURE: Dr. Verstovsek has served as a consultant or advisor to Celgene, Constellation Pharmaceuticals, Incyte, Novartis, and Sierra and has received research funding from Blueprint Medicines, Celgene, CTI BioPharma Corp, Genentech, Gilead Sciences, Incyte, Novartis, NS Pharma, Promedior, and Roche.


1. Verstovsek S, Egyed M, Lech-Maranda E, et al: Robust overall survival and sustained efficacy outcomes during long term exposure to momelotinib in JAK inhibitor naive and previously JAK inhibitor treated intermediate/high risk myelofibrosis patients. 2020 ASH Annual Meeting & Exposition. Abstract 54. Presented December 5, 2020.

2. 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 5:e73-e81, 2018.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

Related Articles

Expert Point of View: Lucia Masarova, MD

Lucia Masarova, MD

Lucia Masarova, MD

Lucia Masarova, MD, Assistant Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, said the updated long-term data for momelotinib show “durable efficacy and exciting outcomes” in patients with myelofibrosis, regardless of...