Ross Levine, MD, of Memorial Sloan-Kettering Cancer Center, New York, was the discussant of the COMFORT-I and COMFORT-II trials.1 He explained that 70% to 90% of patients with myelofibrosis have JAK2 mutations, which appear to be endemic.
“This is a driver mutation, although not the only mutation in myelofibrosis,” he told listeners. “But I would argue that JAK2 is the most attractive target.”
Both COMFORT trials were based on phase I/II trials showing that a majority of patients with myelofibrosis had rapid reduction in spleen size and reduction in associated clinical symptoms. “We don’t know if this is due to inhibition of JAK2 in the tumor cells or systemically,” he commented.
Both phase III trials allowed crossover—COMFORT-I at 24 months and COMFORT-II at spleen enlargement—which may compromise the ability of these studies to show eventual differences in disease-free and overall survival, he continued.
“Spleen size is an important endpoint. It is the major cause of morbidity and poor quality of life for patients with myelofibrosis, so a nonsurgical option to reduce spleen size without limiting toxicity would be of significant benefit for our patients,” Dr. Levine noted. “Both studies met their primary endpoints convincingly. Anemia and thrombocythemia occurred in about 30% of patients but were manageable,” he said.
“[Ruxolitinib] fulfills an important unmet need for myelofibrosis patients. It is well tolerated, and the dosing is easily managed by hematologists/oncologists. This is the first demonstration of an effective targeted therapy in myelofibrosis, and will likely lead to JAK2 inhibition as a treatment for patients with myelofibrosis and splenomegaly,” he stated. ■
Disclosure: Dr. Levine has served as a consultant or advisor with AstraZeneca, Incyte, and TargeGen, and has received honoraria from Novartis.
1. Levine RL: How do we find new mutations and develop novel therapies? 2011 ASCO Annual Meeting. Presented June 6, 2011.