An older patient comes to you with severe night sweats, debilitating fatigue, abdominal pain, weight loss, and itching. High on your differential is myelofibrosis, the proliferative blood disorder that scars the bone marrow, causing abnormal blood counts and a spleen swollen with the effort of producing blood cells.
We think the disease stems from dysregulation of Janus kinase (JAK)-mediated cytokine and growth-factor signal transduction—for about 50% of patients, this comes in the form of a gain-of-function JAK2 mutation.
Median survival from diagnosis is two to four years depending on disease grade, and the treatment options are few: only a handful of patients are candidates for cure with stem cell transplant, and other treatments like blood transfusions and splenectomy are strictly supportive. Recently, a targeted small molecule inhibitor has shown therapeutic promise, but not for the reasons we might suspect.
In early phase studies of the JAK1 and 2 inhibitor ruxolitinib, the drug was associated with weight gain, symptom relief, and decrease in spleen size—whether or not the patients had that common gain-of-function mutation. And now we have phase III results: the Myelofibrosis Study with Oral JAK Inhibitor Treatment I and II (COMFORT-I and II), published in this week’s NEJM.
In the European COMFORT-II trial, researchers randomized 219 subjects with intermediate or high-risk myelofibrosis to receive either ruxolitinib or the best available treatment. Among subjects taking ruxolitinib, 32% showed considerable reduction in spleen volume by MRI or CT at 24 weeks and 28% showed this at 48 weeks, while nobody in the usual treatment group showed this improvement at either time point. At 48 weeks, the average palpated spleen length had decreased by more than half in subjects taking ruxolitinib, while it had increased slightly in subjects on usual therapy. Perhaps more importantly, those taking ruxolitinib had fewer myelofibrosis-related symptoms and fared better on quality of life measures than their peers receiving usual treatment. There was no survival difference between the groups.
The COMFORT-I trial compared the drug to placebo and had similar results, with the added bonus of a survival benefit in the treatment arm. American researchers randomly assigned 309 patients with intermediate or high-risk myelofibrosis to receive ruxolitinib or placebo twice a day. At 24 weeks, 41.9% of treated patients had considerably reduced their spleen size, compared to 0.7% in the placebo group. More than 45% of patients receiving ruxolitinib had greater than 50% improvement in their total symptom score after six months, compared with 5.3% receiving placebo. Thirteen patients died in the ruxolitinib group, compared with 24 in the placebo group. Two patients developed acute myeloid leukemia—both in the ruxolitinib group. In both trials, subjects on ruxolitinib were more likely to develop low red blood cell and platelet counts, but they rarely discontinued the drug as a result.
Last November, the FDA approved the drug based on these studies.
In an accompanying editorial, Ayalew Tefferi of Mayo Clinic in Rochester, MN and senior author on the ruxolitinib safety and efficacy study, writes: “What they failed to demonstrate was histopathologic, cytogenetic, or molecular remissions and the drug was more likely to cause anemia and thrombocytopenia rather than correct them.”
So ruxolitinib is not a cure for a disease process that is still poorly defined. But the real takeaway from these papers, says NEJM Deputy Editor Dr. Dan Longo, is that MDS is “associated with lots of side effects, many of which are probably cytokine mediated.” Ruxolitinib suppresses these cytokines and “the quality of life benefit is quite notable and important from a management point of view. It clearly represents a significant advancement.”
What do you think will be the next big target in myelofibrosis drug development?
What do these studies suggest about the pathophysiology of myelofibrosis?