Primary Myelofibrosis - Episode 4
Ruben A. Mesa, MD, FACP:The COMFORT-I and COMFORT-II trials were pivotal studies that led to the approval of ruxolitinib in patients with myelofibrosisCOMFORT-I being a comparison of ruxolitinib versus placebo in JAK inhibitor-naïve patients with myelofibrosis, and COMFORT-II being a similar study with ruxolitinib versus best alternative therapy in JAK inhibitor-naïve patients. We found, in the short term, that ruxolitinib was superior to either placebo or best alternative therapy for both reduction in splenomegaly and control of symptoms.
Long term, we have identified that there is a survival advantage, as best as we can estimate given the limitations of crossover-designed studies for both trials and for a pooled population. Indeed, there are patients on ruxolitinib who remain on ruxolitinib even from the era of the original phase I and phase II studies from 2007 and 2008 who, long ago, likely would have passed away from the disease. So the benefit on the disease begins with the spleen and symptoms, but the benefit is much more substantial. It is still somewhat difficult to quantify because of the limitations of the crossover design due to a lack of us truly understanding why patients with myelofibrosis progress. But there is a stabilization in responders that occurs with this disease that I think is very meaningful and has contributed to this survival advantage that we have seen.
The inhibition of JAK2, as well as potentially JAK1, has a direct impact on the reduction of the spleen, both with ruxolitinib and with other JAK inhibitors that have been seen. The exact mechanism of response is still not completely understood, but might include a variety of things including the change in the cytokine profile, and the stem cell trafficking that’s occurring in and out of the spleen. The benefits that are seen are seen rapidly and are seen without evidence of tumor lysis. So it does not seem to be a chemotherapy type of effect, in terms of cell killing, but really an impact on likely inflammation, stem cell trafficking, and the cytokine profile.
Transcript edited for clarity.
Case: 72-Year-Old Man Diagnosed With Primary Myelofibrosis