Ruben Mesa discusses Jakafi's potential in treating myelofibrosis.
Patients with intermediate or high-risk myelofibrosis are not are often not expected to live more than three years past their diagnosis. However, research into Jakafi (ruxolitinib) found that many of these patients reacted positively to the drug — over 50 percent remained on the trial after five years.
There are still some hazards associated with the drug, such as potential for anemia and thrombocytopenia; a chance of developing shingles; and an increased possibility of developing non-melanoma skin cancer. However, research continues to test the drug’s effect on patients, including studies combining Jakafi with other agents.
A study called COMFORT-I was presented by Ruben Mesa, a hematologist at the Mayo Clinic in Scottsdale, Arizona at the 2016 European Hematology Association conference, a gathering of thousands of hematologists in Copenhagen, Denmark. CURE spoke with Mesa to discuss the findings of the study and its next steps. The following is edited for brevity and clarity.
Can you give a brief overview of the study?
What did the study find?
Could you give a little background on Jakafi?
The COMFORT-I study was the first and largest randomized phase 3 study in myelofibrosis evaluating Jakafi versus the best alternative therapy in patients with intermediate and high-risk myelofibrosis. Here at this meeting we provided the important five-year follow-up data from that study.In terms of improvements in symptoms, such as splenomegaly, over 50 percent of the patients remain on the active study drug, which is really noteworthy considering the life expectancy of the patients enrolling in the study was probably three years or less. The fact that over half the patients remain on the study further demonstrates the significant survival benefit. In terms of the analysis, we’re able to see there is a clear survival advantage for patients on Jakafi compared with the control arm. It’s noteworthy that the control arm was initially on placebo, but at 81 weeks, everyone had crossed over to Jakafi. The study really compares Jakafi to delayed Jakafi — even still, we saw a strong survival advantage.Jakafi is a JAK2 and FLT3 inhibitor. It’s an inhibitor of the native JAK2. Patients with myelofibrosis have an overly active JAK-STAT pathway, which can be overly activated by the JAK2 V617F mutation, the CALR mutation and the MPL mutation. We have not yet identified a driver mutation in some patients, but they all feed at that same JAK2 spot in terms of that signaling. That’s the key area of inhibition, which is one of the reasons why we’ve seen benefit to the therapy without regard to an individual’s driver mutation status.
What are the next steps for this research?
Were there any toxicities seen with this agent in the five-year data?
Is there potential for this drug to be used in combination with other things?
What are some of the biggest challenges you see in myelofibrosis that you would like to be addressed next?
Additionally, there are a variety of ongoing combination studies to see ways we can further build on the improvements of splenomegaly symptoms. We didn’t see any unexpected late toxicities. In terms of toxicities of Jakafi, there is the potential of anemia and thrombocytopenia, which we have known from the beginning, although I think we can manage them much better these days now that we adjust dosing accordingly. There are also rare, atypical infections, including a 3 to 5 percent chance of contracting shingles. Additionally, there may be a slight increased risk of non-melanoma skin cancer, although it can be difficult to differentiate that from the increased rate of those non-melanoma skin cancers in patients with myeloproliferative neoplasms because of their advanced age and prior hydroxyurea exposure.A variety of combinations are being tested, including combination with cytoreductive therapy such as hypomethylating agents, other novel pathway inhibitors such as PI3K inhibitors, hedgehog inhibitors and other agents to try and improve anemia. At the moment, those efforts are still ongoing. There is not yet a combination that is superior to the single agent. Therefore, at the moment, we do not recommend any, but those studies are being followed with great interest.In myelofibrosis there remains a variety of key, unmet needs. Patients with very advanced disease, such as those who are moving towards acute leukemia, still have a very poor prognosis. How do we impact them in a greater degree?
Additionally, there are residual challenges with anemia or thrombocytopenia in JAK inhibitor trials with pacritinib and momelotinib that are ongoing to see whether they can be of use in that regard. There’s interest in trying to alter the disease course in a better way. Studies such as this one are looking to see if inhibition of fibrosis can have a greater benefit on the disease as well as other novel mechanisms of action, such as telomerase inhibition.