Mechanism of JAK Inhibitors and a Review of Ruxolitinib
John Mascarenhas, MD: So JAK inhibitors are a class of agents. They’re oral agents. There are probably at least a dozen that have been in clinical development. And what they do is potently inhibit a signaling pathway that’s overactive in patients with myelofibrosis that contributes to the inflammatory cytokine milieu that mediates a lot of the symptom burden that we’ve been discussing, whether it’s bone pains or inflammatory symptoms like fevers and night sweats. So much of the symptom burden that is part and parcel to having myelofibrosis is driven in large part by JAK-STAT [Janus kinase–signal transducer and activator of transcription] signaling. And these small molecule inhibitors abrogate that signaling and reduce in a very potent way the inflammation that is mediating those symptoms.
Moshe Talpaz, MD: JAK2 inhibitors are the only approved form of therapy for myelofibrosis. JAK-STAT signaling is a…system in the cell that is associated with proliferation of the cells, lack of interference with the death process of the normal cell, and production of a variety of cytokines. Not surprisingly, the JAK-STAT system seems to be activated in patients with myelofibrosis, regardless of the mutation. By the way, it can be calreticulin mutation, it can be MPL mutation, and it can be JAK2 mutation. All of those activate the JAK-STAT pathway and result in increased proliferation of the cells and increased production of a variety of cytokines. This overproduction of cytokines can explain a lot of the symptoms of the patients—night sweats, weight loss, fatigue, and even anemia. Many of those can be explained by the overproduction of cytokines.
It is well known that JAK2 inhibitors interfere with this overactivity of the JAK-STAT pathway. As a consequence, the cells are less proliferative, so we do see reduction in spleen size as one of the major accomplishments of this therapy. In addition, many of the symptoms subside. The patient starts to gain weight, the patient feels less fatigue, and the patient’s level of energy and appetite approve dramatically, and I have absolutely seen dramatic cases with a transition in 1 day. So the JAK2 inhibitors have a profound effect on the JAK-STAT signaling and consequently lead to inhibition of the disease’s proliferative activity and inhibition of the secondary production of cytokines, which are associated with many of the symptoms and severely affect the quality of life of the patients.
A nice demonstration of that was in the large COMFORT-I study. COMFORT-I compared treatment with ruxolitinib with a placebo controlled. And the effect was rather dramatic. In about 40% of the patients, we noted substantial shrinkage of the spleen. In many of them, the spleen returned to normal size, which means we were unable to palpate it below the costal margin, excellent improvement in symptom controls. And I should state parenthetically many models have been developed to assess, objectively, improvement in symptoms. And those have been nicely demonstrated in the COMFORT-I study. An additional interesting finding, and a surprising finding, was the improvement in survival. And that started fairly early.
We can speculate why there is improvement. The patients who have very poor performance status, severe fatigue, or weight loss have suddenly improved, and that improved the survival or is slowing down the disease process. There are many questions that we need to answer, but the fact is that this form of therapy did improve the survival outlook of the patients.
Ruben Mesa, MD, FACP: Ruxolitinib is a JAK1 and JAK2 inhibitor. We have found that it is beneficial in all patients with myelofibrosis irrespective of their driver mutation status. The reason is that there are 3 main driver mutations in myelofibrosis—JAK2, calreticulin, and MPL. The JAK inhibitor is an inhibitor of the native JAK2. It is not specific to the mutant JAK2. We do believe that regardless of the driver mutation, in all patients, the JAK-STAT pathway is overly active and that inhibition is impactful regardless of the driver mutation status.