MPN Workshop of the Carolinas 2025 | Satiety inhibition in MPNs: the effect of JAKi treatment on leptin levels and body weight

So it’s really not leptin levels itself which is the issue. Body weight is of course a complex thing with many factors regulating it, but it’s been widely recognized that patients on JAK2 inhibitors, particularly ruxolitinib, with which we have the longest experience, tend to gain weight on the drug. And it was initially thought that this was a beneficial effect of the drug because many patients with advanced myelofibrosis have lost a lot of weight and are underweight. But what we found is that it is not just the skinny people who gain weight, it’s everybody. So even people who are obese become even more obese on ruxolitinib. And I had a patient who was really feeling a lot of guilt related to the weight he was gaining, and we decided for a variety of reasons to look into the mechanism of action. And so the reason why we kind of got onto that is because there is a known genetic factor, a signaling pathway that operates in the brain, that is mediated through leptin signaling through a certain area of the brain. Leptin signaling is part of your body’s way to tell you you’ve eaten enough, and so it kind of turns off appetite after you’ve been eating for a while. And what we found was in both humans and in an animal model, that if we use ruxolitinib, that satiety, that feeling like you’ve eaten enough is dampened, and so people tend to eat more. Leptin also does a couple other things. It can kind of increase metabolism. So conversely, when you’re blocking leptin signaling, you’re slowing metabolism. So you’re increasing the amount of eating, the number of calories coming in, you’re decreasing output, and people tend to gain weight. And so I think that there isn’t a magic bullet for that, but it is something that patients should be aware of. And I think our motivation to get involved with this is really out of the sense of guilt that people have around weight gain. And this is a consequence of the drug. It’s a one for one for most people. You take the drug and you’re going to gain weight. And the way to deal with that is to be aware of this potential and to change your dietary habits, lower-calorie snacks that you might carry around with you, and try and increase your exercise level to burn off more calories.

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