Adverse Events Seen with JAK Inhibition in MPN

Rami Komrokji, MD:Maybe we can talk a little about practical management points, highlighting some of the adverse events for each of those JAK2 inhibitors. How do you monitor patients? What are you going to look for? Practical recommendations for the practicing oncologist: what to look for, what are the adverse events, a profile of each of those JAK2 inhibitors.

Prithviraj Bose, MD:At this time, we have only ruxolitinib and fedratinib. For ruxolitinib, it’s a very well-tolerated drug for the most part. Headaches, dizziness, and bruising are the 3 nonhematologic adverse effects that we see, and they’re generally not very bothersome. Anemia and thrombocytopenia are real issues from on-target JAK2 inhibition. You can use some of the alternative dosing we talked about earlier, especially now that that is backed up by the REALISE trial in anemic patients. And you can support the anemia with things like danazol or erythropoietin analogues or something like low-dose thalidomide. All this has been studied. That is something I will often do. And then the anemia does get better. It’s at its worst over the first 12 to 24 weeks and then gets better. Also, it’s been shown that RUX [ruxolitinib]—induced anemia is not prognostically adverse, unlike disease-induced anemia. That’s important to keep in mind. Otherwise, weight gain is something we see. Some patients complain about it. It can be a good thing or a bad thing. Shingles reactivation has been seen more in the PV [polycythaemia vera] patients in the ruxolitinib clinical trials, but you can see it in the MF [myelofibrosis] patients. I vaccinate all of them with the new killed vaccines against shingles. Checking cholesterol once a year is important because RUX [ruxolitinib] can increase cholesterol as well.

With fedratinib, for anemia and thrombocytopenia, this is on-target. There’s really not a way around it with inhibiting JAK2 unless you have a different mechanism like momelotinib does. Other than that, however, because fedratinib inhibits FLT-3 like pacritinib, you can see a fair amount of nausea, vomiting, and diarrhea, which is important to be proactive about. Fedratinib development was initially derailed by the whole Wernicke encephalopathy. Of course, later those cases were analyzed, and only 1 case was found to be a proven case.

Still, given that background, it’s particularly important to make sure patients are not getting malnourished, for example. Thiamine supplementation is sometimes recommended. Some physicians will do it routinely. Others will do it if needed just to prevent something like that from happening. But I would be careful in patients who are malnourished, or an alcoholic—things like that—because they are set up to get something like that. Also, the drug can cause this nausea, vomiting, and diarrhea which can make them have reduced oral intake and things like that. But I think those would be the main concerns, proactively managing the GI [gastrointestinal adverse] effects.

Transcript edited for clarity.

Rami Komrokji, MD:Absolutely. I totally agree with you. I usually will start checking blood counts maybe weekly or every other week when I start those treatments. I always kind of educate the patients that the nadir is going to be around week 8 to 12. If they are tolerating, I try to escalate to a more meaningful dose for spleen response. But close monitoring early on is essential. With fedratinib we do check vitamin B₁level up front. We sometimes give patients prophylactic antiemetics to avoid the GI toxicity that you mentioned. The key is in the first few months of the treatment with the close monitoring of the blood counts. Once you get to that period of time you mentioned, things settle down and the patients can be seen once a month with easier follow-up.