JAK Inhibitors in Myelofibrosis

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Aaron Gerds, MD: The mainstay of therapy for MPNs [myeloproliferative neoplasms] and specifically myelofibrosis have been JAK inhibitors. We now have 3 approved JAK inhibitors: ruxolitinib, which was approved in 2011; fedratinib, which was approved in 2019; and pacritinib, which was approved in 2022. And perhaps we will have a fourth JAK inhibitor, momelotinib, sometime in 2023. They’re all slightly different. You might ask yourself why you need 3 or 4 JAK inhibitors, but they all have slightly different mechanisms of action. They all hit upon JAK2, specifically wild-type JAK2, but the others will have varying effects on other molecules. Ruxolitinib is a well-known JAK1/JAK2 inhibitor. Fedratinib is largely a JAK2 inhibitor that spares JAK1 but also hits FLT3 and some other important molecules. Pacritinib is a JAK2 inhibitor that also spares JAK1 but also hits FLT3 as well as IRAK, and a few other key molecules such as ACVR1. All of these 3 agents have different effects on how they work in patients.

To my earlier point about different subsets of disease, you might apply these JAK inhibitors a bit differently. The key thing here though is a question about survival. Clearly, ruxolitinib has dramatically improved the lives of patients in both quality of life and functionality, and that has likely led to some survival advantage, as seen in pooled analysis of the COMFORT studies. But the key here is this is not putting people into remission like we think of with AML [acute myeloid leukemia]. We’ve got to get AML out of our minds when thinking about survival with these folks. But it has dramatically reduced cytokine levels, and improved quality of life and functionality of patients, thus leading to a survival advantage over other therapies, particularly those best available therapies or even placebos.

Fedratinib did not show a survival advantage necessarily in the JAKARTA studies, primarily because there was a clinical trial hold as well as some contemporary effects of being on trial with ruxolitinib. Similarly with pacritinib, clinical trial holds have obliterated our ability to look at a survival advantage for these patients. But nonetheless, we should consider that JAK inhibitors, if studied properly, probably would lead to a survival advantage over other therapies available for patients with myelofibrosis, similar to what ruxolitinib showed in the COMFORT studies. I definitely think that the improvement in cytokine levels, quality of life, and functionality leading to a survival advantage overall is probably universal for all JAK inhibitors.

But again, I want to make the point that this doesn’t kill off myelofibrosis cells. It doesn’t reverse scar tissue necessarily in large degrees. And so better therapies are certainly needed that can have a deeper effect and deeper disease modification, if I can use that term, for patients with myelofibrosis. But clearly, JAK inhibitors are incredibly important and have dramatically led to better outcomes for patients with myelofibrosis.

Pankit Vachhani, MD: We have a few JAK inhibitors as options to use in our planning. We are quite familiar with the use of ruxolitinib and fedratinib already. Ruxolitinib was approved from the COMFORT studies performed more than a decade ago. The key adverse effects to keep in mind when one uses ruxolitinib is that cytopenias are quite common, and anemia and thrombocytopenia have both been seen. Although these are dose related, and sometimes dose holding or dose reductions can help in such events. Also, hyperlipidemia can occur, and skin cancers, nonmelanoma skin cancers, have been noted. So for patients who are likely to be on ruxolitinib for a long period of time, a dermatologist visit may not be completely out of the ordinary, to set up for such patients. Fedratinib is also a JAK1, JAK2, and FLT3 inhibitor. Much like ruxolitinib, it too causes cytopenias, probably very comparable to ruxolitinib.

However, what does set it apart is that probably because of the FLT3 inhibition that comes with fedratinib, one also sees GI [gastrointestinal] intolerances, like nausea, vomiting, and diarrhea. These happen early in the course, and using prophylactic treatments like ondansetron or Imodium can help and are generally suggested. Also, not to be forgotten is that in a few patients who received fedratinib, Wernicke-Korsakoff encephalopathy was noted, along with low thiamine levels. So a general way of bypassing this or managing the scenario is to check thiamine at baseline and to supplement patients with thiamine and recheck the levels down the line so that we don’t run into these rare Wernicke encephalopathy cases.

Moving on to pacritinib. Pacritinib is a JAK2, ACVR1, and IRAK1 inhibitor, and it also has some FLT3 inhibitory activity. Once again we do see some cytopenias that come about with pacritinib, and along with the previously mentioned FLT3 inhibition, we once again see some GI intolerances in the form of nausea, vomiting, and diarrhea. Just as I mentioned for fedratinib, here too my suggestion is to be preemptive and use ondansetron and/or Imodium, or Lomotil as early as possible in an as-required manner, and try to use it in a preemptive fashion if possible. When it does occur, it is usually early in the course, and patients can usually manage these symptoms and are able to stay on treatment. Momelotinib is a JAK1, JAK2, and ACVR1 inhibitor. GI intolerances and cytopenias have been noted. Previously some cases of peripheral neuropathy were seen, but in the more recent MOMENTUM study, that was not found to be the case in any concerning or significant manner, but one may want to watch out for that as well in their individual patient.

Naveen Pemmaraju, MD: Beyond ruxolitinib, we now have 2 approved JAK inhibitors and 1 more that’s being evaluated in the late stages of development. The second approved JAK inhibitor after ruxolitinib was fedratinib, which was approved in August of 2019 on the basis of the JAKARTA1 and 2 studies, which analyzed fedratinib both in the frontline setting as well as post-ruxolitinib use. That agent was the second approved JAK inhibitor. Interestingly, that agent is also still being evaluated in post-approval studies, which include the FREEDOM studies. It did have a signal for a black box warning of an encephalopathy syndrome, which has been looked at both pre-and post-approval and can be mitigated with patient education, and monitoring and the administration of thiamine, so checking the thiamine levels and replacing as indicated in the package insert.

The third JAK inhibitor is known as pacritinib, which gained FDA approval in February of last year. This agent is generally well tolerated, but does have a signal for diarrhea in the first few weeks to months, which is part of the package label insert. Also one must monitor for cardiac and bleeding events. This pacritinib agent was investigated in multiple trials, including the PERSIST studies, as well as PAC203, and now the PACIFICA trial. Finally, a fourth JAK inhibitor known as momelotinib is under active clinical trial investigation. The phase 3 trial MOMENTUM was published in the The Lancet journal just a few weeks ago, showing positive data in the randomized study of momelotinib vs danazol in patients post-JAK inhibitor with anemia, spleen symptoms.

The field of JAK inhibitors is rapidly evolving. There are other JAK inhibitors that are in active clinical trial investigation in the earlier stages of development, and then certainly we have a whole field expanding now with JAK inhibitor combination studies.

Transcript edited for clarity.