Prithviraj Bose, MD, MD Anderson Cancer Center, Houston, Texas, discusses the currently available Janus kinase (JAK) inhibitors approved for the treatment of patients with myelofibrosis (MF)—ruxolitinib, fedratinib, pacritinib, and momelotinib—and the optimal treatment plans for each drug.

This research was presented at the 2024 Annual Society of Hematologic Oncology (SOHO) meeting in Houston, Texas.

Transcript:

Hi, I'm Prithviraj Bose. I'm a professor in the department of leukemia at MD Anderson Cancer Center in Houston, Texas. I co-lead the section of myeloproliferative neoplasms (MPN) here, [as] MPNs have been my area of research and clinical focus. Today I'll be discussing a little bit about my presentation at the recent SOHO Annual Meeting here in Houston this year on optimizing the selection of currently available JAK inhibitors for myelofibrosis. There are 4 JAK inhibitors currently approved for myelofibrosis in the US. These are ruxolitinib, fedratinib, pacritinib, and momelotinib. They're all a little bit different in terms of their kinomes, their side effect profiles, and where they're best used. They're all align agnostic in terms of their approval. So, there's not a specific line of therapy that is stipulated by the FDA, but one has to consider their relative strengths and limitations.

Ruxolitinib, [which is] the 1 [therapy] that's been there the longest and clearly is the best understood, has the most data out there [which was] approved in 2011, so almost 15 years at this point. Ruxolitinib has a proven survival benefit, and that is something I always keep in the back of my mind. It is possible this is a class effect and all of them would have it, but the fact is it's the only 1 [therapy] that has a demonstrated survival benefit. Again, that could be because a couple of the others were affected by FDA clinical holds. Ruxolitinib is the only 1 [therapy] that [was] compared to placebo or non-JAK treatments, [and] it's the only one with a proven survival benefit. On the flip side, it causes cytopenias. You need a good dose to get the best spleen response. The spleen response is dose-dependent, and the spleen response correlates with survival. It's important to be able to deliver a good dose to get that optimal spleen response that then correlates with survival. The cytopenias must be kept in mind. They're an on-target effect [and] they will happen in a lot of patients. They do get better after about 24 weeks, but they can be a real problem early on [in treatment].

Then, there is that survival benefit. After ruxolitinib is stopped, prognosis is not good. This has been shown in several studies, and again, it's those patients that don't get a good dose like a [ ] type of a dose [that] need transfusions, or don't get a good spleen response, [with] at least a 30% shrinking [measurement]. These are the patients that really don't do well after 6 months of ruxolitinib and across the board, the outcomes are not good in the post-ruxolitinib failure setting.

There is [also] fedratinib [which was] approved in 2019. It is not that widely used, but it's a good drug, a comparable efficacy to ruxolitinib. Safety wise, it's got some (gastrointestinal) GI toxicity that ruxolitinib does not have. Overall, [it is] probably not a drug that has a clear advantage over ruxolitinib, and I use it in second-line in proliferative patients, [so, patients that have good counts, large spleen, etc]. If [patients] fail [with] ruxolitinib, it's a great drug for second-line.

Pacritinib was the third to be approved only in the US so far. This one is a bit unique in its kinome profile. What it's best known for is its ability to work or be safely given to people with very low platelet [counts] In fact, the trials had no lower limit. That is really where I see its value as well in patients with less than 50,000 platelets consistent with its U.S. label. That could be any line of therapy, but that's really where I use it. Now, pacritinib also may have an anemia benefit, but I think the anemia benefit is better with momelotinib, the most recent addition to the JAK inhibitor arsenal, so to speak. This drug is particularly good for anemia, but also [it] gives you the spleen and symptom benefits. It's broadly indicated for myelofibrosis with anemia. So, it could be used frontline in some patients who are significantly anemic to begin with, and certainly in second and later lines where more of the use is.

Overall, I think one has to think about the side effects. [Gastrointestinal side effects] [are] probably big with pacritinib and fedratinib, [and] ruxolitinib and momelotinib [have] their unique aspects as well. I will say that ruxolitinib and momelotinib are by far the most used if you look at the entire sort of [myelofibrosis] spectrum. I won't be going into specific side effects, but there are different ones to watch Overall, I think ruxolitinib [is the most used treatment] for the most part, fedratinib for the second-line, proliferative patients, pacritinib for people with very low platelets, less than 50,000, [and] momelotinib across the board in anemic patients is a good choice as well. Thank you.

Source:

Bose P. Optimizing selection of available JAK inhibitors in MF. Presented at the 2024 Society of Hematologic Oncology meeting. Houston, Texas; September 4-7, 2024.