Which JAK Inhibitor in Myelofibrosis: Deciding Factors in Treatment Selection

Following the implementation of momelotinib (Ojjaara) into the treatment paradigm for patients with intermediate or high-risk myelofibrosis, interest is renewed regarding options with JAK inhibitors for patients with varying comorbidities and myelofibrosis, according to Rebecca Klisovic, MD.

In September 2023 the FDA approved momelotinib for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia.1 Notably, this regulatory approval was supported by findings from the phase 3 MOMENTUM trial (NCT04173494) and data for a subpopulation of patients with anemia in the phase 3 SIMPLIFY-1 trial (NCT01969838), making the agent the first and only therapy indicated for patients with anemia and myelofibrosis.

“Although [there] are positive [updates in myelofibrosis] and it’s great to have options, [they] aren’t a home run for everyone,” Klisovic said in an interview with OncLive^® following an OncLive State of the Science Summit™ on hematologic malignancies which she chaired. “We’d love to see all our patients doing well. Not everybody gets the benefit that we’d like, or patients may have adverse effects that are prohibitive—having some other options to attack other pathways will be critical to moving the goalpost.”

In the interview, Klisovic, chief medical information officer at University Hospitals Seidman Cancer Center located in Cleveland, Ohio, provided an overview of 4 case studies featuring patients who presented with varying types of myelofibrosis and the appropriate treatment avenues for each patient as decided by a panel of oncologists.

OncLive: What do you hope your colleagues took away from your presentation on JAK inhibitors in myelofibrosis?

Klisovic: We looked at updates [from] the last year on the new JAK inhibitor momelotinib, reviewed the clinical trial data related to its recent approval, and looked specifically at some longer-term ruxolitinib [Jakafi] data related to survival advantages for patients.

The key takeaways from that conversation were that it’s amazing that in myelofibrosis we now have multiple treatment options to consider; many of them have subtle differences that may help us in patient selection [to understand] who may be best for each inhibitor. It provides an optimistic outlook for patients with myelofibrosis which when I first started in this field, certainly didn’t exist. This is very exciting for our patient population.

How do you go about the selection of a JAK inhibitor for patients with myelofibrosis?

From the panel discussion, the primary driver of choosing momelotinib upfront would be related to patients who have trouble with anemia. The panel thought that the data from an anemia perspective were positive, so they selected [this option] in patients who had trouble from an anemic standpoint as their first discriminator.

[The panel] also noted that patients who had platelet [counts] lower than 25,000/µL may have to consider pacritinib [Vonjo] instead. However, overwhelmingly, the favor was for momelotinib if patients had anemia [considerations].

Looking to the case presentation of a 71-year-old male with newly diagnosed disease, how would you treat this patient?

The first case we had was a 71-year-old patient with splenomegaly, mild anemia, a high symptom score, and intermediate-2 risk disease. In that patient, the panel commented that they certainly felt that the patient needed treatment based on his spleen, symptoms, and anemia. In that case, there were physicians who favored momelotinib because of the anemia.

There was some discussion about the patient’s symptom burden and spleen, as well as whether survival data related to ruxolitinib early on, so there was some discussion about considering ruxolitinib. However, the predominant recommendation was to think about using momelotinib in that case with mild anemia [present].

What JAK inhibitor would be recommended for the 62-year-old female patient who’d already received ruxolitinib?

In this second-line treatment-naive setting, this patient’s predominant [comorbidities] were anemia, a little bit of symptom scoring, and a fairly big spleen. The panel thought that, again, this would be a patient who may benefit from momelotinib because of the anemia at 7.2g/dL.

This was more of a clear-cut case compared with the former where physicians were on the fence in those discussions, especially since she was refractory to ruxolitinib. That was the first recommendation.

Looking to the third case study, what did the panel conclude to be the optimal treatment approach?

In the case of the 54-year-old female with newly diagnosed disease, she had a combination of both anemia and thrombocytopenia with a platelet count of approximately 34/µL. The discussion was around pacritinib vs momelotinib, and whether that platelet count made physicians a bit nervous given that on the momelotinib trials–depending on which one it was–she may or may not have been eligible for the trial.

The discussion was in favor of pacritinib in this case because of the thrombocytopenia; although, I don’t think momelotinib would have necessarily been a wrong choice either given the inclusion criteria for most of those trials. Overall, physicians favored pacritinib in this case.

What was decided regarding case number 4 with the 40-year-old male patient with newly diagnosed disease?

This was the most interesting discussion. This is a low-risk patient who’s young and we had a great conversation about the early use of a JAK inhibitor–in this case ruxolitinib–to potentially improve overall survival. However, it was called out that this patient would not have qualified for the phase 3 COMFORT-I and COMFORT-II studies [NCT00952289; NCT00934544] because he had low-risk disease.

There was some discussion about whether we need to start treating these patients earlier rather than later, even though they may not otherwise [need] therapy. The question [was asked] about whether ruxolitinib is truly disease-modifying, particularly in a patient who’s young. There was also a comment to strongly think about watching this patient closely for transplant potential, and given his young age, molecular stratification that may help us guide that decision [could have been appropriate], which was not presented in the case. It is important to look for higher-risk mutations that might otherwise change the treatment directory.

Why will it be important to remain vigilant with these treatments as longer-term data emerge?

It’s nice to have some options [but] there were also comments about financial stewardship and where these [therapies] fall in line [with that]. What can we do to help patients who are struggling with copays and [other issues with] very expensive medications? We didn’t talk a ton about longer-term toxicities which we still need to learn about from patients who may be on these drugs for years. That data will continue to mature but are something to keep an eye on.

Regarding the next steps, we’re interested in some of the combination therapies that are coming about. BET inhibitors and BCL2 agents [are exciting], so we are interested in trying to see some of that data come across the finish line.

Is there any ongoing research that you’re currently participating in that you’d like to highlight?

Coming in the next year there are some CAR T-cell therapy trials including some rapid CAR T-cell therapy trials from [our institution] that are coming out; hopefully there will be some mature data in the near future. This rapid turnaround is to address that manufacturing delay that we can see which is particularly relevant for patients who have higher-risk disease and more progressive disease who can’t wait a couple of months to get CAR T-cell therapy.

Reference

Ojaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anemia. News release. GSK. September 15, 2023. Accessed May 1, 2024. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia