Choosing the Right JAK Inhibitor for Effective Myelofibrosis Treatment

Prithviraj Bose, MD

With 4 JAK inhibitors approved in the US and additional agents in development, it is an exciting time for the field of myeloproliferative neoplasms (MPNs). Now, experts face the challenge of determining which treatment is best for each patient.

Ruxolitinib (Jakafi), an established JAK inhibitor, was first approved by the FDA in 2011,¹ showing clear survival benefits. This was followed by the FDA approvals of fedratinib (Inrebic) in 2019,² pacritinib (Vonjo) in 2022,³ and momelotinib (Ojjaara) in 2023.⁴

“Each [JAK inhibitor has] their place depending on the patient's blood counts and other clinical factors," explained Prithviraj Bose, MD, in an interview with Targeted Oncology^TM.

With multiple JAK inhibitors available to choose from, a tailored approach ensures that each patient's specific disease characteristics and comorbidities are considered to maximize efficacy and minimize toxicity during treatment.

In the interview, Bose, professor in the Department of Leukemia at MD Anderson Cancer Center, discussed the multiple JAK inhibitors available for the treatment of patients with MPNs.

Primary myelofibrosis cells in blood flow: © LASZLO - stock.adobe.com

Targeted Oncology: Can you discuss the different JAK inhibitors currently available?

Bose: For ruxolitinib, the first thing I would say about that is that it is the JAK inhibitor with the most clearly demonstrated survival benefit in myelofibrosis. Now, is that an effect just of ruxolitinib and not of the others? We do not know that. It could be a class effect, but the data are the data, and the data are that ruxolitinib is the one that has a clearly shown survival benefit. I think that needs to be considered as we use it, and it is usually the most frequently used frontline drug. Now, where you can get into trouble with ruxolitinib is with cytopenias, low blood counts, and this is a drug that you need to be able to dose well to get the benefit that you are seeking. The dose can get compromised by cytopenias.

That is where I will tie that into the entry of pacritinib and momelotinib. These are easier to use in the setting of cytopenias. In fact, pacritinib has a label for platelets [less than 0 × 10⁹/L], and momelotinib is for patients with anemia in myelofibrosis. So right there, you can see that they have their place more in that cytopenic population, which could be frontline, or, more commonly, in the second line after ruxolitinib. I think those are great additions in the sense that you can give them at good doses despite low blood counts, which becomes difficult with ruxolitinib, like I just said. [They are] certainly very welcome additions to the arsenal.

[Fedratinib] is a good drug, perhaps as good as ruxolitinib from an efficacy standpoint, but really with no clear advantage over ruxolitinib. So, I do not use it in the frontline. I do use it, however, in post-ruxolitinib settings, where the blood counts are good. In those proliferative scenarios, as opposed to the cytopenic scenarios, in the second line and beyond, I do find fedratinib to be a useful drug. It has some toxicities that one has to pay attention to. All patients should get thiamine supplementation, stuff like that, but overall, I would say those are the kind of very high-level points about the 4 drugs.

What are the most critical adverse effects seen and how are they managed in these

patients?

The 4 approved drugs have different [adverse] effects. Ruxolitinib is most known for the cytopenias that it causes, and same with fedratinib. For both of them, anemia, thrombocytopenia, are big. Now we can dose-adjust, try and support the anemia with other agents like danazol, luspatercept [Reblozyl], erythropoiesis-stimulating agents, but then we have to think about some unique [adverse] effects for each drug which are not necessarily hematologic.

With ruxolitinib, weight gain can be a problem in some patients. Shingles and basal and squamous cell skin cancer risk can be significant, especially in [patients] who have had these before. I give the shingles vaccine to every patient that gets ruxolitinib.

With fedratinib and pacritinib, [there are] a lot of [gastrointestinal adverse] effects like nausea, vomiting, and diarrhea. Diarrhea [and nausea are seen more] with pacritinib than fedratinib, but thankfully, mostly early on. We manage these with antiemetics and antidiarrheals, and one has to be proactive about that. I will be remiss not to mention that fedratinib has a black box warning about Wernicke encephalopathy, which is super rare, fortunately, but something that we want to prevent by giving thiamine supplementation and also by checking thiamine levels.

Finally, momelotinib, again, the most recent, can cause thrombocytopenia. That is not trivial. It certainly occurs in about a quarter of the patients. Diarrhea, too, occurs in about a quarter of the patients. Then [there is] some rare stuff, like infections, peripheral neuropathy, but those are fortunately uncommon. There is one unique thing about momelotinib, which is that it can cause this first-dose hypotension. [Patients] are well advised to take it at bedtime, especially towards the beginning.

How do you determine which JAK inhibitor is best for each individual patient?

There is the proliferative patient, and there is the cytopenic patient, also known as myelodepletive, [with] the lower counts, smaller spleen, that sort of situation. In the proliferative patient, I think ruxolitinib [is good]. I did allude to its survival benefit earlier. The drug fedratinib is perhaps as good, but there is no clear advantage over ruxolitinib, and there is some more toxicity than ruxolitinib. So perhaps not much used in the frontline, but it is a great second-line drug when the blood counts are good. Momelotinib is especially good for anemia in any line of therapy, and definitely [in the] second line, but something that comes up for discussion is in the frontline as well, because you can have frontline patients that are anemic. In different trials, momelotinib has shown an equivalent spleen response to ruxolitinib. In one trial it was worse than and in another it was better. It is a little bit hard to know that for sure. But again, my point is that it is a comparable drug to ruxolitinib, and may be preferable in the setting of anemia. However, a survival benefit has only been solidly demonstrated with ruxolitinib.

The way I use pacritinib is on label, which is less than 50,000 platelets, regardless of line of therapy. I think that is where it belongs. That is where it has been studied more than anything else and also clearly does something different, because those patients are usually the hardest. With pacritinib, we see a preserved efficacy, even in that difficult population.

How do you address issues of resistance or inadequate response to these JAK inhibitors and myelofibrosis?

The issue of JAK inhibitor resistance for the longest time has meant ruxolitinib resistance. Now, we have 4 players on the market, and they are all JAK inhibitors. That will complicate the picture some, because we could have second- and third-line JAK inhibitor therapy before we move on to something else. But I think that what we do know is that the patients do not develop mutations at a second site that lead to the drugs starting to fail, which happens in some other areas, like [chronic myeloid leukemia (CML)] and [chronic lymphocytic leukemia (CLL)]. What happens here is less clear at the molecular level, although something called persistence has been described, and there is a novel approach called type II JAK2 inhibitors that may be able to overcome this persistence phenomenon.

There are non-JAK mechanisms of action that are being explored, from telomerase inhibition to PIM kinase inhibition and BET inhibition. There is just a lot out there, all being studied in some way in either the “failure setting” or as an add on when getting this some somewhat suboptimal response to a JAK inhibitor.

Are there any new data or developments that might influence treatment choices?

Now, there is so much to look forward to. There are so many drugs in development in myelofibrosis with a lot of drugs in various stages. There are some that are in phase 3, like pelabresib [CPI-0610], which was big news at the last [American Society of Hematologic Oncology Annual] Meeting and updated at recent meetings. We will wait to see what the [FDA] decides to do with that once the application is filed. The results of the phase 3 trial [NCT04603495] were a little bit mixed, where the spleen end point was met, but the symptoms end point was not met, and this was ruxolitinib plus pelabresib against ruxolitinib and placebo in the frontline setting.

We have luspatercept, which is an established drug for anemia already, and that has completed accrual to a phase 3 study where you add it to a JAK inhibitor in [patients who are] transfusion dependent. Those results are awaited. Also, imetelstat [Rytelo], which was recently approved for lower-risk MDS, is in a phase 3 study in the second-line setting with JAK inhibitor failure for myelofibrosis

Now, we have a slew of earlier-phase studies that are moving along in the add-on setting, or even by themselves in JAK inhibitor failure, and it is important to mention the drugs that we do not have any trial data on but that are super exciting. We have this whole new wave of mutation-specific therapies, mutant-selective JAK inhibitors, type II JAK2 inhibitors that I alluded to earlier. We have immunotherapeutic approaches against CALR which could be an antibody or a bispecific. There are a lot of things coming down the pike which are different and somewhat revolutionary, in the sense that they are looking to target the driver mutation, but in a more efficient way to get deeper responses.

REFERENCES:

1. JAKAFI™ (ruxolitinib) tablets, for oral use. FDA. Accessed September 24, 2024. https://tinyurl.com/pd2ktmhy

2. FDA approves fedratinib for myelofibrosis. News release. FDA. August 16, 2019. Accessed September 24, 2024. https://tinyurl.com/42255mx6

3. FDA approves drug for adults with rare form of bone marrow disorder. News release. FDA. March 1, 2022. Accessed September 24, 2024. https://tinyurl.com/ydub6jav

4. OJJAARA (momelotinib) tablets, for oral use. FDA. Accessed September 24, 2024. https://tinyurl.com/47szrt2w