Current Therapies and the Promising Future of Myelofibrosis Treatment Options

Tajuana Bradley

Lindsey, we’ve talked in the past about treatment considerations. Can we talk a little bit about the currently approved therapies? We have four approved JAK inhibitors now. Can you share with me what you do in terms of selecting a treatment option? What are some of the things that you use to help you with that. And how do you decide to approach adverse events management?

Lindsey Lyle

I’d say that this is a pretty exciting time to be treating patients with myelofibrosis. Compared to past years, we have more FDA-approved options available to us than ever before. As we know, clinical trials are so important, especially in rare diseases. But access to clinical trials can be really challenging, especially for patients who do not live near a major city. As you mentioned, we now have four approved JAK inhibitors for the treatment of myelofibrosis. When deciding on which of the four to select, the NCCN guidelines¹ are a great place to start. These guidelines are based on real, solid evidence for where these particular treatments fit into the treatment paradigm. And each of these JAK inhibitors, while they're all the same class, do have some differences such as in their mechanism of action, their side effect profiles, and there may be some clinical differences as well.

Ruxolitinib was the first approved JAK 1/2 inhibitor for patients with myelofibrosis. It's been approved the longest and is really effective for spleen and symptoms in addition to long-term data showing a survival benefit.² So, I’d say that ruxolitinib is the most widely used therapy for patients with myelofibrosis and is a category 1 NCCN recommendation for patients with platelets >50,000. Fedratinib is the second JAK 1/2 inhibitor to be approved. It can be used either in the frontline setting (category 1) or after a patient has lost a response to a prior JAK inhibitor. Pacritinib (JAK2/IRAK1/ACVR1 inhibitor), based on the label, is approved for patients with platelets < 50,000. It’s been studied in patients with platelets <100,000 due to the reduced myelosuppressive effect of this agent and is included in the NCCN guidelines as a category 1 recommendation for patients with platelets <50,000 and category 2b as frontline treatment if platelets are >50,000 and as second line for those previously treated with another JAK inhibitor. Momelotinib is the most recently approved JAK1/2 and AVCR1 inhibitor and the NCCN guidelines were just updated to include this agent. Momelotinib is indicated for patients with myelofibrosis and anemia. NCCN recommends consideration of momelotinib use in the frontline setting for patients with platelets <50,000 (Category 2B), in those with platelets >50,000, and in patients with anemia and serum EPO >500 mU/mL.¹ Also, this can be considered in the second line setting after prior JAK inhibitor therapy. There is data to support the improvement of transfusion burden in patients who are treated with momelotinib vs danazol, which is a therapy that's sometimes used to improve anemia.

So, that’s a very basic overview of the four JAK inhibitors that are currently approved.

Tajuana Bradley

Thank you for that. What do you know about the side effects of these drugs?

Lindsey Lyle

What we do know is that inhibition of JAK2 and JAK1 can be more myelosuppressive. When we use ruxolitinib, we can have some dose-related side effects from a hematological perspective, so I try to ensure that our patients are aware of this potential side effect, and there are plans for monitoring and dose adjustment if necessary. With fedratinib and pacritinib we know diarrhea occurred at a reasonable frequency, which is not really seen with other JAK inhibitors. So, we need to prepare our patients for this potential.

One of the biggest reasons to understand the safety profile of each therapy and stay up to date on potential AEs is so APs can discuss them with their patients. That way the issues can be identified early and be managed more appropriately. These therapies, especially ruxolitinib, have been shown to have an overall survival benefit, so let's try to keep this patient on therapy as opposed to taking them off when perhaps we could have dose-adjusted or done something different to safely maximize exposure. I'm sure this is something that you encounter a lot, trying to teach the new APs and patients.

Tajuana Bradley

Oh yes, I do.

Lindsey Lyle

How can we continue to effectively treat these patients? What are some of your strategies?

Tajuana Bradley

I agree that education upfront is key. Helping the patients understand how the drug works, why they're taking it, and explaining the side effects upfront is so important. And particularly when you're talking about oral drugs, they need to be aware of what could happen. Data has shown us that patients are more likely to adhere to their treatment plan when they understand and have really good control of their side effects. Having a good, well-balanced diet is key too. I typically do some dietary education, particularly if the patient already has stomach issues. Even with the grading, I've learned that I don't want patients waiting until they're grade 3 to call me about their diarrhea.

Lindsey Lyle

Right, definitely not.

Tajuana Bradley

I want to know about it when it's a grade 1 or 2, because by the time they get to grade 3, we're going to have to hold. When talking to the patient, I may not refer to it as grade 3; I will just say something like, “If you start having more than four to six stools a day, I need to know.” When I'm onboarding, I teach the new APs and others about grading and what that looks like because when we're going from one patient to the next, it helps to know the grades and when and how to intervene. From one chart to the next and one visit to the next, you will be able to help your patients stay on therapy by intervening sooner when toxicities are documented with the grading of that toxicity. If there's not a drug interaction or drug-drug interaction, I'll go ahead and give them something for diarrhea, something for nausea. Typically, I'll go ahead and tell them to take it with food hoping that if there are going to be any GI toxicities, they may be able to mitigate them by eating something.

Lindsey Lyle

Yes, absolutely. Knowledge is key. Education is key. Despite having four currently approved therapies, we know we can still do better for these patients with myelofibrosis. There are a number of available clinical trials and for such a rare disease, the amount of science surrounding this clinical trial space is pretty amazing. Some trials are looking at different monotherapies in patients who have progressed after being treated with a JAK inhibitor or who are refractory to JAK inhibitor therapy. And some agents are being looked at in combination with ruxolitinib in the frontline setting, such as pelabresib,³ navitoclax,⁴ and selinexor,⁵ to name a few. Just like with many other disease states, combinations are being explored. And we know that the approved JAK inhibitors are very good at controlling symptoms and spleen volume. There are some overall survival benefits based on available data, but the question of true disease biology modification is being explored.

I just wanted to touch on three clinical trials that are in later stages that could be of interest. The MANIFEST trial looks at how pelabresib, which is a bromodomain and extraterminal domain (BET) inhibitor, performs when combined with ruxolitinib in the frontline setting. The most recent results of arm 3 of the trial were presented at European Hematology Association 2023 and it showed that the combination demonstrated clinically meaningful, durable improvements in splenomegaly symptoms, and notably was associated with biomarker findings indicating potential disease modification. It also demonstrated a generally favorable safety profile.³ This is certainly encouraging, and I would say that when we think about combination therapies, we want to be sure we're not adding increased toxicities that wouldn't be able to be handled. I imagine that some of these patients are frail, so we do have to keep this in mind.

Tajuana Bradley

Yes, definitely. In terms of treatment selection, there's this whole fit vs frail consideration, and whether the patient will be able to tolerate therapy. We want to keep those considerations in mind, do no harm.

Lindsey Lyle

Exactly. The next study I want to mention is the TRANSFORM- 1 trail, which found that navitoclax in combination with ruxolitinib achieved a clinical benefit in patients with myelofibrosis who were JAK inhibitor naive. The study also assessed change in bone marrow fibrosis grade from baseline and reduction in variant allele frequency.³ So again, we're moving into other biomarkers of disease and how these are potentially playing a role in outcomes. I imagine that we’re going to be seeing some updates on these at ASH. There is also a phase II trial investigating the efficacy and safety of navitoclax, a BCL-X_L/BCL-2 inhibitor, to ruxolitinib in patients who are treated initially with ruxolitinib but have progression or suboptimal response to monotherapy.⁶

And lastly, the BOREAS study looks at the use of navtemadlin, an MDM2 inhibitor, in patients who are relapsed or refractory to JAK inhibitor therapy. These are patients who have been treated with one or two JAK inhibitors. This subset of patients is a very challenging patient population to treat. For the majority of patients, JAK inhibitors work well, so a lack of response or progression through JAK inhibitors can mean that their disease is fairly progressive. The primary endpoint of this trial was to evaluate correlations between biomarkers of disease burden and survival outcomes. At the median follow-up of 32.5 months, there was improved progression-free survival and overall survival correlating with biological markers of disease modification, including reductions in driver gene variant allele frequency and circulating CD 34 positive count.⁷ The phase III of the study is currently enrolling.

Tajuana Bradley

It’s encouraging that there are so many studies looking at new treatment options for MF.

Lindsey Lyle

Yes, it is. When we look at the available treatment options for our patients, not only do we have some exciting clinical trials going on, but we have a number of approved therapies that can fit the needs of our patients. And I think that you would agree with me, Tajuana, it’s not a “one size fits all” situation when it comes to treating our patients. Every patient has different disease characteristics, different ways that their disease is manifesting different comorbidities, and so in selecting treatment, we need to be sure to look at our patient as a whole and to identify where they may best be served by a particular therapy.

Tajuana Bradley

Yes, I totally agree with that.

Lindsey Lyle

Thanks for talking about these important topics with me, Tajuana.

Tajuana Bradley

It’s been my pleasure, Lindsey. It’s great to get together and share our knowledge and experience.