Navigating Emerging Therapies in Myelofibrosis Treatment

Raajit K. Rampal, MD, PhD

The landscape of myelofibrosis therapy is evolving with newer JAK inhibitors like fedratinib (Inrebic), momelotinib (Ojjaara), and pacritinib (Vonjo) added alongside the established ruxolitinib (Jakafi). These agents offer tailored options, especially in managing anemia and platelet counts. However, vigilant monitoring for potential adverse effects is necessary.

While switching JAK inhibitors is a feasible strategy for some patients who are facing resistance or relapse, ongoing clinical trials are exploring newer therapies. From BET and BCL-xL inhibitors to PIM kinase inhibitors and potential immunotherapies, there are exciting advances on the horizon that are fostering a shift toward combined treatments to enhance efficacy.

During the Fifth Annual Miami Cancer Institute Global Summit on Immunotherapies for Hematologic Malignancies, hosted by Guenther Koehne, MD, and Miami Cancer Institute, Raajit K. Rampal, MD, PhD, highlighted the roles of emerging JAK inhibitors as well as additional treatment options on the horizon.

“We are in a situation where there are a lot of novel and interesting therapies. Right now, phase 3 data has just [been] reported out on pelabresib, which is a BET inhibitor, as navitoclax, which is the BCL-xL inhibitor, [and] both look really promising,” explained Rampal, hematologic oncologist at Memorial Sloan Kettering Cancer Center, in an interview with Targeted Oncology^TM.

In the interview, Rampal delved into the dynamic landscape of myelofibrosis therapy, highlighting treatment options beyond JAK inhibition.

Primary myelofibrosis (PMF) cells in blood flow - closeup view 3d illustration: © LASZLO - stock.adobe.comNormal

Targeted Oncology: What are the roles of newer JAK inhibitors like fedratinib and momelotinib?

Rampal: The newer JAK inhibitors seem to have different profiles in terms of what they can do and how we can use them. Drugs like pacritinib can be used regardless of platelet counts, so it gives us another option. Then we have drugs like momelotinib, but also pacritinib, that are useful in patients with anemia, particularly transfusion-dependent anemia. Then fedratinib can be used in the first line, but there is also good data for using it in the second line after ruxolitinib, so these are not all the same. They have different uses [for] different patients.

In what ways are experts managing and minimizing potential adverse events associated with JAK inhibitors?

It really depends on being aware of the potential adverse events and mitigating them early on. Many of these drugs, pacritinib and fedratinib as examples, cause [gastrointestinal] toxicity. So knowing that you need to give patients antidiarrheal medications when they start their treatment is important. Things like being aware of Wernicke encephalopathy with fedratinib, but also being aware of the infectious complications that can arise with things like ruxolitinib and momelotinib.

What are the current strategies for addressing patients who develop resistance or relapse after JAK inhibitors?

Switching from 1 JAK inhibitor to another, there is some data for that in some patients, but I think we have to come up with different and newer therapies. I think that is really where clinical trials enter.

Can you discuss some of the promising emerging therapies for myelofibrosis that target different pathways?

We are in a situation where there are a lot of novel and interesting therapies. Right now, phase 3 data has just [been] reported out on pelabresib, which is a BET inhibitor, as navitoclax, which is the BCL-xL inhibitor, [and] both look really promising. There are things in earlier phases as well like PIM kinase inhibitors. We also have things like MDM2 inhibitors, and now we are at the advent of potentially having immunotherapies with antibodies in the market called calreticulin, which is really exciting.

Is there any growing focus on combining JAK inhibitors with other emerging therapies to improve outcomes?

I think that is exactly where the field is heading right now, and [combinatorial therapy] is a lot of what we are doing.

Are there any significant or ongoing clinical trials investigating new treatment approaches?

There are a number of them. As I mentioned, there are phase 3 trials that have had their 6-month readout. We have got to see what happens with longer-term follow-up. Does it change progression-free survival, overall survival, the depth of response, to the duration of response? All of those things remain to be determined. Of course, there are a number of earlier phase trials that are ongoing.

How is the field of gene therapy and precision medicine evolving in the context of myelofibrosis treatment?

[I am] not sure that we're there yet [as] we are not really doing gene editing therapy. What we are doing is trying to target some of the other mutations. An example of this is patients who have a concurrent IDH mutation where there has now been data to combine a JAK inhibitor and IDH inhibitor in those types of patients.

How are treatment decisions individualized for patients?

That is something where we have to get a little better. There is a genetic part of it, where we need to kind of figure out if there is a way to leverage other mutations, like I just mentioned. That is 1 option. The other option is trying to understand, are there particular patient profiles that are going to be more responsive to certain therapies? We are not there yet. I do not think we know the answer to that, but I think that is where we need to go.

What unmet needs exist in this space?

We need disease-modifying therapy. We need therapies that prevent people from progressing to bone marrow failure or to acute leukemia, and I do not think we are there yet. At least we need more data to substantiate whether that is going to happen. So more to come.

Can you discuss current and emerging treatment options for managing anemia in this patient population?

We have drugs like erythropoietin. There is early data for luspatercept [Reblozyl], which is being studied in phase 3 now. We now have momelotinib and pacritinib, both of which have demonstrated efficacy in terms of anemia.

For those treating patients with myelofibrosis, what are the key things to know?

I think that it is important for people to realize this is not a monolithic disease. The first question is, what are you trying to achieve in a patient? Is it anemia control, symptom control, spleen control, what is the underlying question you are trying to address? The treatment has to be tailored to what it is you are trying to achieve. But it is not a one-size-fits-all disease.