Targeted Agents Beyond Ruxolitinib Necessary in Evolving MPN Paradigm

Gina Columbus

Aaron Gerds, MD

Aaron Gerds, MD

For select patients with myelofibrosis and polycythemia vera (PV), the JAK1/2 inhibitor ruxolitinib (Jakafi) has been an effective option to reduce symptom burden. However, according to Aaron Gerds, MD, additional therapeutic strategies are needed within the myeloproliferative neoplasm (MPN) landscape—potentially with novel mechanisms of action.

“The fact of the matter is, there is only one FDA-approved medication for MPNs to date and we really need more to help take care of our patients,” explained Gerds, an assistant professor in the Department of Hematology and Oncology, Cleveland Clinic.

In PV, ruxolitinib was approved by the FDA in 2014 as a treatment for patients who are resistant or intolerant to hydroxyurea. The drug was initially approved in 2011 for patients with intermediate and high-risk myelofibrosis. Clinical trials of combinations with ruxolitinib have previously been associated with higher levels of toxicity; however, ongoing trials with the PI3K-delta inhibitor umbralisib (TGR-1202; NCT02493530) have peaked interest, said Gerds.

But beyond ruxolitinib, the JAK2 inhibitors pacritinib and fedratinib continue to move through the pipeline after the FDA lifted their clinical holds, as well as studies of antifibrotic agents and telomerase inhibitors. In an interview during the 2018 OncLive® State of the Summit™ on Hematologic Malignancies, Gerds discussed the activity and drawbacks with these systemic agents in MPNs.

OncLive: How has the addition of ruxolitinib shaped the MPN landscape?

Gerds: It can improve patients’ symptoms and perhaps lead to better survival in these folks. The latter [part of that statement] is still somewhat debated, but clearly we can improve patients’ symptoms [with ruxolitinib] in these diseases. The pivotal trials were done in myelofibrosis, which ultimately led to the FDA approval of this medication. Again, it showed that with this medication, we are able to shrink peoples’ spleens and improve their symptoms quite reliably. 

In PV, it has also been shown to help control red blood cell counts in addition to improving symptoms and spleen size. It does have a second-line indication in PV. There have been a couple of phase II studies in essential thrombocytopenia (ET), but it doesn’t carry a label at this point and its role within the treatment matrix of ET is still a little unclear. 

What are some therapies that have shown some promise but, given safety issues and clinical holds, their roles are unclear?

With the discovery of JAK-STAT activating mutations in these diseases, there was a wave of development of JAK inhibitors. It was a very logical thing. Each JAK inhibitor had unique properties; there were some that were JAK1 inhibitors versus JAK2 inhibitors. There were others that were more of a JAK2 inhibitor. There were others that were specific to the V6174 mutation within JAK2.

Many of these drugs also had off-target effects on other tyrosine kinases, which may impact disease burden and response rates. A number of these drugs were coming through, and they have all fallen victim to these 2 things: either serious adverse events (AEs), which put holds on the development of these medications, or response rates that weren’t appreciably different than what we would expect with ruxolitinib. Therefore, it certainly has been interesting to watch the development of these drugs and their progress over time. The drugs notably put on hold by the regulatory bodies for concerns over toxicity were fedratinib and pacritinib. However, these holds are now lifted, the drugs are under further development, and seem to be moving forward. 

Momelotinib is a very interesting medication, because it can inhibit JAK1/2 and lead to spleen responses as well as symptom burden responses. However, we also see a fair number of patients’ anemia improve, which is a very intriguing concept because many of these patients are burdened with anemia, and even transfusion-dependent anemia.

However, the major randomized clinical trials with momelotinib didn’t quite meet their primary efficacy endpoint. There has been a lot of discussion on why that was. Whether it is something with the compound itself, or perhaps [there was something] in the clinical trial design that could have been optimized to show more efficacy for the medication. We are going back to the drawing board for that one and see if it’s worth continuing to further develop this medication for our patients. 

Plenty of combination and triplet regimens have been studied in other hematologic cancers. Will we see more of this in MPNs?

We have seen a number of combination studies done over the last several years, of ruxolitinib plus drug “X,” “Y,” or “Z.” One of the things that we are seeing often with these combination studies is that the drugs together can be pretty toxic and lead to AEs. In myelofibrosis in particular, this is a pretty frail population. They can succumb to AEs pretty readily, so we always need to be cautious when combining therapies; escalate slowly and try to pick agents that don’t have overlapping toxicity profiles to optimize that.

However, a number of studies were done of combinations of ruxolitinib and hypomethylating agents, ruxolitinib and lenalidomide (Revlimid), and ruxolitinib with interferons. For example, there are ongoing studies looking at ruxolitinib plus a PI3K-delta kinase inhibitor and many other compounds that we will hear about more at the various hematologic focused meetings coming up in the future. 

Regarding the 2018 ASH Annual Meeting, what studies are you hoping to hear more about?

Some of the big headlines will be updates from PROUD-PV, which is a randomized study between a newer, longer-acting version of interferon and hydroxyurea in PV. We expect to get updates from the pivotal MPD-RC 112 study looking at frontline treatment of PV and ET with either interferon or hydroxyurea. We also expect to get updates from imetelstat, a telomerase inhibitor, as well as PRM-151, an antifibrotic agent. People have been keyed in on some of those drugs because they have new mechanisms of action and something different from what we already have in our armamentarium. 

Are any of these newer agents targeting molecular abnormalities other than JAK1/2?

Thus far, many of the mutations that we have identified at this point are important for prognosis. There is a small population with mutations that are actionable. For example, there is a small population of patients with myelofibrosis with mutations in the gene IDH2. There is an approved IDH2 inhibitor that is approved for acute myeloid leukemia.

The hope is that we can start to subclassify myelofibrosis, and the MPNs in general, into more mutation-specific subclasses where we can apply these targeted therapies. The studies have yet to be done. The major challenge is that this represents a small part of the population. If you are looking at these specific mutations, it may only be 5% of all patients with myelofibrosis. Therefore, you are already taking a very small pie because it is a rare disease, and you’re making it substantially smaller. Therefore, these studies are hard to do—to understand that there is efficacy and safety in using these medications, particularly in combination for these populations. 

What does the future of MPN treatment look like 5 years from now?

The landscape in 5 years is going to look like a couple of different things. Ruxolitinib will still be a mainstay in treatment; it is a broadly applicable drug with a great track record and it will stick around. We will start to incorporate other treatment strategies based on patients’ disease risk and symptoms. There will be medications to alleviate anemia in the near future; there are certainly a lot of medications looking at that. In patients where anemia is the major issue, we may address that directly with a second medication.

Also, there is a push for antifibrotic agents—anything that can reduce fibrosis and reduce allele burden. We are going to start looking at medications that can do that readily, whether by themselves or in combination with a JAK inhibitor. 

Regarding the available MPN risk models, does there need to be refinement?

Risk models are very imperfect. Often, when we look at the stats to predict how good these models perform in populations, their performance is almost closer to a coin toss than it is to perfection. There is a long way to go. We know that certain mutations have bad prognostic implications, but we often don’t understand how the different mutations interact with each other and how mutations interact with other prognostic factors within the model. While we are making great strides to better predict who has aggressive disease and who does not, there is still a long way to go. 
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