Masarova's Perspective on Targeting New Pathways in MPN Treatment

Lucia Masarova, MD, PhD

The landscape of oncology is rapidly changing, particularly within the realm of hematological malignancies, and experts are constantly looking for and developing novel strategies to combat diseases like myeloproliferative neoplasms (MPNs).

According to Lucia Masarova, MD, PhD, recent advances are shaping the field, specifically surrounding phase 3 studies evaluating combination therapies in frontline MPN treatment. Notably, the TRANSFORM-1 and MANIFEST-2 studies (NCT04472598; NCT04603495) are evaluating the efficacy of combining ruxolitinib (Jakafi) with other agents, such as pelabresib (CPI-0610) and navitoclax.

These 2 studies each seek to expand treatment options beyond JAK inhibitor monotherapy. If positive, these studies can potentially revolutionize the management of MPNs by targeting additional pathways implicated in disease progression.

In an interview with Targeted Oncology^TM, Masarova, assistant professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, elaborated on the latest updates across MPNs, focusing on significant studies and emerging therapeutic approaches.

Targeted Oncology: What are some of the latest updates across MPNs?

Masarova: We are waiting for the top-line results of the phase 3 studies of the frontline ruxolitinib and the navitoclax vs ruxolitinib and placebo, as well as the top-line results of the other combo of ruxolitinib and pelabresib vs ruxolitinib and placebo. Both of those, the TRANSFORM-1 and MANIFEST-2 study studies, are highly expected results. They are coming to see whether we can move from the monotherapy of a JAK inhibitor to the combination of arms of both of the agents. That will expand the field, hopefully, and we will see where it is going to go. There are excellent results for spleen control that are exciting, the symptoms will need to be worked out, so we will see where it goes.

There are other novel molecules and other following proteasome inhibitors, very interesting data this year about other pathways, some data on the MEK pathway, so quite exciting discoveries or movements in the pathogenesis of the disease. Also, some nice transcriptomics or sequencing of the progressed chronic MPN’ to accelerated phase or blastic phase where we do not have any compounds, so hopefully, we will find something soon. The field is moving with huge steps, so we have quite the excitement this year.

A close-up of a red cell with a red blood cell in the background Generative AI: © Bipul Kumar - stock.adobe.com

Can you discuss the MANIFEST-2 study background and findings?

That was a frontline, randomized study that explored patients with newly diagnosed myelofibrosis and treated them in a randomized fashion to either ruxolitinib and placebo or ruxolitinib with pelabresib. The results from the phase 2 studies were quite complicated and had interesting results on either the frontline setting or the add-on cohort, the monotherapy, as well as arm in ET. Now, we are waiting for the top-line, head-to-head comparisons. Press release data from the company showed striking important results on controlling the spleen control, which is always measured as a decrease of 35% spleen volume reduction by imaging, which was almost doubled on the study compared with the single arm [at] about 60-plus percent vs 35.

What I am really excited about is waiting for what the cytokines are going to show us because this agent had a significant property or options to do a disease modification, so really going through the NF-κB and the other pathways that are not hit by the single JAK inhibitor, that will be exciting. In terms of the safety, the combo has been quite tolerable, so I am looking forward to [seeing more].

The navitoclax study with ruxolitinib is another phase 3 trial that had a similar concept, so high-risk patients with myelofibrosis were treated with ruxolitinib and placebo vs ruxolitinib and navitoclax. There were interesting results as well in the spleen control; it was over 60% and only 30-something percent with ruxolitinib single agent with placebo. But the symptoms were similar. For myelosuppression, it was quite significant, which we knew to expect for thrombocytopenia. It was a little bit harder to deliver. We are seeing how that compounds go. Ideally, I would envision having a BCL-XL inhibitor that will be less myelosuppressive. Maybe we are coming into that space, but those 2 results are highly expected because they finally provide an agent beyond the single attack inhibition.

Are there any specific genetic mutations or markers that have gained significance in this space?

The non-JAK or nondriver pathways are significant in how we see these patients. We have learned that there are 2 myelofibrosis subtypes, [primary and secondary]. We have patients who are proliferative; they have big organs, a lot of counts, more symptoms. And then we have patients who are depleted or cytoreduced/cytodepleted where we have more of those additional mutations that look almost like [myelodysplastic syndrome (MDS)]. A lot of these epigenetics are almost like a myelodysplastic feature in patients, and there is always a hard time of delivering a JAK inhibitor, especially ruxolitinib. The novel JAK inhibitors that have additional pathways, like pacritinib [Vonjo] or momelotinib [Ojjaara] which are designed more for cytopenia, would have more of a role in these patients. Still, the additional mutations’ role in driving the prognosis are relevant. We are just learning more about the role of single ASXL1 vs ASXL1 with something vs their interplay with the drivers and a JAK2 allele burden where we have some data emerging. The same goes with a splicing mutation. We know that the splicing is equal, which has been already known, but the high-risk mutations may have a significant role, which definitely opens up the space for drug delivery.

What are the roles of targeted therapies, immunotherapies, or other novel approaches?

I think this landscape of myelofibrosis boomed after we discovered the JAK mutations, then the other calreticulin mutations. Last year, there was a breakthrough with the finding that we can target calreticulin. With JAK inhibition, we have had a couple nice developments. It is the 10-year anniversary of having ruxolitinib in the space for myelofibrosis, and the same is coming for polycythemia vera, which was 2014 when it was approved. The other JAK inhibition is very much needed; we need them all. They have a big role in cytopenic patients where the ruxolitinib does not add much in terms of the cytopenias.

A big help to our patients with thrombocytopenia was with pacritinib, and [for those] with anemia, finally, we had momelotinib, so really big approvals. We can use them in the frontline and second line depending on patient needs. I think that is going to be the biggest thing in this field in the next decade, to figure out how we use that, how do we sequence them, how do we use them to benefit our patients most, who is the best for frontline ruxolitinib, momelotinib, pacritinib, all of these things. It is going to be fun to explore and learn, and then evolve in the non-JAK pathways. We have learned and see that JAK inhibition is not the only thing that drives this very complex disease. There is so much [more]. We learned about the mechanism of how the drugs do not work, which we have expanded on and learned. While there is not only the blastic phase, [but those are also] the patients that would not have optimal spleen and symptom control, cytopenias, and so that has evolved alongside our assessment of symptom scores of how the end point really matters.

Are we using the right end points? We have come up with spleen control, the symptom control, and now, we have anemia as a relevant end point that also is also leading to better survival with some of these drugs. Anemia and cytopenias are going to be the big end points that will have to be assessed. Then, more coming from disease modification, what does it mean? How do we retrieve it? Where is it clinically relevant? What end points actually do correlate with that? I think that is going to be more in the discovery field.

Now we have a couple of drugs, so we have to pay attention to how to use them the best. Adding on additional drugs to prevent resistance and prolong duration of response to assess what is enough, if we are hitting the right end points for long-term outcomes, and more importantly, how do we prevent this progression in terms of a blastic phase? We do not really have anything [there] yet. We have mechanistic ideas; we have seen drugs that could give us a lot of good activity, but we do not know how to deliver them. I think that is one of the largest unmet needs in the space for this decade, to come up with the drugs that would, hopefully, as a part of a disease modification, lock the disease in the chronic phase and prevent it from facing the consequences of acceleration, which I think is the biggest failure we all have in this field.