Exploring Available and Anticipated Therapies for MPNs

Andrew Kuykendall, MD

In recent years, the field of myeloproliferative neoplasms (MPNs) has had several clinical developments, including the novel treatments ruxolitinib (Jakafi), fedratinib (Inrebic), and pacritinib (Vonjo).^1-2

Ruxolitinib was the first JAK1/2 inhibitor to receive FDA approval and has made tremendous strides for patients with myelofibrosis (MF). Then, fedratinib, another JAK2 inhibitor, received regulatory approval in 2019. This option has shown promise in the second-line for patients who are ruxolitinib-resistant with intermediate-2 and high-risk MF.

However, there was an unmet need of severely thrombocytopenic patients with intermediate- or high-risk MF. This was addressed with the regulatory approval of the JAK2/IRAK1 inhibitor, pacritinib, in February 2022.

Now, clinical trials are ongoing to evaluate a new JAK1/2 option, momelotinib, for patients with JAK-inhibitor treated, symptomatic, and anemic patients with MF. Momelotinib is being evaluated in the ongoing phase 3 MOMENTUM trial (NCT04173494). Findings from the study have already shown there to be significant improvements in anemia measures, spleen size, and symptoms for this patient population.

According to Andrew Kuykendall, MD, if the FDA grants an approval for momelotinib in 2023, this will be practice changing for patients with MPNs.

“The main thing that will shake up treatment in 2023 is the anticipated approval of momelotinib. We've seen the positive data from the MOMENTUM study, and we are looking at an approval sometime during the summer of 2023. This is an agent that has been studied in the SIMPLIFY-1 and -2 trials [NCT01969838; NCT02101268] as well as the recently completed MOMENTUM study. This agent is another JAK inhibitor, but it has a little bit of a different niche. It seems to be a little more favorable, and its impact on anemia induces some transfusion independence, and it still has some good effect on spleen and symptoms,” Kuykendall, MD, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida in Tampa, FL, told Targeted Oncology^TM, in an interview.

In the interview, Kuykendall discussed the most recent approvals for MPNs, practice changing abstracts presented at the 2022 American Society of Hematology Annual Meeting (ASH 2022), and what he expects to see in 2023.

What exciting changes have been seen in the MPN space over the past year?

Things with MPNs are changing relatively fast. Going back to November of [2021], we had the approval of ropeginterferon alfa-2b-nj for polycythemia vera, which was kind of the second approval we've had of a polycythemia vera medication, and certainly has transformed how we think about treating that disease with an idea of potential for disease modification. In February [2022], we had the accelerated approval of pacritinib for the treatment of myelofibrosis for patients that have severe thrombocytopenia. It was very exciting to get 2 drugs approved within the context of a year. Then, we have the continued enrollment of many phase 3 clinical trials that are potentially practice changing and may bring new therapeutic options to the table.

Can you discuss some of the new approvals?

With ropeginterferon, for a long time, we've been using interferon formulations within polycythemia vera and essential thrombocythemia, maybe to a lesser extent within myelofibrosis. This is going back to the 90s. We know that it's effective, it can help control counts, and we have seen in small numbers of patients that it may be able to decrease the JAK2 allele burden and potentially could correlate with delayed disease progression and potential disease modification. That's something that has been exciting to patients.

Historically, interferon has been challenged by toxicity, especially the short acting forms. As we got pegylated interferon, we had longer acting, better tolerated, and lower doses, and patients stayed on for a longer period of time, did better, could appreciate some of those durable responses that you get when you're on long term therapy. With ropeginterferon, we've now got an approved agent as opposed to using something off-label. It's given less frequently, so every 2 weeks, and we have seen good long-term data with more robust datasets that have shown the ability to decrease allele fractions and JAK2 mutations. What that's brought to the table is something not completely new, because we've been using interferons, but something that has stronger data to support it. It's something that we can use as an approved on-label medication for many patients. I think it's gotten patients very excited about potentially having something that can alter the natural history of disease.

Pacritinib on the other hand is something that was approved for an unmet need. It's an accelerated approval for patients with thrombocytopenia with less than 50,000 platelets, and for those patients, we don't have many great options. We have ruxolitinib and fedratinib that are approved, but typically, they've been given in patients with over 50,000 platelets. We have struggled to treat these patients with lower platelet counts. Pacritinib has great data in the PERSIST-1 trial and PERSIST-2 trials [NCT01773187; NCT02055781], and in the ongoing PACIFICA study [NCT03165734]. It shows that it can be safely leveraged in these patients with lower platelet counts. We were happy to get the accelerated approval because now, we have an option for those patients, and we're not having to do things off-label or give modified doses. Now, we have something we can fully dose and bring an effective treatment for these patients that have an unmet need.

What abstracts presented at ASH 2022 do you think are practice changing or show potential for patients with MPNs?

There [were] 24 oral abstracts for MPNs this year [at ASH]. One [we saw was] the final dataset from the RUXOpeg study [​​NCT02742324]. It was a combination of ruxolitinib and peg-interferon. This could be immediately changed as both drugs are available to us right now. The question has always been, can we meaningfully combine these 2 agents in MPNs and is there a benefit to doing that? Ruxolitinib is thought of as something that helps with symptoms of the disease, spleen symptoms, and has a survival benefit in myelofibrosis for more of the advanced stages.

Then we have interferon, which is thought of in earlier stages of MPNs and something that has this potential for disease modification that maybe we don't see with ruxolitinib. The idea of reusing them together is something we've talked about for a long time, we've seen early datasets, and we have the final results of the RUXOpeg study, which is an upfront combination of the 2 in intermediate-1 risk patients. We can get some support if we were to leverage this combination. Is that something that we get benefit out of? With the presentation [at ASH], we were able to see some of the impact that interferon has on stem cell populations and see if there is a rationale for leveraging this combination in early phase patients.

Looking ahead, what do anticipate the treatment landscape for MPNs to look like?

I think that we're still going to be kind of gaining data from these phase 2 clinical trials. The main thing that will shake up treatment in 2023 is the anticipated approval of momelotinib. We've seen the positive data from the MOMENTUM study, and we are looking at an approval sometime during the summer of 2023. This is an agent that has been studied in the SIMPLIFY-1 and -2 trials as well as the recently completed MOMENTUM study. This agent is another JAK inhibitor, but it has a little bit of a different niche. It seems to be a little more favorable, and its impact on anemia induces some transfusion independence, and it still has some good effect on spleen and symptoms. We know that anemia is inherent to myelofibrosis, it's going to be a part of everyone's disease course over time. Unfortunately, with ruxolitinib and fedratinib, we've had to often punt that. Patients have had a worsening of their anemia, at least temporarily with those agents. We've said that we will accept that for the spleen and symptom benefits. With momelotinib, maybe we don't have to do that, and this anemic patient population may have an alternative option that could treat multiple aspects of the disease and we won't have to kind of ignore 1 aspect while treating the others. That will probably be the biggest thing that shakes things up.

The other question that we have in polycythemia that was supported with abstracts presented at [ASH 2022] is, where do we leverage interferon vs hydroxyurea vs ruxolitinib. All 3 are approved and utilized within the realm of MPNs, especially polycythemia vera. We have used ropeginterferon more so for this allele fraction, this disease modification aspect, but more data presented on ruxolitinib suggests patients on long-term ruxolitinib who have [polycythemia vera] or [essential thrombocytopenia] may be able to get similar VAF or allele fraction reductions. That may shake things up a bit because we haven't thought of that or seen that. Seeing that this occurs over the long-term is what we think about with ropeginterferon. These allele fractions, this disease burden, and reductions typically take a long time to happen. If we can see that and if we do believe this data coming out with ruxolitinib, that may shake things up as far as how we talk to patients and how we leverage these agents in clinical practice.

REFERENCES:

Masarova L, Bose P, Pemmaraju N, et al. Improved survival of patients with myelofibrosis in the last decade: single-center experience. Cancer. 2022;128(8):1658-1665. doi:10.1002/cncr.34103

Verstovsek S, Parasuraman S, Yu J, et al. Real-world survival of US patients with intermediate- to high-risk myelofibrosis: impact of ruxolitinib approval. Ann Hematol. 2022;101(1):131-137. doi:10.1007/s00277-021-04682-x