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Emerging Agents Propel Progress in MPN Paradigm

Caroline Seymour
Published: Tuesday, Nov 27, 2018

Stephen Oh, MD, PhD

Stephen Oh, MD, PhD

Ruxolitinib (Jakafi) has been an integral aspect of care for patients with myelofibrosis and polycythemia vera (PV), but updates in the development of more selective JAK inhibitors such as momelotinib, pacritinib, and fedratinib are showing encouraging progress in the treatment paradigm, explained Stephen Oh, MD, PhD.

“At this point, it's impossible to say that momelotinib, pacritinib, or fedratinib is really a frontrunner. Rather, I'd say that they potentially offer slight distinctions between each other and ruxolitinib,” said Oh. “I could envision a scenario where if all of these agents were available, there could be specific niches for each of these particular drugs for specific types of patients.”

In 2011, the JAK1/2 inhibitor ruxolitinib (Jakafi) was approved by the FDA for patients with intermediate- and high-risk myelofibrosis. Three years later, it was approved for patients with PV who are intolerant or resistant to hydroxyurea. Although it shows significant symptom reduction in patients with PV, other agents need to be added to the armamentarium.

In an interview during the 2018 OncLive® State of the Science Summit™ on Hematologic Malignancies, Oh, assistant professor of medicine, Division of Hematology, Washington University School of Medicine in St. Louis, Siteman Cancer Center, discussed the use of ruxolitinib in patients with myelofibrosis and PV, and emerging agents and next steps in the field of MPNs.

OncLive: What were the key points of your presentation on myelofibrosis and PV?

Oh: In myelofibrosis, I covered recent developments in terms of prognostication. We’ve been able to incorporate some of the new molecular markers to help stratify patients in terms of their overall prognosis and risk of transmission to acute leukemia.

I also covered some of the important aspects of ruxolitinib and updated the audience on the latest status of the other JAK inhibitors––momelotinib, pacritinib, and fedratinib. I spoke about some of the other options for experimental therapies and where they stand.

In PV, I went over some of the considerations in the use of standard therapies as well as newer therapies, such as ruxolitinib. I also covered some specific scenarios and how to use these different agents.

What are the new prognostic factors for myelofibrosis?

Historically we've used the International Prognostic Scoring System (IPSS), the dynamic IPSS (DIPSS), or the DIPSS-plus for risk stratification. This system does not take into account any of the particular molecular markers in this disease. More recently, we’ve learned about specific driver mutations such as JAK, CALR, and MPL, but also, that many patients harbor concomitant mutations and other driver mutations such as ASXL1, and in some cases, IDH1/2. Some of the more recently published prognostic scoring systems are taking these into account, one of which is the Mutation-Enhanced IPSS 70. This system incorporates some of these high-risk mutations such as ASXL1, so that we can better understand the impact of these types of mutations on long-term prognosis. This is becoming particularly more relevant as many practitioners are beginning to test for these types of mutations in routine clinical practice.

Where do the JAK inhibitors stand in development?

Each of the other JAK inhibitors besides ruxolitinib has had various issues, ranging from safety concerns to FDA holds, in some cases. The unique aspect of momelotinib is that it seems to improve anemia in a subset of patients. The drug was being developed by Gilead Sciences, but was later discontinued. Very recently, the rights to that drug were acquired by Sierra Oncology. At this point, it sounds like there are plans for further development of the drug, but we'll have to see.

The unique aspect of pacritinib, at least in part, is that it seems to be safe for patients even with a very low platelet count. There was an FDA hold for that drug due to safety concerns. That hold was lifted, and a new study is ongoing to determine the lowest dose that can be safely and effectively administered. It'll still be some time before that drug will potentially be approved, but it's still a viable candidate.




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