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The 2022 Tandem Meetings | Unmet needs in MF: managing anemia & improving the efficacy of first and second-line treatments

Srdan Verstovsek, MD, The University of Texas MD Anderson Cancer, Houston, TX, discusses recent advances and unmet needs in myelofibrosis (MF). One important area of unmet need in MF is effective second-line treatments after failure on JAK inhibitors and several ongoing Phase III trials are evaluating the efficacy of agents such as navtemadlin and imetelstat in this setting. In addition, it is important to develop drugs that allow to better manage anemia in patients with MF, as well as to improve the efficacy of JAK inhibitors by combining them with other agents. This interview took place at the Transplantation & Cellular Therapy (TCT) Meetings of ASTCT™ and CIBMTR® 2022 in Salt Lake City, Utah.

Transcript (edited for clarity)

With the advent of the JAK inhibitors, we cover the controlled display in symptoms, and we can cover that in patients with high counts and low counts. We have now, in addition to ruxolitinib, fedratinib, also pacritinib, and in the near future momelotinib may be out there as another JAK inhibitor, which is non-myelosuppressive and improves the anemia. But where do we go from JAK inhibitors?

After JAK inhibitors, even when you sequence one after the other, there is still a need for more...

With the advent of the JAK inhibitors, we cover the controlled display in symptoms, and we can cover that in patients with high counts and low counts. We have now, in addition to ruxolitinib, fedratinib, also pacritinib, and in the near future momelotinib may be out there as another JAK inhibitor, which is non-myelosuppressive and improves the anemia. But where do we go from JAK inhibitors?

After JAK inhibitors, even when you sequence one after the other, there is still a need for more. None of these medications work forever. There is always a limitation in the duration of the benefit. And so, we are looking for other therapies after JAK inhibitors. To simplify, this would be a second line after JAK inhibitors. And in that setting, the biology of disease is much more complicated. There are many other abnormalities that we can target with different drugs. For example, we have a Phase III study underway, comparing navtemadlin, which is a MDM2 inhibitor, an inhibitor of p53 gene activity. That’s probably the simplest way to describe it. This navtemadlin is a pill that is being compared to best available therapy, in a second-line setting, to control the spleen and symptoms.

You have also, a Phase III study with imetelstat, telomerase inhibitor. IV drug over three weeks, which is compared to best available therapy in a second-line setting, to prolong life. Of course, have a study with the survival benefit as the endpoint. This is one aspect of area of unmet need.

The other is more of a benefit on the anemia. If momelotinib will improve that to some degree, we need more specific and more powerful anemia drugs that we can combine with other JAK inhibitors, with ruxolitinib or fedratinib, for example, in that setting. So anemia is area of unmet need. We have underway a Phase III study, placebo controlled, comparing luspatercept to placebo, in people who are on ruxolitinib deriving benefit on the spleen symptoms, but requiring transfusions. The goal is here, elimination of transfusions, transfusion independence.

And of course, area number three of unmet need, is to boost what the JAK inhibitors do. They help many people, but there is always an improvement on the control of spleen symptoms that one can envision. Here, we have Phase III studies underway with medications like a BET inhibitor, pelabresib, or a Phase III study, with navitoclax, BCL-XL inhibitor, or parsaclisib the PI3 kinase inhibitor. These are three drugs that are being added on to ruxolitinib in people who have a spleen and symptom problem, with the goal, comparing it to placebo, to boost that response. So another view of how we can improve our management of our patients.

So you see the areas of second-line, area of anemia second line, in terms of after JAK inhibitors. But then the last one that I described is adding a medication to JAK inhibitors, a combination strategies, are evolving as well. So a lot of activities in myelofibrosis.

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