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SOHO 2020 | New therapies for myelofibrosis

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Srdan Verstovsek

Srdan Verstovsek, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston, TX, outlines novel therapies currently in development for myelofibrosis, including the development of agents that show activity in patients who have failed treatment with JAK inhibitors. Dr Verstovsek also elaborates on luspatercept to be evaluated in anemic myelofibrosis patients treated with JAK inhibitors, as well as navitoclax, a Bcl-xL inhibitor and CPI-610, a bromodomain inhibitor. This interview was recorded via an online conference call with The Video Journal of Hematological Oncology (VJHemOnc).

Transcript (edited for clarity)

The field of myelofibrosis is incredibly active these days. We have numerous studies in different settings and at least about nine different Phase III studies, with six different medications for their possible approval.

So, if we go in order of priority the main issue at the moment, is what to do with the patients who have tried and failed the front-end therapy with the JAK Inhibitor? As we know ruxolitinib has been around as a JAK inhibitor for a long period of time, and it’s useful very much in patients in very extreme and bad quality of life...

The field of myelofibrosis is incredibly active these days. We have numerous studies in different settings and at least about nine different Phase III studies, with six different medications for their possible approval.

So, if we go in order of priority the main issue at the moment, is what to do with the patients who have tried and failed the front-end therapy with the JAK Inhibitor? As we know ruxolitinib has been around as a JAK inhibitor for a long period of time, and it’s useful very much in patients in very extreme and bad quality of life. And fedratinib another JAK inhibitor was approved about a year ago for the same group of patients in the frontline setting. Once the JAK inhibitor do not work anymore, then we have problems. Life expectancy can be just between one and two years, so the major focus on many studies as a single agent, new investigational agents studies are in the second-line setting.

Then we move on to combination studies, where we treat patients with JAK inhibitors and we add other medications to JAK inhibitor in suboptimal response or if they suffer from anemia for example, because the JAK inhibitors control the symptoms and the spleen, but they don’t do much about the cytopenias, and anemia among them is the most problematic one. So, you’ll have studies where you’ll treat the patient with JAK inhibitor, they have anemia you add anemia drug to it. Or there are studies where you treat patients with JAK inhibitors and you add the medication that will boost, all the JAK inhibitors do, more of the spleen more of the symptoms. And that can be from the very beginning of the therapy with JAK inhibitors as well. It doesn’t need to be in suboptimal responders, after some time exposing these patients to JAK inhibitors. Some studies actually investigate combinations from the very beginning of the day one of any therapy.

So, you’re going from a second-line to several optimal responders to the frontline setting. And of course there are studies for patients that are progressing to acute myeloid leukemia, that is when the blasts go up, blast are leukemic cells and if you have more than 20%, and usually you have none in normal blood. But you may have in myelofibrosis two percentages, if it goes above 20 it’s acute leukemia, and we want to prevent that from happening in a transition from normal to abnormal to more than 20 and there are studies focused on that as well. See the whole spectrum, but in terms of the studies that are possibly leading to approval of any medication. So let’s highlight a few. For anemia drug called luspatercept is going to be studied in a phase three anemia study in patients who are on JAK inhibitor and transfusion dependent.

And the goal is obviously to eliminate transfusion dependency. Medications of two different types, navitoclax, which is a Bcl-XL inhibitor and CPI-0610, which is the bromodomain inhibitor, you see affecting different proteins inside the cells, are going to be studied in combination with the ruxolitinib from the day one of therapy of myelofibrosis patients versus ruxolitinib alone. And then you have studies after JAK inhibitor in the second-line setting, like a imetelstat, where it is best therapy to prolong the life of the patients for example or other JAK inhibitors momelotinib, or pacritinib are being studied and fedratinib as well in a second-line setting for patients with low platelets, a different group of patients for different JAK inhibitors. All of this is happening at the same time. So very exciting time for myelofibrosis drug development.

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