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ASH 2016: Highlights in MPN
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Exciting and new developments in MPN are highlighted in key abstracts presented at the ASH meeting in San Diego in December, 2016.

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Hello, my name is Srdan Verstovsek. I'm a Professor of medicine in the Leukemia Department at MD Anderson Cancer Center in Houston. Here, I'm reviewing the most important findings that American Society of Hematology Meeting, 2016.

We'll start with a poster on a pooled overall survival analysis. Over five-year data from COMFORT-I and COMFORT-II trials of ruxolitinib in myelofibrosis. Here, after five years, the combination of the two studies was analyzed in terms of overall survival. It's quite clear, that earlier institution of ruxolitinib prolongs the life of the patients. It is about three years of survival advantage of the patients that were exposed to ruxolitinib comparing to those that were never, ever exposed to ruxolitinib. Or, if they were exposed to ruxolitinib at a later time point during their life, the extension of life is about a year and a half. That was independent of any characteristic of the patients at the time of enrollment.

Follow up to this study is another important presentation on what they call a LANDMARK survey, which was a quality of life and productivity survey of the patients living with the disease, myeloproliferative neoplasms, which went beyond just looking at the symptoms that they suffered from, which are very well known by this time and age.

Here, we were looking at the disease impact on daily activities, impact on patient's work, and overall activity impairment, which is significant. This applies to patients with ET (essential thrombocythemia), polycythemia vera (PV), as well as myelofibrosis, where one would think that patients with more benign conditions, ET and PV, have relatively less impact of the disease on their daily activities, work, and overall impairment. This is not so, based on this report.

There is also a report of a JUMP study, which is an open-label, multicenter, single-arm, expanded-access study of ruxolitinib and myelofibrosis in more than 2,200 patients around the globe. We just confirmed in a community setting that, indeed, ruxolitinib is very active for spleen and symptoms with notable mild suppression that is not usually a reason to stop the therapy. Manageable mild suppression in community setting does not lead to early stopping of the therapy. As shown in a JUMP study, over time, in fact, the results get better and better, in terms at least on the spleen response.

The long-term aspects of ruxolitinib on patients that are taking it that have myelofibrosis were highlighted by looking at patient's bone marrow over time. Dr. Kvasnicka presented a bone marrow morphology in patients with myelofibrosis enrolled in COMFORT-I study. It showed that after four years of therapy, a good proportion of the patients, in fact, have improvement in bone marrow fibrosis grade. One of the aspects of the benefits of the therapy in patients that are sustained on a good, effective dose of ruxolitinib over time.

Moving on to studies with interferon, we would like to highlight the final results of the PROUD-PV study, a randomized, controlled, Phase 3 study comparing Roche peginterferon, a new, a long-term version of interferon, which is given under skin every two weeks, to hydroxyurea in patients with PV. Relatively more prevalent disease, but less aggressive than myelofibrosis, where we worry about blood cell count, in particular. To some degree, also about the symptoms in the spleen, but the goal of therapy is to decrease the thrombotic risk. In this randomized study, patients that were naïve to cytoreductive therapy, or previously exposed to hydroxyurea, which about a third were, but less than three years in duration, were randomized to receive Roche peginterferon for hydroxyurea. After 12 months of randomization, the efficacy was analyzed and the responses between two arms were about the same.

This was indeed non-inferiority study, where complete hematological response was about 45% on both arms. Continuation of that study beyond one year was highlighted by information that, in fact, as I would say expected after longer period of time, after three to five years of therapy, there should be perhaps even a superiority of interferon to hydroxyurea. This is something that we will follow up in the next year presentation.

In terms of the tolerance, hydroxyurea indeed was causing more of side effects in this particular study than Roche peginterferon, perhaps identifying a quality of interferon here, which is much better tolerated because it's given so infrequently. On the other hand, another Phase 3 study, which is the global Phase 3 study comparing hydroxyurea and a different form of peginterferon, this is pegylated interferon alpha-2a, or also known as Pegasys. After 12 months of follow up in this ongoing study, so these are preliminary findings, again we did see non-inferiority. The same result between the arms treated with hydroxyurea or Pegasys, as noted, a different form of a long-acting interferon. That was shown at multiple levels. Non-inferiority for control of the blood cell count, phlebotomy, and other aspects that we worry when we talk about polycythemia vera.

Moving on to something more exciting, a new medication that in pilot study was tested in patients with myelofibrosis and significant anemia. A very small, ongoing study, only 19 patients presented so far. This is an antibody that is injectable under the skin every three weeks. Two doses were tested and about 40% response rate in the lower dose, actually, 0.75 mg/kg, with activity even in the higher dose. The unmet need that this drug potentially can cover, which is anemia and myelofibrosis, for which there is absolutely no therapy, is in fact only a highlight of these preliminary findings, and hopefully we will have this drug further developed, in many more patients. Combination studies, hopefully, will also happen in the very near future.

Finally, to conclude with a late-breaking abstract that was presented in oral session at the end of ASH, these are results of the PERSIST-2 study, which is a Phase 3 study comparing pacritinib, another JAK2 inhibitor, comparing it to best available therapy in patients that had platelets below 100,000. Best available therapy arm allowed patients to be prescribed ruxolitinib if judged reasonable by the treating doctor.

In this particular study, patients were required to have low platelets because this is area of unmet need.  Ruxolitinib can be used, but very low dose can be used, only in patients that have platelets between 50 and 100, and not in patients that have platelets below 100. Low platelets can develop on therapy with ruxolitinib precluding proper efficacy of this agent, so certainly an area of unmet need. Here, in this randomized study, pacritinib was better than best available therapy arm for control of the spleen. However, it was not better for the control of the symptoms. In subgroup analysis, one of the arms, and there were two arms of pacritinib, one of the arms that the pacritinib was given twice a day was better than best available therapy arm. That gives us a signal that perhaps further work needs to be done to define proper dose schedule and the area of proper use of pacritinib in patients with myelofibrosis.

With that, I will conclude the summary of most important findings reported at this year's Annual American Society of Hematology Meeting. Thank you.