In this interview we discuss symptoms and prognosis for patients with polycythemia vera and essential thrombocythemia and the treatment of myelofibrosis.
Ruben A. Mesa, MD
As part of our coverage of the National Comprehensive Cancer Network’s (NCCN) 11th Annual Hematologic Malignancies Congress, held September 30–October 1 in New York, we spoke with Ruben A. Mesa, MD, of the Mayo Clinic Cancer Center in Scottsdale, Arizona. At this year’s congress, Dr. Mesa gave a presentation on the evolving management of patients with myeloproliferative neoplasms (MPNs) and myelofibrosis. Dr. Mesa helped author new NCCN guidelines for MPNs that were released earlier this week and include treatment recommendations for myelofibrosis.
- Interviewed by Ian Ingram
Cancer Network:Dr. Mesa, what symptoms do patients with polycythemia vera and essential thrombocythemia often present with? And what is the prognosis for these patients?
Dr. Mesa: They can present in a variety of ways. Sometimes they’ll present because their physicians at the time of a general physical find elevation in their counts in their peripheral blood. So, sometimes they are asymptomatic and the physician finds they have a very high hematocrit, a very high white blood cell count, or a very high platelet count. Other times they can present in the setting of having had a vascular event-thrombosis or bleeding, sometimes unexpected deep vein thrombosis, portal vein thrombosis, or thrombosis to an atypical area such as a sagittal vein thrombosis. They can also have unexpected bleeding, heart attack, or stroke. Finally, they can present with other symptoms related to the high counts-itching is a common symptom, sometimes that can be severe and unexplained. People can have frequent headaches, vascular type symptoms, or pain in the skin called erythromelalgia. So, they can present with a range of these difficulties, sometimes with all of them, but sometimes they are found solely on the basis of an abnormal blood test.
As for prognosis, these patients can experience quite a broad range of impacts on their health, ranging from a life expectancy very much similar to age-matched controls in the general population to being much more limited. There are a variety of things that help inform us how a patient’s prognosis will unfold, including their age, whether they’ve had any vascular events, and increasingly the mutation profile in the blood that we believe is integrally related to the disease.
Cancer Network:Currently, allogeneic stem cell transplantation (allotransplant) is the only curative treatment for patients diagnosed with myelofibrosis, yet only about 10% of patients are eligible. What are some of the barriers to transplant in these patients?
Dr. Mesa: Myelofibrosis is a disease that has quite a heterogeneous disease course, and quite a range on its impact on life expectancy, with some individuals having a life expectancy of less than 2 years from the time of diagnosis, while others might live up to 10 years or more. The very limited use of allotransplant is really for several reasons. Many patients with myelofibrosis are older and as we age, particularly above age 65, allotransplant becomes increasingly prohibitive. It can still be an option, but the return on the risk diminishes. There can be many complications and there can be challenges obtaining a matched donor, although there are experimental works underway with both haploidentical transplant and cord blood transplant, which are helping to expand its utilization. I suspect over time that the percentage of individuals who are able to undergo transplant will likely grow as we are able to further expand the pool of donors with new types of transplantation, and the safety of transplantation continues to increase with both better conditioning regimens and more precise patient selection depending upon the patient’s prognosis.
Cancer Network:In patients with myelofibrosis who are ineligible for transplant, what is the recommended treatment approach?
Dr. Mesa: In 2016 we primarily have one US Food and Drug Administration (FDA)-approved therapy for myelofibrosis, which is ruxolitinib. In the recommendations that my colleagues and I had put forward, we identified it as standard of care for individuals with intermediate-2 and high-risk myelofibrosis, particularly those with splenomegaly symptoms who are not moving on to stem cell transplant or participating in a parallel clinical trial. It was also a consideration for individuals with lower-risk disease if significantly symptomatic.
Cancer Network:The FDA put a full clinical hold on pacritinib earlier this year following reports of patient deaths in the phase III PERSIST-2 trial. Might there still be a role for this agent in the treatment of myelofibrosis?
Dr. Mesa: There are two drugs in very mature phase III programs: momelotinib, a JAK1/JAK2 inhibitor, for which data should be expected in the near future from those phase III trials, and pacritinib, which is a JAK2/FLT3 inhibitor. Two trials studied pacritinib vs best alternative therapy: the PERSIST-1 trial, which included individuals with no barrier for marked thrombocytopenia or anemia; and PERSIST-2, for those individuals with a platelet count of less than 100,000. Pacritinib was placed on a clinical hold because, despite good data from the PERSIST-1 study in terms of efficacy for splenomegaly symptoms, it appeared that as compared with best alternative therapy, there was a higher rate of mortality on the study than had been anticipated. The FDA placed a hold to allow time for that data to be reviewed in depth as well as to await data from the PERSIST-2 study. The investigators had at least hypothesized that, based on the lack of any specific signal of a pattern of toxicity with pacritinib, the excess mortality may have been due to adverse patient entry into the clinical trial, specifically patients with marked thrombocytopenia, who are known to have very poor prognosis. There are subsequent analyses that are going on with longer-term data from PERSIST-1 and now PERSIST-2. I am hopeful that the agent will be able to come off of the clinical hold at some point in the future, but obviously that will depend on the data and the review by the FDA of all the available information.
Cancer Network:Is there anything else you would like to add on this important topic?
Dr. Mesa: I would add that both for treating providers as well as for patients it’s a time to be very hopeful and excited about the increasing number of options for patients with MPNs. As I mentioned, we have these initial guidelines for treatment in myelofibrosis, and subsequent guidelines are coming soon for the treatment of essential thrombocythemia and polycythemia vera. There are multiple agents in development-the advanced JAK2 inhibitors that I mentioned (pacritinib and momelotinib), as well as many other drugs-PRM-151, imetelstat, and even ruxolitinib combinations, which are all ongoing. I anticipate, as with other areas in hematologic malignancies, we’re going to see an increasing number of options, and I’m hopeful that the guidelines will help provide some guidance for treating physicians as they try to navigate their many options.
Cancer Network:Thank you for joining us today, Dr. Mesa.
Dr. Mesa: Great, thank you for having me.