Initiating Treatment in Myelofibrosis


Srdan Verstovsek, MD:When we see patients with myelofibrosis in the clinic, we usually look at the prognosis of the patients to be able to refer them to a bone marrow transplant. Beyond that, we look at the clinically relevant abnormalities that we can correct to control the patient’s quality of life. So, we are really talking about control of signs and symptoms of the disease. There are 3 major areas of concern. One is failing bone marrow that leads to anemia, in particular. So, anemia is a target for therapy. The second one is progressive splenomegaly and the liver enlargement in many of the patients. About 80% of the patients will have very big spleens, many times the size of normal, with a lot of symptoms. And area number 3 of concern is poor quality of life—inability to work, bone aches and pains, night sweating, itching, and low-grade fevers. For these 3 areas, we have medications that we can implement. When these problems are clinically relevant, they affect the patients. So, for anemia, we have anemia-directed therapies like Danazol, erythropoietin, thalidomide, or lenalidomide. For symptoms in the spleen, we have a JAK inhibitor, ruxolitinib, as the first ever approved therapy for this condition. And perhaps there are some other more traditional ways of looking, such as hydroxyurea, cladribine, or lenalidomide use for the spleen.

Undertherapy of patients with myelofibrosis is quite problematic because traditionally we did not have much to offer to the patient. Therefore, we were waiting for patients to really be in such a dire situation only to be able to provide palliative care when the patient was in a dying mode. However, we now know that new ways of therapy—JAK inhibitors, in particular—can provide survival benefit of the patients. Therefore, if the patient had symptomatic spleen or symptoms from the disease in general—loss of weight, night sweating, low-grade fevers, itching, fatigue, weakness—these are good reasons to initiate therapy earlier, rather than later, in patients with myelofibrosis, which controls those symptoms and signs, and we did prolong survival. That is the main message that I try to project in a community setting: not to wait until the patient is so debilitated from the disease, but to initiate therapy when we see, first, a compromised quality of life.

It is important to appreciate the disease. Myelofibrosis does change over time, and that can be seen in different ways. That can be seen as progressive splenomegaly, that can be seen as worsening bone marrow failure with anemia, or disability that comes from weight loss, inability to walk, night sweating, and bone aches and pains. But these issues usually are not associated with age. It is really a natural way of progression of the disease, by possible acquisition of different genetic abnormalities that leads to progressive features. Age has little to do with initiation of the therapy, and the spleen size usually does not have the direct correlation with the need to intervene. It is really the symptomatic splenomegaly that is important, that needs to be treated, rather than its size per se.

Ruxolitinib is a JAK inhibitor that inhibits the super-active JAK/STAT pathway. The hyperactive JAK/STAT pathway is an underlying biological problem in myelofibrosis. With that, we have antiproliferative and anti-inflammatory effects on the body of the person. That means that there is a smaller spleen and there is also improvement in quality of life. People gain weight and work more. They’re able to live longer, with control of symptoms and signs of the disease. We are not eliminating the disease—that’s an important distinction. There is no complete response. There is just very good control of signs and symptoms. The body composition improves, the weight goes up, and, therefore, people live longer.

These are results that we have now confirmed by looking back in time at the outcome of the patients from the 2 randomized studies that led ruxolitinib to be approved. These are called the COMFORT-I and COMFORT-II studies, where ruxolitinib was compared to other very good medications that have activity in this condition or placebo. And even in those studies where these patients in the control arms were allowed to cross over and be given ruxolitinib, we witnessed prolongation of life in the patients that were treated with ruxolitinib from the very beginning. That leads me conclude, and others in the field agree, that we should not really wait for patients to be very advanced with the features of advanced myelofibrosis for us to treat them. Patients that are symptomatic or have symptomatic splenomegaly at any stage of their disease are good candidates for therapy with ruxolitinib, with JAK inhibitors, and with potential to extend their life, too.

The field of myelofibrosis is rapidly changing. We established the disease name 10 years ago and the factors that would mean that the patient is responding to new therapies. With this backbone, we were able to develop new medications, and now we are in the situation where patients even live longer, with good control of signs and symptoms of the disease. So, the diagnostic process, prognostication, therapeutic decision making, and improvements in our ability to target new biological markers in this disease are rapidly evolving. Hopefully, in the next couple of years, we’ll have another 1 or 2 medications approved to help our patients with myelofibrosis.

Transcript edited for clarity.

January 2016

  • A 59-year-old male presents to his physician with symptoms of fatigue and abdominal pain lasting 3 months; he also reports increased bruising
    • Physical Exam: Spleen is palpable, 6 cm. below left costal margin
  • CBC with differential
    • RBC; 3.20 x 1012/L
    • HGB; 9.3 g/dL
    • HCT; 34%
    • MCV; 93.1 fL
    • WBC; 12.1 x 109/L
    • PLT; 247 x 109/L
    • PB BLASTS; 0%
  • Genetic testing showsJAK2V617Fmutation
  • Bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis
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