The Prognosis of Myelofibrosis

Srdan Verstovsek, MD:We are witnessing here a relatively young gentleman with myelofibrosis. The bone marrow shows increased reticulin fibrosis. There is the presence of anemia, and there are abnormalities in white cell types. The patient has the symptoms and an enlarged spleen. These are all clues that would lead one to combine them together and make a diagnosis of a myelofibrosis.

There is one clinical relevant factor here that is of concern on blood cell count, and this is significant anemia. There is another one, which is symptomatic splenomegaly. So, this is a patient who is in the need of therapy actually. Once we have a diagnosis, we would assess his risk of dying, then consider referral to a bone marrow therapist, and then assess a need for introduction of certain medications to counteract clinically irrelevant abnormalities in his blood cell count on physical exam.

We would usually first start with testing the prognosis of the patient. This is done with the International Prognostic Scoring System, or IPSS. There are 5 factors that are involved: age over 60; white cell count over 25,000; blast in blood; hemoglobin less than 10; and systemic symptoms. And with the systemic symptoms, there are 3 in particular: significant weight loss, night sweating, and low-grade fevers.

If we apply these 5 factors, we would divide patients in 4 different groups: without any, that would be a low-risk patient; with 1, intermediate-1 risk patient; with 2 out of 5, intermediate-2 risk patient; and 3 or 4 or 5 out of 5, that’s a high-risk patient for early untimely death. This particular case appears to have intermediate-1 risk disease because there is only significant anemia from the 5 factors.

The patient with intermediate-1 risk disease has projected survival from diagnosis of about 8 years. This is in comparison, for example, to intermediate-2, which is about 4 years’ median survival, or high-risk patients that have a 2-years median survival. Low-risk patients have a median survival of 11 years. This is important knowledge because we would like to refer patients that have a survival of less than 5 years to a bone marrow transplant. This is an intermediate-1 grade patient. Therefore, it is not quite clear that there would be immediate benefit to refer this patient for the bone marrow transplant. It would be perhaps wiser to treat patients for clinical relevant abnormalities with medications and only upon a progression of the disease to refer to a transplant.

Risk assessment is usually assessed by traditional ways of looking at the symptoms, blood cell count, and age of the patient. This is the so-called International Prognostic System, or IPSS. There are variations, like the Dynamic International Prognostic Scoring System, or DIPSS, where we can add some additional factors from blood, like low platelets, or transfusion requirements, or even cytogenetic or chromosomal abnormalities. However, at this time and age when we can, relatively with some ease, test patients for different genetic abnormalities that are known to contribute to the aggressiveness of the disease, the question is how to combine the traditional way of prognostication, with IPSS, with the genetical amount that is relatively easy and accessible to us, at least in academic centers.

There are other known genetic abnormalities that would lead patients to progress faster. There is no quite clear way to combine that information that we can gather from genetic testing with traditional prognostication. For example, in this particular case, this is an intermediate-1 group patient who would have a projected survival of about a year. Let’s say that we do genetic prognostication in this case. In my particular center, we test for about 50 different mutations other than driver mutations. And let’s say that this patient has one of the bad prognostic factors. This is, for example, IDH1, IDH2, EZH2 or ASXL1. If the patient has 1 or 2 of those 4, that is bad prognosis for him. How do we combine genetic prognostication with traditional prognostication? Whether we should refer this patient with the intermediate-1 prognosis to transplant is an open question and a debate in the MPN circles.

Working in academic centers makes me see patients that are more advanced. The knowledge about the biology prognostication and therapy of mild thrombosis is markedly increasing in a community setting now that we have opportunity to do something about the disease to treat patients successfully. So, my colleagues in the community setting are eager to learn more. The referral pattern, therefore, for me in an academic center, is that I see patients that will not do well—with the more aggressive features or a shorter life expectancy. If you talk about prognosis, that would be the majority of the patients that are intermediate to high risk. About 60% would be between these 2 groups, and only 40% would be low-risk or intermediate-1.

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