Myelofibrosis: Understanding the Biology and Diagnosis

Srdan Verstovsek, MD:The underlying biology of all myeloproliferative neoplasms is the same. It’s a hyperactivity of the intracellular signaling path of the JAK/STAT pathway. However, there are many other mutations, other than those, that activate the JAK/STAT pathway. And in myelofibrosis in particular, there are 3. This isJAK2V617F,calreticulin(CALR) mutations, andMPLmutations. But apart from those, because they are also present in essential thrombocythemia, for example, we know that many other factors lead to different clinical scenarios. So, myelofibrosis appears to be more aggressive among the myeloproliferative neoplasms because of additional genetic abnormalities, or chromosomal abnormalities, that lead to a more aggressive clinical picture and untimely death.

Diagnostic criteria of myeloproliferative neoplasms, MPN, are based on similar factors that need to be combined. Usually, that is a clinician who does the combination of the factors, and the crucial one is the bone marrow exam. You need to have a presence of the myelofibrosis disease and no other disease that would cause fibrosis—for example, overt myelofibrosis. But there are other genetic factors, presence of all of the driver mutations—theJAK2V617F,MPLmutation, or calreticulin mutation. Then there is a need for having some of the analysis in blood cell count: anemia, or very high white blood cell counts, or physical exam abnormalities. I’m talking about the big spleen, all leuko-erythroblastosis, another factor in the blood cell count. And finally, there is also a need to have abnormalities in chemistry, which is abnormality in LDH, or lactate dehydrogenase. So, a combination of the chemistry, blood cell count, a physical exam, and a bone marrow exam are leading one to diagnose a myelofibrosis.

There are many other conditions that can cause a fibrosis in the bone marrow. The most common ones are autoimmune problems, like rheumatoid arthritis, or some other autoimmune or inflammatory conditions that can actually lead to inflammatory fibrosis in a bone marrow. In the disease itself, it appears that fibrosis in the bone marrow in myelofibrosis is a reactive process. So, there is a high degree of inflammation present in myelofibrosis, and one cannot easily distinguish between fibrosis related to autoimmune process, for example, from this disease itself. There are infections that can cause fibrosis. There are other diseases of the bone marrow, like hairy cell leukemia, a disease of lymphocytes, that can cause fibrosis. So, there is a whole area of other conditions—from benign to infectious, from autoimmune to malignant ones—that can cause fibrosis, and one needs to be cautious not to associate just the presence of fibers with the disease called myelofibrosis.

Acute myeloid leukemia is the most common cause, as a single cause, over that of patients with myelofibrosis. However, overall, only about 20% of the patients will transform to acute myeloid leukemia. The rest of the patients, 80% of the patients, die from complications of having myelofibrosis. Because it’s the most common cause, the question is whether we can prognosticate who can actually expect to progress and whether we can do anything about it. This is not that easy.

There are some factors that are associated with a high risk that come from, for example, looking at their blood cell count. Low platelets are known to be a factor. Increased risk of blasts, particularly over 10% in the blood or bone marrow, would lead one to progress to acute myeloid leukemia. Or, for example, there’s transfusion dependency. If you turn to the biology, then abnormalities in chromosomes—particularly either from 17 and certain genetic abnormalities like ASXL1, EZH2, IDH1, and IDH2, and several others, like p53, for example—are associated with a high risk of progression or progressive events on its own to acute myeloid leukemia. These are easy to access in every day management, and if we see those, perhaps there is a need to push patients to do the transplant sooner rather than later. Once the patient transforms to acute myeloid leukemia, this is a very difficult situation to treat.

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