Understanding Drivers of Progression in Myelofibrosis
Insights From:Srdan Verstovsek, MD, PhD, University of Texas MD Anderson Cancer Center;Daniel J. DeAngelo, MD, PhD, Dana-Farber Cancer Institute;Kim-Hien T. Dao, DO, PhD, Oregon Health & Science University
Srdan Verstovsek, MD, PhD: Myelofibrosis is one of the myeloproliferative neoplasms, a chronic disease of the bone marrow. It is, unfortunately, the aggressive type. It does affect the life expectancy of the patients. The average survival is about 5 to 7 years. Unlike other myeloproliferative neoplasms, the name implies that these myeloid cells—they’re the bone marrow cells—grow without control and overwhelm the bone marrow and blood.
In myelofibrosis, we have a reaction to a presence of malignant cells, in terms of a production of certain cytokines in the bone marrow by bone marrow stroma that leads to a formation of the fibers in bone marrow. So, it’s a reactive process that is limiting the growth of the cells. The primary problems in myelofibrosis are not that there are usually too many cells, but rather too few cells, and the reaction of a body to a malfunctioning bone marrow by increasing the size of the spleen. About 80% to 90% of the patients have a very big spleen. The liver can also be enlarged in about 40% of the patients. So, malfunctioning bone marrow, anemia—low platelets in some patients—and low white cell count coupled with a very large spleen, enlargement of the liver, and very poor quality of life—bone aches and pains, night sweating, low-grade fevers, itching, night sweating, fatigue, weakness, cachexia—in patients don’t do well. These three factors together affect the patients, and the survival is short.
It’s a disease that we would perhaps even call chronic leukemia. Many patients come and say, “Is it cancer?” Yes, it is a cancer; it does kill people. It’s not even benign cancer. It is a chronic disease that shortens life expectancy. Sometimes it’s confusing just because we use “myelofibrosis” as a name, which is a description of bone marrow itself. The underlying biological problem is hyperactivity of the JAK/STAT pathway, as is in other myeloproliferative neoplasms, essential thrombocythemia, and polycythemia vera. There are reasons for this intracellular signaling pathway to be active and lead to a disease: mutations. And the three what we call, perhaps incorrectly, driver mutations that lead to hyperactivity of the JAK/STAT pathway are exclusively chartered by JAK2 V617F, calreticulin mutation, and MPL mutation. These three mutations lead to hyperactivity of JAK/STAT pathway as uniform biological abnormality in every patient. And even if you don’t test patients for any of these driver mutations, which is advisable as part of the diagnostic process, you know that there is a hyperactivity of the JAK/STAT pathway in that patient.
Daniel J. DeAngelo, MD, PhD: Myelofibrosis is part of the constellation of diseases known as the chronic myeloproliferative disorders. It’s an interesting disease. It has a chronicity to it; thus, the name. Patients can have a wide range of clinical outcome. It can be a very indolent disease going on decades or it can be a disease that is rapidly progressive. It’s unclear exactly as to what specifically demarcates a patient with rapidly progressive versus advanced disease. But some of the molecular markers have been shown to be prognostic. For example, in addition to the principle causes or the drivers of the myelofibrosis—which include JAK2, MPL or “mipple” as it’s called, or calreticulin, CALR, mutations—additional mutations, such as ASXL1, have been shown to be a worsening factor or a predictor of more advanced disease.
In addition, the clinical characteristics that demarcate a patient who is likely to have more aggressive or more advanced disease include patients with rapidly enlarging spleen size, patients who have increased circulating blasts. That tends to be a big issue, specifically in patients who end up progressing to acute leukemia. And the other issues, at least the ones that I find in my clinical practice that are particularly worrisome, are patients who develop constitutional symptoms early in the course of their disease. Constitutional symptoms include fevers, pruritus, and the one that I find to be the most troubling is early satiety leading to weight loss. Once that starts to develop, patients tend to have a more rapid decline.
Srdan Verstovsek, MD, PhD: The progression of the disease is a problem. About 20% of the patients with myelofibrosis do change to acute myeloid leukemia. We can’t really predict very well who will or who will not transform at the beginning, but we do have, otherwise, some knowledge about the outcome of the patients. Apart from the transformation from acute myeloid leukemia, which happens in 20% of patients, other patients die from the myelofibrosis itself. The cause of that may be liver failure because of liver infiltration, pulmonary hypertension because of pulmonary infiltration, or cardiac failure because cardiac output goes up, bleeding from the GI tract in relation to portal hypertension, cachexia, bleeding, thrombosis, infections, and multiple different factors. It’s difficult to say one factor leads to death. But we have tools, prognostic factors, that we do implement at the beginning, when we diagnosis patients with myelofibrosis, to assess the risk of dying; not related to transformation, but otherwise dying from the disease itself.
And there are five factors usually that are implemented: age over 60, having a blast in the blood, hemoglobin less than 10, white cell count over 25, or having systemic symptoms, particularly low-grade fevers, night sweating, and weight loss. And we can divide patients into four different groups: low-risk, have none of the five; intermediate 1, one of the five; intermediate 2: risk of dying, two out of the five; and then high risk of dying earlier on if they have three, four, or five of these factors.
Now, the years of life that we are talking about range from 11 years for low-risk, 8 years for an intermediate 12, 4 years for intermediate 2, and 2 years for high-risk. The primary reason for assessment of risk of dying is to see if transplant is a possibility and to refer patients for the transplant. That is usually applicable for the younger and fit patients, but we even do this quite often in older people. At MD Anderson Cancer Center, we do transplant in patients up to 75 years of age. We utilize a risk assessment of dying in patients that have intermediate 2 or high-risk disease, so life expectancy of 2 to 4 years. We try to do a transplant if possible.