Myeloproliferative neoplasms (MPNs) are a group of blood cancers originating in the bone marrow, the soft, spongy tissue inside bones where blood cells are produced. These conditions involve the overproduction of specific blood cell types, such as red blood cells, white blood cells, or platelets. While MPNs are distinct from acute leukemias, they share a common bone marrow origin and can sometimes progress to acute leukemia.
What Are Myeloproliferative Neoplasms
Myeloproliferative neoplasms are chronic blood disorders where the bone marrow produces an excessive amount of one or more types of blood cells. This overproduction can lead to an elevated count of red blood cells, white blood cells, or platelets in the bloodstream. MPNs are classified as blood cancers because they involve abnormal and uncontrolled growth of blood cells.
These conditions differ from acute leukemias as MPNs generally develop slowly over many years. However, both MPNs and acute leukemias arise from acquired mutations within hematopoietic stem cells, the immature cells in the bone marrow that give rise to all blood cell types. The abnormal stem cells in MPNs gain a selective advantage, leading to their clonal expansion and the characteristic overproduction of mature blood cells.
Common Types of MPNs
There are several types of MPNs, with three being most commonly recognized: Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF). Each type involves the overproduction of a specific blood cell line and is often associated with particular genetic mutations.
Polycythemia Vera (PV)
PV is characterized by an overproduction of red blood cells, which can make the blood thicker and increase the risk of blood clots. Over 90% of PV patients have a specific mutation in the Janus kinase 2 (JAK2) gene, known as JAK2 V617F. This mutation leads to continuous activation of signaling pathways that promote blood cell growth.
Essential Thrombocythemia (ET)
ET involves the overproduction of platelets, which are cell fragments involved in blood clotting. About 50-60% of ET patients have the JAK2 V617F mutation. Other mutations occur in different genes, such as CALR (calreticulin) in 20-25% of cases or MPL (myeloproliferative leukemia virus oncogene) in about 3-5% of cases. These mutations are generally considered mutually exclusive.
Primary Myelofibrosis (PMF)
PMF is a more aggressive MPN characterized by the buildup of scar tissue in the bone marrow, which impairs its ability to produce healthy blood cells. This scarring can lead to reduced blood cell counts and often an enlarged spleen. Like PV and ET, PMF is frequently associated with JAK2 (around 55%), CALR (about 35%), or MPL (around 8%) mutations, which contribute to the abnormal cell growth and fibrosis.
Symptoms and Diagnosis
The symptoms of MPNs can vary widely among individuals, with some people experiencing no symptoms at all, especially in the early stages. When symptoms do appear, they often develop gradually and can include fatigue, night sweats, unexplained weight loss, and generalized itching, particularly after bathing. An enlarged spleen, known as splenomegaly, is also a common finding, which can cause abdominal discomfort or a feeling of fullness. Specific symptoms may relate to the elevated blood cell counts, such as bleeding or clotting issues in ET, or redness and burning sensations in the hands and feet for PV.
Diagnosing an MPN involves a combination of tests to assess blood cell levels, examine bone marrow, and identify genetic mutations. A complete blood count (CBC) is a standard blood test that measures the number of red blood cells, white blood cells, and platelets. A peripheral blood smear may also be performed to examine blood cells under a microscope for any abnormalities. A definitive diagnosis often requires a bone marrow aspiration and biopsy, where a small sample of bone marrow is taken to look for abnormal cells, changes in cell production, and the presence of fibrous tissue. Genetic testing for mutations like JAK2, CALR, and MPL is also routinely performed to confirm the diagnosis and classify the specific MPN type.
Managing MPNs
Managing myeloproliferative neoplasms focuses on controlling symptoms, reducing the risk of complications, and slowing disease progression. Treatment approaches vary depending on the specific type of MPN, the patient’s symptoms, and their overall risk profile. For asymptomatic or low-risk patients, a “watch and wait” approach with regular monitoring may be adopted.
Medications are commonly used to manage MPNs. Low-dose aspirin is often prescribed to help prevent blood clots, particularly in ET and PV. Cytoreductive agents, such as hydroxyurea, are used to lower high blood cell counts by reducing the bone marrow’s production of these cells. Interferon, another medication, can stimulate the immune system and slow blood cell production. For patients with myelofibrosis, or those with PV whose symptoms are not controlled by other treatments, JAK inhibitors like ruxolitinib may be prescribed to reduce spleen size and alleviate symptoms such as fatigue and itching.
In cases of Polycythemia Vera, phlebotomy, which involves the removal of a specific amount of blood, is a common procedure to reduce the red blood cell count and blood thickness. This helps to decrease the risk of blood clots. For certain high-risk MPN cases, particularly myelofibrosis, an allogeneic stem cell transplant is the only potentially curative treatment option. This procedure involves replacing the patient’s diseased bone marrow with healthy stem cells from a donor but carries significant risks.
MPNs and Their Link to Acute Leukemia
While myeloproliferative neoplasms are chronic conditions, a subset of patients can experience disease progression to a more aggressive form of blood cancer, most notably Acute Myeloid Leukemia (AML). AML is a rapidly progressing cancer of the blood and bone marrow, characterized by the uncontrolled growth of immature white blood cells called myeloblasts. These abnormal cells accumulate in the bone marrow, interfering with the production of healthy blood cells.
The risk of transformation to AML varies among MPN subtypes, with primary myelofibrosis carrying the highest risk, estimated to be about 10-20% over time. For Polycythemia Vera, the risk is around 5%, and for Essential Thrombocythemia, it is less than 5%. Several factors can increase this risk, including certain genetic mutations beyond the primary MPN drivers, such as ASXL1, EZH2, IDH1, IDH2, U2AF1, and TP53 mutations. The duration of the MPN and, in some instances, prior therapies may also play a role in this transformation. When MPN progresses to AML, it requires immediate and aggressive treatment due to its rapid and severe nature.