Myeloproliferative disorders (MPDs) are now more accurately referred to as Myeloproliferative Neoplasms (MPNs). These are a group of slow-growing blood cancers that originate in the bone marrow. MPNs are characterized by the overproduction of one or more types of mature blood cells, including red blood cells, white blood cells, and platelets. A genetic change causes hematopoietic stem cells to produce an excess of blood cells, leading to an imbalance and potential complications over time.
Understanding How These Disorders Develop
Normal blood cell production, a process called hematopoiesis, is a tightly regulated system where hematopoietic stem cells in the bone marrow divide and mature into specific blood cell types as needed. This regulation relies on specific signals, primarily from growth factors and cytokines, which instruct the stem cells to proliferate and differentiate. Myeloproliferative neoplasms develop when this intricate control mechanism is disrupted by acquired genetic changes. This means the mutation is not typically inherited but occurs spontaneously within a single stem cell.
The majority of MPNs are linked to mutations that constitutively activate the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathway. The most common is the JAK2 V617F mutation, which is found in over 95% of Polycythemia Vera (PV) patients and about half of those with Essential Thrombocythemia (ET) or Primary Myelofibrosis (PMF). This mutation causes the JAK2 protein to remain constantly active, driving the uncontrolled production of blood cells. Other driver mutations include those in the CALR (Calreticulin) and MPL genes. These mutations are typically found in ET or PMF patients who lack the JAK2 mutation, and they are instrumental in the classification of the specific MPN subtype.
The Major Categories of Myeloproliferative Disorders
Polycythemia Vera (PV) and Essential Thrombocythemia (ET)
MPNs are categorized based on the primary cell type overproduced or how the bone marrow is affected. Polycythemia Vera (PV) is defined by the overproduction of red blood cells, which increases hemoglobin and hematocrit, making the blood thicker and slower flowing. Essential Thrombocythemia (ET) involves the primary overproduction of platelets, caused by an increase in megakaryocytes in the bone marrow. This excess of platelets can significantly elevate the risk of both abnormal clotting and bleeding events. Both PV and ET generally follow a slow course for many years.
Primary Myelofibrosis (PMF)
Primary Myelofibrosis (PMF) is characterized by the accumulation of scar tissue, or fibrosis, within the bone marrow. This scarring progressively impairs the marrow’s ability to produce blood cells effectively, often resulting in anemia. The impairment also causes a shift of blood production to organs like the spleen and liver. PMF can also arise as a progression from either PV or ET.
Chronic Myeloid Leukemia (CML)
Chronic Myeloid Leukemia (CML) is historically included as a major MPN type due to its unique genetic signature. CML is defined by the massive overproduction of white blood cells, particularly granulocytes. The cause is the presence of the Philadelphia chromosome, a translocation between chromosomes 9 and 22. This translocation creates the BCR-ABL fusion gene that drives the leukemia.
Recognizing Signs and Confirming Diagnosis
Symptoms
Many patients experience vague or non-specific symptoms, especially in the early stages, and some are diagnosed incidentally during routine blood work. Common systemic signs include unexplained fatigue, fever, drenching night sweats, and unintentional weight loss, often referred to as “B symptoms.” Specific issues caused by abnormal cell counts include intense itching (pruritus) or a feeling of fullness due to an enlarged spleen (splenomegaly).
Diagnosis
Diagnosis begins with a Complete Blood Count (CBC), which quantifies red cells, white cells, and platelets. An elevated red cell count suggests PV, while a sustained high platelet count suggests ET. If the CBC is abnormal, a physician will perform a bone marrow aspiration and biopsy to physically examine the architecture of the marrow. Genetic testing is indispensable for confirmation, analyzing blood samples for driver mutations like JAK2 V617F, CALR, MPL, and the BCR-ABL fusion gene.
Current Treatment and Management Strategies
General Management
The primary goals of MPN treatment are to minimize symptoms, prevent life-threatening complications like blood clots or bleeding, and slow the progression of the disease. For low-risk patients, often those who are younger with mild symptoms, regular monitoring and “watchful waiting” may be appropriate. Anti-platelet therapy, such as low-dose aspirin, is often prescribed to reduce the risk of microvascular clotting in both PV and ET.
Cytoreductive and Targeted Therapies
In Polycythemia Vera, therapeutic phlebotomy is the standard intervention to reduce excess red blood cell volume and lower the hematocrit level. If blood counts remain high or symptoms are uncontrolled, cytoreductive therapies are used to suppress bone marrow production. The most common drug for this purpose is Hydroxyurea, an orally taken chemotherapy agent. Targeted therapies, such as Janus kinase (JAK) inhibitors like Ruxolitinib, directly target the hyperactive JAK-STAT pathway, particularly benefiting Myelofibrosis patients by reducing spleen size and improving systemic symptoms. Allogeneic stem cell transplantation is the only potentially curative option, but it is typically reserved for younger, higher-risk patients with advanced disease due to its significant risks.