Myeloproliferative neoplasms (MPN) are a group of hematological malignancies of low incidence characterized by clonal hematopoietic stem cells of myeloid lineages with mature appearance. MPN are classified into subtypes by the detection of the Philadelphia chromosome (Ph+) and/or the BCR-ABL1 fusion gene to confirm diagnosis of chronic myeloid leukemia (CML) or BCR-ABL1 negative MPN. The three classical Philadelphia chromosome (BCR-ABL1)-negative (Ph-) MPN include:
- Polycythemia vera (PV)
- Essential thrombocythemia (ET)
- Myelofibrosis (MF)
Of these three subtypes, the incidence of MF is much lower than the other two.
Of the three classical Ph-negative MPN subtypes, MF is the most serious as it is associated with the shortest survival (median survival of 5–7 years depending of risk factors). It is characterized by bone marrow fibrosis, bone marrow failure with cytopenias (anemia, thrombocytopenia, leukopenia) and/or variable degrees of thrombocytosis or leukocytosis as well as extra-medullary hematopoiesis resulting in progressive splenomegaly. MF is also associated with chronic, burdensome debilitating constitutional symptoms, including fatigue, night sweats, pruritus, abdominal discomfort, loss of appetite/early satiety, unintentional weight loss, and bone, chest, and abdominal pain.
Polcythemia vera (PV)
Approximately 45% of patients with MPN suffer of PV. PV is associated with a 65% 15-year survival rate, and a 20 year median survival. It is predominantly characterized by an increase in platelet and white blood cell counts, and red blood cell mass which are results of clonal stem cell proliferation of the erythroid, myeloid and megakaryocytic cell lineages. The increase of red cell mass causes hyper-viscosity of the blood which is responsible for most symptoms observed in early stages of the disease such as headaches, fatigue, hypertension, visual and hearing symptoms, skin reddening, and pruritus. Even though PV is often asymptomatic at early stages, severe constitutional symptoms and symptomatic splenomegaly occur in advanced-stages, and greatly impair the quality of life of PV patients.
Essential thrombocythemia (ET)
ET is characterized by persistent thrombocytosis, a result of megakaryocyte hyperplasia, and the absence of significant fibrosis in the bone marrow. Often diagnosed by ruling out other causes of thrombocytosis, ET does not have a specific phenotype. ET has a female predominance and patients with ET have a median survival of 22.6 years and a 15-year survival 73%, which is similar to a healthy population matched by age and gender. ET is commonly asymptomatic, but can give rise to clinical findings such as deep vein thrombosis, hemorrhage, vascular occlusive events (leading to neurological, cardiac or peripheral disabilities), and mild splenomegaly. Patients suffering of ET may have weakness, headache, tingling sensations of the extremities, and gout.
To date, the only curative modality for MPN is allogenic hematopoietic stem cell transplantation (AHSCT). Other treatments are largely palliative, and have a limited role in modifying disease history. These treatments aim at improving the quality-of life of patients by treating MPN related symptoms. Their use is poorly standardized and may be associated significant side effects.
The recent discovery of the role of JAK2-activating mutations in MPN and the subsequent development of JAK inhibitors are the most important and promising therapeutic advances for MPN patients. These novel therapies ushered a new era of hope for these patients. These drugs act by blocking the proliferation of neoplastic cells by disrupting the JAK2-STAT signalling and by abrogating inflammatory cytokine signalling which is dependent on JAK kinases. As a result, fast development of JAK2 inhibitors has been undertaken by many large pharmaceutical companies in the past decade and several molecules are presently in various stages of clinical development. Thus, these novel therapies are expected to change dramatically the management of MPN in years to come.