Myeloproliferative Disease

Myeloproliferative diseases (MPDs) are a heterogeneous group of disorders characterized by cellular proliferation of one or more hematologic cell lines in the peripheral blood, distinct from acute leukemia.

According to the French-American-British (FAB) classification, chronic myeloproliferative diseases consist of the following four diseases:

• Chronic myelogenous leukemia (CML), shown in the image below
• Polycythemia vera (PV)
• Essential thrombocythemia (ET)
• Primary myelofibrosis (MF), previously known as agnogenic myeloid metaplasia (AMM)

Peripheral smear of a patient with chronic myelogenous leukemia (CML) shows leukocytosis with extreme left shift and basophilia.

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In 2002, the World Health Organization (WHO) proposed an alternate classification schema for these diseases, adding chronic neutrophilic leukemia (CNL) and chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES). ^[2] The WHO updated its classification in 2008 and changed the nomenclature from “chronic myeloproliferative disease” to “myeloproliferative neoplasms”. ^[3]  In 2016, the WHO further revised its classification of hematopoietic tumors and now recognizes several major categories of myeloid malignancies including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap, mastocytosis, eosinophilia‐associated myeloid/lymphoid neoplasms with specific mutations (e.g., PDGFR) and myeloid neoplasms with germline predisposition. ^[4] For a comparison of the FAB and 2016 WHO classification systems, see the table below.

Table. Comparison of FAB and WHO Classifications of Myeloproliferative Neoplasms (MPN) (Open Table in a new window)

In some patients, conditions overlap, and clear categorization may be difficult. Myeloproliferative disease may evolve into one of the other myeloproliferative conditions, transform to acute leukemia, or both.

Some evidence indicates that myeloproliferative diseases arise from malignant transformation of a single stem cell. Involvement of erythropoiesis, neutrophilopoiesis, eosinophilopoiesis, basophilopoiesis, monocytopoiesis, and thrombopoiesis occurs in the chronic phase of CML. Some evidence also indicates that lymphocytes are derived from primordial malignant cells. This is based on observations that a single isoenzyme for glucose-6-phosphate dehydrogenase (G6PD) is present in some T and B lymphocytes in women with CML who are heterozygous for isoenzymes A and B.

Data from glucose-6-phosphate dehydrogenase (G6PD) studies, cytogenetic analyses, and molecular methods have established the clonal origin of myeloproliferative diseases; this clonality potentially occurs at different stem cell levels. An attribute common to these disorders appears to be an acquired activating mutation in the gene coding for various tyrosine kinases.

In chronic myelogenous leukemia, the tyrosine kinase activity of the bcr-abl hybrid gene is increased. In polycythemia vera, essential thrombocythemia, and myelofibrosis (see the following images), the prevalent genetic lesion appears to be a valine to phenylalanine substitution at amino acid position 617 (V617F) within the Janus kinase 2 (JAK2) gene. ^{[5, 6, 7, 8]} This produces hypersensitivity to erythropoietin. At least in myelofibrosis patients the leukemic transformation is probably not related to JAK-2 (V617F) mutation status. ^[9]

Peripheral smear of a patient with essential thrombocythemia (ET) shows markedly increased number of platelets. Some of the platelets are giant (arrow).

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Peripheral smear of a patient with agnogenic myeloid metaplasia (myelofibrosis) shows leukoerythroblastosis. This photomicrograph also shows giant platelets.

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A study by Anand et al found that JAK2 mutations generate expansion of later myeloid differentiation compartments, in which homozygous expression of the mutation confers an added proliferative advantage at the single-cell level. The findings suggest that JAK2 inhibitors may control myeloproliferation; however, they may have limited efficacy in eradicating leukemic stem cells. ^[10]

Systemic mastocytosis has been linked with the D816 mutation of the KIT gene. The FIP1L1-PDGFR mutation has been identified in a subgroup of people with systemic mastocytosis with eosinophilia (SM-eos). ^[11]

Nangalia et al reported that somatic mutations in the CALR gene exist in the majority of patients without JAK2 and MPL mutations, who comprise about 68% of patients with essential thrombocythemia and 88% of patients with primary myelofibrosis. On clonal analyses, CALR mutations were found in the earliest phylogenetic node, a finding consistent with its role as a possible initiating mutation. ^{[12, 13, 14]}

As with other malignant disorders, the precise cause of myeloproliferative disease is unknown. The etiology is complex, incompletely understood, and likely a multistep process involving more than one gene.

Philadelphia chromosome, t(9:22), is found in most patients who have chronic myelogenous leukemia. Even when Philadelphia chromosome testing is negative, the gene bcr-abl, formed as result of t(9:22), tests positive in patients with chronic myelogenous leukemia using molecular techniques. Bcr-abl encodes a fusion protein with tyrosine kinase activity, which is constitutively expressed and is regarded as the central mechanism that underlies the chronic phase of chronic myelogenous leukemia. ^[15]

In a retrospective study of 11,000 patients in Sweden with myeloproliferative neoplasm, the authors reviewed the incidence of acute myeloid leukemia (AML) and myelodysplastic syndrome that were secondary to treatment; the study found that treatment with radioactive phosphorus but not hydroxyurea increased the risk of myelodysplastic syndrome and AML. ^[16]

The American Cancer Society estimates that 8990 new cases of chronic myelogenous leukemia (CML) will be diagnosed in the United States in 2019. ^[17]  CML accounts for more than half of myeloproliferative disease cases. The incidence of polycythemia vera in the United States is approximately 5-17 cases per 1 million population per year. True incidences of essential thrombocythemia and myelofibrosis are not known because epidemiological studies on these disorders are inadequate.

The incidence of polycythemia vera is 0.02-2.8 per 100,000 per year ^{[18, 19]} ; Japan has the lowest incidence. Essential thrombocythemia has an incidence of 0.1-1.5 per 100,000 per year. Myelofibrosis has an international incidence of 0.4-0.9 per 100,000 per year.

CML appears to affect all races with approximately equal frequency. In a study from northern Israel, the incidences of polycythemia vera, essential thrombocythemia, and myelofibrosis in Ashkenazi Jews were 10-fold higher than in Sephardic Jews, and 20-fold higher than in Arabs. ^[3]

The female-to-male ratio is 1:1.4. The American Cancer Society estimates that new cases of CML will be diagnosed in 5250 males and 3740 females in 2019. ^[17]

Most cases encountered in clinical practice are in patients aged 40-60 years. Myeloproliferative diseases are uncommon in people younger than 20 years and are rare in childhood.

The current (2008-2014) 5-year relative survival rate for adults (ages 20 and older) is 67% for CML. Survival rates for CML hav more than tripled, up from 22% in the mid-1970s, in large part due to the discovery and use of targeted drugs over the past two decades. The American Cancer Society estimates that 1040 deaths from chronic myelogenous leukemia (CML) will occur in 2019. ^[17]  

Exact mortality and morbidity rates of other myeloproliferative diseases are unknown.

Patients are at risk of both thrombotic and hemorrhagic events. Thrombotic and hemorrhagic events are particularly common in polycythemia vera (PV) and essential thrombocythemia (ET). Thrombosis is the cause of death in 30-40% of patients. A particularly serious thrombotic event that may be associated with polycythemia vera is Budd-Chiari syndrome, which is due to hepatic venous or inferior venal caval thrombosis.

Patients are at risk of developing secondary acute leukemia from their underlying disorder as well as their treatment.