Myeloproliferative neoplasm

The myeloproliferative neoplasms (MPNs), previously myeloproliferative diseases (MPDs), are a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplastic syndrome and acute myeloid leukemia, although the myeloproliferative diseases on the whole have a much better prognosis than these conditions. The concept of myeloproliferative disease was first proposed in 1951 by the hematologist William Dameshek.^[1] In the most recent World Health Organization classification of hematologic malignancies, this group of diseases was renamed from "myeloproliferative diseases" to "myeloproliferative neoplasms".^[2] This reflects the underlying clonal genetic changes that are a salient feature of this group of disease.

The increased numbers of blood cells may not cause any symptoms, but a number of medical problems or symptoms may occur. The risk of thrombosis is increased in some types of MPN.

Classification

Although not a malignant neoplasm like other cancers, MPNs are classified within the hematological neoplasms. There are four main myeloproliferative diseases, which can be further categorized by the presence of the Philadelphia chromosome:

In 2008, the World Health Organization listed these diagnoses as types of MPD:^[3]

• Chronic myelogenous leukemia (BCR-ABL1–positive)
• Chronic neutrophilic leukemia
• Polycythemia vera
• Primary myelofibrosis
• Essential thrombocythemia
• Chronic eosinophilic leukemia (not otherwise specified)
• Mastocytosis

Causes

All MPNs arise from precursors of the myeloid lineages in the bone marrow. The lymphoid lineage may produce similar diseases, the lymphoproliferative disorders (acute lymphoblastic leukemia, lymphomas, chronic lymphocytic leukemia and multiple myeloma).

Most Philadelphia chromosome negative cases have an activating JAK2 or MPL mutation.^[4] Mutations in CALR have been found in the majority of JAK2 and MPL-negative essential thrombocythemia and myelofibrosis.^[5][6] In 2005, the discovery of the JAK2V617F mutation provided the first evidence that a fraction of persons with these disorders have a common molecular pathogenesis.^{[7][8][9][10]} Patients with JAK2V617F-negative polycythemia vera are instead positive for another class of activating JAK2 mutations - the JAK2 exon 12 mutations.^[11]

A subset may additionally have mutations in the genes LNK, CBL, TET2, ASXL1, IDH, IKZF1 or EZH2; the pathogenetic contribution of these mutations is being studied.

Diagnosis

Depending on the nature of the myeloproliferative neoplasm, diagnostic tests may include red cell mass determination (for polycythemia), bone marrow aspirate and trephine biopsy, arterial oxygen saturation and carboxyhaemoglobin level, neutrophil alkaline phosphatase level, vitamin B₁₂ (or B₁₂ binding capacity), serum urate^[12] or direct sequencing of the patient's DNA.^[13]

According to the WHO Classification of Hematopoietic and Lymphoid Neoplasms 2008 myeloproliferative neoplasms are divided into categories by diagnostic characteristics as follows:^[3]

Chronic myelogenous leukemia (CML)

With the defining translocation t(9;22);Philadelphia chromosome, BCR-ABL translocation which has three breakpoints:

• u-BCR-ABL (p230): leads to CML with usual neutrophilia and basophilia
• minor-BCR-ABL (p190): leads to CML which has a tendency to become acute lymphoblastic leukemia (ALL), usually precursor B ALL and rarely precursor T ALL
• major-BCR-ABL (p210): usual breakpoint

Essential thrombocythemia (ET)

ET is associated with the JAK2 V617F mutation in up to 55% of cases^[14] and with an MPL (thrombopoietin receptor) mutation in up to 5% of cases:^[15]

• Cellular phase - increased large megakaryocytes with fibrosis and little increase in other bone marrow elements
• Fibrotic phase - collagenous fibrosis with lack of marrow elements

These disorders are still being revised according to more specific genetic mutations and how often patients end in a fibrotic marrow event.

Polycythemia vera (PV)

PV is associated most often with the JAK2 V617F mutation in greater than 95% of cases, whereas the remainder have a JAK2 exon 12 mutation:

• Cellular phase - increased megakaryocytes which cluster, reticulin fibrosis, later trichrome fibrosis, and increased myeloid and erythroid precursors
• Fibrotic phase - collagenous fibrosis with lack of marrow elements

Primary myelofibrosis (PMF)

Primary myelofibrosis (PMF) is associated with the JAK2V617F mutation in up to 50% of cases, the JAK2 exon 12 mutations in 1-2% of cases, and the MPL (thrombopoietin receptor) mutation in up to 5% of cases:

• Prefibrotic/cellular phase - increased, small and atypical megakaryocytes which cluster, reticulin fibrosis, later trichrome (collagenous) fibrosis, and increased myeloid precursors
• Fibrotic phase - collagenous fibrosis with lack of marrow elements

Treatment

While investigational drug therapies exist, no curative drug treatment exists for any of the MPDs. The goal of treatment for ET and PV is prevention of thrombohemorrhagic complications. The goal of treatment for MF is amelioration of anemia, splenomegaly, and other symptoms. Low-dose aspirin is effective in PV and ET. Tyrosine kinase inhibitors like imatinib have improved the prognosis of CML patients to near-normal life expectancy.^[4]

Recently, a JAK2 inhibitor, namely ruxolitinib, has been approved for use in primary myelofibrosis.^[16] Trials of these inhibitors are in progress for the treatment of the other myeloproliferative neoplasms.

References

External links

• Myeloproliferative Disorders at the US National Library of Medicine Medical Subject Headings (MeSH)
• MPN Research Foundation
• Myeloproliferative Disorders Website of The CMPD Education Foundation
• Myeloproliferative Disorders in practice
• Myeloproliferative Disorders Research Consortium
• MPN Info via Cancer.gov
• Spotlight on MPN
• Myeloproliferative Neoplasm Website, MPN Patient Research Hub, PV Reporter