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Myeloproliferative neoplasms

Last updated: December 19, 2021

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Myeloproliferative neoplasms (MPNs) are a group of disorders characterized by a proliferation of normally developed (nondysplastic) multipotent hematopoietic stem cells from the myeloid cell line. The most common (classic) MPNs are chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Clinical findings overlap significantly between these conditions and the initial diagnostic workup is the same, including blood work (e.g., CBC, peripheral smear), genetic testing, and, if needed, bone marrow studies. Blood tests demonstrate myeloid cell proliferation: Granulocytes are increased in CML, thrombocytes in ET, and all three myeloid lines are increased in PV. PMF has an initial hyperproliferative phase often followed by pancytopenia as a result of progressive bone marrow failure. Elevated uric acid levels and gout may be seen in all MPNs as a result of increased cellular breakdown. Genetic markers can provide further information for diagnosis and also help guide treatment. The Philadelphia chromosome is present in almost all cases of CML. Driver mutations (e.g., JAK2, CALR, MPL) affecting the JAK-STAT signaling pathway are the main diagnostic markers for the remaining classic MPNs. Less common MPNs, which are not associated with the driver mutations, include chronic eosinophilic leukemia (CEL), chronic neutrophilic leukemia, and myeloproliferative neoplasm, unclassifiable. Treatments for all MPNs primarily focus on the prevention of known complications (e.g., thrombohemorrhagic events) and the alleviation of symptoms with combinations of medications and/or procedures including platelet inhibitors, cytoreduction, phlebotomy, targeted therapy, transfusions of blood products, and splenectomy. Patients are kept under close observation because of the risk of developing acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation is the only curative treatment.

See also ”Polycythemia vera” and ”Chronic myeloid leukemia” for further detail on these conditions.

Conditions [1]

According to the WHO classification, the following disorders are myeloproliferative neoplasms:

All MPNs can potentially progress to AML. [2]

Clinical features [3]

These can occur with varying frequency, depending on the underlying MPN.

Diagnostics [1][4]

  • Indications include:
  • MPNs may also be seen incidentally when routine blood work shows abnormal cell counts on CBC.

Initial studies

Confirmatory studies [5][6][7]

  • Genetic testing: required to diagnose MPNs
    • Initial mutation screening
    • Subsequent mutation testing: Extended panels may detect atypical driver mutations, nondriver mutations (e.g., CSF3R), and high-molecular risk mutations. [7]
  • Bone marrow biopsy: often required to definitively confirm a diagnosis

With the exception of CML, all of the classic MPNs have varying degrees of JAK2 mutations, which can be used as a diagnostic marker. [7][8]

Diagnostic comparison of classic MPNs [1][4]

The WHO has established diagnostic criteria for each of the MPNs (See “Tips and links” for full criteria). Laboratory findings seen in classic MPNs are included in the following table.

Comparison of classic myeloproliferative neoplasms [1][4][6]

Clinical and laboratory studies Percentage of patients with mutations [7][8] Bone marrow
Essential thrombocythemia
  • JAK2: 50–60%
  • CALR: 26%
  • MPL: 4%
  • ↑ Large mature megakaryocytes
  • No increase of granulocytic or erythroid precursors
Polycythemia vera
Primary myelofibrosis
  • JAK2: 50–60%
  • CALR: 18–32%
  • MPL: 5–9%
Chronic myeloid leukemia
  • Hypercellularity
  • ↑ Myeloid:erythroid ratio

MPNs have overlapping presenting features, mutations, and diagnostic findings. A patient's diagnosis may change if their condition progresses over time (e.g., PV may transform into myelofibrosis; PMF may transform into AML). [4][11]

Treatment overview [8][12]

The choice of treatment depends on the underlying diagnosis, the presence of risk factors, and any comorbidities. [8]

  • Low-risk MPNs are often managed with observation.
  • High-risk or symptomatic MPNs are managed with a combination of symptomatic management, treatment to delay disease progression, and, in rare cases, allogeneic stem cell transplantation.

Supportive care

Disease-specific therapy

Background

Clinical features [3]

Diagnostics [1][4]

PMF is a diagnosis of exclusion, while secondary myelofibrosis is typically diagnosed as part of the monitoring of the preceding MPN (e.g., PV, ET). Other causes of bone marrow fibrosis must be ruled out before the diagnosis can be made; see “Differential diagnoses.” [8]

As PMF progresses (i.e., overt fibrotic phase), extramedullary hematopoiesis becomes more prominent with signs of pancytopenia and splenomegaly. [1][4]

In myelofibrosis, RBCs shed tears (teardrop cells) because they have been forced out of the fibrosed bone marrow (extramedullary hematopoiesis).

Differential diagnoses [17]

Treatment [8][12][18]

Risk scores and screening for high-risk features are used to stratify risk and determine treatment. [19]

High-risk features [19][20]

Supportive care

Disease-specific therapy

Complications [8]

Background

Clinical features [8]

Diagnostics [1][4]

ET is a diagnosis of exclusion and requires ruling out other causes of elevated platelets, such as reactive thrombocytosis and other MPNs (e.g., prefibrotic myelofibrosis, PV). [8]

Isolated thrombocytosis is characteristic of ET; however, it may be also seen in early PV and early PMF. [8]

Differential diagnoses

Treatment [8][12][24]

Risk scores and screening for high-risk features are used to stratify risk and determine treatment. [19][25]

Low and intermediate-risk patients

High-risk patients

Treat in order to prevent thrombohemorrhagic events.

Complications [8]

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