Overview of the myeloproliferative neoplasms

Literature review current through: Aug 2014. | This topic last updated: May 28, 2014.
INTRODUCTION
An overview of the classic myeloproliferative neoplasms (MPN, myeloproliferative diseases [MPD];
Polycythemia vera PV
Essential thrombocythemia ET
Primary myelofibrosis PMF
Chronic myeloid leucemia LMC
CLASSIFICATION OF HEMATOLOGIC MALIGNANCIES
The hematopoietic pluripotent stem cell is capable of both self-renewal and a stepwise
differentiation, after a stochastic determination, into either the lymphoid or myeloid lineage.
Thus, during normal hematopoiesis, there exists a cellular hierarchy headed by a stable population
of pluripotent stem cells, which generate lineage-specific progenitors differentiating into the
various types of mature blood cells.
Effective hematopoiesis is facilitated by the interactive functions of hematopoietic growth factors,
various sets of receptors, and the bone marrow microenvironment.
An operational classification of hematologic malignancies separates lymphoid from myeloid
processes (figure 1).
Each of these is in turn classified as being acute or chronic, depending upon the proportion of
morphologically and immunophenotypically immature precursors (blasts) in the bone marrow.
Thus, the myeloid hematologic malignancies are divided into acute myeloid leukemia (bone
marrow blasts of 20 percent or more) and the chronic myeloid disorders (bone marrow blasts less
than 20 percent).

Conceptual organization of hematologic malignancies

Organization of tumors of the hematopoietic and lymphoid tissues as described by the World Health
Classification 2008.
Swerdlow SH, Campo E, Harris NL, et al. (Eds). World Health Organization Classification of Tumours of
Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008.
Graphic 56283 Version 2.0

The chronic myeloid disorders
The chronic myeloid disorders encompass several clinicopathologic entities.
Conceptually, they can be organized into those which either display (the myelodysplastic
syndromes) or do not display (myeloproliferative neoplasms) significant dysmyelopoiesis:
The myelodysplastic syndromes (MDS) are characterized by dysplastic bone marrow hyperplasia
or even occasional hypoplasia, associated with variable degrees of peripheral blood cytopenia
with or without monocytosis.
The paradox between the proliferative bone marrow and the cytopenic peripheral blood picture in
the MDS may be explained by increased intramedullary myeloid precursor cell apoptosis.
The myeloproliferative neoplasms (MPNs), unlike MDS, usually exhibit terminal myeloid cell
expansion in the peripheral blood.
According to the 2008 WHO Classification System, the MPNs are operationally classified into
"classic" and "atypical" MPNs.
Classic MPNs include polycythemia vera,
essential thrombocythemia,
chronic myeloid leukemia (CML),
primary myelofibrosis (PMF),
chronic neutrophilic leukemia,
chronic eosinophilic leukemia,
and mast cell disease.
Atypical MPNs include those chronic myeloid disorders that are currently not classifiable as either
MDS or classical MPN: chronic myelomonocytic leukemia,
juvenile myelomonocytic leukemia,
atypical CML, and
unclassifiable MDS/MPN.
Clonal studies in the chronic myeloid disorders
Genetic and enzyme studies based upon X-chromosome inactivation patterns have revealed a
multipotent progenitor cell origin for the neoplastic clone in both MDS and MPN.
Furthermore, the clonal process may develop at different progenitor cell levels in different patients,
resulting in lineage heterogeneity.
The clonal progenitor cell may or may not involve T and B lymphocytes.
Studies using refined methods of X-linked DNA analysis have demonstrated polyclonal
hematopoiesis in some patients with essential thrombocythemia and monoclonal hematopoiesis in
healthy elderly women.
However, the utilization of JAK2V617F mutation analysis has revealed that patients with
"polyclonal" essential thrombocythemia also display the mutation.
Therefore, X chromosome-based clonal assays might not be adequate in detecting a minor clonal
population against a polyclonal background.
These observations underline the heterogeneity, among patients, of the pathogenesis of the
MPNs.
They also raise the possibility that monoclonal hematopoiesis may antedate rather than follow the
mutations described below which then give rise to MPN or MDS.
Familial disease
Familial clustering of polycythemia vera (PV), essential thrombocytosis (ET), and primary
myelofibrosis (PMF) has been well described.
Abnormalities which have been described in such families have included mutations in the JAK2,
MPL, CBL, TET2, or CALR genes, most often somatic but occasionally germline.
In a study of 458 adult patients with apparently sporadic disease, familial involvement was noted
in 8.7, 6.0, and 8.2 percent of those with PV, ET, or PMF, respectively.
In a population-based study from Sweden involving 11,039 patients with MPN, their 24,577 first-
degree relatives had significantly increased risks of PV (Relative risk (RR) 5.7), ET (RR 7.4), and
unclassifiable MPN (RR 7.5), and a borderline increased risk of CML (RR 1.9; 95% CI 0.9-3.8)
[16].
Patients with familial disease developed similar complications and disease evolution as those with
sporadic disease. Age distribution between parent and offspring and telomere length shortening
provided evidence for disease anticipation in one study [15]. However, this age difference between
parent and offspring was not seen in the large population-based study from Sweden [16].
Presence of the JAK2 mutation does not appear to represent the genetic predisposing factor
[15,20-24], although it might indicate which family members are at higher risk of developing one of
the MPNs at a future date.
Observations such as the above, as well as diagnostic criteria for PV and ET, may not pertain to
children, owing to known mutations in several other genes (eg, hereditary mutations of the
erythropoietin receptor, thrombopoietin, MPL genes) in families with polycythemia or ET
presenting in childhood.

THE CLASSIC MYELOPROLIFERATIVE DISEASES
Diagnosis
Among the classic MPNs, only CML is genetically characterized by the reciprocal chromosomal
translocation between chromosomes 9 and 22, t(9;22).
This translocation is associated with a shortened chromosome 22 (the Philadelphia chromosome)
in 95 percent of the cases.
In the remaining cases, t(9;22) can be demonstrated by either fluorescence in situ hybridization
(FISH) or reverse transcriptase polymerase chain reaction techniques for detection of BCR-ABL.
While cytogenetic abnormalities are common in primary myelofibrosis and uncommon in essential
thrombocythemia, no specific cytogenetic abnormality in the MPNs other than CML has been
identified to date.
The discovery that JAK2 mutations are found in virtually all patients with PV and approximately 50
percent of those with either ET or PMF, has refined current diagnostic criteria in classic MPN:
Polycythemia vera (PV) is considered to be present when an otherwise unexplained increased
hematocrit/red blood cell mass is accompanied by the presence of a JAK2 mutation along with a
decreased erythropoietin level.
Primary myelofibrosis (agnogenic myeloid metaplasia, chronic idiopathic myelofibrosis) is
characterized by the presence of bone marrow fibrosis that cannot be attributed to another
myeloid disorder such as CML, PV, ET, or MDS.
Essential thrombocythemia (ET) is a diagnosis of exclusion, representing clonal or autonomous
thrombocytosis not classifiable as PV, PMF, CML, or MDS.
Within the context of the MPNs, an elevated red cell mass is specific for PV.
Occasionally both CML and MDS may present with either isolated thrombocytosis suggesting ET,
or associated bone marrow fibrosis suggesting myelofibrosis.
As a result, the diagnostic work up of patients with suspected MPN should always include
cytogenetic studies and careful morphologic evaluation to exclude the presence of t(9;22) (CML)
and dysmyelopoiesis (myelodysplastic syndrome), respectively.
Although most of the chronic myeloid disorders are classifiable as MDS, CML, PV, ET, or PMF,
some are difficult to categorize and may be referred to as atypical MPNs.
Rare patients expressing both BCR-ABL and a JAK2 mutation have been described.
Complications
The three major complications of the MPNs include clonal evolution,
thrombosis,
and bleeding.
Malignancies and clonal evolution
As a group, the MPNs are predisposed to clonal evolution and disease transformation to
myelodysplasia and/or acute leucemia.
The propensity to transform into acute myeloid leukemia differs among the subgroups, being
highest for CML (greater than 90 percent in the absence of effective therapy) and least for ET
(less than 5 percent).
Patients with PV have an approximately 10 and 25 percent chance of transforming into a
myelofibrotic stage at 10 and 25 years of follow-up, respectively.
The risk for clonal evolution in the MPNs is related to disease-related as well as treatment-related
factors.
Treatment of MPN-associated acute leucemia
Leukemic/blast phase transformation (LT) of an MPN is difficult to treat.
Current consensus is to induce such patients into complete remission using AML-like induction
chemotherapy followed by allogeneic hematopoietic cell transplantation (HCT).
However, few reports suggest the potential value of such an approach

Thrombosis and bleeding
Another biologic complication shared among the MPNs is the significant risk of
thrombohemorrhagic complications, most pronounced in PV and ET.
The thrombotic complications include arterial and venous thromboses and microcirculatory
disorders such as erythromelalgia and visual and neurologic symptom.
Why this occurs is not well understood, although serial in vivo activation of leukocytes, vascular
endothelium, platelets, and the coagulation system has been postulated.
Erythromelalgia is associated with platelet consumption and platelet thrombi in the
microvasculature; both the shortened platelet survival and symptoms can be ameliorated by
aspirin but not heparin or coumadin, suggesting that a prostaglandin synthase product in platelets
plays an important role.
Major thrombotic events can occur in patients who otherwise have few clinical and laboratory
features of polycythemia vera (PV).
Examples include splanchnic vein thrombosis (eg, Budd-Chiari syndrome, portal, splenic, or
mesenteric vein thrombosis), in whom the ensuing portal hypertension and hypersplenism may
mask the increase in blood cell counts.
PV should be suspected in patients with these diagnoses, particularly women under the age of 45.
The bleeding episodes are usually mild, with spontaneous bleeding primarily occurring in patients
with high platelet counts (eg, acquired von Willebrand disease); both quantitative and qualitative
changes in platelet function may contribute.
Because of the variable risks of blastic transformation and thrombosis-associated deaths, overall
survival in the MPNs ranges from a "near-normal" life expectancy in patients with essential
thrombocythemia to a median of less than five years in patients with PMF [64].
Other complications
A study revealed an increased risk of osteoporotic bone fractures in patients with MPNs when
compared with the general population, with a step-wise increasing pattern from ET (HR 1.19) to
PV (HR 1.82) to CML (HR 2.67).
The cause is unknown, although the presence of comorbidities (eg, smoking, alcohol-related
diagnoses) did not explain the increased fracture risks.
Symptoms and quality of life
In addition to the major complications noted above (eg, thrombosis, hemorrhage, evolution to
AML), patients with MPN also suffer from a number of debilitating symptoms, interfering with their
quality of life. The frequency of self-reporting for the following complaints were as follows:
Fatigue 81 percent
Pruritus 52 percent
Night sweats 49 percent
Bone pain 44 percent
Fever 14 percent
Weight loss 13 percent
A Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) has been devised and
prospectively validated as an assessment tool for patients with MPNs embarking on clinical trials.
This form has been further modified to include an abbreviated version (the MPN-SAF Total
symptom score) that focuses on the most representative and clinically relevant MPN symptoms,
which include the following 10 items:
fatigue, early satiety, abdominal discomfort, inactivity,
concentration problems, night sweats, itching, bone pain,
fever, and weight loss.
However, significant symptom heterogeneity exists within each MPN subtype, sometimes
independent of disease features or prognosis.

SUMMARY
Overview
The myeloproliferative neoplasms (MPNs) exhibit terminal myeloid cell expansion in the peripheral
blood, resulting in various combinations of erythrocytosis, leukocytosis, thrombocytosis, bone
marrow hypercellularity/fibrosis, and splenomegaly.
The MPNs are predisposed to clonal evolution and disease transformation (eg, myelofibrosis,
myelodysplastic syndrome, acute leukemia), along with a significant risk of thrombohemorrhagic
complications
Classification
The classic MPNs include polycythemia vera (PV), essential thrombocythemia (ET), chronic
myeloid leukemia (CML), primary myelofibrosis (PMF), chronic neutrophilic leukemia, chronic
eosinophilic leukemia, and mast cell disease.
Atypical MPNs include those chronic myeloid disorders which are currently not classifiable as
belonging to either the myelodysplastic syndrome or classical MPN.
These include chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical
CML, and unclassifiable myelodysplastic syndrome (MDS)/MPN.
The vast majority of patients with PV, ET, and PMF will have a mutation in either the JAK2,
CALR, or MPL genes.
Diagnosis
CML is characterized by a reciprocal chromosomal translocation between chromosomes 9 and
22 (ie, t(9;22)). (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)
PV is diagnosed when an otherwise unexplained increased hemoglobin/hematocrit/red blood cell
mass is accompanied by the presence of a JAK2 mutation along with a decreased erythropoietin
level. (See "Clinical manifestations and diagnosis of polycythemia vera".)
PMF is characterized by a leukoerythroblastic blood picture, splenomegaly, and bone marrow
fibrosis that cannot be attributed to another myeloid disorder. (See "Clinical manifestations and
diagnosis of primary myelofibrosis".)
ET is a diagnosis of exclusion, representing clonal or autonomous thrombocytosis not classifiable
as PV, PMF, CML, or MDS. (See "Diagnosis and clinical manifestations of essential
thrombocythemia".)