Randi_EU Haematology 04/03/2010 17:10 Page 52
Haematological Maligancies Myeloproliferative Disorders
Table 1: The Italian Association of Paediatic into secondary MF.
26,27
However, no clear dose-dependent correlation
Haematology-Oncology Experience of Paediatric
has been found in ET between the burden of the JAK2 allele and
Essential Thrombocythaemia
clinical symptoms;
28
in general, both PV and ET mutated cases have
a worse prognosis than wild-type patients.
27,29
Other mutations have
Number of patients 90
Male/female 28/62
been found in patients with Ph-MPD: somatic gain-of-function
Median age at diagnosis (range) 6.75 years (1 month – 17 years)
mutations affecting JAK2 exon 12 are identified in 25% of PV patients
Median follow-up duration (range) 5 (2–11 years)
without the classic V617F mutation
30
and isolated elevated
Clinical symptoms and signs None: 49%
haematocrit without WBC or platelet increase. About 1% of ET and 5%
Headache: 19% of PMF cases carry acquired mutations in the thrombopoietin-
Splenomegaly: 18%
receptor gene (MPLW515K/L).
31
Vein thrombosis: 4%
Nose bleeding: 2%
The discovery of JAK2 and other gene mutations is so important that
Various: 8%
the World Health Organization (WHO) updated the 2001 criteria for
Mean platelets x 10
9
/l (range) 1,260 (611–4,020)
Ph-MPD in 2008.
32
The diagnosis of PV is now established in patients
WBC x 10
9
/l 11.75
with the two following criteria: increased haemoglobin or haematocrit
JAK2V617F/WT 16/65 (24%)
EEC-positive 17/28 (60%)
or elevated red blood cell (RBC) mass and the presence of JAK2V617F
Monoclonality 15/32 (46%)
or a similar mutation. In the few cases without any mutation, a minor
criterion is needed (bone marrow trilineage myeloproliferation,
MPL/TPO mutation None
Treatment adopted None: 31%
subnormal serum EPO level or spontaneous endometrial epithelial
Aspirin: 32% cell [EEC] growth).
Anagrelide: 29%
IFN-α: 19%
Since the JAK2V617 mutation is found in only about 50% of ET, it is
Hydroxyurea: 32%
diagnosed in the presence of the following conditions:
All patients are Italian. No cases of familial essential thrombocythaemia are reported.
IFN = interferon; WBC = white blood cell.
a sustained platelet count over 450x10
9
/l;
large and mature megakaryocyte proliferation in the bone marrow;
thrombocytosis is very frequent in children, the incidence of ET is no evidence of PV, PMF or other causes of reactive/secondary
considered to be very low.
17
thrombocytosis; and
a clonal marker such as JAK2V617F.
Bone marrow fibrosis occurs rarely as an evolution of paediatric
malignancies, rheumatic diseases, sickle cell anaemia, infectious Clinical Picture and Treatment of
diseases, vitamin D deficiency rickets and severe combined Myeloproliferative Disorders in Adults
immunodeficiency. PMF is the most rare Ph-MPD (estimated PV patients have a classic polyglobulic face with peripheral
incidence 0.4–0.7/100,000 persons/year)
18
and usually affects acrocianosis, which is not present in ET and PMF. Most patients with
elderly people, reducing life expectancy.
19
Fewer than 3% of cases Ph-MPD have splenomegaly and some also have liver enlargement.
occur in patients under 30 years of age, and PMF is only anecdotal In all Ph-MPD patients, thrombotic and haemorrhagic events are
in childhood. quite common; primary events involve both arteries and veins, and
secondary events are either spontaneous or complications of
Diagnosis of Polycythaemia Vera, trauma or surgical procedures. These diseases can transit from one
Essential Thrombocythaemia and clinical phenotype to another and sometimes it is very difficult to
Primary Myelofibrosis in Adults establish which Ph-MPD is involved (undefined MPD). Both PV and
Multiple research groups have recently reported the occurrence in ET can transform in myelofibrosis and all Ph-MPD can evolve into an
Ph-MPD of a somatic, acquired mutation (valine-617 to phenylalanin- acute leukaemia.
V617F) in the JAK2 kinase auto-inhibitory domain.
20–24
JAK2 is a protein
involved in signalling transduction, and the V617F mutation determines The treatment of Ph-MPD is aimed at reducing the thrombotic
a constitutive activation of JAK2, which continuously stimulates risk and controlling cell counts without increasing the risk of
STAT5,
20,22,23
leading to a proliferation of normally maturing cells. transformations. The haematocrit control in PV is obtained
with phlebotomies. At present, a hematocrit lower than 45%
Currently, such a mutation is considered a specific biological marker is considered the goal of therapy.
33
The use of low-dose aspirin
34
is
for Ph-MPD, playing a major role in pathogenesis. In fact, it is present effective in controlling both primary and secondary thrombosis in
in almost all patients affected by PV and in about half of those with PV, and on this basis aspirin is also commonly used in ET.
35
ET and MF.
21
Expression of mutant JAK2V617F has been suggested to Cytoreductive drugs are able to reduce platelet and WBC counts
induce kinase activation in haematopoietic cell lines, and and thrombotic complications,
36
and in PMF has been described to
homozygous JAK2 mutation is associated with pronounced trilinear control spleen enlargement.
14,37
megakaryocyte, erythroid and granulocyte myeloproliferation.
20,22,23
JAK2V617F-mutated patients display different clinical and laboratory Myeloproliferative Disorders in Children
findings, including higher white blood cell (WBC) count, haemoglobin A few cases of PV in childhood have been published,
14,38–41
all
concentration and haematocrit and lower platelet count compared presenting with plethora and very high haematocrit levels. In 10
with wild-type patients.
25
ET and PV JAK2-mutated patients exhibit a children JAK2V617F, in two JAK2 exon 12 mutations and in five JAK2
higher risk of cardiovascular events and a more frequent evolution wild-type have been described.
42
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