Dr. Zaidan Jayed
MYELOPROLIFERATIVE NEOPLASMS
These make up a group of chronic conditions characterised
by clonal proliferation of marrow precursor cells, and
include:
1.
polycythaemia rubra vera (PRV),
2.
essential thrombocythaemia,
3.
myelofibrosis. Are non-leukemic.
4.
chronic myeloid leukemia.
Although the majority of patients are classifiable as having
one of these disorders, some have overlapping features and
there is often progression from one to another, e.g. PRV to
myelofibrosis. The recent discovery of the molecular basis of
these disorders will lead to changes in classification and
treatment; a mutation in the gene on chromosome 9
encoding the signal transduction molecule JAK-2has been
found in more than 90% of PRV cases and 50% of those with
essential thrombocythaemia and myelofibrosis.
Mutations in the calreticulin gene (CALR), which produces a
chaperone protein that protects proteins moving from the
endoplasmic reticulin to the cytoplasm, have been found in a
further 25% of patients with essential thrombocythaemia.
Less commonly, mutations can be detected in the
thrombopoietin receptor gene MPL.
Myelofibrosis
In myelofibrosis, the marrow is initially hypercellular, with
an excess of abnormal megakaryocytes which release
growth factors, e.g.
platelet derived growth factor
, to the
marrow
microenvironment,
resulting
in
a
reactive
proliferation of fibroblasts. As the disease progresses, the
marrow becomes fibrosed.
Most patients present over the age of 50 years, with lassitude,
weight loss and night sweats. The spleen can be massively
enlarged due to extramedullary haematopoiesis (blood cell
formation outside the bone marrow), and painful splenic
infarcts may occur.
The characteristic blood picture is leucoerythroblastic
anaemia, with circulating immature red blood cells
(increased reticulocytes and nucleated red blood cells) and
granulocyte precursors (myelocytes). The red cells are shaped
like teardrops (teardrop poikilocytes), and giant platelets may
be seen in the blood. The white count varies from low to
moderately high, and the platelet count may be high, normal
or low.
Urate levels may be high due to increased cell breakdown,
and folate deficiency is common. The marrow is often
difficult to aspirate and a trephine biopsy shows an excess of
megakaryocytes, increased reticulin and fibrous tissue
replacement. The presence of a JAK-2mutation supports the
diagnosis.
Management and prognosis
Median survival is 4 years from diagnosis, but ranges from 1 year to
over 20 years.
Treatment is directed at control of symptoms, e.g. red cell
transfusions for anaemia. Folic acid should be given to prevent
deficiency.
Cytotoxic therapy with hydroxycarbamide may help control
spleen size, the white cell count or systemic symptoms.
Splenectomy may be required for a grossly enlarged spleen or
symptomatic pancytopenia secondary to splenic pooling of cells
and hypersplenism.
HSCT may be considered for younger patients.
Ruxolitinib, an inhibitor of JAK-2, has recently been licensed
for use is effective at reducing systemic symptoms and
splenomegaly.
Essential thrombocythaemia
Increased proliferation of megakaryocytes results in a raised
level of circulating platelets that are often dysfunctional.
Prior to making a diagnosis of essential thrombocythaemia
(ET), reactive causes of thrombocytosis must be excluded.
The presence of a JAK-2mutation, CALR or, rarely, MPL
mutation supports the diagnosis but is not universal. Patients
present at a median age of 60 years with vascular occlusion or
bleeding, or with an asymptomatic isolated raised platelet
count.
A small percentage (5%) transform to acute leukaemia and
others to myelofibrosis.
It is likely that most patients with ET benefit from lowdose
aspirin to reduce the risk of occlusive vascular events. Low
risk
patients
(age
<40
years,
platelet
count
<1500
×10power9/L and no bleeding or thrombosis) may not
require treatment to reduce the platelet count.
For those with a platelet count above 1500 ×10power9/L, with
symptoms, or with other risk factors for thrombosis such as
diabetes or hypertension, treatment to control platelet
counts
should
be
given.
Agents
include
oral
hydroxycarbamide
or
anagrelide,
an
inhibitor
of
megakaryocyte
maturation.
Intravenous
radioactive
phosphorus may be useful in old age.
Polycythaemia rubra vera
Polycythaemia rubra vera (PRV) occurs mainly in patients
over the age of 40 years and presents either as an incidental
finding of a high haemoglobin, or with symptoms of
hyperviscosity, such as lassitude, loss of concentration,
headaches, dizziness, blackouts, pruritus and epistaxis.
Some patients present with manifestations of peripheral
arterial disease or a cerebrovascular accident. Venous
thromboembolism may also occur. Peptic ulceration is
common, sometimes complicated by bleeding. Patients are
often plethoric and many have a palpable spleen at diagnosis.
The diagnosis of PRV now rests upon the demonstration of a
high haematocrit and the presence of the JAK-2 V617F
mutation (positive in 95% of cases).
In the occasional JAK2negative cases, a raised red cell mass
and absence of causes of a secondary erythrocytosis must be
established.
The spleen is enlarged, neutrophil and platelet counts are
frequently raised, an abnormal karyotype may be found in
the marrow, and in vitro culture of the marrow can be used to
demonstrate autonomous growth in the absence of added
growth factors.
Management and prognosis
Aspirin reduces the risk of thrombosis. Venesection gives prompt
relief of hyperviscosity symptoms. Between 400 and 500 mL of
blood (less if the patient is elderly) are removed and the
venesection is repeated every 5–7 days until the haematocrit is
reduced to below 45%. Less frequent but regular venesection will
maintain this level until the haemoglobin remains reduced because
of iron deficiency.
Suppression of marrow proliferation with hydroxycarbamide or
interferon-alfa may reduce the risk of vascular occlusion, control
spleen
size
and
reduce
transformation
to
myelofibrosis.
Radioactive phosphorus (5 mCi of 32P IV) is reserved for older
patients, as it increases the risk of transformation to acute
leukaemia by 6 to 10 fold.
Median survival after diagnosis in treated patients exceeds 10
years. Some patients survive more than 20 years; however,
cerebrovascular or coronary events occur in up to 60% of
patients.
The disease may convert to another myeloproliferative
disorder, with about 15% developing acute leukaemia or
myelofibrosis.
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