Myeloproliferative disorders (MPD) are chronic
diseases caused by clonal proliferation of bone marrow
stem cells leading to excess production of one or more
haemopoietic lineage.
The clinical syndromes include
 polycythaemia rubra vera (red cells),
 essential thrombocythaemia (platelets),
 chronic myeloid leukaemia (white cells) and
 myelofibrosis in which there is a reactive fibrosis of the
marrow and extramedullary haemopoiesis in the liver
and spleen.
Intermediate forms may occur and the diseases may all
transform into acute myeloid leukaemia.
Chronic
myeloid
leukaemia
This is a clonal myeloproliferative disorder characterized by an
increase in neutrophils and their precursors in the
peripheral blood with increased cellularity of the marrow as
a result of an excess of granulocyte precursors.
Without treatment, CML progresses from an initial chronic
phase (CP) characterized by marrow hyperplasia and
increased numbers of circulating differentiated myeloid
cells followed by advanced phases of disease (accelerated
phase [AP] and blast crisis [BC]) marked by a block in
differentiation, an accumulation of blasts, and a depletion
of normal hematopoietic cells, especially white blood cells
and platelets.
CML was the first malignant disease found to be
consistently associated with a specific cytogenetic
abnormality, the Philadelphia chromosome (Ph),
resulting in the formation of the BCR–ABL fusion
oncogene.
Study of BCR–ABL has led to sensitive methods to detect
residual disease and predict outcome and to “targeted”
therapy aimed at inhibiting abnormal tyrosine kinase
activity resulting from the BCR–ABL fusion oncogene.
In addition, CML was one of the first diseases
demonstrated to be curable by hematopoietic cell
transplantation (HCT).
Aetiology
 Aetiology is unknown.
 Radiation may play a role in some cases, because
persons exposed to high-dose irradiation, including
survivors of the atomic bomb, have a significantly
increased risk of leukemia, and high-dose irradiation
of myeloid cell lines in vitro induces the expression of
BCR–ABL transcripts indistinguishable from those
that characterize CML.
Pathophysiology
Chronic myelogenous leukemia was recognized as a distinct entity, associated with
massive splenomegaly and leukocytosis without other explanations, in the mid1800s.
The modern history of CML was initiated by Nowell and Hungerford in 1960. They
used newly developed techniques to detect a small chromosome in metaphase
preparations of marrow cells from CML patients. This abnormal chromosome was
the first consistent chromosomal abnormality in human malignancies and was
termed the Philadelphia chromosome after the city of its discovery.
Rowley showed that the Philadelphia chromosome resulted from a translocation
between chromosomes 9 and 22 [t(9; 22)(q34;q11)].
The genes involved in this translocation were cloned in the 1980s, and the t(9 : 22)
translocation was shown to result from the fusion of the BCR (breakpoint cluster
region) gene on chromosome 22 to the ABL (Abelson leukemia virus) gene on
chromosome 9, with formation of the BCR–ABL fusion oncogene.
This fusion gene encodes a 210-kDa protein with greatly increased tyrosine kinase
activity, which is now believed to be the principal cause of the chronic phase of
CML.
The disease is of stem cell origin as the Ph chromosome is present in erythroid,
granulocytic, megakaryocytic and T-lymphoid precursors.
 Chronic myelogenous leukemia is the most common of the
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myeloproliferative diseases and represents 15% to 20% of all
new leukemia cases.
The annual incidence of CML is 1 to 1.5 cases per 100,000
population per year.
The median age at diagnosis is 67 years and the incidence
sharply rises with age.
The disease occurs slightly more often in men than in
women.
Chronic myelogenous leukemia may occur in children but
only approximately 10% of cases occur in subjects between 5
and 20 years of age, and represent only 3% of all childhood
leukemias.
The disease usually transforms from a relatively stable
chronic phase to an acute leukaemia phase (blast
transformation).
Phases
Chronic
2. Accelerated phase
3. Blast crisis
1.
Most (>90%) CML patients present in chronic phase
(CP). CML is often diagnosed incidentally during
routine examination or examination for another
illness.
Symptoms
 Presenting symptoms include weight loss, night
sweats, itching, left hypochondrial pain, gout.
 Priapism, visual disturbance and headaches caused by
hyperviscosity (WBC >250 Ґ 109/L) are less frequent.
 Splenomegaly, often massive, occurs in over 90% of
cases.
Laboratory Findings
 Raised white cell count (often 50 Ґ 109/L or more), mainly neutrophils
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and myelocytes (granulocytes at all stages of differentiation in
peripheral blood cells. Circulating granulocytes are usually normal in
appearance, but with low leucocyte alkaline phosphatase score).
Although the proportion of eosinophils is usually not increased, the
absolute eosinophil count is usually increased. The absolute basophil
count is almost always increased in CML. The proportion of basophils is
usually less than 15% in chronic-phase patients, but may rarely be higher.
The platelet count is elevated in 50% of patients at the time of diagnosis.
Thrombocytopenia is rare at diagnosis and usually is a sign of progression
toward accelerated phase.
Raised serum uric acid.
Bone marrow is hypercellular. The granulocytic/erythroid ratio is
increased to 10 : 1 to 30 : 1, with increased granulopoiesis and reduced
erythropoiesis. Presence of more than 10% blasts indicates
transformation to accelerated phase.
Cytogenetic analysis of bone marrow cells shows the Philadelphia
chromosome in >95% of metaphases. The BCR-ABL fusion gene is
detectable by FISH or polymerase chain reaction (PCR) assays.
 Fluorescent in situ
hybridization (FISH).
Accelerated Phase
General, accelerated phase is characterized by symptoms
of fever, night sweats, weight loss and bone pain,
difficulty in controlling counts using conventional
therapy, increased numbers of blasts and early
myeloid cells in marrow and peripheral blood, and
evidence of karyotypic evolution
Blast Crisis
 The blast phase of CML resembles acute leukemia.
Blast crisis is defined as having more than 20% blasts
in the bone marrow or peripheral blood, the presence
of large aggregates and clusters of blasts in the bone
marrow biopsy, or the development of extramedullary
blastic infiltrates.
 Blasts may be of myeloid or lymphoid lineage.
Course and progress
 Patients are typically well during the ‘chronic phase’.
 The main cause of death is transformation into acute
leukaemia, which may occur at any stage, even at
presentation.
 Median survival is currently about 4 years.
 Staging to predict prognosis uses age, spleen size, blood
blast cell and platelet counts.
 There may be an accelerated phase of variable duration in
which anaemia, thrombocytopenia, splenic enlargement
and marrow fibrosis occur. Transformation is usually
accompanied by additional morphological and
chromosome abnormalities
Hematologic Response
 A complete hematologic remission is defined as the
achievement of normal WBC and platelet counts and
normal differential, and disappearance of all
symptoms and signs of CML.[
 A partial hematologic response is defined as a
decrease in the WBC count to less than 50% of the
pretreatment level, or the normalization of the WBC
count accompanied by persistent splenomegaly or
immature cells in the peripheral blood.
Cytogenetic Response
 Complete: Ph-negative = 0%
 Major: Ph-positive = 1% to 35%
 Minor: Ph-positive = 36% to 65%
 Minimal: Ph-positive = 66% to 95%
 None: Ph-positive < 95%
Molecular Response
 Complete: BCR–ABL transcripts nonquantifiable and
nondetectable
 Major: BCR–ABL transcripts ≤0.10%
Treatment.
Chronic
phase
Busulfan (BU) chemotherapy for CML was introduced
in the 1950s. Busulfan was administered in doses of 4
to 6 mg/day and then held when the WBC count fell to
30 × 109/L. The drug effect could persist for weeks,
and the counts could fall further after therapy was
discontinued. Busulfan therapy was associated with
serious adverse effects, including prolonged aplasia,
pulmonary fibrosis, and a syndrome simulating
adrenal insufficiency.
Treatment. Chronic phase
Treatment with hydroxyurea (HU) was started as an
alternative to busulfan. Hydroxyurea therapy is usually
initiated at doses of 1 to 6 g/day in an attempt to lower
counts. Hydroxyurea administered at doses of 1 to 2
g/day is then used to maintain blood counts in the
normal range. Hydroxyurea is less toxic than busulfan.
Its major adverse effect is reversible marrow
suppression.
Because neither drug results in significant selective
suppression of the Ph-positive clone, the aim of therapy
with these agents is to control disease and symptoms.
Hydroxyurea is now commonly used to achieve control of
counts simultaneous with or prior to initiation of
treatment with imatinib or other disease-specific
therapies.
Treatment. Chronic phase
 α-interferon (IFN) may also control the white cell count
and may delay the onset of acute transformation,
prolonging overall survival by 1–2 years. The best
responders to IFN become Ph-negative, but usually remain
BCR-ABL-positive, and have the best prognosis.
 The potential mechanisms by which IFN works in CML are
not understood, but may include inhibition of increased
proliferation, correction of the adhesion defect of the
malignant progenitor in CML, or stimulating an immune
response to CML. Rates for complete and partial
cytogenetic remissions range from 0% to 38%.
Treatment.
Chronic
phase
 Because the tyrosine kinase activity of BCR–ABL
plays a critical role in cellular transformation, it is an
attractive target for inhibition.
 Imatinib (Glivec). This is a specific inhibitor of the
tyrosine kinase encoded by BCR-ABL. It controls the
blood count and causes the marrow to become Ph
negative in a high proportion of cases, though nearly all
remain positive for the BCR-ABL fusion messenger RNA
when tested by PCR. The chronic phase is prolonged and
the rate of acute transformation is reduced. Side effects
include nausea, skin rashes and muscle pains. Imatinib in
combination with other drugs is also valuable in the
therapy of Ph+ALL and blast transformation of CML.
Glivek
 At a chronic stage 80-91% have a complete hematologic
remission, 49-61% have major cytogenetic response and 3036% have complete elimination of Ph+ cells
 At accelerated phase: 63-69% have a complete hematologic
remission, 20-24% have major cytogenetic response and 1417% have complete elimination of Ph+ cells
 While prolongating glivek treatment (9-12 months) the rate
of major cytogenetic response rises to до 74-81%.
 Even in the blast crisis the Glivec treatment gives positive
results: 26-29% have a complete hematologic remission, 4961% have major cytogenetic response and 6-7% have
complete elimination of Ph+ cells
The duration of Glivec treatment
 3 months – complete hematologic remission
 6 months– major cytogenetic response
 12 months– complete cytogenetic response
 18 months– major molecular response
An alternative to Glivek
 Tasigma (nilonitib) – the second-line drug for
patients at a chronic phase and at an accelerated
phase. Is used in case of resistancy to Glivec. 50% of
patients have major cytogenetic response.
Treatment. Chronic phase
 Allogeneic stem cell transplantation (SCT) before
the age of 50 from an HLA matching sibling offers a
70% chance of cure in the chronic phase but 30% or
less once acceleration has occurred.
 HLA-matched unrelated donor (MUD) SCT is less
successful in curing the disease because of higher
morbidity and mortality. Transfusion of donor
lymphocytes may be valuable in eliminating BCRABLpositive cells in cases of relapse post-SCT.
Treatment. Acute phase
 Therapy as for acute leukaemia, AML or ALL with the
addition of imatinib may be given, but the prognosis is
poor.
Myelofibrosis
 Myelofibrosis (myelosclerosis, agnogenic myeloid
metaplasia) is characterized by splenomegaly,
extramedullary haemopoiesis, a leucoerythroblastic
blood picture and replacement of bone marrow by
collagen fibrosis.
 Myelofibrosis is a clonal disease as well.
 In PMF, there is a profound hyperplasia of
morphologically abnormal megakaryocytes and
clonal populations of monocytes that may be
responsible for the marrow fibrosis due to the local
release of fibrogenic growth factors
Aetiology and pathophysiology
 The primary defect is within the haemopoietic stem cell;
 Chromosome abnormalities are common, but they are
different
 Fibrosis results from a reactive non-neoplastic
proliferation of marrow stromal cells.
 Very important feature – the ability of malignant cells for
extramedullar spread, infiltration with malignant cells of
the spleen, liver, lymph. nodes, others.
Epidemiology
 0,5-1,5 cases per 100,000 persons per year
 The average age at diagnosis of PMF is approximately
65 years, and most patients are diagnosed between 50
and 69 years of age.
Clinical features
The first stage (onset):
 panmyelosis is common;
 Symptoms due to erythrocytosis, thrombocytosis (Thrombotic
episodes ). Thrombosis may be venous (cerebral venous sinus
thrombosis, splanchnic vein thrombosis, deep vein thrombosis,
pulmonary thromboembolism) or arterial (stroke, transient
ischemic attacks, retinal artery occlusion, myocardial infarction,
angina pectoris, and peripheral arterial disease). The cellular phase
of PMF with thrombocytosis and presence of cardiovascular risk
factors such as hypertension, smoking, hypercholesterolemia, and
diabetes are the independent predictors of thrombosis.
Hyperviscosity may lead to headaches and visual disturbance.
 Spleen is not enlarged very much.
 This stage has much in common with polycythemia vera and is often
called as subleucemic myelosis.
Clinical features
The second, fibrotic stage
 Splenomegaly is very massive. Spleen often takes half of
the stomach. Patients may merely complain of a dull, heavy
sensation in the left upper quadrant. Pain of extreme
severity, simulating an acute abdominal emergency, is
produced by splenic infarction.
 Anemia (myelofibrosis, hypersplenism)
 Haemorrhage. Bleeding may be trivial, as manifested by
petechiae and ecchymoses, or it may be life-threatening as
a result of uncontrollable esophageal bleeding. It may
result from thrombocytopenia or poor platelet function
The terminal stage:
 Polyorganic complications.
 The reason of death may be acute esophageal bleeding
(portal hypertension)
 Transformation into acute leycosis in some patients
Laboratory features
 Normochromic normocytic anaemia.
 Leucocytosis and thrombocytosis with circulating
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megakaryocyte fragments occur early; leucopenia and
thrombocytopenia occur later.
Blood film: red cell poikilocytosis with teardrop forms and
circulating red cell and white cell precursors
(leucoerythroblastic picture)
Serum LDH is raised. Liver function tests are often
abnormal because of extramedullary haemopoiesis.
NAP score is usually raised.
Bone marrow aspiration is usually unsuccessful (‘dry tap’);
the trephine biopsy shows increased cellularity, increased
megakaryocytes and fibrosis
Treatment
 Chemotherapy (e.g. hydroxyurea) for patients with
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hypermetabolism and myeloproliferation.
Thalidomide improves marrow function and reduces spleen
size in about a third of cases.
Supportive therapy with red cell transfusions, folic acid and
occasionally platelet transfusions. Iron chelation may be
needed.
Allopurinol to prevent hyperuricaemia and gout.
Splenectomy or splenic irradiation to reduce symptoms from
splenomegaly, anaemia or thrombocytopenia (selected
patients only).
Allogeneic bone marrow transplantation has cured a few
younger patients (<50 years).
Prognosis
 Median survival is about 5 years; acute leukaemia
occurs in about 20%.
POLYCYTHEMIA VERA
PV is a clonal, chronic, progressive myeloproliferative
disorder (MPD) often of insidious onset, characterized
by an absolute increase in red cell mass and also usually
by leukocytosis, thrombocytosis, and splenomegaly.
PV leads to excessive proliferation of erythroid, myeloid,
and megakaryocytic elements within the bone
marrow.
Epidemiology
 0,6-1,6 cases per 100,000 persons per year
 The average age at diagnosis of PMF is approximately
60 years. May occur in young people
Clinical features
 Raised RCM causes a ruddy complexion and
conjunctival suffusion; hyperviscosity may lead to
headaches and visual disturbance.
 Thrombosis (e.g. deep vein thrombosis (DVT), Budd–
Chiari syndrome, which results from hepatic venous or
inferior vena caval thrombosis and obstruction) is also
caused by hyperviscosity and increased platelets.
 Haemorrhage, especially gastrointestinal, may occur.
 Excess histamine secretion from basophils leads to
increased gastric acid and peptic ulcer is frequent.
Polycythaemia rubra
vera: patient with
plethora.
Arterial thrombotic events account for two-thirds of such
events, with venous thrombotic events representing the
remainder.
Ischemic stroke, myocardial infarction, and transient
ischemic attacks are the most common arterial
thrombotic events. Patients may also present with deep
venous thrombosis in the lower extremities, pulmonary
embolism, or peripheral vascular occlusions
Differential diagnosis
Secondary or reactive polycythaemia may occur in conditions where arterial oxygen
saturation is reduced, leading to a physiological rise in EPO, or when EPO levels are
inappropriately raised (e.g. caused by secretion of EPO by a renal neoplasm).
Relative polycythemia
1. Decreased plasma volume—reduced fuid intake, marked loss of body fuids
(diaphoresis, vomiting, diarrhea, “third-spacing”)
2. Overfilling of blood in collection vacuum tubes
AbsolutepPolycythemia
 Secondary polycythemia :
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Pulmonary disease
Hypoventilation syndromes—sleep apnea, Pickwickian syndrome
Smokers' polycythemia, carbon monoxide intoxication due to industrial exposure
Postrenal transplantation erythrocytosis
Tumors—renal cell carcinoma, Wilms tumor, hepatic carcinoma, uterine
leiomyomata, virilizing ovarian tumors, vascular cerebellar tumors
Miscellaneous renal and hepatic disorders—solitary renal cysts, polycystic kidney
disease, renal artery stenosis hydronephrosis, viral hepatitis
Endocrine disorders—Cushing's syndrome, primary aldosteronism
Androgen use
Erythropoietin use
The following additional tests are occasionally required:
 Chest X-ray; arterial blood gas analysis to exclude lung
disease.
 Haemoglobin oxygen dissociation curve to identify a
variant haemoglobin with increased oxygen affinity.
 Serum EPO assay.
Treatment
 Thrombosis is the main cause of morbidity and
mortality and its incidence can be reduced by
maintaining the PCV below 0.45 and platelets below
600 Ґ 109/L. Aspirin (75 mg daily) is often used to
inhibit platelet function.
 Regular venesection is used initially to lower the PCV.
 Busulfan may be given orally. It has a more prolonged
action than hydroxyurea and more side-effects and is
now more rarely used.
Prognosis
 Median survival is about 16 years.
 Up to 30% of patients develop myelofibrosis .
 Acute myeloid leukaemia occurs in up to 5% of
patients