Team P (,) sec B2 HEMA2012

CHRONIC MYELOPROLIFERATIVE
DISORDERS
Erly Samson-Cruz,MD,FPCP
Internist-Hematologist

Polycythemia vera
chronic idiopathic myelofibrosis
essential thrombocytosis
chronic myeloid leukemia
pathophysiology involves the clonal expansion of a multipotent
hematopoietic progenitor cell with the overproduction of one or
more of the formed elements of the blood
may transform into acute leukemia naturally or as a
consequence of mutagenic treatment
POLYCYTHEMIA /ERYTHROCYTOSIS
increase in circulating red blood cells above normal
elevated Hgb
o Men 170g/L
o women 150g/L
elevated Hct
o Men >50%
o women >45%

REAL/ABSOLUTE
primary (P. vera)
secondary ( appropriate or inappropriate)
associated with increases in EPO levels
o physiologically adapted appropriate elevation based on
tissue hypoxia (lung disease, high altitude, CO
poisoning, high-affinity hemoglobinopathy)
o abnormal overproduction (renal cysts, renal artery
stenosis, tumors with ectopic EPO production)
APPARENT/SPURIOUS/RELATIVE
decrease in plasma volume
Gaisbocks syndrome
Pointers in the history
o Smoking history
o Living at high altitude
o History of congenital heart disease
o PUD
o Sleep apnea
o Chronic lung disease
o Renal disease
Manifestations
majority are asymptomatic
some with symptoms related to increase red cell mass or
underlying disease process
symptoms related to hyperviscosity and thrombosis
neuro symptoms
o vertigo
o tinnitus
o headache
o visual disturbances
Physical examination
ruddy complexion
splenomegaly
cyanosis or evidence of a right-to-left shunt
cor pulmonale

A. POLYCYTHEMIA VERA
clonal disorder involving a multipotent hematopoietic progenitor
cell in which there is accumulation of phenotypically normal red
cells, granulocytes, and platelets in the absence of a
recognizable physiologic stimulus
2 per 100,000 persons
ETIOLOGY
unknown
nonrandom chromosome abnormalities such as 20q-, trisomy 8
or 9 have been documented in a small percentage of untreated
polycythemia vera patients
no consistent cytogenetic abnormality has been associated with
the disorder and no specific genetic defect has yet been
identified
CLINICAL FEATURES
massive splenomegaly
high hemoglobin or hematocrit
aquagenic pruritus
uncontrolled erythrocytosis
o neurologic symptoms
o systolic hypertension
o venous or arterial thrombosis
o easy bruising, epistaxis, or gastrointestinal hemorrhage
o hyperuricemia
DIAGNOSIS
red cell mass determination
o 51Cr-tagged red cells
o polycythemia vera, in contrast to erythropoietin-driven
erythrocytosis plasma volume is frequently elevated
plasma erythropoietin level
o useful diagnostic test in patients with isolated
erythrocytosis
elevated plasma erythropoietin level
o hypoxic cause for erythrocytosis
o autonomous erythropoietin production
pulmonary function
evaluate renal and hepatic anatomy
plasma erythropoietin level
normal erythropoietin level
o hypoxic cause for erythrocytosis
o polycythemia vera
arterial oxygen saturation is normal
low or unmeasurable
o most likely polycythemia vera

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Other Laboratory tests:
RBC count
MCV
RDW
Elevated leukocyte alkaline phosphatase
Elevated blood uric acid level
Elevated serum vitamin B12 or B12-binding capacity
bone marrow aspirate and biopsy will provide no specific
diagnostic information
CRITERIA FOR CLINICAL DIAGNOSIS OF PV
1. Elevated red cell mass
2. Normal arterial oxygen saturation
3. Splenomegaly
4. In the absence of splenomegaly:
o leukocytosis and thrombocytosis
COMPLICATIONS
related directly to the increase in blood viscosity associated with
elevation of the red cell mass
indirectly to the increased turnover of red cells, leukocytes, and
platelets and the attendant increase in uric acid and cytokine
production
Erythromelalgia
o syndrome of unknown etiology primarily involving the lower
extremities
o manifested usually by erythema, warmth, and pain of the
affected appendage and occasionally digital infarction
o occurs with a variable frequency in patients with a
myeloproliferative disorder
o responsive to salicylates
TREATMENT
Maintenance of the hemoglobin level is mandatory to avoid the
thrombotic complications
=140 g/L in men
=120 g/L in women
o Phlebotomy
chemotherapy to reduce splenomegaly, leukocytosis, or pruritus
o hydroxyurea
o IFN-a
o allopurinol
salicylates for erythromelalgia
Allogeneic bone marrow transplantation may be curative in
young patients

Prognosis
expected to live long and useful lives when their red cell
mass is effectively managed with phlebotomy
chemotherapy is never indicated to control the red cell mass
unless venous access is impossible

B.

CHRONIC IDIOPATHIC MYELOFIBROSIS

agnogenic myeloid metaplasia (AMM)
myelofibrosis with myeloid metaplasia (MMM)
clonal disorder of a multipotent hematopoietic progenitor cell
of unknown etiology characterized by marrow fibrosis,
myeloid metaplasia with extramedullary hematopoiesis, and
splenomegaly
uncommon disease
primarily afflicts individuals in their sixth decade

ETIOLOGY
etiology is unknown
nonrandom chromosome abnormalities such as 20q-, 13q-,
and trisomy 1q are not uncommon
o no specific cytogenetic abnormality
fibrosis is associated with overproduction of transforming
growth factor and thrombopoietin
fibroblasts in chronic idiopathic myelofibrosis are not part of
the neoplastic clone
CLINICAL FEATURES
no specific signs or symptoms associated
most patients are asymptomatic at presentation
splenic enlargement
mild hepatomegaly
anemia, mild
abnormal blood counts during a routine examination
hyperuricemia and secondary gout
PBS features of extramedullary hematopoiesis
leukocyte and platelet counts are either normal, increased or
low
LDH and serum alkaline phosphatase levels can be elevated
leukocyte alkaline phosphatase can be low, normal, or elevated
marrow may be unaspirable due to the myelofibrosis
bone x-rays may reveal osteosclerosis
DIAGNOSIS
diagnosis by exclusion
extramedullary hematopoiesis
o teardrop-shaped red cells
o nucleated red cells
o myelocytes and promyelocytes
marrow is usually not aspirable due to increased marrow
reticulin
marrow biopsy hypercellular marrow with trilineage hyperplasia
and increased megakaryocytes
occurrence of autoimmune abnormalities such as immune
complexes, antinuclear antibodies, rheumatoid factor, or a
positive Coombs' test
Cytogenetic analysis of blood or marrow is useful
o to exclude CML
o for prognostic purposes
circulating CD34+ cells is markedly increased
COMPLICATIONS
median survival of only 5 years (range 1 to 15 years)
marrow failure with transfusion-dependent anemia and
increasing organomegaly
prone to deep-seated tissue infections, particularly of the
lungs
can evolve from a chronic phase to an accelerated phase
with constitutional symptoms and increasing marrow failure
~10% of patients develop an aggressive form of acute
leukemia for which therapy is usually ineffective

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important prognostic factors for disease acceleration include

o Anemia
o Thrombocytopenia
o Age
o presence of complex cytogenetic abnormalities
o constitutional symptoms
(unexplained fever, night sweats, wt loss)
nonrandom cytogenetic abnormality is associated with a
shortened life span, and the presence or development of
multiple cytogenetic abnormalities is highly indicative of
disease acceleration

TREATMENT
no specific therapy exists for chronic idiopathic myelofibrosis
anemia may be exacerbated by deficiency of folic acid or iron,
and in rare instances, pyridoxine therapy has been effective
Splenectomy may also be necessary if splenomegaly impairs
alimentation and should be performed before cachexia sets in
Allopurinol can control significant hyperuricemia
Hydroxyurea useful for controlling organomegaly
IFN2-a may cause reversal of myelofibrosis
Glucocorticoids are used to control autoimmune complications
and may ameliorate anemia alone or in combination with
thalidomide
Allogeneic bone marrow transplantation should be considered
in younger patients

C. ESSENTIAL THROMBOCYTOSIS
Essential thrombocythemia
idiopathic thrombocytosis
primary thrombocytosis
hemorrhagic thrombocythemia
a clonal disorder of unknown etiology involving a multipotent
hematopoietic progenitor cell and is manifested clinically by the
overproduction of platelets without a definable cause
an uncommon disorder
no clonal marker distinguishes it from the more common
nonclonal, reactive forms of thrombocytosis
occur at any age in adults
occurs without symptoms or disturbances of hemostasis
female predominance
clinical criteria have been proposed to distinguish it from the
other chronic myeloproliferative disorders, which may also
present with thrombocytosis but have differing prognoses and
treatment
o do not establish clonality
o useful only in identifying
CML
polycythemia vera
myelodysplasia

ETIOLOGY
thrombopoietin enhances the proliferation of its target cells but
also enhances the reactivity of their end-stage product, the
platelet
thrombopoietin enhances the survival of multipotent
hematopoietic stem cells
clonality of essential thrombocytosis established by the use of
of X-linked DNA polymorphisms, and by the identification of
nonrandom, although variable, cytogenetic abnormalities

CLINICAL FEATURES
most often identified incidentally when a platelet count is
obtained during the course of a routine evaluation
no symptoms or signs are specific for essential thrombocytosis
Physical examination is generally unremarkable except
occasionally for mild splenomegaly
massive splenomegaly is more characteristic of the other
myeloproliferative disorders, particularly polycythemia vera or
idiopathic myelofibrosis
blood smear remarkable for the number of platelets present,
some of which may be very large
leukocyte alkaline phosphatase score is either normal or
elevated
prolonged bleeding time and impaired platelet aggregation can
be present
marrow biopsy usually reveals both megakaryocyte hyperplasia
and hypertrophy
slight increase in marrow reticulin may be present, but if
extensive, another diagnosis should be considered
presence of stainable iron
no consistently identifiable abnormality is notable, even
involving chromosomes 3 and 1 where the genes for
thrombopoietin and its receptor Mpl, respectively, are located
DIAGNOSIS
determine if it is a consequence of another disorder
Cytogenetic evaluation is mandatory to determine if the
thrombocytosis is due to CML or a myelodysplastic disorder
such as the 5q- syndrome
anemia and ringed sideroblasts are not features of essential
thrombocytosis, but they are features of idiopathic refractory
sideroblastic anemia, in which thrombocytosis can also
occur
presence of massive splenomegaly should suggest the
possibility of another myeloproliferative disorder
COMPLICATIONS
>1 106/uL
o very high platelet counts are associated primarily
with hemorrhage due to acquired von Willebrand
disease
<1 106/uL
o associated with thrombosis
TREATMENT
asymptomatic patient
o requires no therapy
symptoms must be clearly identified to be a consequence of
the elevated platelet count
if platelet reduction is deemed necessary on the basis of
neurologic symptoms refractory to salicylates
o IFN-a
o anagrelide, a quinazolin derivative, can reduce the
platelet count, but neither is uniformly effective nor
without significant side effects
o Hydroxyurea considered only if these agents are
not effective or tolerable
bleeding associated with thrombocytosis
o e-aminocaproic acid

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Team P (,) sec B2 HEMA2012

D. CHRONIC MYELOGENOUS LEUKEMIA
INCIDENCE
1.5 per 100,000 people per year
age-adjusted incidence is higher in men than in women (2.0
versus 1.2)
incidence of CML increases age
CML incidence decreased slightly between 1973 and 1999
(1.9 versus 1.5)
DEFINITION
diagnosis is established by identifying a clonal expansion of a
hematopoietic stem cell possessing a reciprocal translocation
between chromosomes 9 and 22
Untreated, the disease is characterized by the inevitable
transition from a chronic phase to an accelerated phase and on
to blast crisis
ETIOLOGY
No clear correlation with exposure to cytotoxic drugs
no direct evidence of a viral etiology
Cigarette smoking has been shown to accelerate the
progression to blast crisis and therefore has an adverse effect
on survival in CML
large doses of radiation can induce CML
CLINICAL PRESENTATION
Physical Findings
minimal to moderate splenomegaly
mild hepatomegaly, ocassionally
Lymphadenopathy and myeloid sarcomas
prognosis is poor
.
Phases
o Chronic phase
o Accelerated phase
o Blastic phase
Hematologic Findings
Elevated white blood cell counts, with various degrees of
immaturity of the granulocytic series
Usually <5% circulating blasts and <10% blasts and
promyelocytes
Platelet counts are almost always elevated at diagnosis
normochromic normocytic anem
Leukocyte alkaline phosphatase is characteristically low in CML
cells
Serum levels of vitamin B12 and vitamin B12-binding proteins
are generally elevated
Phagocytic functions normal at diagnosis and remain normal
during the chronic phase
Histamine production secondary to basophilia is increased in
later stages, causing pruritus, diarrhea, and flushing
marrow cellularity, primarily of the myeloid and megakaryocytic
lineages
marrow blast percentage is generally normal or slightly elevated
marrow or blood basophilia, eosinophilia, and monocytosis may
be present
Disease acceleration
defined by the development of increasing degrees of anemia
cytogenetic clonal evolution
blood or marrow blasts between 10 and 20%
blood or marrow basophils =20%
platelet count <100,000/ul

Negative neutrophil alkaline phosphatase reaction

Negative neutrophil alkaline phosphatase (NAP) reaction. A low NAP
score is seen in 95% of cases of chronic granulocytic leukaemia. This
test is redundant if there is ready availability of karyotypic or molecular
genetic analysis to detect t(9;22) and BCR-ABL fusion respectively. To
compare with a normal neutrophil alkaline phosphatase reaction click
on compare.

Blast crisis
defined as acute leukemia
blood or marrow blasts = 20%
hyposegmented neutrophils may appear
blast cells can be classified based on morphologic,
cytochemical, and immunologic features
half the cases are myeloid
one-third lymphoid
10% erythroid
the rest are undifferentiated
DIAGNOSIS
Chromosomal Findings / cytogenetic hallmark
found in 90 to 95% of patients
t(9;22)(q34;q11.2)
Philadelphia chromosome
presence of a shortened chromosome 22 (22q-)arises from
the reciprocal 9;22 translocation
TREATMENT
Allogeneic SCT
only curative therapy for CML
when feasible, the treatment of choice
complicated by a high early-mortality rate owing to the
transplant procedure
outcome of SCT depends on multiple factors including
(1) the patient (e.g., age and phase of disease)
(2) the type of donor [e.g., syngeneic (monozygotic twins) or
HLA-compatible allogeneic, related or unrelated]
(3) the preparative regimen
(4) GVHD
(5) posttransplantation treatment.
Imatinib mesylate (Gleevec, STI571) 400 mg/d
functions through competitive inhibition at the adenosine
triphosphate (ATP) binding site of the Abl kinase, which leads to
inhibition of tyrosine phosphorylation of proteins involved in
Bcr/Abl signal transduction
most patients with Imatinib induces apoptosis in cells
expressing Bcr/Abl. therapy
95% of patients achieved complete hematologic remission
60% achieved major cytogenetic remission
complete cytogenetic remission rate of 41%
Those who did not achieve at least a major cytogenetic
remission following 3 months of therapy had a higher risk of
disease progression to the accelerated/blastic phases of the
disease
Patients in the accelerated/blastic phases of the disease are
less sensitive to imatinib, and the treatment outcome is less
favorable

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Team P (,) sec B2 HEMA2012

Interferons
treatment of choice before imatinib
potent, pleiotropic biologic effects, spanning a spectrum of
antiviral, microbicidal, immunomodulatory, and antiproliferative
properties
downregulate the expression of several oncogenes and
cytokines
upregulate the expression of IFN regulatory factor-1 (a
transcriptional activator with antioncogenic activity), adhesion
molecules, and the histocompatibility genes
inhibit angiogenesis and induce a cellular immune response

Autologous SCT
could potentially cure CML
normal hematopoietic stem cells appear with increased
frequency in the blood of patients with CML during the recovery
phase after chemotherapy and G-CSF
A role for imatinib before stem cell collection to achieve minimal
residual disease and following transplantation to maintain this
status is currently being investigated
only a few cases have been reported to successfully engraft
following imatinib therapy. Therefore such approaches should
be performed only in clinical trials.

Chemotherapy
rapid lowering of white blood cell counts
reduction of symptoms, reversal of symptomatic splenomegaly

Leukapheresis and Splenectomy

Intensive leukapheresis
o may control the blood counts in chronic-phase CML
o expensive and cumbersome
o useful in emergencies where leukostasis-related
complications such as pulmonary failure or
cerebrovascular accidents
o treatment of pregnant women in whom it is important to
avoid potentially teratogenic drugs

o
o
o

o
o
o

o
o

Hydroxyurea
ribonucleotide reductase inhibitor
initial dose is 1 to 4 g/d, halved with each 50% reduction of
the leukocyte count
cytogenetic remissions are uncommon
Homoharringtonine (HHT)
plant alkaloid derived from a tree, Cephalotaxus fortuneii sp.
Harringtonii
blocks peptide bond formation after binding of the
aminoacyl-transfer RNA to the ribosome
patients whose disease progressed during treatment with
IFN-a or who were in later chronic phase (>1 year from
diagnosis)
72% complete hematologic responses
15% major cytogenetic responses
use of HHT before IFN-a in early chronic phase
92% complete hematologic response rate
27% major cytogenetic response rate
Toxicity is mainly related to myelosuppression

o
o

Busulphan
alkylating agent that acts on early progenitor cells
not recommend because of its serious side effects
myelosuppression
pulmonary, endocardial, and marrow fibrosis
Addison-like wasting syndrome

Arsenic trioxide
mechanism(s) of action of in non-APL leukemias is
unknown
initial studies of arsenic trioxide in Bcr/Abl-expressing cell
lines demonstrated downregulation of Bcr/Abl expression as
well as activation of apoptosis

o
o
o

Splenectomy
used in the past because of the suggestion that evolution
to the acute phase might occur in the spleen
o symptomatic relief of painful splenomegaly unresponsive
to chemotherapy
o For significant anemia or thrombocytopenia associated
with hypersplenism
o Splenic radiation is used rarely to reduce the size of the
spleen
o

Blast Crisis
treatment for all forms of blast crisis is generally ineffective
with imatinib
52% achieved hematologic remission (21% complete
hematologic remission)
median overall survival was 6.6 months
patients who achieve complete hematologic remission
or whose disease returns to a second chronic phase
should be considered for allogeneic SCT
other approaches include induction chemotherapy tailored to
the phenotype of the blast cell followed by imatinib, with or
without additional chemotherapy and SCT
Blast crisis following initial therapy with imatinib carries a dismal
prognosis
END

Intensive combination chemotherapy

used in chronic-phase CML
with 30 to 50% of patients achieving complete cytogenetic
responses but short-lived
being used today only to mobilize normal progenitors in the
blood in order to collect circulating stem cells for autologous
transplantation

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ACUTE MYELOID LEUKEMIA
INTRODUCTION
heterogeneous group of diseases characterized by
infiltration of the blood, bone marrow, and other tissues by
neoplastic cells of the hematopoietic system
based on untreated course, the myeloid leukemias have
traditionally been designated acute or chronic
INCIDENCE
~3.6 per 100,000 people per year
age-adjusted incidence is higher in men than in women (4.4
versus 3.0)
incidence increases with age
1.7 in individuals <65 years
16.2 in those >65
ETIOLOGY
Implicated in the development of AML
Heredity
Radiation
chemical and other occupational exposures
drugs
No direct evidence suggests a viral etiology

Bone marrow aspirate from a patient with M0 AML showing

agranular blasts which were negative with myeloperoxidase, Sudan
black B and esterase stains

Peripheral blood film in M1 AML showing type I and type II blasts

and a promyelocyte. In this case the blasts were heavily
vacuolated

Bone marrow aspirate in M2 acute myeloid leukaemia stained with

a myeloperoxidase stain showing fine granular positivity in the
cytoplasm of the blast cells. This positive reaction shows that the
leukaemia is myeloid not lymphoid.

CLASSIFICATION
Morphology
Cytochemistry
Immunophenotype
Cytogenetic and molecular techniques
I.

Morphologic Classification
Dx established by the presence of > 20% myeloblasts in
blood and/or bone marrow
Myeloblasts have nuclear chromatin that is uniformly fine or
lacelike in appearance and large nucleoli (2 to 5 per cell)
Presence of cytoplasmic granules, Auer rods, or the nuclear
folding and clefting characteristic of monocytoid cells

French, American, and British (FAB)

dx established by the presence of > 30% myeloblasts in the
marrow
eight major subtypes, M0 to M7 based on morphology and
cytochemistry

WHO classification
dx established by the presence of > 20% myeloblasts in
blood and/or bone marrow
incorporating molecular (including cytogenetic), morphologic
(multilineage dysplasia), and clinical features (such as prior
hematologic disorder) in defining disease entities
*WHO modified the FAB schema by reducing the number of blasts
required for a diagnosis.
II.

Cytochemical Classification
positive myeloperoxidase reaction in >3% of the blasts may
be the only feature
distinguishing AML from Acute Lymphoblastic Leukemia
(ALL)

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Team P (,) sec B2 HEMA2012

III.

IV.

Peripheral blood film in M4 AML showing two monoblasts and a

myeloblast. Note that monoblasts are large cells with voluminous
cytoplasm. Their nuclei are sometimes lobulated and the cytoplasm
may be vacuolated. The myeloblast is a smaller cell with a higher
nucleocytoplasmic ratio. This myeloblast is a type I myeloblast. M4
AML is also referred to as acute myelomonocytic leukaemia
BMABone marrow aspirate (M4 AML) in M4 AML showing a
monoblast, a monocyte and a number of myeloblasts.

Bone marrow aspirate in M5 acute myeloid leukaemia showing a

positive reaction for a-naphthyl acetate esterase, indicative of 'nonspecific esterase' activity. Esterases are classified as specific or
chloroacetate esterase, which is specific for the granulocytic
lineage, and non-specific esterases, which are positive in
monocytes and megakaryocytes and to a variable extent in other
cells

Immunophenotypic Classification
studied by multiparameter flow cytometry
example
M0
demonstration of the myeloid-specific
antigens CD 13 or 33
M7
expression of the platelet-specific
antigens CD41 and/or CD61
Chromosomal Classification
most important pretreatment prognostic information in AML
two cytogenetic abnormalities invariably assoc with a specific
FAB group
t(l5;17)(q22;q12) with M3
inv(16)(p13q22) with M4Eo
recurring chromosomal abnormalities in AML have been
associated with specific clinical characteristics
associated with younger age are t(8;21) and t(l5;17)
with older age, del(5q) and del(7q)
myeloid sarcomas associated with t(8;21)
Disseminated intravascular coagulation (DIC) with t(15;17)
molecular study of many recurring cytogenetic abnormalities
has revealed genes that may be involved in leukemogenesis
t(15;17) encodes a chimeric protein, Pml/Rara, which is
formed by the fusion of the retinoic acid receptor-a (RARa)
gene from chromosome 17 and the promyelocytic
leukemia (PML) gene from chromosome 15
molecular aberrations are used for diagnosis and detection of
residual disease after treatment
molecular aberrations are also useful for classifying risk of
relapse in patients without cytogenetic abnormalities

CLINICAL PRESENTATION
Symptoms
nonspecific symptoms
consequence of anemia, leukocytosis, leukopenia or leukocyte
dysfunction, or thrombocytopenia
fatigue or weakness
anorexia and weight loss
fever
bleeding/ easy bruising
occasionally
bone pain, lymphadenopathy, nonspecific cough
headache, or diaphoresis
rarely
mass lesion located in the soft tissues, breast, uterus,
ovary, cranial or spinal dura, gastrointestinal tract, lung,
mediastinum, prostate, bone, or other organs (granulocytic
sarcoma, or chloroma)
more common in patients with 8;21 translocations

Blood film from an infant with Down's syndrome with M7 AML or

acute megakaryoblastic leukaemia showing megakaryoblasts and
one NRBC. The lineage of the blasts was identified by
immunocytochemistry with a CD61 monoclonal antibody. Down's
syndrome is associated with a greatly increased incidence of M7
AML
Bone marrow aspirate from a case of M7 AML presenting with the
clinical features of acute myelofibrosis. The cytoplasmic blebs are
typical of a megakaryoblast but are not specific for this lineage.

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Physical Findings
fever, splenomegaly, hepatomegaly, lymphadenopathy, sternal
tenderness, and evidence of infection and hemorrhage
significant GI bleeding, intrapulmonary hemorrhage, or
intracranial hemorrhage occur most often in APL
bleeding associated with coagulopathy in monocytic AML
retinal hemorrhages are detected in 15% of patients
Infiltration of the gingivae, skin, soft tissues, or the meninges with
leukemic blasts at diagnosis is characteristic of the monocytic
subtypes (FAB5 M4 and M5)
Hematologic Findings
Anemia is usually present at diagnosis
usually normochromic normocytic
reduced reticulocyte count
erythrocyte survival is decreased by accelerated destruction
active blood loss also contributes to the anemia
Platelet counts
<100,000/ul are found at diagnosis in ~75% of patients
about 25% have counts <25,000/ul
morphologic and functional platelet abnormalities can be
observed, including large and bizarre shapes with abnormal
granulation and inability of platelets to aggregate or adhere
normally to one another
Median presenting leukocyte count is about 15,000/ul
25 to 40% of patients have counts <5000/ul
20% have counts >100,000/ul
<5% have no detectable leukemic cells in the blood
Poor neutrophil function may be noted functionally by
impaired phagocytosis and migration and morphologically
by abnormal lobulation and deficient granulation
Pretreatment Evaluation
evaluate the overall functional integrity of the major organ
systems
Assess factors that have prognostic significance, either for
achieving complete remission (CR) or for predicting the duration
of CR
Leukemic cells should be obtained and cryopreserved for
future use
as new tests and therapeutics become available
All patients should be evaluated for infection
Prompt replacement of the appropriate blood components, if
necessary
Initiation of chemotherapy may aggravate hyperuricemia, and
patients are usually started immediately on allopurinol or
rasburicase and hydration at diagnosis
PROGNOSTIC FACTORS
Many factors influence the likelihood of entering CR, the length
of CR, and the curability of AML
CR is defined after examination of both blood and bone marrow
ANC must be =1500/ul
platelet count =100,000/ul
Circulating blasts should be absent
Bone marrow cellularity should be >20% with trilineage
maturation
bone marrow should contain <5% blasts, and Auer rods
should be absent
Extramedullary leukemia should not be present
patients in CR to detect residual disease
RT-PCR to detect AML-associated molecular
abnormalities
FISH to detect AML-associated cytogenetic aberrations
Age at diagnosis is the most important pretreatment risk factors
advancing age associated with a poorer prognosis
leukemic cells in elderlypatients differs biologically

Performance status, independent of age, also influences ability

to survive induction therapy and thus respond to treatment
Chromosome findings at diagnosis are an independent
prognostic factor
Patients with t(8;21), inv(16), or t(15;17) have good
prognoses
no cytogenetic abnormality have a moderately favorable
outcome when treated with high-dose cytarabine
complex karyotype, inv(3), or -7 have a very poor
prognosis
history of an antecedent hematologic disorder are other
pretreatment clinical features that are associated with a lower
CR rate and shorter survival time
Secondary AML developing after treatment with cytotoxic
agents for other malignancies is extremely difficult to treat
successfully
high presenting leukocyte count is an independent prognostic
factor
FAB classification diagnosis has been found to be an
independent prognostic factor in some series.
Expression of the MDR1 gene adversely influences outcome
several treatment factors correlate with prognosis in AML,
including
achievement of CR,rapidity with which the blast cells
disappear from the blood after the institution of therapy
patients who achieve CR after one induction cycle have
longer CR durations than those requiring multiple cycles

TREATMENT
I. Induction Chemotherapy
initial goal is to quickly induce CR
most commonly used CR induction regimens consist of
combination chemotherapy with cytarabine and an anthracycline
Cytarabine is a cell cycle S-phase-specific antimetabolite that
becomes phosphorylated intracellularly to an active triphosphate form
that interferes with DNA synthesis
Adm as continuous IV infusion at 100-200 mg/m2/day for 7 days
Anthracyclines are DNA intercalaters
mode of action is inhibition of topoisomerase II, leading to DNA
breaks
Daunorubicin, 45 to 60 mg/m2, intravenously on days 1, 2, and 3
or
Idarubicin at 12 or 13 mg/m2 per day for 3 days in conjunction
with cytarabine by 7-day continuous infusion is at least as
effective and may be superior to daunorubicin in younger
patients
Etoposide added to regimen does not increase the CR rate but may
improve the CR duration

After induction chemotherapy, the bone marrow is examined to

determine if the leukemia has been eliminated
If >5% blasts exist with =20% cellularity, retreat with cytarabine
and an anthracycline in doses similar to those given initially, but
for 5 and 2 days
Patients who fail to attain CR after two induction courses
should immediately proceed to an allogeneic SCT if an
appropriate donor exists ,applied to patients <65 to 70 y/o
with acceptable end-organ function

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Team P (,) sec B2 HEMA2012

7 and 3 cytarabine/daunorubicin regimen

65 to 75% of adults with de novo AML achieve CR
Two-thirds achieve CR after a single course of therapy
one-third require two courses
about 50% of patients who do not achieve CR have a drugresistant leukemia
50% do not achieve CR because of fatal complications of
bone marrow aplasia or impaired recovery of normal stem
cells
High-dose cytarabine-based regimens have very high CR rates
after a single cycle of therapy
produced CR rates similar to those achieved with standard
7 and 3 regimens
CR duration was longer after high-dose cytarabine than
after standard-dose cytarabine
The hematologic toxicity is greater than 7,3 regimens
o Myelosuppression
o pulmonary toxicity
o significant and occasionally irreversible cerebellar
toxicity

II.

Postremission Therapy
designed to eradicate any residual leukemic cells
to prevent relapse and prolong survival

High-dose cytarabine
more effective than standard-dose cytarabine
significantly prolonged CR and increased the fraction cured
in patients with favorable [t(8;21) and inv(16)] and normal
cytogenetics
no significant effect on patients with other abnormal
karyotypes
SCT as postremission option
improved duration of remission with allogeneic SCT
compared to autologous SCT or chemotherapy alone
overall survival is generally not different, the improved
disease control with allogeneic SCT is erased by the
increase in fatal toxicity
Supportive Care
Measures geared to supporting patients through several weeks
of granulocytopenia and thrombocytopenia
should be treated in centers expert in providing supportive
measures for their management
Both G-CSF and GM-CSF have reduced the median time to
neutrophil recovery by an average of 5 to 7 days
Multilumen right atrial catheters should be inserted
Adequate and prompt blood bank support is critical to therapy
of AML
Platelet transfusions to maintain a platelet count >10,000 to
20,000/ul
RBC transfusions to keep the hemoglobin level >80 g/L (8 g/dL)
Blood products leukodepleted by filtration should be used to
avert or delay alloimmunization as well as febrile reaction
Blood products should also be irradiated to prevent graftversus-host disease (GVHD
Prophylactic administration of antibiotics in the absence of fever
is controversial
Early initiation of empirical broad-spectrum antibacterial and
antifungal antibiotics has significantly reduced the number of
patients dying of infectious complications
An antibiotic regimen adequate to treat gram-negative and
gram-positive organisms should be instituted at the onset of
fever in a granulocytopenic patient after clinical evaluation
Specific antibiotic regimens should be based on antibiotic
sensitivity data obtained from the institution at which the patient
is being treated

Promyelocytic Leukemia
Tretinoin
45 mg/m2 per day orally until remission is documented
plus concurrent anthracycline chemotherapy appears to be
the safest and most effective treatment for APL
drug that induces the differentiation of leukemic cells
bearing the t(15;17)
not effective in other forms of AML
does not produce DIC
produces another complication called the retinoic acid
syndrome
Treatment complication
Retinoic acid syndrome
Occurring within the first 3 weeks of treatment
characterized by fever, dyspnea, chest pain,
pulmonary infiltrates, pleural and pericardial effusions,
hypoxia
related to adhesion of differentiated neoplastic cells to
the pulmonary vasculature endothelium
Glucocorticoids, chemotherapy, and/or supportive
measures can be effective treatment
mortality rate is about 10%
Arsenic trioxide
produces meaningful responses in up to 85% of patients
refractory to tretinoin
The use of arsenic trioxide is being explored as part of
initial treatment in clinical trials of APL
The detection of minimal residual disease by RT-PCR
amplification of the t(l5;17) chimeric gene product appears to
predict relapse
Relapse
once relapse occurs after the standard induction and
postremission chemotherapy patients are rarely cured with
further standard-dose chemotherapy
Long-term disease-free survival is 30 to 50% with allogeneic
SCT in first relapse or in second remission
Chemotherapy is administered prior to allogeneic transplant if
the AML is rapidly progressing
The most important factors predicting response at relapse are
the length of the previous CR, whether initial CR was achieved
with one or two courses of chemotherapy, and the type of
postremission therapy
treatment with novel approaches should be considered if SCT is
not possible
For elderly patients (age >60)
gemtuzumab ozogamicin (Mylotarg) is another alternative
an antibody-targeted chemotherapy consisting of the
humanized anti-CD33 antibody linked to calicheamicin, a
potent antitumor antibiotic
CR rate in response to this therapy is ~30%
effectiveness of this agent in early relapsing (<6 months)
or refractory AML patients is limited, possibly due to
calicheamicin being a potent Mdr1 substrate
toxicity: myelosuppression, infusion toxicity, and
venoocclusive disease
Currently, studies are examining the efficacy of this treatment in
combination with chemotherapy for both young and older
patients with previously untreated AML
END

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Team P (,) sec B2 HEMA2012

ACUTE LYMPHOBLASTIC
LEUKEMIA

a neoplastic disease that results from somatic mutation in a

single lymphoid progenitor cell at one of several discrete stages
of development
immunophenotype at diagnosis reflects level of differentiation
achieved by the dominant clone
most common malignancy under age of 15 years
25% of all cancers
76% of all leukemias
M>F in all age groups
RISK FACTORS
Genetic syndrome
Down Syndrome
10-30 fold increased risk of leukemia
< 3 y/o AML M7
Older age
ALL
Autosomal recessive dses with increased chromosomal
fragility
Ataxia Telagiectasia
Bloom syndrome
Nijmegen breakage syndrome
Constitutional/Acquired Immunodeficiency states
Congenital X linked agammaglobulinemia
Ig A deficiency
Variable immunodeficiency

Environmental Factors
exposure to diagnostic x-rays ( in utero)
parental cigarette before or during pregnancy
pesticide exposure
maternal alcohol consumption
increased consumption of dietary nitrites
most cases unknown

CLINICAL FEATURES OF ALL

Insidious or acute
features reflect the degree of marrow failure and extent of
extramedullary spread
fever
o induced by pyrogenic cytokines
o results from infection
o resolves within 72 hours after start of induction
anemia manifestations
o fatigue and lethargy
o dyspnea
o dizziness
bone pain, arthralgia, limp
o common in pediatric population
o less severe in adults
o leukemic infiltration of periosteum
less common
o headache
o vomiting
o alteration of mental function
o oliguria
o anuria
occassionally
o IC bleeding
o Life threatening infection
very rarely
o no s/sx
o detected during routine examination

PHYSICAL FINDINGS
Pallor
Petechiae
Ecchymosis
Bone tenderness
Organomegaly (liver, spleen, LN)
Anterior mediastinal mass
o SVC syndrome
o SMS
Enlargement of scrotum
Uncommon
o Ocular involvement
o Subcutaneous nodules
o Enlarged salivary gland
o Cranial nerve palsy
o Priapism
o Cord compression
Infiltration of other lymphoid organs
LABORATORY FEATURES
Anemia
Neutropenia
Thrombocytopenia

WBC
0.1-1500 x 109/L
Median 10-12 x 109/L
>100 x 109/L
10-16% of patients
<0.5 x 109/L
20-40% rendering
High risk for infection
BMA
>20% lymphoblast
other cell lineage depressed
Hypereosinophilia
Increased LDH
Increased BUA
Coagulopathy, mild

DIAGNOSIS AND CELL CLASSIFICATION

1. MORPHOLOGY
Lymphoblast
Small with scanty, often light blue cytoplasm
a round, clefted or slightly indented nucleus
fine to slightly coarse and clumped chromatin
inconspicuous nucleoli
some are large with prominent nucleoli and moderate amount
of cytoplasm, with a admixture of smaller blasts
ALL-L1
ALL-L2
ALL-L3

2.

CYTOCHEMICAL ANALYSIS
special stains to discriminate between ALL and AML
stains that do not react with lymphoblasts
o myeloperoxidase
o Sudan black
o Non specific esterases
Stain that is positive in 70% of ALL cases
o Periodic Acid Schiff

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Team P (,) sec B2 HEMA2012

3.

4.

IMMUNOLOGIC CLASSIFICATION
lymphoblast lack specific morphologic and cytochemical
features
immunophenotyping is essential part of the diagnostic
evaluation
Highly sensitive markers
o CD 19
for B lineage cells
o CD 7
for T lineage cells
o CD 13 and 33 for myeloid cells
Highly specific marker
o CD 79a for B lineage cells
o cytoplasmic CD3 for
T lineage cells
cytoplasmic myeloperoxidase for myeloid cells
GENETIC CLASSIFICATION
arises from a lymphopoietic progenitor cell that has sustained
specific genetic damage leading to malignant transformation
and proliferation

DIFFERENTIAL DIAGNOSIS
ITP
o Assoc recent viral infection
o Large platelet
o Normal Hgb
o No leukocyte abnormalities
Aplastic Anemia
o Hepatosplenomegaly and LAD are rare
o Absent skeletal changes
o Hypocellular BMA
IM other viral infections
o Serologic evidence of EBV infection
Round cell tumors
Neuroblastoma
Rhabdomyosarcoma
Retinoblastoma
o Primary lesions may be found with solid tumors
o Disseminated tumor cells
often present in characteristic aggregates
absent
immunophenotypic
char
of
lymphocytes
THERAPY
SUPPORTIVE CARE
Metabolic Complications
Hyperuricemia
Hyperphosphatemia
Secondary Hypocalcemia
o IV hydration
o Sodium Bicarbonate to alkalinize the urine
o Allopurinol inhibit the de novo purine syn in leukemic blast
cells, and can reduce the peripheral blast cell count before
chemotherapy
o Phosphate binder (eg. Al Hydroxide, CaCO3 or acetate)
Hyperleukocytosis
WBC > 200x 109 /L
Leukopheresis
Exchange transfusion in small children
Pre induction with low dose glucocorticoids, adding vincristine
and cyclophosphamide

Infection Control
Broad spectrum antibiotic until infection is excluded
Special precaution during Remission Induction chemotherapy
o Reverse protective isolation
o Air filtration
o Elimination of contact with people with infectious
o Avoid potentially contaminated food products
Raw cheese
Uncooked vegetables
Unpeeled fruits
o Antiseptic mouthwash
o Sitz baths
o G-CSF
Hasten the recovery from neutropenia
Reduce the complication of intensive chemotherapy
Does not improve the EFS rate
o Prophylaxis for Pneumocystis carinii pneumonia
Co-Trimoxazole 3 days per week
Hematologic support
Platelet transfusion
o For overt bleeding
o Prophylactic transfusion for Platelet ct < 10x 109 /L
o Higher threshold for fever or infection
PRBC transfusion
o Anemia
o Marrow suppression
Granulocyte transfusion
o Rarely needed
ANTILEUKEMIC THERAPY
Remission Induction
to induce CR with restoration of normal hematopoiesis
Glucocorticoid
Vincristine
o Binding to tubulin a protein found n the cytoplasm
of cells
o Leads to inhibition of the process of assembly at
the mitotic spindle arresting cells in metaphase and
inducing apoptosis
o Neurotoxicity >6mg/m2
L asparaginase for children
o capable of rapidly depleting the serum level of Lasparagines, Induces an asparagines deficiency in
lymphoid malignant cells
Anthracycline for adults
o Forming complex with DNA and topoisomerase II,
leading to double stranded DNA strand breaks
CR rate 97-99% in children
70-90% in adults
Intensification/Consolidation
Administered after remission induction
Administration of high doses of multiple agents not used
during induction phase
Readministration of the induction regimen
Appears to improve outcome of treatment
Continuation Therapy
Prolonged continuation therapy needed to kill residuals,
slowly dividing leukemic cells or to suppress their growth
allowing apoptosis to occur
Reduced the likelihood of relapse
2- 3 years
MTX weekly
6Mercapto purine daily

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Team P (,) sec B2 HEMA2012

Therapy for CNS
CNS frequent sanctuary for leukemic cells
Intrathecal CNS
Cranial irradiation 1200cGy provide protection against CNS
relapse
Allogeneic Stem Cell transplant
Beneficial in some high-risk cases/unfavorable prognosis
o Ph Chromosome + ALL
o t(4;11)
Poor initial response to induction therapy or those who require
extended induction therapy to attain remission
COURSE and PROGNOSIS
RELAPSE
Reappearance of leukemic cells at any site in the body
Occur during treatment or within the first 2 years after
completion
Marrow most common site of relapse
TREATMENT SEQUELAE
Death rate among older patients 30%
Neurotoxicity
Cardiotoxicity
Neuropsychiatric and
Endocrine abnormalities
Development of second cancer
o Brain tumor
o AML
PARAMETERS

PROGNOSTIC FACTORS

GOOD

POOR

WBC

Low(<50,000)

High

Age

1-10 years

>10, infants

CALLA( CD10)

Present

Absent

Lymphoid cell type

Early B cell

T cell

Cytogenetics

Normal

Abnormal

FAB

L1

L2

END
God bless in our midterm exam guys
Mwah Mwah mwah tsup tsup tsup

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