ACUTE LEUKAEMIAS

1
ACUTE LEUKAEMIAS Major advances in the
understanding and treatment in recent years has
enabled the possibility of a cure for some acute
leukaemias, e.g. Common Childhood ALL. The
aetiology of acute leukaemias is generally
unknown. Certain viruses and ionising radiation
are possible causes. Children are usually
afflicted by lymphoid leukaemias (good
prognosis). Adults contract mainly non-lymphoid
leukaemias (poor prognosis).
2
CLINICAL PRESENTATION Symptoms of acute leukaemia
are largely the result of interference with
normal haemopoiesis. Reduction in red cell
production anaemia. Reduction in platelet
production bleeding. Reduction in white cell
production infection. Generally it is not
possible on clinical presentation to
differentiate lymphoid from myeloid leukaemia.
3
CLINICAL SIGNS pallor lymphadenopathy hepatospleno
megaly sternal tenderness purpura /
petechiae retinal haemorrhages mouth ulcers gum
hypertrophy (monocytic type)
4
Acute monocytic leukaemia Gingival hypertrophy
5
Acute leukaemia GVHD after BM transplantation.
6
GVHD resulting from unsuccessful BM transplant.
7
LABORATORY FINDINGS Hb is invariably low (30-80
g/L) WBC is usually high (especially
lymphoblastics and monocytics). Can be normal or
low. Plts usually dangerously low PBF shows
varying proportion of blast cells. Generally it
is not possible to differentiate myeloblasts from
lymphoblasts by morphology alone.
8
Coagulation Studies M3 is associated with
disseminated intravascular coagulation (DIC) and
must be distinguished from other forms of AML.
BM Aspirate Infiltration by blasts (gt30 blasts
"frank" acute leukaemia). Cytochemistry Myelop
eroxidase, Sudan black B, esterases and PAS are
most useful.
9
Immunologic Classification (Cell
markers) Availability of monoclonal antibodies
has facilitated the classification of most cell
types. Monoclonals are used in
immunocytochemistry (e.g. APAAP) or can be
utilised in light scattering flow-cell cytometry.
Other Markers e.g. Terminal deoxynucleotidyl
transferase (Tdt) raised in lymphoid, low in
myeloid.
10
Cytogenetics A growing number of chromosome
abnormalities are associated with the acute
leukaemias. Most are structural abnormalities
involving translocations.
11
MANAGEMENT Cytotoxic chemotherapy, radiotherapy
and bone marrow transplantation. The goal is to
eradicate the leukaemic cell mass while giving
supportive care. In children with ALL
postremission therapy includes central nervous
system (CNS) prophylaxis. PROGNOSIS Young
patients do better than old. Patients presenting
with low white counts do better. Must achieve
complete remission (no signs of leukaemia and
return of normal haematology parameters) to
prolong survival.
12
CHRONIC LEUKAEMIAS
CHRONIC GRANULOCYTIC LEUKAEMIA is a disease of
generally unknown aetiology. Radiation has been
implicated, e.g. post atomic bomb cases. The
majority of patients are aged between 30 and 60
yrs. A distinct juvenile type takes a rapidly
malignant course. The disease is one of
insidious onset, often only detected during
routine physical or blood tests
13
SYMPTOMS Non-specific usually patients present
with anaemia and splenomegaly. Tiredness,
lethargy, loss of apetite and loss of
energy. Hypermetabolism (increased sweating,
weight loss and intolerance to heat).
14
LABORATORY FINDINGS   Hb Moderate anaemia
usually between 70 and 110 g/L. WBC Markedly
elevated mainly granulocytic series usually
above 50 x 109/L (mean 250 x 109/L). Plt Normal
or raised. PBF Spread of cells from blasts (low
numbers) to mature granulocytes 20 to 50 are
myelocytes. NAP Neutrophil alkaline phosphatase
score is markedly reduced (usually
lt5). BM Hypercellular with no fat spaces in
fragments. Developing cells are mostly
myeloid. Chromosome Analysis Philadelphia
positive (t 9q 22q-). Juvenile CGL is
Philadelphia negative.
15
Philadelphia Chromosome t 9q 22q?.
16
MANAGEMENT There are two phases in the natural
progress of the disease. 1. Chronic or benign
phase (average duration 3 years). Patients are
asymptomatic. High WBC can be controlled with
chemotherapy, e.g. Busulphan. Treatment is kept
at a minimal level. 2. Blast crisis or malignant
phase Resistant to chemotherapy and survival is
usually less than 6 months. Patients usually
(70) will die with symptoms similar to those of
acute leukaemia. BM transplantation techniques
are now being used with some degree of success
and offer a possible cure.
17
CHRONIC LYMPHOCYTIC LEUKAEMIA Rare in the East,
more common in the West. CLL is a disease of the
elderly and is rarely seen in patients below 40
years of age. Male to female ratio is
21. Patients are often asymptomatic. Lymphocytosi
s is an early feature (usually gt15 x 109/L).
18
SYMPTOMS Non-specific tiredness, loss of
weight, symptoms of anaemia, repeated infections
(especially respiratory), superficial lymph node
enlargement and splenomegaly (usually mild).
19
LABORATORY FINDINGS Hb Normal or moderately
reduced. WBC Raised (20 - 1000 x 109/L) mean 130
x 109/L. Plts Normal or marginally
low. PBF Mostly small, mature looking,
lymphocytes (many smear cells present). BM Infilt
rated (gt20) with similar cells as in
PBF. Immunoglobulin Levels Usually
hypogammaglobulinaemia (explains why prone to
infection).
20
STAGING OF CLL 0 lymphocytosis only (15 x 109/L
or more) 1 enlarged superficial lymph nodes 2
enlarged liver or spleen 3 anaemia (Hb lt110
g/L) 4 thrombocytopenia (lt 100 x 109/L)
21
MANAGEMENT OF CLL May remain symptom free for
many years. Treated with chlorambucil and
steroids in stages 2, 3 and 4. Survival varies
from lt1 year to gt10 years. Patients usually die
of infections, bone marrow failure or a second
malignancy (common in CLL).
22
MYELOPROLIFERATIVE DISORDERS (MPDs) MPDs are
characterised by both haemopoietic and fibroblast
proliferation in the bone marrow. Haemopoietic
tissue in the liver and spleen is also
reactivated (extramedullary haemopoiesis). MPDs
include chronic myeloid leukaemia
(CML) polycythaemia rubra vera
(PRV) idiopathic myelofibrosis
(IM) essential thrombocythaemia (ET)
23

• Neoplastic transformation of a multipotential
  stem cell (e.g. CFU-GEMM) results in abnormal
  myeloproliferation. Classification is based on
  the predominant type of cell affected.
• MPDs share certain characteristics
• insidious onset
• age group gt40 years
• extramedullary haemopoiesis
• BM fibrosis
• chromosomal abnormalities
• likely to terminate in acute leukaemia

24
IDIOPATHIC MYELOFIBROSIS (IMF) Myelofibrosis is
characterised by excessive fibrous (reticular)
tissue in the BM. Myelosclerosis (increase in
collagen fibers) and osteomyelosclerosis (new
bone formation) may also occur. Extramedullary
haemopoiesis (myeloid metaplasia) gives rise to
splenomegaly. The PBF gives a leucoerythroblastic
picture (immature leucocytes and NRBCs). Teardrop
poikilocytes are produced as red cells squeeze
through fibrotic sinusoids in the BM and spleen.
25
BM fibrosis occurs secondary to the mutation of a
haemopoietic stem cell. Pathogenesis of the
original defect is considered separately. Myelofib
rosis results from the accumulation of collagen
produced by fibroblasts in response to stimuli
from the abnormal clone of haemopoietic cells.
Absence of increased red cell mass
(polycythaemia) and negative Philadelphia
chromosome (CML) helps to exclude other chronic
MPDs from the differential diagnosis.
26
POLYCYTHAEMIA RUBRA VERA (PRV) An increased red
cell mass due to an increase in the RBC is
referred to as an absolute polycythaemia. Relative
polycythaemia occurs when the PCV is increased
due to contraction or reduction of plasma
volume. PRV must be differentiated from other
absolute polycythaemias secondary polycythaemia
(arising from tissue hypoxia and erythropoietin
drive) and idiopathic erythrocytosis. The NAP is
useful in differentiating PRV (high score) from
secondary polycythaemia (normal score). Total
leucocyte and platelet counts are also usually
increased in PRV. Red cells are often hypochromic
and microcytic due to exhaustion of storage iron.
27
ESSENTIAL THROMBOCYTHAEMIA (ET) ET is a clonal
disorder resulting from a mutant multipotential
stem cell primarily affecting thrombopoiesis. Mark
ed thrombocytosis (Plt 600 - gt2500 ? 109/L) and
abnormal platelet function are evident. The BM
shows increased numbers of megakaryocytes without
any apparent cause of reactive thrombocytosis.
Absence of the Philadelphia chromosome and
normal red cell mass (Hb lt130 g/L) helps
differentiate ET from other chronic MPDs.
28
Symptomatic patients present with bleeding (e.g.
nose bleeds) or signs of vaso-occlusion (e.g.
necrosis of the extremities, fingers and
toes). Intravascular clumping of platelets can
lead to thrombosis particularly with very high
counts. Either platelet pheresis or chemotherapy
reduces the platelet mass. The presence of giant
platelet forms (megathrombocytes) and
megakaryocyte fragments may interfere with
automated platelet counts and necessitate manual
platelet counting procedures.
29

• MYELODYSPLASTIC SYNDROMES (MDS)
• The term "myelodysplastic syndromes" has been
  adopted to better categorise those conditions
  thought to represent "preleukaemic" states, e.g.
• preleukaemias
• refractory anaemia
• refractory sideroblastic anaemias
• smouldering leukaemias
• dysmyelopoiesis
• subacute leukaemias
• acute myeloproliferative syndromes

30
Myelodysplastic syndromes arise from mutation of
a pluripotential haemopoietic stem
cell. Erythropoiesis, leucopoiesis and
thrombopoiesis are all affected. The MDS clone
proliferates and progressively replaces normal
haemopoietic tissue. Cells derived from the
mutated clone differentiate more slowly than
normal and so the marrow becomes hypercellular
but less efficient in producing mature cells for
the peripheral blood.
31
The mechanism causing the MDS mutation is assumed
to be caused by chemical, radiation or viral
injury. Chromosome 5 is the most frequently
affected (except in CMML). Some patients may have
a genetic predisposition and rapidly progress
into acute leukaemia. This is a disease of the
elderly (lt10 of patients are below the age of
40).
32
The FAB workgroup have established five subtypes
of MPDs 1. RA Refractory anaemia without
ringed sideroblasts (lt5 myeloblasts in bone
marrow). 2. RARS Refractory anaemia with ringed
sideroblasts (gt15 ringed sideroblasts). Also
referred to as acquired idiopathic sideroblastic
anaemia (AISA).
33
3. RAEB Refractory anaemia with excess blasts
(5-20 myeloblasts in BM). 4. RAEB-T Refractor
y anaemia with excess blasts in transformation
(20-30 myeloblasts in BM). Included to bridge
the gap between RAEB (20 blasts) and AML (30
blasts). 5. CMML Chronic myelomonocytic
leukaemia. If not for the monocytosis this
leukaemia may be mistaken for RAEB. Chromosome
analysis may be required to make the diagnosis.
34
FAB criteria for the classification of ANLL
(M1-M7) and MDS requires standardisation in
reporting the percentage of myeloblasts. The
historical definition of a blast cell size,
chromatin pattern, N/C ratio, presence of
nucleoli and absence of granules (except Auer
rods) is now referred to as Type I. Type II
myeloblasts are larger, have a lower N/C ratio
and contain 1-6 nonspecific azurophilic
granules. Cells with more granules are classified
as promyelocytes.
35
All nucleated cells, including erythroid, are
normally included in a BM differential count.
Classification of AML and MDS requires erythroid
cells be excluded from the calculation of the
myeloblast percentage. e.g. Nucleated red cell
precursors (60) myeloblasts (10) others
(30) 60 from 100 40 (which becomes 100 for
the calculation of the myeloblast
percentage). Thus, myeloblasts are 10 in 40 or
25.
100
36
To distinguish between RAEB and AML with gt50
erythroid cells in the BM the erythroid cells are
excluded from the differential count. If gt30 of
the remaining cells are blasts, the diagnosis is
M6. When lt50 of all nucleated cells are
erythroid but gt30 of the other cells are blasts
a diagnosis of AML is likely. The erythroid cells
should still be excluded before reporting the
percentage of blast cells to confirm the
diagnosis of AML. When lt30 of all nucleated
cells are blast cells the diagnosis is MDS.