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WHITE
BLOOD
Virchow 1845
LEUKEMIAS
Leukemias are usually diseases
of unknown etiology
Abnormal
Proliferation
of
Uncontrolled
WBC
Widespread
Leukemia
33%
CNS
20%
Lymphomas
11%
8%
USA
Incidence
Of
Pediatric
Cancer
< 15 yrs
(1970)
Neuroblastomas
6%
Sarcoma
6%
4%
3%
1%
Wilms
Bone
Retinoblastoma
Liver
Ovarian
Testicular
Leukemia
33%
CNS
20%
Lymphomas
11%
8%
USA
Incidence
Of
Pediatric
Cancer
< 15 yrs
(1970)
Neuroblastomas
6%
Sarcoma
6%
4%
3%
1%
Wilms
Bone
Retinoblastoma
Liver
Ovarian
Testicular
ADULT
3% USA
10% KSA
ACUTE
CHRONIC
SHEIKHA
MYELOID/ LYMPHOID
STEM CELLS
(CD34)
LYMPHOID
STEM CELLS
LYMPHOCYTES
HEMOPOIESIS
MYELOID
STEM CELLS
GRANUOCYTES
SHEIKHA
MYELOID/ LYMPHOID
STEM CELLS
(CD34)
LYMPHOBLASTS
LYMPHOCYTES
HEMOPOIESIS
MYELOBLASTS
GRANUOCYTES
CD34
SHEIKHA
MYELOID/ LYMPHOID
STEM CELLS
(CD34)
LYMPHOBLASTS
LYMPHOCYTES
HEMOPOIESIS
MYELOBLASTS
GRANUOCYTES
SHEIKHA
MYELOID/ LYMPHOID
STEM CELLS
(CD34)
LYMPHOBLASTS
LYMPHOCYTES
HEMOPOIESIS
MYELOBLASTS
GRANUOCYTES
Lymphoblasts
Myeloblasts
ALL
AML
CLL
CML
Lymphocytes
Granulocytes
SHEIKHA
MYELOID/ LYMPHOID
STEM CELLS
(CD34)
LYMPHOID
STEM CELLS
LYMPHOCYTES
HEMOPOIESIS
MYELOID
STEM CELLS
RBC
WBC
PLATELET
MYELOID/ LYMPHOID
STEM CELLS
(CD34)
MYELOID
PRONORMOBLAST
EARLY
NORMOBLAST
INTERMEDIATE
STEM CELLS
MYELOBLAST
MONOBLAST
NORMOBLAST
LATE
NORMOBLAST
RETICULOCYTE
RBC
HEMOPOIESIS
PRO
MONOCYTE
MONOCYTE
PRO-MYELOCYTE
MYELOCYTE
META-MYELOCYTE
BAND
or
STAB
GRANULOCYTES
MEGAKARYOBLAST
MEGAKARYOCYTE
PLATELET
SHEIKHA
LYMPHOID
MYELOID/ LYMPHOID
HEMOPOIESIS
STEM
CELLS
(CD34)
STEM CELLS
Pro-B
Pre-T
Pre-B
Thymocyte
Peripheral T Cells
B- Virgin
B- Mature
THelper
TSupp.
LPC
PLASMA
CELL
CD34
SHEIKHA
MYELOID/ LYMPHOID
STEM CELLS
(CD34)
LYMPHOID
STEM CELLS
HEMOPOIESIS
MYELOID
STEM CELLS
ACUTE
CHRONIC
LYMPHOCYTES
GRANULOCYTES
SHEIKHA
HEMOPOIESIS
MYELOID/ LYMPHOID
STEM CELLS
(CD34)
LYMPHOID
STEM CELLS
LYMPHOCYTES
L
Y
M
P
H
O
I
D
ACUTE
CHRONIC
M
Y
E
L
O
I
D
MYELOID
STEM CELLS
GRANULOCYTES
Lymphoblasts
Myeloblasts
Lymphocytes
Granulocytes
Lymphoblasts
Myeloblasts
ALL
AML
CLL
CML
Lymphocytes
Granulocytes
SHEIKHA
MYELOID/ LYMPHOID
STEM CELLS
(CD34)
MYELOID
STEM CELLS
PRONORMOBLAST
AML
CML
HEMOPOIESIS
MONOBLAST
MYELOBLAST
MEGAKARYOBLAST
PRO-MYELOCYTE
MYELOCYTE
META-MYELOCYTE
RBC
MONOCYTE
BAND
or
STAB
GRANULOCYTES
PLATELET
SHEIKHA
LYMPHOID
STEM CELLS
MYELOID/ LYMPHOID
HEMOPOIESIS
STEM
CELLS
(CD34)
Pro-B
Pre-T
Pre-B
B- Virgin
Thymocyte
ALL
Peripheral T Cells
B- Mature
CLL
LPC
THelper
TSupp.
PLASMA
CELL
a
i
m
e
k
eu ro m
L
e
f
t
u
Ac su lts
t
s
e
e
a
r
rr ed
A
n
n
i
o
a
i
t
t
s
a
u
r
L
S
u
A
t
W
M a s ing
E
F
N
O
u
E
E
R
Ca
S
N
N
E
F
O
P
L
X
I
E
E
T
S T HE
A
I
T
T
N
A
RE
E
F
F
I
D
LEUKEMIAS
TYPES
AGE
INCIDENCE
PRESENTATION
BONE
Anemia
Neutropenia
Thrombocytopenia
MARROW
CNS
BONE
SKIN
LYMPHATICS
etc
OTHERS
AGE
IL
CH
EN
DR
ALL
AML
CLL
CML
le
dd
Mi
e
Ag
Elderly
YOUNG BOYS
AGE
son
Grand
Father
Elderly
Big Brother
ALL
AML
CLL
CML
Father
LAB DIAGNOSIS
AML
Cell Morphology
FAB W.H.O.
Classifications
Special Stains
Immunological
Studies
Chromosomal
Changes
FAB CLASSIFICATION
AML
M0
M1
M2
M7
M6
M5
M3
M4
AML
ProNormoblast
Monoblast
Myeloblast
Megakaryoblast
Promyelocyte
20%
FAB CLASSIFICATION
M1
AML
ProNormoblast
Monoblast
Myeloblast
Megakaryoblast
+
Promyelocyte
25-30%
FAB CLASSIFICATION
M2
AML
ProNormoblast
Monoblast
Myeloblast
Megakaryoblast
Promyelocyte
FAB CLASSIFICATION
AML
Acute Hypergranular
Promyelocytic Leukemia
M3
APL
AML
ProNormoblast
Monoblast
Myeloblast
Megakaryoblast
Promyelocyte
20-25%
FAB CLASSIFICATION
AML
M4
AML
ProNormoblast
Monoblast
Myeloblast
Megakaryoblast
Promyelocyte
Monoblasts, promonocytes, or
account for 80% or more of
In M5a, 80% or more of all the monocytic
Negative for MPO and usually positive for
In the well-differentiated subtype M5b,
10%
monocytes
the NEC
cells are monoblasts
nonspecific esterase.
<80% are monoblasts.
FAB CLASSIFICATION
M5
AML
ProNormoblast
Monoblast
Myeloblast
Megakaryoblast
Promyelocyte
5%
FAB CLASSIFICATION
AML Erythroleukemia
M6
AML
ProNormoblast
Monoblast
Myeloblast
Megakaryoblast
Promyelocyte
5%
FAB CLASSIFICATION
M7
FAB CLASSIFICATION
AML
M0
AML
M5
ProNormoblast
Monoblast
M1
Myeloblast
Promyelocyte
M3
M7
Megakaryoblast
AML
ProNormoblast
M4
Monoblast
Megakaryoblast
Myeloblast
M2
M6
Promyelocyte
ALL
FAB CLASSIFICATION
L1
ALL
L2
L3
ACUTE LYMPHOBLASTIC LEUKEMIAS
FAB CLASSIFICATION
Lymphoblasts:
Small & Monomorphic
L1
ALL
FAB CLASSIFICATION
Lymphoblasts:
Large & Heterogeneous
ALL
L2
FAB CLASSIFICATION
Burkitt ALL
ALL
L3
ACUTE LYMPHOBLASTIC LEUKEMIAS
ACUTE LEUKEMIAS
FAB CLASSIFICATION
ALL
L1
L2
L3
M0
M1
M2
AML
M7
M6
M5
M3
M4
ACUTE LEUKEMIAS
FAB CLASSIFICATION
SPECIAL STAINS
M1
L2
LYMPHOBLAST
MYELOBLAST
M5
MONOBLAST
ACUTE LEUKEMIAS
FAB CLASSIFICATION
SPECIAL STAINS
M1
MYELOBLAST
M5
MONOBLAST
L2
LYMPHOBLAST
*Sudan Black
*Myeloperoxidase
*Specific Esterase
DE
Non-Sp
ecific Es
terase
PAS
ACUTE LEUKEMIAS
FAB CLASSIFICATION
SPECIAL STAINS
M1
MYELOBLAST
*Sudan Black
*Myeloperoxidase
ACUTE LEUKEMIAS
FAB CLASSIFICATION
SPECIAL STAINS
MYELOBLAST
Specific
Esterase
DE
MONOBLAST
NonSpecific
Esterase
ACUTE LEUKEMIAS
FAB CLASSIFICATION
SPECIAL STAINS
LYMPHOBLAST
PAS
ACUTE LEUKEMIAS
FAB CLASSIFICATION
SPECIAL STAINS
M1
MYELOBLAST
M5
MONOBLAST
L2
LYMPHOBLAST
*Sudan Black
*Myeloperoxidase
*Specific Esterase
DE
Non-Sp
ecific Es
terase
PAS
5% to 20% of cases
are difficult to
classify by the
FAB system
SHEIKHA
LYMPHOID
STEM CELLS
MYELOID/ LYMPHOID
HEMOPOIESIS
STEM
CELLS
(CD34)
Pro-B
Pre-T
Thymocyte
Pre-B
B- Virgin
B- Mature
Peripheral T Cells
ALL Immunophenotyping
Leukemia Immunophenotyping
ALL or AML?
SmIg
Pallor
Infection
Infection
Oral
Candidiasis
Pneumonia
Purpura
Mucosal Bleeding
Extensive Bruising
Retinal Bleed
Cerebral Bleed
Gum
Hypertrophy
Lymphadenopathy
Leukemic Infiltrate
Testicular
Leukemia
Papilledema
Lytic
Skull
Lesions
Mediastinal Involvement
WBC in AML
100 cells/L to more than 1,000,000 cells/L
~ 15% to 20%
< 50,000/L.
Platelets in AML
Thrombocytopenia is invariably present
In > half of patients, it is less than
50,000/L.
Counts of less than 20,000/L are common.
Giant platelets and poorly granulated
platelets with functional abnormalities
can occur
Thrombocytopenia is due to decreased
platelet production, reduced
megakaryocytes, or DIC.
Marrow in AML
Hypercellular marrow aspiration & Biopsy with
> half leukemic cells (more than 30% in FAB & >20%
in W.H.O.)
The marrow biopsy may be hypocellular, especially
in elderly men and in patients with an antecedent
hematologic disorder (i.e., PNH, Fanconi's anemia,
or MDS) or therapy-related AML
Patients with AML rarely have fewer than 30% bone
marrow blasts but more than 30% peripheral blasts
Patients with AML, especially those with M6 or M7
or a preceding MDS, may show morphologic
abnormalities in the erythroid, granulocytic, and
megakaryocytic lineages
TREATMENT
of
AML
AML Treatment
The goal is to reduce and eventually
eradicate the leukemic cell population while
restoring normal hematopoiesis
Both normal and leukemic cells coexist at
diagnosis & effective therapy will
sufficiently reduce the leukemic cell burden
to allow re-growth of normal myeloid
progenitors.
Non-neoplastic cells repopulate the marrow
after chemotherapy-induced remissions in most
patients
Empiric Antibiotics
Platelet Concentrate
Protective Isolation
Tumor Necrolysis
Hydration, Allopurinol
G-CSF GM-CSF
APL DIC
Factors, Heparin & ATRA
AML Induction
Current induction protocols usually involve drug
regimens with two or more agents, including
anthracycline and cytarabine.
Cytarabine is the single most effective drug
Prolonged exposure (5 to 10 days) to cytarabine at the
commonly used dosages of 100 to 200 mg/m2/day was
recommended.
CALGB showed that the combination of cytarabine and
thioguanine was superior to single-agent cytarabine
for inducing CR
Remission Induction
CR is the reduction of blasts to <5% in
the marrow & restoration of normal
marrow function without evidence of
extramedullary leukemia .
Blood counts should approach normal
values and any organomegaly,
lymphadenopathy, or other extramedullary
evidence of leukemia should resolve.
Normal clinical performance status
AML
Remission-Induction Regimens
Drug
Dosage
(mg/m2)
Route
Course 1
(day)
Course
(day)
Daunorubicin
45
i.v.
1, 2, 3
1, 2
1-5
Daunorubicin
60
i.v.
1, 2, 3
1, 2
Cytarabine
100
i.v. q12h
1-7
1-5
Thioguanine
100
p.o. q12h
1-7
1-5
Mitoxantrone
12
i.v.
1, 2, 3
1, 2
Cytarabine
100
1-5
Cytarabine
3000
i.v. q12h
1, 2
8, 9
-Asparaginase
6000 U/m2
i.m.
%CR in AML
Regimen
Ara-C & Daunorubicin
7-and-3
DAT
Ara-C & Mitoxantrone
High-dose Ara-C
Children
Age <60
Age >60
79
70
31
73
58
34
82
70
51
80
46
67
Metabolic Complications
Metabolic complications of AML may result from
both spontaneous and treatment-induced leukemic
cell lysis. Tumor lysis can lead to
hyperuricemia, hyperkalemia & hyperphosphatemia
with concomitant
hypocalcemia and hyperphosphaturia.
The increase in uric acid is caused by
catabolism of purines and may result in
precipitation of uric acid in the renal
collecting system with subsequent renal failure.
Uric acid nephropathy is avoided by prompt
attention to intravenous hydration,
alkalinization of the urine, and administration
of allopurinol
Leukostasis in AML
Extreme leukocytosis early morbidity and mortality
White thrombi are seen when WBC >150,000/L, but
especially when >300,000/L
(white thrombi) affects blood flow in the lung,
brain, and other organs and eventually leads to
infarction and hemorrhage
The blasts can also compete for oxygen in the
microcirculation and invade and damage vessel walls
Stupor
Coma
Retinal
Engorgement
ARDS
Priapism
Leukostasis can occur in any organ, but the brain and lung appear
to be the major target organs.
Transfusion in AML
Encourage RBC transfusion
prior to Induction
Marrow suppression
?
Leukocyte-poor
Blood
Risk of Bleeding
?
Fresh-frozen
Packed RBC
?
Irradiated Blood
Multiple Units
DIC in AML
APL (M3)
M5
Start Chemotherapy & Control Sepsis
ATRA in APL
FFP
PLATELET
?Heparin
Fever in AML
Infection
Occult or Overt
Leukemia
itself
Amphotericin B
Liposomal Amphotericin
The
M.D.
Anderson
Relapsed AML
806
Patients
On High
Ara-C
OS
At
5 years
5%
Survival
after a
relapse
of
AML
is
very poor
5 year survival
Of
CR
16%
%5-yaer DFS
===========
0
%5-year OS
=========
10
Maintenance
13
19
Maintenance and
intermediate-dose
consolidation x 2
24
33
Intensive consolidation x 1
24
29
Autologous BMT
55
53
Allogeneic BMT
40
45
AML in PREGNANCY
Standard antileukemic chemotherapy
can be administered safely during
the second and third trimesters
In a report of 7 cases and a review of the literature, Reynoso
presented 50 live births among 58 cases of leukemia during
pregnancy, of whom 28 were born premature and 4 had low birth
weight for gestational age.
33% of the newborns exposed to chemotherapy during the third
trimester had cytopenias at birth.
A single newborn had congenital malformations.
EFS
Elderly AML
Treatment of older patients with AML requires special
considerations because of both patient-related and
leukemia-related factors.
Older adult patients often have a poor performance status
and therefore do not tolerate intensive chemotherapy.
Therapy is frequently complicated by concomitant organ
system (especially cardiovascular, pulmonary, and renal)
disease.
AML in older patients is also associated with poor
prognostic characteristics
Elderly AML
ii
Elderly patients have a greater risk of early death from
drug toxicity or infection.
They also have more resistant leukemia than do younger
patients
CR rates for patients older than 60 years have ranged
between 40% and 50%, well below those observed in
younger patients
Elderly AML iv
Low-dose cytarabine has been used on the assumption that it is less toxic
than conventional-dose cytarabine. There is also in vitro but not in vivo
evidence that low-dose cytarabine induces differentiation of leukemic
blasts (630). In a recently reported randomized trial comparing low-dose
cytarabine (20 mg/m2 for 21 days) with an intensive chemotherapy
regimen (rubidazone 100 mg/m2 for 4 days and cytarabine 200 mg/m2
for 7 days) in patients over 65 years of age with de novo AML, there were
a higher number of cases of CR with intensive chemotherapy, but with
low-dose cytarabine there was a lower early death rate, resulting in
similar OSs (628). The ECOG randomized older patients with AML to
either full-dose induction with DAT or attenuated-schedule (reduceddose) DAT and found no difference in the CR rate (28%) or survival (631).
Prognostic factors important in predicting response and outcome in older
adults include age greater than 67 years and CD7 expression, and
abnormal karyotype and CD14 expression, respectively
Favorable
Value
Cytogenetics
t(8;21)inv16
Secondary AML
Not present
Age
<60 yr
Leukocyte count
<100,000/L
FAB subtype
M1/M2/M4/M5
Auer rods
Present
Albumin
>3.5 g/dL
Creatinine
<1.1 mg/dL
Low
Fibrinogen
>250 mg%
Using a combination of
CDs specifically
recognizing B-cell, Tcell, and myeloid
antigens, it is possible
to distinguish AML from
ALL in 95% to 99% of
cases
Immunophenotyping of AML
CD
M1/M2 M3 M4/M5 M6 M7
CD11b
++
CD13
++
CD14
++
CD15
++
++
CD33
++
++
++
++
++
CD34
++
BFM in Children
The BFM Study Group has identified low-risk
and high-risk groups of children with AML.
11q
23
Meningeal
Infiltration
AL
CRANI
W
MARRO
SION
EXTEN
Epidural
Brain
Parenchymal
Leucostasis
5-20%
Of
AML
Meningism
Root Pain
Paraesthesia
AML in SKIN
Leukemia cutis
2% to 13%
M5 AML
~Extramedullary infiltration at other sites
Small (2-mm to 5-mm) raised pink or salmon-colored nodules or bluishgray, firm, rubbery nodules
The skin lesions are painless and are most common on the extremities
or trunk but may involve the face, scalp, and other areas
Chloroma
2% of AML have discrete tumors
Chloroma
Myeloblastoma
Granulocytic Sarcoma
The Orbit
Bone
Anwar Sheikha,
MD, FRCP, FRCPath, FACP
Senior Consultant Clinical & Lab. Hematologis
Classification of
Leukemias
F.A.B.
W.H.O.
F.A.B. Classification
AML
ALL
MDS
MPD
F.A.B. Classification
AML
M1 M2
M0
M3
M4 M5
M6
M7
F.A.B.
AML
M1 M2
M0
M3
M4 M5
M6
M7
F.A.B. Classification
ALL
L1
L2
L3
F.A.B. Classification
RA
RAEB
MDS
RARS
CMML
RAEB-t
MDS
Classification of
Leukemias
W.H.O.
Classification of
Leukemias
W.H.O.
AML
MPD
MDS
MPD
MDS
Classification of
Leukemias
W.H.O.
MPD
CML
MPD?
Ph
CNL
CEL
ET
MF
PRV
Classification of
Leukemias
W.H.O.
CMML
MDS
MPD
aCML
JMML
Classification of
Leukemias
W.H.O.
RA
5q-
RARS
RCMD
RAEB
MDS
MDS?
Classification of
Leukemias
W.H.O.
AML
with recurrent
Cytogenetic
translocations
AML with
Multilineage dysplasia
AML
not otherwise
categorized
AML
Classification of
Leukemias
W.H.O.
AML
with recurrent
Cytogenetic
translocations
t(8:21)
98% of APC
AML
40% of M2
80% of M4Eo
t(15;17)
11q23
inv(16)
20% of M4 & M5
Classification of
Leukemias
W.H.O.
AML
AML with
Multilineage dysplasia
Classification of
Leukemias
W.H.O.
AML
M0
M1
M2
M4
Classification of
Leukemias
W.H.O.
AML
M3
M5
AML
not otherwise
categorized
M6
M7
ABL* APMF
*
CML
The First Disease
Lymphoblasts
Myeloblasts
ALL
AML
CLL
CML
Lymphocytes
Granulocytes
CD34
C
WBC
M
L
CLL