LEUKEMIAS

WHITE
BLOOD
Virchow 1845

Assam El Din El Tarazawi

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

ACUTE MYELOID LEUKEMIA

LAB DIAGNOSIS

AML

Cell Morphology
FAB W.H.O.
Classifications
Special Stains
Immunological
Studies
Chromosomal
Changes

ACUTE MYELOID LEUKEMIA

FAB CLASSIFICATION

AML

M0
M1
M2

M7
M6

M5
M3
M4

AML
ProNormoblast

Monoblast

Myeloblast

Megakaryoblast

Promyelocyte

large, poorly differentiated myeloblasts represent 90%

or more of the nonerythroid cells.
At least 3% of the myeloblasts stain positive for MPO

20%

ACUTE MYELOID LEUKEMIA

FAB CLASSIFICATION

AML AML without Differentiation

M1

Two types of M1 blasts have been defined.

Type I blasts are primitive cells that lack
granules and usually contain one or more
nucleoli.
Type II blasts are slightly larger, have a
lower N/C ratio, and contain one to six
azurophilic granules.
Unlike in promyelocytes, the nucleus of the
type II blast is central, the nuclear
chromatin is uncondensed, and the Golgi
zone is not prominent.

AML
ProNormoblast

Monoblast

Myeloblast

Megakaryoblast

+
Promyelocyte

30% and 89% of the nonerythroid cells are myeloblasts

Auer rods are often visible.
Myeloblasts are MPO positive

25-30%

ACUTE MYELOID LEUKEMIA

FAB CLASSIFICATION

AML AML with Differentiation

M2

AML
ProNormoblast

Monoblast

Myeloblast

Megakaryoblast

Promyelocyte

Heavy azurophilic granulation

Nuclear size varies greatly
Nuclei are often bilobed or kidney-shaped.
Some cells contain bundles of Auer rods (Faggot cells)
Leukemia cells strongly positive for MPO
Microgranular variant
8-15%

ACUTE MYELOID LEUKEMIA

FAB CLASSIFICATION

AML

Acute Hypergranular
Promyelocytic Leukemia

M3

APL

APL Agranular Type

AML
ProNormoblast

Monoblast

Myeloblast

Megakaryoblast

Promyelocyte

Myeloblasts, promyelocytes, myelocytes, & other

Granulocytic precursors account for >30% of the NEC but <80%
Monocytic cells account for up to 20% of the NEC
Double Esterase positive.
Auer rods may be present.

20-25%

ACUTE MYELOID LEUKEMIA

FAB CLASSIFICATION

AML

Acute MyeloMonoblastic Leukemia

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.

ACUTE MYELOID LEUKEMIA

FAB CLASSIFICATION

AML Acute Monoblastic Leukemia

M5

AML
ProNormoblast

Monoblast

Myeloblast

Megakaryoblast

Promyelocyte

>50% of the nucleated marrow cells are erythroid.

Erythroblasts usually strongly PAS positive
Myeloblasts represent 30% or more of the NEC

5%

ACUTE MYELOID LEUKEMIA

FAB CLASSIFICATION

AML Erythroleukemia

M6

AML
ProNormoblast

Monoblast

Myeloblast

Megakaryoblast

Promyelocyte

Large and small megakaryoblasts with high N/C ratio

Cytoplasm is pale and agranular
Standard cytochemical stains not definitive
PPO and platelet-specific antibodies often positive
Factor VIII may be positive.

5%

ACUTE MYELOID LEUKEMIA

FAB CLASSIFICATION

AML Acute Megakaryoblastic

Leukemia

M7

ACUTE MYELOID LEUKEMIA

FAB CLASSIFICATION

AML

M0

AML with Minimal

Differentiation

Large, agranular myeloblasts,

sometimes resembling lymphoblasts of FAB subtype L2.
Stain negative for MPO and Sudan black.
Express CD13 or CD33
2-3%

AML
M5
ProNormoblast

Monoblast

M1
Myeloblast

Promyelocyte

M3

M7
Megakaryoblast

AML

ProNormoblast

M4

Monoblast

Megakaryoblast

Myeloblast

M2
M6

Promyelocyte

ACUTE LYMPHOBLASTIC LEUKEMIA

FAB CLASSIFICATION

ALL

FAB CLASSIFICATION

L1
ALL

L2
L3
ACUTE LYMPHOBLASTIC LEUKEMIAS

FAB CLASSIFICATION
Lymphoblasts:
Small & Monomorphic

L1

ALL

ACUTE LYMPHOBLASTIC LEUKEMIAS

FAB CLASSIFICATION
Lymphoblasts:
Large & Heterogeneous

ALL

L2

ACUTE LYMPHOBLASTIC LEUKEMIAS

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

In the 10% to 20% of cases in

which morphology and
cytochemistry are inconclusive or
insufficient to distinguish AML and
ALL, immunophenotype analysis
provides the diagnosis in virtually
all cases

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

TdT & CALLA

TdT & HLA-DR

T Antigen & TdT

CSF Cytospin TdT

Testicular TdT & CALLA

ALL or AML?

TdT & Myeloid

SmIg

TdT & Cyt.u

Pallor

Infection

Infection

Oral
Candidiasis

Pneumonia

Purpura

Mucosal Bleeding

Extensive Bruising

Retinal Bleed

Cerebral Bleed

Gum
Hypertrophy

Lymphadenopathy

Leukemic Infiltrate

Testicular
Leukemia

Leukemic Skin Infiltrate

Papilledema

Lytic
Skull
Lesions

Mediastinal Involvement

WBC in AML
100 cells/L to more than 1,000,000 cells/L
~ 15% to 20%

> 100,000/L, but most

< 50,000/L.

The highest counts in M4 and M5, whereas patients with M3,

except the microgranular variant of APL, tend to have a low
leukocyte count at diagnosis.
Most patients have < 1000 neutrophils/L and a variable
percentage of blasts.
~ 10%, no peripheral blasts are detectable.
Other leukocyte abnormalities may be present, including
Pelger-Huet or hypogranular mature neutrophils

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

Before the late 1940s, there was no treatment available.

From 1970 to 1985, NCI introduced 83 drugs
into clinical trial. Amsacrine, 5-azacytidine, doxorubicin,
etoposide & mitoxantrone have been shown to be active in AML.
During the 1960s, the anthracyclines (doxorubicin,
daunorubicin) and cytarabine (cytosine arabinoside), the two
most active agents in the treatment of AML, entered clinical
trial.
Improvements in supportive care made it safe and feasible to
treat patients with myelosuppressive therapies.
Carefully designed clinical trials, and increasing numbers of
physicians trained in the complex medical treatment of
patients with leukemia, also contributed to increased
survival rates

AML Survival by AGE

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

Supportive Care in AML

Central Venous Access

Empiric Antibiotics

Red Cell Transfusion

EPO not effective

Platelet Concentrate

Protective Isolation

Tumor Necrolysis
Hydration, Allopurinol

G-CSF GM-CSF

APL DIC
Factors, Heparin & ATRA

Supportive Care in AML

With the exception of APL, the treatment of AML is
rarely an emergent situation, but rather is subacute.
The initial hours of treatment are directed toward
stabilizing the patient with respect to metabolic
parameters, bleeding, fever and infection, and other
life-threatening problems
An indwelling central venous catheter (e.g., Hickman
or Broviac) should be placed by a surgeon early in the
treatment course unless the patient has APL. This
access facilitates administration of chemotherapy,
antibiotics, and blood components and also permits
repetitive sampling of blood for diagnostic purposes

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

Cytarabine (7-and-3) 100-200

Continuous i.v. infusion 1-7

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

Continuous i.v. infusion 1-7

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

Consolidation & Maintenance Treatment

The leukemic cell burden is reduced by at
least 2 to 3 logs (109 to 1012 cells) during
the remission-induction period.
Additional therapy is required to eradicate
the residual leukemia.
Therapy administered to patients after CR has
been referred to as either consolidation,
intensification (both imply intensive
chemotherapy rendering the bone marrow
temporarily hypoplastic or aplastic
associated with blood product support), or
maintenance treatment (implies less
intensive, usually outpatient chemotherapy
often not requiring blood product support

The induction of CR is successful in 70% to 80% of

children and adults who are younger than 60 years
with AML.
Lower remission rates are seen in older adults and in
patients with therapy-related AML or certain
cytogenetic findings.
The cause of the lower remission rates in older
adults may be attributable to the inability of the
older patient to tolerate intensive chemotherapy,
reluctance to administer intensive chemotherapy in
this setting, and more resistant leukemia cells

Marrow should be assessed within 10 to 14 days

Follow-up marrow aspirates in the absence of
additional chemotherapy usually show CR.
If it is difficult to distinguish leukemic blasts or
promyelocytes from a recovering myeloid picture, a
bone marrow sample should be obtained again in
several days.
If the repeat marrow shows persistence of blasts, a
second induction cycle should commence.
Approximately 2/3who achieve CR do so after one
cycle of induction, and the remainder after a second
course

The most common lesions of the oral cavity

during remission induction are superficial
infections due to C. albicans. This infection is
easily controlled by
Nystatin suspension 1 million IU q6h or
clotrimazole troches 10 mg four times a day.
Herpes simplex is the most common viral pathogen
isolated from mucosal lesions.
I.V. Acyclovir 250 mg/m2 q8h for 7 to 14 days
Chemotherapeutic agents are frequently
responsible for oral mucositis and esophagitis
during remission induction

Necrotizing Enterocolitis in AML

The most serious intraabdominal complication
during remission induction is typhlitis
necrotizing enterocolitis
It is an inflammatory cellulitis of the distal
ileum, cecum, ascending colon & appendix
Occurs in the setting of neutropenia & cytotoxic
drug-related mucosal injury.
Fever, right lower quadrant pain & diarrhea.
diarrhea
Gram-negative bacillary & occasionally anaerobs
Treated by cessation of oral feeding, parenteral
nutrition & broad-spectrum antibiotics.

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.

. The immediate goal of therapy is to lower rapidly the

peripheral blast count.
Hydroxyurea 3 g/m2/day orally for 2 days.
Leukapheresis once daily.
Leukapheresis is recommended for the patient who already has
clinical signs and symptoms of leukostasis.
In the newly diagnosed patient with AML and a leukocyte count
greater than 150,000/L, it is critical to initiate promptly
remission-induction chemotherapy along with intravenous hydration
and allopurinol

Transfusion in AML
Encourage RBC transfusion
prior to Induction
Marrow suppression

?
Leukocyte-poor
Blood

Risk of Bleeding

?
Fresh-frozen
Packed RBC

?
Irradiated Blood

Platelet Transfusion in AML

Very Important
1 unit per 10 kg B.Wt.
Threshold Platelet Count for
Prophylactic Platelet Transfusion
? 10,000/uL
Single Donor

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

Respiratory, dental, sinus, perirectal, urinary tract, skin

Empiric Broad-Spectrum Antibiotics

If Neutropenia & fever persists to the second to fourth week of induction,
Consider
Candida albicans or Aspergillus species

Amphotericin B

Liposomal Amphotericin

The
M.D.
Anderson
Relapsed AML

806
Patients
On High
Ara-C

1st Relapse Post-Relapse

Median Survival
CR
33%
18
weeks

OS
At
5 years
5%

Survival
after a
relapse
of
AML
is
very poor

5 year survival
Of
CR
16%

The most important prognostic factors in relapsed and refractory AML

is the duration of first CR

Escalating Intensity of Post-remission Therapy in

Patients < 55 Years in Five ECOG Trials
Post-Remission Therapy
===================
Observation

%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.

Long-Term Survival in Childhood AML

CCSG
4-year survival from 19% to 36% for 1000 AML children
treated on CCSG protocols between 1972 and 1983
The risk of death or relapse in each year of followup decreased progressively from a high of 43% in the
first year to 8% by the fourth year and remained
close to 5% for the next 5 years .

The German BFM Study Group

>300 children with AML between 1978 and 1986
with intensive induction and consolidation 2 years of maintenance

EFS

from 38% to 49%

Long-Term Survival in Adult AML

ECOG
1974-1996
10% 30 to 40%
Age older than 60 years was an adverse prognostic
factor for relapse-free survival in the CALGB trials as
well as in other studies of older adults with AML.
The detection of MRD
by immunophenotyping is useful in predicting relapse

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 iii

A large proportion of patients with AML are over 65 years of age.
Some investigators questions treating older patients with AML
A study conducted by the Dutch-Belgian Hematology-Oncology
Cooperative Group (HOVON) compared immediate standard
induction chemotherapy versus supportive care with or without mild
cytotoxic therapy (given only for relief of progressive symptoms
related to an increased leukemic cell burden)
supportive care yielded only extremely poor results.
Complete remission was not achieved in the supportive care group,
compared with a 58% CR rate in the chemotherapy-treated group.
There was also a significantly longer survival for the latter group
(median survival, 21 vs. 11 weeks).

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

High CR rates (55%) can be achieved in older

adults with mitoxantrone plus etoposide without
cytarabine (633). In a single-institution experience
of 784 patients with newly diagnosed AML, there
has been little, if any, improvement in the
outcome of treatment of older (>60 years) adults
(634) (Fig. 15-15).

Patient Characteristics Related to CR Rate

Characteristic

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

Leukemia blast self-renewal

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

++

Favorable Risk factors in AML

Patient Characteristics Related to Complete
Remission Rate CharacteristicFavorable
ValueCytogeneticst(8;21) or inv(16)Secondary
acute myelogenous leukemiaNot presentAge<60
yrLeukocyte
count<100,000/LFrench/American/British
subtypeM1, M2, M4, M5Auer
rodsPresentAlbumin>3.5 g/dLCreatinine<1.1
mg/dLLeukemia blast selfrenewalLowFibrinogen>250 mg%

DFS of APL on ATRA +

BFM in Children
The BFM Study Group has identified low-risk
and high-risk groups of children with AML.

The low-risk group accounted for 37% of the

patients who achieved remission and included

those with M1 and Auer rods, M2 with leukocyte
counts lower than 20,000/L, M3, and M4 with
eosinophilia.

The 6-year relapse-free survival was 91% for the

low-risk children and 42% for those in the highrisk category

11q

23

Infants (median age, 6 months)

M4 or M5 AML,
Hyperleukocytosis
Frequent coagulation abnormalities
Eraly Relapse

CNS involvement in AML

HEMA
TO
GENO US

Meningeal
Infiltration
AL
CRANI
W
MARRO
SION
EXTEN

Epidural

Brain
Parenchymal
Leucostasis

5-20%
Of
AML

ICP Nausea/ Vomiting/ Lethargy/ Headache/ Papilledema

Meningism

Cranial nerve Palsy

Root Pain

Paraesthesia

CNS involvement in AML

COMMON IN:
M4 & M5
WBC
Lysozyme
Inv(16)
LDH
Extramedullary spread at other sites

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

May antedate bone marrow involvement

or
may be a harbinger of imminent marrow relapse

Chloroma
2% of AML have discrete tumors
Chloroma
Myeloblastoma
Granulocytic Sarcoma
The Orbit
Bone

Para-nasal sinuses Brain

Spinal cord
Breast Skin & Subcutaneous tissues

Called chloromas because of greenish color from MPO

Recent Advances in the Management

of Leukemias

Anwar Sheikha,
MD, FRCP, FRCPath, FACP
Senior Consultant Clinical & Lab. Hematologis

Recent Advances in the Management of Leukemias

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

Recent Advances in the Management of Leukemias

Classification of
Leukemias

W.H.O.

Recent Advances in the Management of Leukemias

Classification of
Leukemias

W.H.O.
AML

MPD
MDS
MPD

MDS

Recent Advances in the Management of Leukemias

Classification of
Leukemias

W.H.O.

MPD

CML

MPD?

Ph

CNL
CEL

ET
MF

PRV

Recent Advances in the Management of Leukemias

Classification of
Leukemias

W.H.O.
CMML

MDS
MPD

aCML
JMML

Recent Advances in the Management of Leukemias

Classification of
Leukemias

W.H.O.

RA

5q-

RARS
RCMD
RAEB

MDS

MDS?

Recent Advances in the Management of Leukemias

Classification of
Leukemias

W.H.O.

AML
with recurrent
Cytogenetic
translocations

AML with
Multilineage dysplasia

AML

not otherwise
categorized

AML & MDS

Therapy-related

AML

Recent Advances in the Management of Leukemias

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

Recent Advances in the Management of Leukemias

Classification of
Leukemias

W.H.O.
AML

AML with
Multilineage dysplasia

Recent Advances in the Management of Leukemias

Classification of
Leukemias

W.H.O.
AML

AML & MDS

Therapy-related

M0
M1

M2

M4

Recent Advances in the Management of Leukemias

Classification of
Leukemias

W.H.O.
AML

M3

M5

AML

not otherwise
categorized

M6

M7

ABL* APMF
*

CML
The First Disease

The First Disease

The 1st disease for which the term leukemia was used
(Virchow 1845; White Blood)
The 1st malignancy ~ with a recurring chromosomal
abnormality (Philadelphia Chromosome)
The first disease in which the associated chromosomal
abnormality was found to result from the translocation of
genetic material from one chromosome to another to form
fusion gene (BCR/ABL)
The first disease in which the fusion gene was recognized
as giving rise to an abnormal fusion protein fundamental
in the pathogenesis of the disease.
The first disorder in which a therapeutic
agent Glivec has been designed to
specifically target the molecular defect

Lymphoblasts

Myeloblasts

ALL

AML

CLL

CML

Lymphocytes

Granulocytes

CD34

C
WBC

M
L

CLL