Conditions characterised by

abnormal proliferation of leucopoietic

tissue and appearance of immature
forms of white cells in the peripheral
blood.

Acute Leukemias
Results from proliferation of young forms of
leucocytes at a stage when they do not enter the
circulation as readily as they do when more mature.

:Classification
.acute lymphoblastic L *
-----> more common
acute myeloblastic*
.L
* acute monocytic L.

ACUTE LEUKEMIAS
Def:
Heterogenous group of neoplastic discases
characterized. by proliferation of atypical elements
which originates from the stem cells of the
hematopoietic system.
the uncontrolled and progressive proliferation
of these cells lead to:- Replacement of normal marrow
- Invasion of peripheral blood
-Infiltration of various organs and tissues

:-Relative frequency
Type

Children ( 14 years)

Adults >14 years

Lymphoblastic

65-80

10-25

Myeloblastic

6-25

20

Myelomonocytic

2-6

20

Monocytic

2-6

1-10

Promyelocytic

1-2

10

Erythroid

0-1

Megakaryocytic

0-1

Etiology:Unknown, some factors seem to be implicated: A- Environmental factors:Ionizing radiation; mainly AML but ALL less important
Chemical substances; prolonged exposure to certain
substances (benzene, phenylbutazone, chloramphenicol,
anticancer drugs, alkylating agents, natulan) --->
incidence of leukemia mainly AML
Onset often preceeded by a state of bone marrow
hypoplasia, peripheral pancytopenia
(preleukemic syndrome).

B-Genetic:May act by facilitating envirnomental factors.

C- Viruses:Based on experiments with laboratory animal, has
never proved humans. Typical products of viruses
have been identified in some adult patients.
With T.ALL:HTLV (human T cell lymphotrophic virus) in T cell
ALL and hairy cell leuk.

D- Immunological Factors: Patient with acquired or congenital immune

deficiency syndrome or subjected to prolonged
immunosuppresive treatment has incidence of
leukemia.

Differential Diagnosis :
------------------------------------------D.D. between various forms of acute
leukemia
is
mainly
on
cytomorphologic,
cytochemical criteria rather than on clinical data,
which are often superimposable.
age: may accur at any age but in general:
-A.L.L --- > the peak incidence in 1st 6 years of
life. Uncommon after age of 20
-A.M.L.--- >more commonly at slightly older age
groups centering around the teen-age or adolescent
period
-A. Monocytic leuk. --->no specific age group.

Clinical Picture
1- Fever: moderate or high grade, usually irregular and shoots up when
2ry infection occur
2-rapidly developing marked asthenia.
3- rapidly developing severe anaemia ---> marked pallor.
4-severe bone ache allover the body
5-Severe sore throat
6- bleeding tendency from --->----- > gums.
-------> skin
--------> orifices
--------->int. organs.
7-tender bones
8- joint pain (bleeding & infiltration)
9-L.N. enlargement in --->------> A.L.L.
---->A.M.L.
---->A. Monocytic L.
10-spleen & Liver enlargement.
11-Chloromas :- more in A.M.L. (subperiosteal tumor like masses)
12-C.N.S --->Focal Hge or infection of nerves or meningies.

Blood Picture :A.L.L :

* R.B.Cs ---> severe form of normocytic
ncrmochromic anemia occurs early.
* W.B.cs ---> ( ) 10,000 --- 100,000 Or more but
40% are leukopenic
- Lymphocytes are likely to be the predominant cells.
- The diagnosis is established by detecting lymphoblastes in
the peripheral smear.
(N.B. Lymphoblastes :
large cells with clear cytoplasm,
prominant nucleus, definite nucleole.
Diff. From mycloblastes :- absent specific granules of
cytoplasm, -ve peroxidase stain
-PAS +ve - Sudan Black -ve or weekly +ve
* platelets : usually < 100.000
may be completetly absent.

2- Myeloblastic Leuk
- W.B.Cs. count as A.L.L.
- Leukopenia is as likely to occur as A.L.L
- The cells are peroxidase +ve, PAS ve, Sudan
black +ve , acid phosphatase +ve
- In 10 - 20% :Auer bodies are present rod like structures.
in cytoplasm of------------> myeloblast
-------------> monoblast

3- Monocytic Leukemia:
- monoblast in the peripheral blood. Stain PAS
-ve, Sudan B +ve, Peroxidase -ve acid phosphatase +ve

Bone marrow aspiration:

Massive proliferation of blast cells even when leukopenia
exist.
* A.L.L-----> lymphoblast
* A.M.L---->myeloblast
*A. monocytic----> monoblasts and monocytes.
*Radiology :-Sketetat involvement in almost all children and 50% of
dults.
* diffuse osteoprosis
* periosteal elevation
* osteolytic lesions
* radiolucent metaphyseal bands.

Diff- diagnosis :The combination of * anemia

* thrombocytopenia
* bone marrow prolif.
primitive white cells is found only in leukemia.

(1)From other causes of sore throat + Fever as:* vincent angina.

*diphtheria.
*infectious, mononucleosis.
*aplastic anemia.
*agranulocytosis.
(2) from other causes of parpura :* I.T.P
*Aplastic anemia.

(3) Lymphadenopathy + splenomegally:* infective mononucleosis

*H.D. .N.H.L. (by blood picture)..
(4) Lymphocytosis :in :.
* whooping caugh
*infective lyrmphocytosis.
(white cells mature, R.B.Cs and platelets are normal).
(5) Rheumtic Fever

Name

AML with characteristic

abnormalities

Description

ICD-O

Includes: AML with translocations

between chromosome 8 and 21
[t(8;21)] (ICD-O 9896/3); RUNX1/
RUNX1T1
with
inversions
in
AML
chromosome 16 [inv(16)] (ICD-O
genetic 9871/3); CBFB/MYH11
Multiple
AML with translocations between
chromosome 15 and 17 [t(15;17)]
(ICD-O 9866/3); RARA;PML
Patients with AML in this category
generally have a high rate of
remission and a better prognosis
compared to other types of AML.

AML with multilineage dysplasia

This category includes patients who

have
had
a
prior
myelodysplastic syndrome (MDS) or
myeloproliferative disease (MPD) that
M9895/3
transforms into AML. This category of
AML occurs most often in elderly
patients and often has a worse
prognosis.

AML and MDS, therapy-related

This category includes patients who

have had prior chemotherapy and/or
radiation and subsequently develop
AML or MDS. These leukemias may M9920/3
be
characterized
by
specific
chromosomal abnormalities, and
often carry a worse prognosis.

AML not otherwise categorized

Includes subtypes of AML that do not

M9861/3
fall into the above categories.

aaa

Name

Cytogenetics

M0

minimally differentiated acute myeloblastic leukemia

M1

acute myeloblastic leukemia, without maturation

M2
M3

acute myeloblastic leukemia, with granulocytic maturatio t(8;21)(q22;q22), t(6;9)

n
promyelocytic, or acute promyelocytic leukemia (APL)
t(15;17)

M4

acute myelomonocytic leukemia

M4eo

eosinophilia myelomonocytic together with bone marrow inv(16), t(16;16)

M5

or ) M5a (acute monoblastic leukemia

acute monocytic leukemia (M5b)

M6

including erythroleukemia, acute erythroid leukemias

(M6a) and very rare pure erythroid leukemia (M6b)

M7
M8

acute megakaryoblastic leukemia

acute basophilic leukemia

inv(16)(p13q22),
del(16q)
del (11q), t(9;11),
t(11;19)

t(1;22)

The FAB classificationSubtyping of the various forms of

ALL used to be done according to the
French-American-British (FAB) classification,[18] which
was used for all acute leukemias (including
.acute myelogenous leukemia, AML)
ALL-L1: small uniform cells
ALL-L2: large varied cells
ALL-L3: large varied cells with vacuoles (bubble-like
features)
Each subtype is then further classified by determining the
surface markers of the abnormal lymphocytes, called
immunophenotyping. There are 2 main immunologic
types: pre-B cell and pre-T cell. The mature B-cell ALL
(L3) is now classified as Burkitt's lymphoma/leukemia.
Subtyping helps determine the prognosis and most
appropriate treatment in treating ALL

WHO proposed classification of acute

lymphoblastic leukemia
The recent WHO International panel on ALL
recommends that the FAB classification be
abandoned, since the morphological
classification has no clinical or prognostic
relevance. It instead advocates the use of the
immunophenotypic classification mentioned
.below
Acute lymphoblastic leukemia/lymphoma- 1
Synonyms:Former Fab L1/L2
i.
Precursor B acute lymphoblastic leukemia/ly
mphoma
[19]
:. Cytogenetic subtypes
t(12;21)(p12,q22) TEL/AML-1
t(1;19)(q23;p13) PBX/E2A
t(9;22)(q34;q11) ABL/BCR
T(V,11)(V;q23) V/MLL
. ii
Precursor T acute lymphoblastic leukemia/ly
mphoma
lymphoma/Burkitt's leukemia- 2

Treatment:Combination chemotherapy
in order to :*
*
*
*

obtain synergestic action

minimize side effects.
attacks leukemic cells in different phases of mitosis.
delay the onset of resistance of the malignant cells.

Acute L. Leuk. effective drugs are

1- vincristine-----> arrest cell mitosis
2- predinsone ----> Lyrmpholysis
3-6.M.P. ----> inhibit DNA synthesis.
4-Methotrexate ----> inhibit RNA and protein
synthesis
5-Doxorubich (adriamycin)----> inhibit DNA
synthesis
6-L- asparaginase

Phase

Description

Agents

The aim of
remission
induction is to
rapidly kill most
tumor cells and
Combination of
get the patient into
Prednisolone or
remission. This is
dexamethasone
defined as the
(in children),
presence of less
Remission
vincristine,
than 5% leukemic
induction
asparaginase, and
blasts in the bone
daunorubicin
marrow, normal
(used in Adult
blood cells and
ALL) is used to
absence of tumor
induce remission
cells from blood,
and absence of
other signs and
symptoms of the
.disease

Intensification Intensification uses high doses of intravenous multidrug

chemotherapy to further reduce tumor burden. Since ALL cells sometimes penetrate
the Central Nervous System (CNS), most protocols include delivery of
chemotherapy into the CNS fluid (termed intrathecal chemotherapy). Some centers
deliver the drug through Ommaya reservoir (a device surgically placed under the
scalp and used to deliver drugs to the CNS fluid and to extract CNS fluid for various
tests). Other centers would perform multiple lumbar punctures as needed for testing
and treatment delivery. Typical intensification protocols use vincristine,
cyclophosphamide, cytarabine, daunorubicin, etoposide, thioguanine or
mercaptopurine given as blocks in different combinations. For CNS protection,
intrathecal methotrexate or cytarabine is usually used combined with or without
cranio-spinal irradiation (the use of radiation therapy to the head and spine). Central
nervous system relapse is treated with intrathecal administration of hydrocortisone,
.methotrexate, and cytarabine

Maintenance therapy The aim of maintenance

therapy is to kill any residual cell that was not
killed by remission induction, and
intensification regimens. Although such cells
are few, they will cause relapse if not
eradicated. For this purpose, daily oral
mercaptopurine, once weekly oral methotrexate
, once monthly 5-day course of intravenous
vincristine and oral corticosteroids are usually
used. The length of maintenance therapy is 3
.years for boys, 2 years for girls and adults

These drugs must be used sequentially and in

combinations:-

a-Induction therapy:* To obtain apparent clinical & hematological remission

* 2 or 3 drugs used
- Vincristine 1.4 mg/m2 I.V. once weekly for 4 weeks...
- prednisone lmg/kg body weight P.O. daily
- L. asparaginase
or Adriamycin

b- Consolidation theraby:*to decrease total no. of residual malignant cells to

10G cells or less.

* e.g. Methotrexate : 15 mg/m2I.M. daily For 3 - 5
days..
followed by cystarabine 100 mg/ m2 I.V. twice
daily for 3-5 days.

c- C.N.S. prophylaxis
by

* cranial irradiation 1800 2400 R

* Intra thecal (l.T.) Methotrexate in
mg/ m2 for 5 injection. (twice weekly).

d- Prolonged maintenance :~
* 2-3 years
* Methotrexate 15 mg/ m2 once or twice weekly
I.M.
* 6 M.P 1-2.5 mg/kg daily P.O.
*Cyclophosphamide: 200mg/ m2 p.o. weekly.

Acute Non Lymphoblastic L.

-The

initial objectives is the induction of a CR. (reduction of

marrow blasts to less than 5%, increase in neutrophils in the
peripheral blood to l.5x 106 /L. or more and of platelets to
100x 106/L. or more.).
-Then consolidation therapy follows, for which identical
drugs are used (the aim is further reduction of leukemic
cells).
- Both in induction and consolidation, high dosage of drugs
are given to produce temporary marrow aplasia.

-After the marrow have recovered from consolidation

therapy, maintenance therapy is given at monthly intervals
usually for 2-3 years, aiming for a further stepwise
reduction of remaining leukemic cells without making the
marrow splastic
-The cornerstone of remission induction and consolidation
chemotherapy is a combination of cytosine-arabinoside and
daunorubicin resulting in 50% CR rates.
-Drugs used for maintenance: cytosine-arabinoside, 6thioguanine, cyclophosphamide and daunarubicin.
However the value of maintenance treatment is
marjinal.

complications :(1)Severe bone ache or massive C.N.S infiltration.

---- > Local irradiation
(2)C.N.S. involvement:
----> intrathecal Mtx. 12 mg I.T./3 days + cranial
irradiation
(3)Fever.
(4)Hge.
(6)Hyperuricemia

Prognosis
(1) A.L.L

----->C.R. ----> 90% of children.

----> 60% of adults.
----> Cure in 70% of children. and 35% of adults.
Allogenic bone marrow transplantation is the only form of
therapy for patients with drug -resistant disease
(2) A.N.L.L.----->C.R is up to 50%
- only about 25% remain disease free after 5 years and can expect to
be cured
However, bone marrow transplantation if preformed during First
remission can improve survival and it has been suggested to be
preformed in all patients younger than 50 years and who have available
HLA identical donor

Risk Category

Abnormality

year survival-5

Relapse rate

Favorable

t(8;21), t(15;17),
inv(16)

70%

33%

Normal, +8, +21,

+22, del(7q),
del(9q), Abnormal
Intermediate
11q23, all other
structural or
numerical changes

48%

50%

del(5q),, 7, -5Abnormal 3q,

Complex
cytogenetics

15%

78%

Adverse

Prognosis[ edit]
The survival rate has improved from zero four decades ago, to 20-75
percent currently, largely due to clinical trials and improvements in
bone marrow transplantation (BMT) and stem cell transplantation (SCT)
.technology
Five-year survival rates evaluate older, not current, treatments. New drugs,
and matching treatment to the genetic characteristics of the blast cells, may
improve those rates. The prognosis for ALL differs between individuals
:depending on a variety of factors
. Sex: females tend to fare better than males
Ethnicity: Caucasians are more likely to develop acute leukemia than
African-Americans, Asians and Hispanics and tend to have a better
. prognosis than non-Caucasians
Age at diagnosis: children between 110 years of age are most likely to
develop ALL and to be cured of it. Cases in older patients are more likely
to result from chromosomal abnormalities (e.g. the Philadelphia
. chromosome) that make treatment more difficult and prognoses poorer
White blood cell count at diagnosis of less than 50,000/l
Cancer spread into the Central_nervous_system (brain or spinal cord) has
. worse outcomes
Morphological, immunological, and genetic subtypes
Patient's response to initial treatment
Down's Syndrome such as Genetic disorders

the study of characteristic large, Cytogenetics

changes in the chromosomes of cancer cells, is
an important predictor of outcome.[13]
Some cytogenetic subtypes have a worse
prognosis than others

Cytogenetic change

Risk category

Philadelphia chromosome

Poor prognosis

t(4;11)(q21;q23)

Poor prognosis

t(8;14)(q24.1;q32)

Poor prognosis

Complex karyotype (more

than four abnormalities)

Poor prognosis

Low hypodiploidy or near

triploidy

Poor prognosis

High hyperdiploidy
(specifically, trisomy 4, 10,
17)

Good prognosis

del(9p)

Good prognosis