01 Acute Leukemia

8/10/2019 01 Acute Leukemia

1/43

8/10/2019 01 Acute Leukemia

2/43

Conditions characterised by abnormalproliferation of leucopoietic tissue and

appearance of immature forms of white

cells in the peripheral blood.

8/10/2019 01 Acute Leukemia

3/43

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.

8/10/2019 01 Acute Leukemia

4/43

Classification:

* acute lymphoblastic L.

-----> more common

* acute myeloblastic L.

* acute monocytic L.

8/10/2019 01 Acute Leukemia

5/43

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

-I nvasion of peripheral blood-Infiltration of various organs and tissues

8/10/2019 01 Acute Leukemia

6/43

Relative frequency :-

Adults >14 yearsChildren ( 14 years)Type

%%

10-2565-80Lymphoblastic

206-25Myeloblastic

202-6Myelomonocytic

1-102-6Monocytic

101-2Promyelocytic

30-1Erythroid

10-1Megakaryocytic

8/10/2019 01 Acute Leukemia

7/43

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 marrowhypoplasia, peripheral pancytopenia

(preleukemic syndrome).

8/10/2019 01 Acute Leukemia

8/43

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 cellALL and hairy cell leuk.

8/10/2019 01 Acute Leukemia

9/43

D- Immunological Factors: -

Patient with acquired or congenital immune

deficiency syndrome or subjected to prolonged

immunosuppresive treatment has incidence of

leukemia.

8/10/2019 01 Acute Leukemia

10/43

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 afterage of 20

-A.M.L.--- >more commonly at slightly older agegroups centering around the teen-age or adolescent

period

-A. Monocytic leuk.--->no specific age group.

8/10/2019 01 Acute Leukemia

11/43

Clinical Picture1- 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.

8/10/2019 01 Acute Leukemia

12/43

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.

8/10/2019 01 Acute Leukemia

13/43

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, PASve, 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

8/10/2019 01 Acute Leukemia

14/43

8/10/2019 01 Acute Leukemia

15/43

8/10/2019 01 Acute Leukemia

16/43

8/10/2019 01 Acute Leukemia

17/43

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.

8/10/2019 01 Acute Leukemia

18/43

8/10/2019 01 Acute Leukemia

19/43

Diff- diagnosis :-

The combination of * anemia

* thrombocytopenia

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

8/10/2019 01 Acute Leukemia

20/43

(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.

8/10/2019 01 Acute Leukemia

21/43

(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

8/10/2019 01 Acute Leukemia

22/43

Name Description ICD-O

AML with characteristic geneticabnormalities

Includes: AML with translocations

between chromosome 8 and 21

[t(8;21)] (ICD-O 9896/3);

RUNX1/RUNX1T1

AML with inversions in chromosome

16 [inv(16)] (ICD-O 9871/3);

CBFB/MYH11AML 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.

Multiple

AML with multilineage dysplasia

This category includes patients who

have had a prior myelodysplasticsyndrome (MDS) or

myeloproliferative disease(MPD) that

transforms into AML. This category of

AML occurs most often in elderly

patients and often has a worse

prognosis.

M9895/3

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

be characterized by specific

chromosomal abnormalities, and

often carry a worse prognosis.

M9920/3

AML not otherwise categorizedIncludes subtypes of AML that do not

fall into the above categories.M9861/3

8/10/2019 01 Acute Leukemia

23/43

aaa Name Cytogenetics

M0 leukemiamyeloblasticminimally differentiated acute

M1 leukemia, without maturationmyeloblasticacute

M2 leukemia, with granulocyticmyeloblasticacutematuration

t(8;21)(q22;q22), t(6;9)

M3 (APL)acute promyelocytic leukemiapromyelocytic, or t(15;17)

M4 leukemiamyelomonocyticacuteinv(16)(p13q22),

del(16q)

M4eo eosinophiliatogether with bone marrowmyelomonocytic inv(16), t(16;16)

M5monocyticacutea) or5(Mleukemiamonoblasticacute

b)5(Mleukemiadel (11q), t(9;11),t(11;19)

M6, including erythroleukemiaacute erythroid leukemias

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

M7 acute megakaryoblastic leukemia t(1;22)

M8 acute basophilic leukemia

8/10/2019 01 Acute Leukemia

24/43

The FAB classificationSubtyping of the various forms of

-American-FrenchALL used to be done according to the

which was used for all]18[,British (FAB) classification

,acute myelogenous leukemiaacute leukemias (including

AML).

ALL-L1: small uniform cells

ALL-L2: large varied cells

like-(bubblevacuoles: large varied cells with3L-ALLfeatures)

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

/leukemia.Burkitt's lymphoma) is now classified as3(L

Subtyping helps determine the prognosis and most

appropriate treatment in treating ALL

8/10/2019 01 Acute Leukemia

25/43

WHO proposed classification of acute

lymphoblastic leukemia

The recent WHO International panel on ALL

recommends that the FAB classification be

abandoned, since the morphologicalclassification has no clinical or prognostic

relevance. It instead advocates the use of the

immunophenotypic classification mentioned

below.

1- Acute lymphoblastic leukemia/lymphoma

Synonyms:Former Fab L1/L2Precursor B acute lymphoblastici.

]19[. Cytogenetic subtypes:leukemia/lymphoma

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/MLLPrecursor T acute lymphoblasticii.

leukemia/lymphoma

/lymphomaBurkitt's leukemia-2

Synonyms:Former FAB L3

Biphenotypic acute leukemia-3

8/10/2019 01 Acute Leukemia

26/43

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.

8/10/2019 01 Acute Leukemia

27/43

8/10/2019 01 Acute Leukemia

28/43

Phase Description Agents

Remission

induction

The aim of

remission

induction is to

rapidly kill most

tumor cells and

get the patient into

remission. This is

defined as thepresence of less

than 5% leukemic

blasts in the bone

marrow, normal

blood cells and

absence of tumor

cells from blood,

and absence of

other signs andsymptoms of the

disease.

Combination of

orPrednisolone

dexamethasone

(in children),,vincristine

, andasparaginase

daunorubicin

(used in Adult

ALL) is used to

induce remission

8/10/2019 01 Acute Leukemia

29/43

Intensification Intensification uses high doses of intravenous multidrug

chemotherapy to further reduce tumor burden. Since ALL cells sometimes penetrate

), most protocols include delivery ofCNSthe Central Nervous System (

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,

orthioguanine,etoposide, daunorubicin,cytarabine,cyclophosphamidegiven as blocks in different combinations. For CNS protection,mercaptopurine

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

,hydrocortisonenervous system relapse is treated with intrathecal administration of

methotrexate, and cytarabine.

8/10/2019 01 Acute Leukemia

30/43

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, once weekly oralmercaptopurine

day course of-5, once monthlymethotrexate

and oral corticosteroidsvincristineintravenous

are usually used. The length of maintenance

therapy is 3 years for boys, 2 years for girls and

adults.

8/10/2019 01 Acute Leukemia

31/43

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

8/10/2019 01 Acute Leukemia

32/43

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.

8/10/2019 01 Acute Leukemia

33/43

c- C.N.S. prophylaxis

by * cranial irradiation1800 2400 R

* Intra thecal (l.T.) Methotrexate in

mg/m2 for 5 injection. (twice weekly).

8/10/2019 01 Acute Leukemia

34/43

d- Prolonged maintenance :~

* 2-3 years* Methotrexate 15 mg/m2once or twice weekly

I.M.

* 6M.P 1-2.5 mg/kg daily P.O.

*Cyclophosphamide: 200mg/ m2 p.o. weekly.

8/10/2019 01 Acute Leukemia

35/43

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.

8/10/2019 01 Acute Leukemia

36/43

8/10/2019 01 Acute Leukemia

37/43

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 + cranialirradiation

(3)Fever.

(4)Hge.

(6)Hyperuricemia

8/10/2019 01 Acute Leukemia

38/43

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 tobe cured

- However, bone marrow transplantation if preformed dur ing Fir st

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

8/10/2019 01 Acute Leukemia

39/43

Risk Category Abnormality 5-year survival Relapse rate

Favorablet(8;21), t(15;17),

inv(16)70% 33%

Intermediate

Normal, +8, +21,

+22, del(7q),

del(9q), Abnormal11q23, all other

structural or

numerical changes

48% 50%

Adverse

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

Abnormal 3q,

Complexcytogenetics

15% 78%

8/10/2019 01 Acute Leukemia

40/43

8/10/2019 01 Acute Leukemia

41/43

] Prognosisedit[

The survival rate has improved from zero four decades ago, to 20-75

boneand improvements inclinical trialspercent currently, largely due to

(SCT)stem cell transplantation(BMT) andmarrow transplantation

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.

are more likely to develop acute leukemia thanCaucasiansEthnicity:and tend to have a betterHispanicsandAsians,Americans-African

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

) hasspinal cordorbrain(Central_nervous_systemCancer spread into the

worse outcomes.

Morphological, immunological, and genetic subtypes

Patient's response to initial treatment

Down's Syndromesuch asGenetic disorders

8/10/2019 01 Acute Leukemia

42/43

, the study of characteristic largeCytogenetics

, iscancer cellsofchromosomeschanges in the]13[an important predictor of outcome.

Some cytogenetic subtypes have a worse

prognosis than others

8/10/2019 01 Acute Leukemia

43/43

Cytogenetic change Risk categoryPhiladelphia chromosome Poor prognosis

t(4;11)(q21;q23) Poor prognosis

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

(morekaryotypeComplex

than four abnormalities) Poor prognosis

or nearhypodiploidyLow

triploidyPoor prognosis

hyperdiploidyHigh

(specifically, trisomy 4, 10,

17)

Good prognosis

del(9p) Good prognosis