Conditions characterised by Conditions characterised by abnormal proliferation of leucopoietic abnormal proliferation of leucopoietic tissue and appearance of immature tissue and appearance of immature forms of white cells in the peripheral forms of white cells in the peripheral blood.blood.

Acute LeukemiasAcute Leukemias

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

ClassificationClassification::

* * acute lymphoblastic Lacute lymphoblastic L..

-----> more common-----> more common

* *acute myeloblastic acute myeloblastic LL..

* acute monocytic L.* acute monocytic L.

ACUTE LEUKEMIASACUTE LEUKEMIAS

Def:Def: Heterogenous group of neoplastic discases Heterogenous group of neoplastic discases characterized. by proliferation of atypical elements characterized. by proliferation of atypical elements which originates from the stem cells of the which originates from the stem cells of the hematopoietic system.hematopoietic system. the uncontrolled and progressive proliferation the uncontrolled and progressive proliferation of these cells lead to:-of these cells lead to:- - Replacement - Replacement of normal marrowof normal marrow

-- Invasion Invasion of peripheral bloodof peripheral blood-Infiltration of various organs and tissues-Infiltration of various organs and tissues

Relative frequencyRelative frequency-: -:

TypeTypeChildren (≤ 14 years)Children (≤ 14 years)Adults >14 yearsAdults >14 years

%%%%

LymphoblasticLymphoblastic65-8065-8010-2510-25

MyeloblasticMyeloblastic6-256-252020

MyelomonocyticMyelomonocytic2-62-62020

MonocyticMonocytic2-62-61-101-10

PromyelocyticPromyelocytic1-21-21010

ErythroidErythroid0-10-133

MegakaryocyticMegakaryocytic0-10-111

Etiology:-Etiology:-Unknown, some factors seem to be implicated: -Unknown, some factors seem to be implicated: -A- Environmental factors:-A- Environmental factors:-•Ionizing radiation; mainly AML but ALL less importantIonizing radiation; mainly AML but ALL less important•Chemical substances; prolonged exposure to certain Chemical substances; prolonged exposure to certain substances (benzene, phenylbutazone, chloramphenicol, substances (benzene, phenylbutazone, chloramphenicol, anticancer drugs, alkylating agents, natulan) anticancer drugs, alkylating agents, natulan) ---> ---> incidence of leukemia mainly AMLincidence of leukemia mainly AML

Onset often preceeded by a state of bone marrow Onset often preceeded by a state of bone marrow hypoplasia, peripheral pancytopeniahypoplasia, peripheral pancytopenia (preleukemic syndrome).(preleukemic syndrome).

B-Genetic:-B-Genetic:- May act by facilitating envirnomental factors. May act by facilitating envirnomental factors.

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

D- Immunological Factors: -D- Immunological Factors: -

Patient with acquired or congenital immunePatient with acquired or congenital immune deficiency syndrome or subjected to prolongeddeficiency syndrome or subjected to prolonged immunosuppresive treatment has ↑ incidence of immunosuppresive treatment has ↑ incidence of leukemia.leukemia.

Differential Diagnosis :Differential Diagnosis :--------------------------------------------------------------------------------------

D.D. between various forms of acute D.D. between various forms of acute leukemia is mainly on cytomorphologic, leukemia is mainly on cytomorphologic, cytochemical criteria rather than on clinical data, cytochemical criteria rather than on clinical data, which are often superimposable.which are often superimposable.

ageage:: may accur at any age but in general: may accur at any age but in general:-A.L.L --- >-A.L.L --- > the peak incidence in 1st 6 years of the peak incidence in 1st 6 years of

life. Uncommon afterlife. Uncommon after age of 20age of 20-A.M.L.--- >-A.M.L.--- >more commonly at slightly older age more commonly at slightly older age

groups centering around the teen-age or adolescent groups centering around the teen-age or adolescent periodperiod

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

Clinical PictureClinical Picture1- Fever: moderate or high grade, usually irregular and shoots up when 1- Fever: moderate or high grade, usually irregular and shoots up when

2ry infection occur2ry infection occur2-rapidly developing marked asthenia.2-rapidly developing marked asthenia.3- rapidly developing severe anaemia 3- rapidly developing severe anaemia ---> ---> marked pallor.marked pallor.4-severe bone ache allover the body4-severe bone ache allover the body5-Severe sore throat5-Severe sore throat6- bleeding tendency from 6- bleeding tendency from --->----- >--->----- > gums. gums. -------> -------> skinskin -------->--------> orifices orifices --------->--------->int. organs.int. organs.7-tender bones7-tender bones8- joint pain (bleeding & infiltration)8- joint pain (bleeding & infiltration)9-L.N. enlargement in 9-L.N. enlargement in --->------> --->------> A.L.L.A.L.L.

---->---->A.M.L. A.M.L. ---->---->A. Monocytic LA. Monocytic L..

10-spleen & Liver enlargement.10-spleen & Liver enlargement.11-Chloromas11-Chloromas :- :- more in A.M.L. more in A.M.L. ((subperiosteal tumor like masses)subperiosteal tumor like masses)12-C.N.S -12-C.N.S --->-->Focal Hge or infection of nerves or meningies.Focal Hge or infection of nerves or meningies.

Blood Picture :Blood Picture :-- A.L.L : * R.B.Cs A.L.L : * R.B.Cs --->---> severe form of normocytic severe form of normocytic ncrmochromic anemia occurs early.ncrmochromic anemia occurs early. * W.B.cs * W.B.cs --->---> ( ) 10,000 --- 100,000 Or more but ( ) 10,000 --- 100,000 Or more but 40% are leukopenic40% are leukopenic- - Lymphocytes are likely to be the predominant cells.Lymphocytes are likely to be the predominant cells.-- The diagnosis is established by detecting lymphoblastes in The diagnosis is established by detecting lymphoblastes in the peripheral smear.the peripheral smear. (N.B. Lymphoblastes :(N.B. Lymphoblastes : large cells with clear cytoplasm, large cells with clear cytoplasm, prominant nucleus, definite nucleole.prominant nucleus, definite nucleole.Diff. From mycloblastes :- absent specific granules of Diff. From mycloblastes :- absent specific granules of cytoplasm, -ve peroxidase staincytoplasm, -ve peroxidase stain-PAS +ve - Sudan Black -ve or weekly +ve -PAS +ve - Sudan Black -ve or weekly +ve * platelets : usually < 100.000* platelets : usually < 100.000may be completetly absent.may be completetly absent.

2- Myeloblastic Leuk2- Myeloblastic Leuk

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

3- Monocytic Leukemia3- Monocytic Leukemia:: -- monoblast in the peripheral blood. Stain PAS -monoblast in the peripheral blood. Stain PAS -ve, Sudan B +ve, Peroxidase -ve acid phosphatase +veve, Sudan B +ve, Peroxidase -ve acid phosphatase +ve

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

Diff- diagnosis :Diff- diagnosis :--

The combination of * anemiaThe combination of * anemia * thrombocytopenia* thrombocytopenia * bone marrow prolif. è * bone marrow prolif. è primitive white cells is found only in leukemia.primitive white cells is found only in leukemia.

(1)(1)From other causes ofFrom other causes of soresore throat + Fever as:-throat + Fever as:-

* vincent angina.* vincent angina. *diphtheria.*diphtheria. *infectious, mononucleosis.*infectious, mononucleosis. *aplastic anemia.*aplastic anemia. *agranulocytosis.*agranulocytosis.

(2) (2) from other causes of parpura :from other causes of parpura :--

* I.T.P* I.T.P *Aplastic anemia.*Aplastic anemia.

(3) Lymphadenopathy + splenomegally:-(3) Lymphadenopathy + splenomegally:- * infective mononucleosis* infective mononucleosis

*H.D. .N.H.L. (by blood picture)..*H.D. .N.H.L. (by blood picture)..

(4)(4) Lymphocytosis :Lymphocytosis :in :. in :. * whooping caugh* whooping caugh

*infective lyrmphocytosis.*infective lyrmphocytosis.(white cells mature, R.B.Cs and platelets are normal).(white cells mature, R.B.Cs and platelets are normal).(5)(5) Rheumtic FeverRheumtic Fever

NameDescriptionICD-O

AML with characteristic genetic abnormalities

•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/MYH11 •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.

Multiple

AML with multilineage dysplasia

This category includes patients who have had a prior myelodysplastic syndrome (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

aaaNameCytogenetics

M0minimally differentiated acute myeloblastic leukemia

M1acute myeloblastic leukemia, without maturation

M2acute myeloblastic leukemia, with granulocytic maturation

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

M3promyelocytic, or acute promyelocytic leukemia (APL)t(15;17)

M4acute myelomonocytic leukemiainv(16)(p13q22), del(16q)

M4eomyelomonocytic together with bone marrow eosinophiliainv(16), t(16;16)

M5acute monoblastic leukemia) M5a (or

acute monocytic leukemia (M5b)del (11q), t(9;11), t(11;19)

M6acute erythroid leukemias ,including erythroleukemia

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

M7acute megakaryoblastic leukemiat(1;22)

M8acute basophilic leukemia

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.1 -Acute lymphoblastic leukemia/lymphoma

Synonyms:Former Fab L1/L2i.

Precursor B acute lymphoblastic leukemia/lymphoma

. Cytogenetic subtypes:[19] 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/lymphoma

2 -Burkitt's leukemia/lymphoma

Synonyms:Former FAB L33 -Biphenotypic acute leukemia

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 mitosis2- 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

PhaseDescriptionAgents

Remission induction

The aim of remission

induction is to rapidly kill most tumor cells and

get the patient into remission. This is

defined as the presence 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 and

symptoms of the disease.

Combination of Prednisolone or dexamethasone

(in children), vincristine,

asparaginase, and daunorubicin

(used in Adult ALL) is used to

induce remission

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 inThese drugs must be used sequentially and in combinations:-combinations:-

a-Induction therapy:a-Induction therapy:--

* To obtain apparent clinical & hematological remission * To obtain apparent clinical & hematological remission * 2 or 3 drugs used* 2 or 3 drugs used - Vincristine 1.4 mg/m2 I.V. once weekly for 4 weeks...- Vincristine 1.4 mg/m2 I.V. once weekly for 4 weeks... - prednisone lmg/kg body weight P.O. daily- prednisone lmg/kg body weight P.O. daily - L. asparaginase- L. asparaginase or Adriamycinor Adriamycin

b- Consolidation theraby:-b- Consolidation theraby:-

**to decrease total no. of residual malignant cells to to decrease total no. of residual malignant cells to 10G cells or less.10G cells or less.

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

c- C.N.S. prophylaxis

by * cranial irradiationby * cranial irradiation 1800 2400 R1800 2400 R * Intra thecal (l.T.) Methotrexate in* Intra thecal (l.T.) Methotrexate in mgmg// m2 m2 for 5 injection. (twice weekly).for 5 injection. (twice weekly).

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

Acute Non Lymphoblastic L.

-The initial objectives is the induction of a CR. (reduction of The initial objectives is the induction of a CR. (reduction of marrow blasts to less than 5%, increase in neutrophils in the marrow blasts to less than 5%, increase in neutrophils in the peripheral blood to l.5x 106peripheral blood to l.5x 106 / /L. or more and of platelets to L. or more and of platelets to 100x 106/L. or more.).100x 106/L. or more.).-Then consolidation therapy follows, for which identical -Then consolidation therapy follows, for which identical drugs are used (the aim is further reduction of leukemic drugs are used (the aim is further reduction of leukemic cells).cells).- Both in induction and consolidation, high dosage of drugs - Both in induction and consolidation, high dosage of drugs are given to produce temporary marrow aplasia.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, 6-thioguanine, cyclophosphamide and daunarubicin. However the value of maintenance treatment is marjinal.

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

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

PrognosisPrognosis((1) A.L.L1) A.L.L

----->C.R. ----> 90% of children.----->C.R. ----> 90% of children. ----> ----> 60% of adults60% of adults..

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

Risk CategoryAbnormality5-year survivalRelapse rate

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

inv(16)70%33%

Intermediate

Normal, +8, +21, +22, del(7q),

del(9q), Abnormal 11q23, all other

structural or numerical changes

48%50%

Adverse

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

Complex cytogenetics

15%78%

[edit ]PrognosisThe 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 1–10 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/µl 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 Genetic disorders such as Down's Syndrome

Cytogenetics ,the study of characteristic large changes in the chromosomes of cancer cells, is

an important predictor of outcome.[13]

Some cytogenetic subtypes have a worse prognosis than others

Cytogenetic changeRisk category

Philadelphia chromosomePoor 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