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THE LEUKEMIA definition

Leukemia comprises a group of diversediseases that result from the neoplastictransformation of hematopoietic progenitors. Leukemia is a biologically heterogenousdisorder – leukemogenesis may developedat any point during the multiple stages oflymphoid differentiation.

THE LEUKEMIAS etiology and incidence

The childhood leukemias represent about 35% of all childhoodmalignancies.

Acute lymphoblastic leukemia (ALL) accounted for about 1800 of thesecases in the US (an incidence rate of 3,5 /100 000 / year).There is a peak incidence of ALL – 2-5 years of age.• the exact cause of leukemia is unknown• viral infections• ionizing radiation (gamma radiation)• electromagnetic fields• chemical and drugs - exposure to benzene, chlorambucil,

cyclosporin, tobacco, growth hormone• genetic factors- occurrence of familial cases; high incidence in twins;

frequent association with some constitutional karyotypic aberrations, genetic instability syndromes or genetic diseases

• immune deficiency – Wiskott-Aldrich syndrome, ataxiateleangiectasia.

CLASSIFICATIONS

ACUTE LEUKEMIA CHRONIC LEUKEMIA95% 5%

monoculture blast cells more mature cells

• lymphoblastic (HR, SR and IR) • myelogenous (HR, SR)

* myelogenous- adult form- juvenile form

CLINICAL FEATURES OF ALL

• the onset of disease may be insidious or acute• replacement of normal bone marrow by leukemic cells re sults in

anemia, neutropenia, thrombocytopenia• anemia- fatique, weakness, pallor, lethargy

thrombocytopenia - bleeding, cutaneous bruises, purpur a, petechiae, epistaxis, melena, gingival bleeding, gastrointesti nal and intracranialhemorrhage (PLT counts of less than 20 000 / mm 3)

• neutropenia- fever, opportunistic infections• leukemic cells may infiltrate almost any organ of th e body -• enlargement of the liver and spleen (75% of patient s) - anorexia, feeling

of abdominal fullness, weight loss• lymphadenopathy (50% of patients)• CNS involvement (present in less than 10% of cases at diagnosis)• leukemic infiltration of bone or joints or expansion of the marrow - bone

and joint pain• enlargement of the kidneys - asymptomatic• priapism - result of sludging of leukocyte - rich blood in the penile

vasculature or leukemic involvement of sacral nerve ro ots• skin involvement - nodular purpuric lesions of the fa ce and trunk (seen

in congenital leukemia)

Clinical and Laboratory Features at Diagnosis in Child ren with ALL l68

53 30 17

43 45 12

28 4725

84 15 1

Laboratory FeaturesLeukocyte count (mm3)

<10,00010,000-49,000>50,000

Hemoglobin (g/dL)<7.07.0 to 11.0>11.0

Platelet count (mm')<20,000 .20,000-99,000> 100,000

Lymphoblast morphologyLI L2 L3

61 4823 50 63 68

Symptoms and Physical FindingsFeverBleeding (e.g., petechiae or purpura) Bone painLymphadenopathySplenomegalyHepatosplenomegaly

Percentage of Patients

Clinical and/or Laboratory Feature

DIFFERENTIAL DIAGNOSIS OF ACUTE LEUKEMIA

* infectious mononucleosis(generalized lymphadenopathy, splenomegaly, skin rash, purpuric lesions, the presence of large immature cells in the peripheral blood)= the presence of heterophile antibody, a positive mononucleosis spot test,

* infectious lymphocytosis

* pertussis(fever, a very high leukocyte count)

* idiopathic thrombocytopenic purpura (ITP)

* aplastic anemia(pancytopenia, infecion, bleeding manifestation,WITHOUT lymphadenopathy, hepatosplenomegaly, blast cells in peripheral blood)

* rheumatic disease(rheumatic fever, juvenile rheumatoid arthritis)

* neuroblastoma(pseudorosettes in BM specimen = clumps of neuroblastoma cells)= an abdominal mass, abdominal calcification observed on X -ray films, elevetedcatecholamine levels

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Neuroblastoma

ACUTE LYMPHOBLASTIC LEUKEMIA

MorphologyThe French - American - British working group (FAB) classifications:L1 , L2, L3

Cytochemistrypositive reaction with periodic acid - Schiff (PAS) stainnegative reaction with Sudan black stain and myeloperoxidasepositive immunofluorescent stain - for the enzyme terminal deoxynucleotidyltransferase (TdT) in T cell and non-T non-B cell ALL.

Immunophenotypic studiespro-B cell – 5-10%; early pre-B cell – 55-65%; pre-B – 20-25% transistional – 2-3%B-cell- the rarest form of ALL – 2-3% of cases of ALL in childrenT-cell – 13-15% of cases of ALL in children

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Cytogenetic abnormalitiesan abnormal karyotype is detected in 70-95% of ALL dependi ng on the

technique used

t(8;14) - < 3% of childhood ALL (B cell; L3)

t(12;21)(p13;q22) – 20-25% of BCP-ALLGene TEL/AML1

t(1;19)(q23;p13) – 5% of pre-B ALL

t(4;11)(q21;q23)- 2-3% of all ALL (pro-BALL) Gene MLL/AF4

t(9;22)(q34;q11) – 2-3% of childhoodALL Gene BCR/ABL

High hyperdiploid with > 50 chromosomes;

Hyperdiploid with 47-50 chromosomes;

Pseudodiploid (46 chromosomes withstructural or numerical abnormalities);

Diploid (normal 46 chromosomes);

Hypodiploid (< 46 chromosomes);

Structural abnormalitiesNumerical abnormalities

DIAGNOSTIC EVALUATION

• Blood tests – whole blood count including platelets• Differential blood count• Lactate dehydrogenase (LDH)• Electrolytes (Ca, K, Na, phosphate, Mg)• Renal function (creatine, urea, uric acid)• Liver function tests (GOT, GPT, bilirubin)• Coagulation tests(Pt, patrtial thromboplastin time, fib rinogen,

antithrombin III, D dimer)• Immunoglobulin levels (Ig G, M, A, E)• Urinalysis• Bone marrow diagnostics (BM aspiration, trephine biop sy)• CNS diagnostics ( cerebrospinal cell count, protein, gl ucose levels,

cytospin preparation) + cranial CT or MR; EEG; neurologi cexamination

• Cardiology (ECG, echocardiography)• Diagnostic imaging ( chest x-ray/ abdominal sonography f or liver,

spleen, kidney size

Prognostic factors

t(4;11); t(9;22)t(12;21)Chromosomaltranslocations

< 1.16>= 1.16DNA index

< 45> 50Chromosome count

On day 15- M3On day 33- M2/M3

On day 15- M1/M2On day 33- M1

Response to initialtherapy (bone marrow on day 15, 33)

>1< 1Response to initial 7-day prednisone monotherapyplus one IT MTX on day 1(blasts x 10 9/l blood)

>= 25 000< 25 000WBC (x 109 /l)

< 1 year> 1-< 6 yearsAge

UnfavorableFavorableFactor

ALL IC-BFM 2002Antileukemic drugs

• Steroids (Pred)• Vinca alkaloids (VCR)• L-asparaginase• Anthracyclines (DNR)• Folic acid metabolites (MTX)• Purine antagonists (6-MP)• Pyrimidine antagonists (ara-C)• Alkylating agents (Cyc)

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ACUTE NONLYMPHOCYTIC LEUKEMIA

The acute myeloid leukemias are clonal malignantdisorders of the progenitor cells of the granulocyte, monocyte, erythroid and megakaryocyte lineages.All types of ANLL account for about 15-20% of all acuteleukemias in children. AML is the most common acute leukemia in children less than 1 year of age.

Subtypes of Nonlymphocytic Leukemia

FAB cIassification

M1M2M3

M4M5

M6M7

Acute nonlymphocytic leukemia (ANLL)Myeloblastic, no maturationMyeloblastic, some maturationHypergranular promyelocytic

MyelomonocyticMonocytic

ErythroleukemiaMegakaryocytic

Chronic myelocytic leukemia (CML)Adult form .Chronic phase

Blast crisisJuvenile form

Congenital leukemia

Type

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CLINICAL FEATURES

• clinical manifestations of ANLL, like ALL, are mostly a result of leukemic cell infiltration of the marrow thatreplaces normal marrow components,

• collections of leukemic blasts can form lokalized massesin soft tissues, skin, gonads, bones, and sinusesoccasionally, these masses contain a large amount ofthe enzyme myeloperoxidase, which gives them a greenish colour (they are then termed chloromas),

• a characteristic of AMoL is infiltration of the gingiva, lungs, meninges,

• gastrointestinal tract, hepatosplenomegaly andlymphodenopathy - 50% of patients

• bone and joint pain,

Stratification

AML FAB M7

AML FAB M6AML FAB M4Eo; inv.(16)

AML FAB M5AML FAB M1/M2; t(8;21)

AML FAB M4AML FAB M1/M2 with Auer rouds

AML FAB M1/M2 without Auerrouds

AML + Down syndrom

AML FAB M0AML FAB M3; t(15;17)

HRSR

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TREATMENT

lnduction of remission is much more difficult than in patients with ALL. Therapy is associated with severe marrow aplasia and pancytopenia (requiring transfusions of the various blood components and intense supportive care for infection).From 10-30% of patients may die from infection or hemorrhagic complications as a result of therapy.Remission can be obtained in 60-85% of children with ANLL.Consolidation – Reinduction - Maintenance therapy

Allogeneic HSCT into patients with ANLL in remission (this form of treatment is particularly successful in children during firstremission and when HLA -identical sibling is avalaible) -complete remission for a period of 2 years in 70% to 80% of children.

CHRONIC MYELOGENOUS LEUKEMIA

is uncommon in children, accounting less than 5% of all childhood leukemias.two distinct types:- the adult form- the juvenile form

THE ADULT FORM

- a differential count - cells represent all stages of development of thegranulocyte series, from the most immature myeloblasts to normal, maturepolymorphonuclear leukocytes

- bone marrow examinations - hypercellular marrow overpopulated withgranulocytes in all stages of development. The granulocyte/ erythroid ratio is10: 1 to 50: 1 rather than the usual 2: 1 to 5: 1

- chromosomal abnormalities - the Philadelphia chromosome - the result of a deletion in the long arm of chromosome 22, which becomes translocated to another chromosome, usually chromosome 9 (in 80% to 90% of all patientswith CML)

CHRONIC MYELOCYTIC LEUKEMIA

SIGNS AND SYMPTOMS

• lymphadenopathy• hemorrhage (as a result of thrombocytopenia)• splenomegaly• an erythematous facial rash• increase in myeloid cells consisting of

granulocytes and monocytes

COURSE AND TREATMENT

CML progresses through three distinct phases :

*preclinical stage - may last months to years- slight leukocytosis with a left shift- patients are asymptomatic* the chronic phase - typical signs and symptoms of CML have developed* the acute phase - the blast crisis - malaise, fatique, weight loss,

recurrence of splenomegaly, the appearance of lymphadenopathy

CHEMOTHERAPY (busulfan, 6-mercaptopurine, hydroxyurea)- to control the abnormal granulocyte proliferation (10 000-20 000/mm3)

ALLOGENIC HAEMATOPOIETIC STEM CELL TRANSPLANTATlON