leukemia in children

Epidemiology. Approximately 2,800 children are diagnosed with ALL in the United States annually. It has a striking peak incidence between 2–6 yr of age and occurs slightly more frequently in boys than in girls.

IntroductionLeukemia – the most common malignancy in

childhood.Acute leukemia– 97% Acute lymphoblastic leukemia– 75% Acute myeloblastic leukemia– 20%Chronic leukemia– 3% Chronic myelogenous leukemia (Ph positive) Juvenile myelomonocytic leukemia ( JMML)

LeukemiaThe most common childhood cancer ( 1/3 of

pediatric malignancies ).Acute lymphoblastic leukemia (ALL) represents

about 75 % (peak incidence at age 4 years).Acute myeloid leukemia (AML) accounts for

about 20 % of leukemia (stable from birth through age 10)

Others : CML

Acute Lymphoblastic LeukemiaIn the United States, about 3,000 children each year

are found to have ALL Peak incidence occurs from 3 to 5 years of age.

Acute Lymphoblastic Leukemiathe most common symptoms of

leukemia:fever, anemia, bleeding and/or bruising, reccurent infections ,persistant weakness or tiredness,

achiness in the bones or joints, difficulty breathing (dyspnea) , adenohepatosplenomegaly

Clinical manifestations

Bone marrow failure & Organ infiltrationCommon symptoms Fever ( 60%) Malaise ( 50%) Pallor ( 40%)

EtiologyUnknown ( usually)Hereditary Down’s syndrome Leukemia in siblingsChemicals Chronic benzene exposure Alkylating agents Ionizing radiationPredisposing hematological disease

( MPD, AA)Viruses ( HTLV-1)

Diagnostic criteriaALL is often difficult to diagnose.The early signs may be similar to the flu or other

common diseases.

Diagnostic criteriabone marrow aspiration and biopsy complete blood count (CBC) additional blood tests, genetic, molecular

tests computerized tomography scanmagnetic resonance imaging (MRI)x-ray ultrasoundlymph node biopsy spinal tap/lumbar puncture

Diagnostic criteriaPeripheral blood: anemia,thrombocytopenia,

variable white cell count with or without blasts.Bone marrow: hyper-or hypo-cellularity with excess

of blasts (blasts>30% of nucleated cells).

Diagnostic criteriaCytochemistry study and surface marker study

confirm the lymphoid origin .

V-25 Leukemic cells in acute lymphoblastic leukemia characterized by round or convoluted nuclei, high nuclear/cytoplasmic ratio and absence of cytoplasmic graulnes.

Differential diagnosisAML. MDS.Non-Hodgkin‘s lymphoma with bone marrow

involvement or with leukemic change.Aplastic anemiaHIV infectionsEBVCMVSystemic form of juvenile chronic arthritis

Acute lymphoblastic leukemia

Laboratory examinationsFull blood count Coagulation screening – especially AML

M3.Biochemical screeningChest radiographyBone marrow aspirationImmunophenotypingCytogenetics & molecular studiesLumbar puncture ( CNS involvement)

ComplicationsCerebral hemorrhage, pulmonary hemorrhage or

other vital organ hemorrhage.Infection(sepsis or septic shock ) , pulmonary

edema.Tumor lysis syndrome.Hyper KHyperPo4).Coagulopathy before or after chemotherapy. Anemia.

Risk Grouping of TPOG (ALL)Standard RiskHigh Risk– CNS leukemia, cranial nerve

palsy, testicular leukemia, pre-B ALL t(1;19) or E2A-PBX1 fusion

Very High RiskWBC > 100000/mm3

T – cell< 1y/oLymphoblastic lymphoma with bone

marrow lymphoblasts > 25%t(9;22) or BCR-ABL fusiont(4;11) or MLL-AF4 fusionOther MLL gene rearrangementHypodiploidy ( chr 44 or less)

Poor Prognosis (I) Acute lymphoblastic leukemia

RelapseBone marrow– the most common site, blast cell increaseCNS– IICP ( vomiting, headache, papilledema, lethargy) Convulsion Behavior disturbanceTestis– painless swelling

Survival rates75 % to 80% of children with ALL survive at least 5

years from diagnosis with current treatments that incorporate systemic therapy (e.g., combination chemotherapy) and specific central nervous system (CNS) preventive therapy (i.e., intrathecal chemotherapy with or without cranial irradiation).

TreatmentChemotherapy – reach to remission (blast<5%) CNS prophylaxis Intrathecal C/T

Cranial irradiation Bone marrow transplantation

Management and treatmentHydration, prevention of hyperuricemia and

tumor lysis syndrome.Antibiotics, may need the 3rd generation of

cephalosporin or other strong antibiotics, even antifungal agents.

Management and treatmentBlood transfusion(component therapy) Nutritional support Bone marrow transplantation Growth factor

TreatmentThe primary treatment for ALL is chemotherapy.Radiation therapy may be used in certain casesBone marrow transplantation is being studied in

clinical trials.

Treatment : ChemotherapyPrednisone: Used in induction and reinduction therapy and

also given as intermittent pulses during continuation therapy.

toxicity : fluid retention, increased appetite, transient

diabetes, acne, striae, personality changes, peptic ulcer, immunosuppression, osteoporosis, growth retardation; caution in diabetes, fungal infections, and osteonecrosis

Vincristine: toxicity :

Peripheral neuropathy manifested by constipation, ileus, ptosis, vocal cord paralysis, jaw pain, abdominal pain, loss of deep tendon reflexes; reduce dosage with severe peripheral neuropathy; bone marrow depression; local ulceration with extravasation, SIADH

Asparaginaselocal rash, hives, anaphylaxis; bone marrow

depression, hyperglycemia, hepatotoxicity, and bleeding may occur.

DaunorubicinMyelosuppression and thrombocytopenia;

may cause cardiac arrhythmias immediately following administration and cardiomyopathy after long-term use; nausea, vomiting, stomatitis, and alopecia; extravasation may occur, resulting in severe tissue necrosis; caution with impaired hepatic, renal, or biliary function.

Methotrexate (Folex PFS)Hematologic, renal, GI, pulmonary, and

neurologic systems; discontinue if significant drop in blood counts; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested)

TreatmentInduction:(10 weeks)Prednisolone,Vincristine,Idarubicin, Asparaginase,cyclophosphamine,cytarabine, 6-MP,TIT.Consolidation:(8 weeks)6-MP,MTX,TITReinduction:(7 weeks)Dexamethasone, ,Vincristine,Idarubicin, Asparaginase,cyclophosphamine,cytarabine, 6-MP,TIT.

Blood Cell Formation

Acute Leukemia:AML versus ALLAdults - 85% of acute leukemia is AMLChildren-85% of acute leukemia is ALLLeukemic Blast morphology

AML: cytoplasmic granules, Auer rods, more cytoplasm, 2-5 nucleoli

ALL: no cytoplasmic granules, minimal cytoplasm, 1-2 nucleoli

AML:FAB classification

French American British classification

M0-M7 based on morphology, and special cytochemical studies

Historically, distinguishing AML M0 from ALL was a major clinical problem

AMLFAB classificationM0,M1, M2: Myeloblasts with no, little or

some granulocytic maturationM3: Promyelocytic leukemia

M4: Myelomonocytic or eosinophilic

M5: Monocytic

M6: Erythroleukemia

M7: Megakaryoblastic

Not all that useful except for M3 or APL

Auer rods = AML

Acute Leukemia:AML vs. ALLCytochemistry AML ALLMyeloperoxidase + -Sudan black + -Non-specific esterase + (M4,5) -

PAS + (M6) +

Acid phosphatase + (M6) +

AML Treatment:Induction ChemotherapyAnthracycline (Idarubicin) for 3 days

and Cytosine arabinoside (Ara-C) for 7 days (3+7, Younger/fit patients only)

Three to 5 weeks of pancytopenia

Supportive care red cell and platelet transfusions, prophylactic antibacterial, antifungals and antivirals

AML Treatment:Allogeneic Transplant

Advantages

Stem cells from HLA-matched sibling or unrelated individual allow high dose therapy and are free of leukemia

Immunologic graft versus leukemia effect (GVL).Results in decreased rate of leukemic

relapse

Chronic myelogenous leukemia (CML)

The myeloproliferative diseases (MPDs) are clonal stem cell disorders characterised by leukocytosis, thrombocytosis, erythrocytosis, splenomegaly, and bone marrow hypercelularity

They are divided into polycythemia vera (PV), essential thrombocytosis (ET), myelofibrosis and chronic myelogenous leukemia (CML)

●CML results from a somatic mutation in a pluripotential lymphohematopoietic cell

●CML is characterized by increased granulocytic cell line, associated with erythroid and platelet hyperplasia

●The disease usually envolves into an accelerated phase that often terminates in acute phase

chronic phase 3-5 years

accelerated phase

blastic phase 3-6 months

Translocation t(9;22)(q34;q11)

The bcr/abl fusion protein Uncontrolled kinase activity1. Deregulated cellular proliferation2. Decreased adherence of leukemia cells to the

bone marrow stroma3. Leukemic cells are protected from normal

programmed cell death (apoptosis)

Clinical features

30 percent of patient are asymptomatic at the time of diagnosis

Symptoms are gradual in onset: easy fatigability, malaise, anorexia, abdominal

discomfort, weight loss, excessive sweating● Less frequent symptoms: Night sweats, heat intolerance- mimicking

hyperthyroidism, gouty arthitis, symptoms of leukostasis (tinnitus, stupor), splenic infartion (left upper-quadrant and left shoulder pain), urticaria (result of histamine release)

● Physical signs: Pallor, splenomegaly, sternal pain

Laboratory features

The hemoglobin concentration is decreasedNucleated red cells in blood filmThe leukocyte count above 25000/μl (often above

100000/μl), granulocytes at all stages of development

Hypersegmentated neutrophilsThe basophiles count is increasedThe platelet count is normal or increasedNeutrophils alkaline phosphatase activity is low or

absent (90%)

Laboratory features (2)

The marrow is hypercellular (granulocytic hyperplasia)

Reticulin fibrosisHyperuricemia and hyperuricosuriaCytogenetic test- presence of the Ph

chromosomeMolecular test – presence of the BCR-ABL

fusion gene

Differential diagnosisPolycythemia veraMyelofibrosisEssential thrombocytemiaExtreme reactive leukocytosis

Treatment

Oral chemotherapeutic agents (hydroxyurea, busulfan)

Interferon alfaImatinib mesylate (Glivec, Gleevec)-

Inhibits activity of mutant tyrosine kinase by blocking ATP binding

Allo- SCT

Blast phase (blast crisis) of CML• Criteria of blast phase1. Blasts ≥20%2. extramedullary tumors

• Phenotype of blasts1. Mieloblasts - 50%2. Limphoblasts - 30%3. Megakarioblasts – 10%4. Acute myelofibrosis