The Price of Survival Acute Lymphocytic (ALL) Leukemia in Children
LEUKEMIA IN CHILDREN
description
Transcript of 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