Transcript 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.
Introduction
 Leukemia – 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)
Leukemia
 The 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 Leukemia
 In 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 Leukemia
 the 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 infiltration
 Common symptoms
Fever ( 60%)
Malaise ( 50%)
Pallor ( 40%)
Etiology
 Unknown ( usually)
 Hereditary
Down’s syndrome
Leukemia in siblings
 Chemicals
Chronic benzene exposure
Alkylating agents
 Ionizing radiation
 Predisposing hematological disease ( MPD, AA)
 Viruses ( HTLV-1)
Diagnostic criteria
 ALL is often difficult to diagnose.
 The early signs may be similar to the flu or other
common diseases.
Diagnostic criteria
 bone marrow aspiration and biopsy
 complete blood count (CBC)
 additional blood tests, genetic, molecular
tests
 computerized tomography scan
 magnetic resonance imaging (MRI)
 x-ray
 ultrasound
 lymph node biopsy
 spinal tap/lumbar puncture
Diagnostic criteria
 Peripheral 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 criteria
 Cytochemistry 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 diagnosis
 AML.
 MDS.
 Non-Hodgkin‘s lymphoma with bone marrow
involvement or with leukemic change.
 Aplastic anemia
 HIV infections
 EBV
 CMV
 Systemic form of juvenile chronic arthritis
Acute lymphoblastic leukemia
Laboratory examinations
 Full blood count
 Coagulation screening – especially AML M3.
 Biochemical screening
 Chest radiography
 Bone marrow aspiration
 Immunophenotyping
 Cytogenetics & molecular studies
 Lumbar puncture ( CNS involvement)
Complications
 Cerebral hemorrhage, pulmonary hemorrhage or
other vital organ hemorrhage.
 Infection(sepsis or septic shock ) , pulmonary edema.
 Tumor lysis syndrome.
 Hyper K
 HyperPo4).
 Coagulopathy before or after chemotherapy.
 Anemia.
Risk Grouping of TPOG (ALL)
 Standard Risk
 High Risk– CNS leukemia, cranial nerve palsy,
testicular leukemia, pre-B ALL t(1;19) or E2A-PBX1
fusion
Very High Risk
 WBC > 100000/mm3
 T – cell
 < 1y/o
 Lymphoblastic lymphoma with bone
marrow lymphoblasts > 25%
 t(9;22) or BCR-ABL fusion
 t(4;11) or MLL-AF4 fusion
 Other MLL gene rearrangement
 Hypodiploidy ( chr 44 or less)
Poor Prognosis (I)
 Acute lymphoblastic leukemia
Relapse
 Bone marrow– the most common site,
blast cell increase
 CNS– IICP ( vomiting, headache,
papilledema, lethargy)
Convulsion
Behavior disturbance
 Testis– painless swelling
Survival rates
 75 % 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).
Treatment
 Chemotherapy – reach to remission (blast<5%)
 CNS prophylaxis
Intrathecal C/T
Cranial irradiation
 Bone marrow transplantation
Management and treatment
 Hydration, prevention of hyperuricemia and
tumor lysis syndrome.
 Antibiotics, may need the 3rd generation of
cephalosporin or other strong antibiotics, even
antifungal agents.
Management and treatment
 Blood transfusion(component therapy)
 Nutritional support
 Bone marrow transplantation
 Growth factor
Treatment
 The primary treatment for ALL is chemotherapy.
 Radiation therapy may be used in certain cases
 Bone marrow transplantation is being studied in
clinical trials.
Treatment : Chemotherapy
Prednisone:
 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
Asparaginase
 local rash, hives, anaphylaxis; bone marrow
depression, hyperglycemia, hepatotoxicity,
and bleeding may occur.
Daunorubicin
 Myelosuppression 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 lowdose steroids may be administered
concomitantly with MTX (possibility of increased
toxicity with NSAIDs, including salicylates, has
not been tested)
Treatment
Induction:(10 weeks)
 Prednisolone,Vincristine,Idarubicin,
Asparaginase,cyclophosphamine,cytarabine,
6-MP,TIT.
Consolidation:(8 weeks)
 6-MP,MTX,TIT
Reinduction:(7 weeks)
 Dexamethasone, ,Vincristine,Idarubicin,
Asparaginase,cyclophosphamine,cytarabine,
6-MP,TIT.
Blood Cell Formation
Acute Leukemia:
AML versus ALL
 Adults - 85% of acute leukemia is AML
 Children-85% of acute leukemia is ALL
 Leukemic 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
AML
FAB classification
 M0,M1, M2: Myeloblasts with no, little or some
granulocytic maturation
 M3: 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. ALL
 Cytochemistry
 Myeloperoxidase
 Sudan black
 Non-specific esterase
 PAS
 Acid phosphatase
AML
+
ALL
-
+
+ (M4,5)
+ (M6)
+
+ (M6)
-
+
AML Treatment:
Induction Chemotherapy
 Anthracycline (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).
in decreased rate of leukemic relapse
Results
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

1.
2.
3.
Uncontrolled kinase activity
Deregulated cellular proliferation
Decreased adherence of leukemia cells to the bone
marrow stroma
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 decreased
 Nucleated red cells in blood film
 The leukocyte count above 25000/μl (often above




100000/μl), granulocytes at all stages of development
Hypersegmentated neutrophils
The basophiles count is increased
The platelet count is normal or increased
Neutrophils alkaline phosphatase activity is low or
absent (90%)
Laboratory features (2)
 The marrow is hypercellular (granulocytic hyperplasia)
 Reticulin fibrosis
 Hyperuricemia and hyperuricosuria
 Cytogenetic test- presence of the Ph chromosome
 Molecular test – presence of the BCR-ABL fusion gene
Differential diagnosis
 Polycythemia vera
 Myelofibrosis
 Essential thrombocytemia
 Extreme reactive leukocytosis
Treatment
 Oral chemotherapeutic agents (hydroxyurea,
busulfan)
 Interferon alfa
 Imatinib mesylate (Glivec, Gleevec)Inhibits activity of mutant tyrosine kinase
by blocking ATP binding
 Allo- SCT
Blast phase (blast crisis) of CML
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2.
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2.
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4.
Criteria of blast phase
Blasts ≥20%
extramedullary tumors
Phenotype of blasts
Mieloblasts - 50%
Limphoblasts - 30%
Megakarioblasts – 10%
Acute myelofibrosis