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Diagnosis and Management Of Acute Leukemia in Children and
Adolescents
Grand RoundsSeptember 20, 2010St. Elizabeth Hospital, Lafayette, Indiana
Bassem. I. Razzouk, MD, FAAPMedical Director, St. Vincent Children’s Center For Cancer & Blood Diseases
Pediatric Cancer IncidenceUSA
Year Population < 20 yrs
Incidence per 105
New cases per year
1998 72,935,000 16.7 12,183
1999 73,120,000 16.8 12,321
2000 73,306,000 17.0 12,448
Childhood Cancer
Hematopoiesis
PLURIPOTENTSTEM CELL
COMMITTEDPROGENITOR
CELL
RECOGNIZABLE BONE MARROW
PRECURSOR CELL
MATURE BLOOD CELL
myeloblastmonoblast
pronormoblast red cellneutrophilmonocyte
basophil
platelet
CFU-Baso
CFU-Eos
CFU-GM
BFU-E/CFU-E
eosinophil
pre-T
pre-B
myeloidprogenitor
cell
lymphoidprogenitor
cell
lymphoblast
lymphoblast
T-cell
B-cell& plasma cell
MIXED PROGENITOR
CELL
CFU-Meg megakaryocytepluripotentstem cell
Myeloid Maturation
myeloblast promyelocyte myelocyte metamyelocyte band neutrophil
MATURATIONMATURATION
Adapted and modified from U Va website
Principles of leukemogenesis
• A multistep process
• Neoplastic cell is a hematopoietic pleuripotent cell or early myeloid cell
• Dysregulation of cell growth and differentiation (associated with mutations)
• Proliferation of the leukemic clone with differentiation blocked at an early stage
Classification of Leukemias
Acute Chronic
Myeloid origin
Lymphoid origin
Acute Myeloid Leukemia (AML)
Acute Lymphoblastic Leukemia (ALL)
Chronic Myeloid Leukemia (CML)
Chronic Lymphocytic Leukemia (CLL)
Acute Leukemia• Accumulation of blasts in the marrow
Epidemiology
• Childhood leukemia represents 12% of all leukemias; 60% of all acute lymphoblastic leukemias
• Leukemia is the most common cancer diagnosed in children at 4.3/100.000
Epidemiology
• ALL/AML = 5
• Peak incidence
–ALL: 2 to 5 years
–AML: 1 year, increases with age
• Boys > girls
–T-cell 4 times greater incidence
–Infant leukemia > in girls
Significance of Acute Leukemia
• A hematologic urgency/emergency
• Usually fatal within weeks to months without chemotherapy
• With treatment, moderate to high morbidity ( acute and long term) due to disease or treatment-related complications
• Notify Peds H/O promptly if acute leukemia is suspected
Causes of Acute Leukemias
• Idiopathic (most)
• underlying hematologic disorders
• chemicals, drugs
• ionizing radiation
• viruses (HTLV I)
• hereditary/genetic conditions
Predisposing Factors• Genetic Syndromes
– Down syndrome: 10-20 times increased incidence (600 times in megakaryoblastic type)
– Bloom syndrome– Neurofibromatosis– Schwachman syndrome– Ataxia Telangiectasia– Klinefelter syndrome
Ataxia-Telangactasia
Predisposing Factors• Familial aggregation
– Concordance in Twins
• High birth weight
• Ionizing radiation
• Non-ionizing radiation (?EMF)
• Alcohol consumption/cigarette smoking
• Breast feeding has protective effect
Clinical Manifestations
• Symptoms due to:– marrow failure
– tissue infiltration
– leukostasis
– constitutional symptoms: Fever, weight loss, night sweats, anorexia
– other (DIC)
• Usually short duration ( 4-8 weeks)
Clinical PresentationVery heterogenous
–Pallor
–Petechiae
–Hepatosplenomegaly
–Adenopathy
–Fever
–Bony pain
Clinical Presentation
Infiltration of tissues/organs
• Enlargement of liver, spleen, lymph nodes
• Gum hypertrophy
• bone pain
• other organs: CNS, skin, testis, any organ
Gum Hypertrophy
Chloromas
• Granulocytic Sarcoma (myeloblastoma)
– Localized mass of primitive myeloid cells that infiltrate extramedullary sites
– Involvement of every organ system has been reported
Leukostasis
• Accumulation of blasts in microcirculation with impaired perfusion
• lungs: hypoxemia, pulmonary infiltrates
• CNS: stroke
• Mostly seen with WBC >> 50 x 109/L in AML and > 100 X109/L in ALL
Differential Diagnosis• Juvenile Rheumatoid Arthritis- caution to use
steroids / oral methotrexate before completely ruling out leukemia
• Mycobacterial infections ( TB & non-TB)• Infectious mononucleosis• Aplastic anemia• Neuroblastoma• Rhabdomyosarcoma• Hypereosinophilic syndrome
Laboratory Data• White blood cell count: variable• Hemoglobin levels: low• Platelet count: low• Serum chemical values
– Uric Acid and LDH: elevated– Calcium: elevated
• Chest X-ray: Mediastinal Mass; Preferable to do CXR with initial diagnosis of asthma, especially if you plan to use steroids
• Coagulation screening: abnormal
WBC< 10.000 53%10,000-49,000 30%> 50,000 17%
Newly Diagnosed Patients with Leukemia- Work-up
• Establish a diagnosis Peripheral blood and bone marrow studies Morphology Immunopathology (cell markers) Cytogenetics Molecular Genetics• Risk assessment • Protocol enrollment- patients enrolled on clinical
trials have better outcome• Consent Process
Bone Marrow Aspirate/Biopsy
• Necessary for diagnosis: Aspirate for ALL; Aspirate/biopsy for AML
• Useful for determining type
• Useful for prognosis
• Acute leukemias are defined by the presence of > 20% blasts (AML) or 25 % blasts (ALL) in bone marrow (% of nucleated marrow cells)
Diagnosis
Morphology, cytochemistry and immunophenotype
Leukemia
•Acute vs. Chronic•Lymphoid vs. Myeloid
ALL
AML
Auer rods in AML
Cytochemistry
MPO ANB ANALymph - - -Myelo + - -Mono - + +, diffuse
Megak - - +, granular
Morphology/Cytochemistr
y
Key Points In ALL And AML
• The childhood acute leukemias are a very heterogeneous group of diseases
• Accurate diagnosis is important
• Selection of optimal therapy is pivotal
Blood Cells
Immunophenotype
Immunologic Classification
CD3, CD7, CD10, CD19, CD79Lymphoid
Myeloid M6/M7 CD41a, CD61, and CD42b
FVIII Hemoglobin
Lymphoid Vs. M0-M7
Classification - ALL
Immunophenotype Frequency (%)
Early pre-B 57
Pre-B 25
Transitional 1
B-cell 2
T-cell 15
Classification - AML
Genetics of Childhood ALL
• B-lineage ALL
Translocation Fusion Incidence Cure
rates
t(12;21) TEL-AML1 25% 90%
t(1;19) E2A-PBX1 5-6% 75%
t(4;11) MLL-AF4 2-5% 35%
t(9;22) BCR-ABL 3-5% <30%
(70 % ) with TKI’s
AML-associated chromosomal abnormalities
Abnormality Fusion FAB Incidence
t(8;21) AML1-ETO M2 15%
inv (16) CBFβ-MYH11 M4Eo 8-12% t(15;17) PML-RAR M3 8- 10%
t(9;11) MLL-AF9 M4,M5 7%
t(11;19) MLL-ELL M4, M5 1%
t(1;22) Unknown M7 1%
PROGNOSTIC FACTORS
DISEASE Tx
Heterogeneity Intensity
Specificity
Prognostic Factors - ALL• Initial white blood cell count
• Age at diagnosis
• Immunophenotype
• Genetic Features
• Extramedullary involvement ( CNS, testis)
Response to therapyResponse to therapy
ALL- Risk Groups
St. Jude Estimated COG
Low 40% Standard
Standard 50% High
High 10% Very High
Prognostic Factors- AML• Favorable
– Age < 1 year of age– Genetics: t(15;17), inv16, t(8;21) and t(1;22)– Down syndrome
• Intermediate – Genetics: normal karyotype, other 11q23– Residual disease after induction
• High-risk– Cytogenetics: -7, -5, t(6;9), complex karyotype– AML arising from MDS– Persistent disease after induction
Risk Assignment
• Provisional risk assignment at diagnosis
• Definitive assignment at end of induction therapy after evaluation of response to early therapy is available
• The objective of rigorous risk assignment is to avoid over- or under-treatment
Principles of Treatment• combination chemotherapy
– first goal is complete remission– further Rx to prevent relapse
• supportive medical care– transfusions, antibiotics, nutrition,
metabolic /electrolyte abnormalities• psychosocial support
– patient and family
Therapeutic Concepts in ALL
• Induce a complete remission and restore normal hematopoiesis avoiding excessive toxicity
• Reduce inapparent leukemia with short-term, high-dosage cytocidal therapy early in remission when the child is well and drug sensitivity is greatest
• Prevent CNS leukemia (concept of sanctuary)• Use prolonged combination chemotherapy to
eradicate residual disease when there is no evidence of leukemia
Basic Therapy in Childhood ALL
• Induction Treatment 4-8 wk• Consolidation treatment (intensification) 2-10 wk• Continuation treatment (maintenance) 2-3 y• Reinduction therapy (delayed intensification) 2-7 wk• CNS-directed therapy 1-2 y• Cessation of therapy 2.5 y for girls, 3.5 y for boys
Facts about Childhood ALL• Long-term Event Free Survival ( EFS) greater than
80%• Accomplished by
– Multiagent Chemotherapy– CNS-Directed Therapy– Improved Supportive Care– Trageted therapy with tyrosine kinase inhibitors (
Gleevec and others) for Philadelphia positive ALL
– Treatment of adolescents and young adults ( up to 30 years) on “Pediatric Inspired protocols”
Survival of ALL According to Treatment Era at St. Jude
0 5 10 15 20 25 30 35 40
Years from Diagnosis
0
0.9
1
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
XV (2000–Present) n=254
XIII–XIV (1991–99) n=465
XI–XII (1984–91) n=546
X (1979–83) n=428
V–IX (1967–79) n=828
I–IV (1961–66) n=90
Pediatric AML TreatmentPediatric AML Treatment• Standard Induction Therapy
• 80%-90% achieve hematologic CR• Differentiation therapy : All trans retinoic acid ( ATRA) for
specific variant ; acute promyelocytic leukemia ( APL); which needs emergency treatment since patients present with bleeding
• Post-remission Therapy• Historical controls suggest High dose Ara-C consolidation
improves outcome• Recent data suggest 60-70% of children with matched
family donors achieved cure with Allo transplant, but data is conflicting
• Maintenance Therapy• No data demonstrates efficacy
AML97 (n=40)
AML87 (n=41)
AML91 (n=63)
AML80 (n=65)
AML83 (n=45)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 5 10 15 20 25
Time (years)
Results of St. Jude AML Trials
Supportive Care• Patient stabilization
– Metabolic : hydration, alkalinization, allopurinol , and occasionally Rasbruicase ( recombinant urate oxidase) for tumor lysis syndrome
– Hemorrhage (DIC)- FFP, platelets– Infection- Braod spectrum antibiotics (Cefipeme)– Leukostasis- leukapheresis in AML /early
therapy• Central Venous Catheter• Blood Products ( irradiated, leukoreduced, CMV
negative until CMV status is known)
Hematopoietic Stem Cell transplantation
• Permits “rescue” from otherwise excessively toxic treatment especially in relapsed/refractory cases
• Additional advantage of graft-vs-leukemia effect in allogeneic transplants
• Less used for Philadelphia positive ALL, CML, and AML with tyrosine kinase inhibitors and better outcome with chemotherapy
• Trade-off for allogeneic transplantation: greater anti-leukemic effect but more toxicity
Side Effects of Therapy-Acute
• Nausea/vomiting/mucositis/hair loss• Neutropenia/Anemia/Thrombocutopenia• Infections/fever• Extravsation of vesicants ( Vincristine,
Anthracyclines)- Central line• Weight loss/anorexia- Nutritional Support• SIADH- VCR/Cyclophosphamide• Hemorraghic cystistis- Cyclophosphamide;
Hydration/MESNA
Long term Side effects• Neuro-Cognitive abnormalities: High-dose and
intrathechal Methotrexate, Cranial irradiation• Second cancers : Cyclo/Etoposide, radiation• Cardiomyopathy: Anthracyclines ( dose
dependent)• Sterility: cyclophosphamise, Stem cell
transplantation, Radiation• Endocrine abnormalities: radiation• Employment problems/Insurance• Psycho-social support: parents /siblings• Obesity: ? Females, ? Cranial radiation