diagnosis and management of acute leukemia in children and adolescents grand rounds september 20,...
TRANSCRIPT
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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
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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
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Childhood Cancer
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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
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Myeloid Maturation
myeloblast promyelocyte myelocyte metamyelocyte band neutrophil
MATURATIONMATURATION
Adapted and modified from U Va website
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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
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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)
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Acute Leukemia• Accumulation of blasts in the marrow
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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
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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
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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
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Causes of Acute Leukemias
• Idiopathic (most)
• underlying hematologic disorders
• chemicals, drugs
• ionizing radiation
• viruses (HTLV I)
• hereditary/genetic conditions
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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
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Ataxia-Telangactasia
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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
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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)
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Clinical PresentationVery heterogenous
–Pallor
–Petechiae
–Hepatosplenomegaly
–Adenopathy
–Fever
–Bony pain
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Clinical Presentation
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Infiltration of tissues/organs
• Enlargement of liver, spleen, lymph nodes
• Gum hypertrophy
• bone pain
• other organs: CNS, skin, testis, any organ
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Gum Hypertrophy
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Chloromas
• Granulocytic Sarcoma (myeloblastoma)
– Localized mass of primitive myeloid cells that infiltrate extramedullary sites
– Involvement of every organ system has been reported
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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
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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
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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
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WBC< 10.000 53%10,000-49,000 30%> 50,000 17%
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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
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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)
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Diagnosis
Morphology, cytochemistry and immunophenotype
Leukemia
•Acute vs. Chronic•Lymphoid vs. Myeloid
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ALL
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AML
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Auer rods in AML
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Cytochemistry
MPO ANB ANALymph - - -Myelo + - -Mono - + +, diffuse
Megak - - +, granular
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Morphology/Cytochemistr
y
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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
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Blood Cells
Immunophenotype
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Immunologic Classification
CD3, CD7, CD10, CD19, CD79Lymphoid
Myeloid M6/M7 CD41a, CD61, and CD42b
FVIII Hemoglobin
Lymphoid Vs. M0-M7
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Classification - ALL
Immunophenotype Frequency (%)
Early pre-B 57
Pre-B 25
Transitional 1
B-cell 2
T-cell 15
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Classification - AML
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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
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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%
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PROGNOSTIC FACTORS
DISEASE Tx
Heterogeneity Intensity
Specificity
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Prognostic Factors - ALL• Initial white blood cell count
• Age at diagnosis
• Immunophenotype
• Genetic Features
• Extramedullary involvement ( CNS, testis)
Response to therapyResponse to therapy
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ALL- Risk Groups
St. Jude Estimated COG
Low 40% Standard
Standard 50% High
High 10% Very High
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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
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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
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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
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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
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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
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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”
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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
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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
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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
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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)
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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
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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
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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