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