Acute Lymphoblastic LeukemiaAn Overview

Aziza Shad, MD

Case 1• History:

3yo boy presents to Emergency Department with a 5 day history of back pain and pain/difficulty walking

• On exam: Febrile with pallor, bruising, petechiae, mild hepatosplenomegaly

• Labs:CBC: Hgb 6.0g, Hct 18.0, Plts 11k, WBC 13.6 (10p, 60l, 24 atypical lymphocytes, 6 blasts) ANC 136CHEM: K normal, Uric acid 7.0 ↑, LDH 2200 ↑• CXR: Reported as normal

Peripheral smear

Maslak, P. ASH Image Bank 2004;2004:101159

Blasts with scant cytoplasm and prominent nucleoli

Bone marrow aspirate and biopsy

• BMA: Blasts have a high nuclear to cytoplasmic ratio and lack granules in the cytoplasm

Maslak, P. ASH Image Bank 2002;2002:100400 and 100526

BMBx: Bone marrow architecture is replaced by monotonous population of blasts

Diagnosis?

Acute Leukemia(most likely ALL)

Maslak, P. ASH Image Bank 2004;2004:101200

Making the diagnosis:

Morphology and Immunophenotype

Morphologic classification –

French American British (FAB) subtypes

L1 – 85%Small, uniform cell sizeFine, homogeneous chromatinScant cytoplasmInconspicuous nucleoli

L2 – 14%Large, heterogeneous cell sizeIrregular, clefted nucleiVariable amount of cytoplasmNucleoli usually visible

L3 – 1%Large, homogeneous cell sizeProminent vacuolizationBasophilic cytoplasmNucleoli usually visible

Leukemia is a Bone Marrow Diagnosis!

Introduction

• Leukemia accounts for about a third of all childhood cancers

• About 80% of children with leukemia have ALL • 17% have AML • The remainder have rare forms of chronic

leukemia

Pediatric Acute Lymphoblastic Leukemia

• Most common cancer of childhood• Affects children from 0 -20 years• Peak incidence is between 3 -6 years• Untreated, life expectancy is days to weeks• Modern risk-based therapy has brought the

cure rate up to 75 -85%• for some sub-groups, the cure rate is close to

90%, for others, it is < 20%

Acute Lymphoid LeukemiaAcute Lymphoid Leukemia Incidence by Age Incidence by Age

AGE IN YEARS

NU

MB

ER

OF C

AS

ES

0

20

40

60

80

100

120

140

0 2 4 6 8 10 12 14

Epidemiology of Pediatric ALL• Most common form of childhood leukemia

• 2,500-3,000 children annually in U.S. (3 per 100,000)

• Sibling relative risk is 2-4x

• Monozygotic twin concordance 25% - highest in infancy, no increased risk after 7 years of age – mechanism in monozygotic twins is shared in utero

circulation, with transfer of preleukemic from one twin to the other

Pathophysiology

• Most cases – cause unknown• Inherited genetic syndromes:

• Downs syndrome, Bloom’s syndrome, Nijmegen breakage syndrome, ataxia telangiectasia

• Environmental exposures

Ionizing radiation, benzene, prior chemotherapy• Other possible environmental influences

• High birth weight, parental tobacco/alcohol, maternal diet, exposure to pesticides or solvents, prenatal vitamins (protective)

• Symptoms directly related to marrow infiltration– Decreased WBC : fevers, infections

– Decreased RBC :signs and symptoms of anemia

– Decreased platelets: bruising, bleeding

– Marrow infiltration: bone pain, limp

– Extramedullary infiltration : lymphadenopathy, hepatosplenomegaly, mediastinal mass

Clinical Presentation

Remember…

• A given case may have several symptoms or only a few

• A normal CBC does not rule out leukemia!• Back pain/limp in pediatrics is a red flag and

requires work-up• Before treating any child with steroids for any

reason, stop and think about whether leukemia is in the differential diagnosis

Differential Diagnosis

• Non Malignant conditions:• Juvenile rheumatoid arthritis

• Infectious Mononucleosis

• ITP

• Pertussis and Parapertusis

• Aplastic Anemia

• Other viral illnesses

Differential Diagnosis

• Malignancies:• Neuroblastoma

• Retinoblastoma

• Rhabomyosarcoma

• NHL

• Other small round blue cell tumors

• Hyper-eosinophilia, other aplastic presentations

Standard Work-up for ALL

• History and Physical Exam• CBC, electrolytes, LDH, Uric acid• Peripheral smear• Chest X-Ray• Bone marrow aspirate and biopsy with special stains• Immunophenotyping ( flow cytometry)• Cytogenetics• Molecular diagnostics

Immunophenotype

CD138

CD

10

CD22

CD

19

Sid

e-s

catt

er

CD45

Molecular genetics

• Favorable risk– TEL-AML1 (ETV6-RUNX1) fusion,

t(12;21)– Hyperdiploidy (esp triple trisomies –

chr 4, 10, 17; or double trisomies – chr 4, 10)

• High risk– Philadelphia chromosome, t(9;22)– MLL rearrangement (11q23)– Hypodiploidy (<44 chromosomes)

fusion signal

Back to our patient…

• Received hydration, PRBC and platelet transfusions, tumor lysis lab monitoring and prophylaxis (allopurinol)

• Consented to start induction chemotherapy• Bone pain and fevers resolve within a few

days, discharged home to follow up for ongoing outpatient chemotherapy

• What is his prognosis?

Cure Rates

• Over the last 50 years, survival rates for childhood cancer have risen from 10% to almost 80%

• Remarkable progress has been made in the past decade in the treatment and understanding of leukemia

• Collaborative clinical trials implementing risk-stratified therapy have dramatically improved cure rates in ALL

• Outcome in ALL has gone from a 6-month median survival to an 80% overall cure rate

1975-781972-75

0 2 4 86 10

80

60

40

20

100

Years after Study Entry

%

Survival

1989-93

1983-89

1978-83

1970-72

1968-70

3,402

3,711

2,9841,313

936

499

402

Years of Diagnosis

Number ofChildren

16,131Total Number ofPatients Treated:

1993-95 1,585

1995-97 1,299

Legend: Survival of CCG Patients with Newly-Diagnosed Acute Lymphoblastic Leukemia, 1968-1997. Bleyer A, Hather N, Personal Communication

Prognostic Factors in Childhood ALL

• Age• WBC count at presentation• Immunophenotype• Recurrent chromosomal abnormalities• Response to initial therapy• These prognostic factors have been used to stratify

therapy following induction remission• Gene expression analysis• Pharmacogenomics

Risk adapted therapy for Pediatric ALL

• Standard, high or very-high risk groups– Patients with ‘high risk’ features get intensified

chemotherapy– Patients with ‘very-high risk’ features are

candidates for BMT– ‘Low risk’ group being studied – reduced intensity

treatment

Prognostic Factors in Childhood ALL

• Clinical and Lab featuresClinical and Lab features

• Leukemia cells characteristics

• Response to initial therapy

Prognostic Variables

• Clinical and Lab Variables:• Age:

– 1-9 yrs Best outcome 5 yr EFS 88%– 10-15 yrs 73%– >15 yrs 69%– < 12 mths 44%– < 6 mths poor outcome

• Infants: Poor outcome– MLL gene, Increased WBC, CNS Leukemia– CD10 Negative– Poor initial response

Pui et al, Lancet 2008

Prognostic Variables

• Clinical and Lab Variables:• WBC Count at Presentation:

– Increasing WBC confer a poor outcome especially in patients with Precursor B-cell ALL

– T-cell ALL patients with WBC > 100k have a higher risk of CNS relapse

Prognostic Variables

• Leukemic Cell Characteristics:• Immunophenotype:Immunophenotype:• Precursor B ALL: CD19, CD10 (cALLa), HLA-DRPrecursor B ALL: CD19, CD10 (cALLa), HLA-DR

80%- 85% of ALL80%- 85% of ALL 80% CD10 positive80% CD10 positive

• Early pre-B (no sIg or cyIg) Early pre-B (no sIg or cyIg) • Pre-B (cy Ig)Pre-B (cy Ig)• B-cell (sIg) 3% (FAB L3, CMYC gene trans)B-cell (sIg) 3% (FAB L3, CMYC gene trans)Mature B-cell phenotype no longer confers a poor prognosisMature B-cell phenotype no longer confers a poor prognosis

Prognostic Variables

• Leukemic Cell Characteristics:• Immunophenotype:• T- Cell ALL : CD2, CD7, CD5, CD3

Males, Older Age, High WBC, Mediastinal mass

12 % of ALLT-cell phenotype no longer confers a poor prognosis T-cell phenotype no longer confers a poor prognosis

Prognostic Variables

• Cytogenetics:• Favorable Prognosis

– High Hyperdiploidy: 51 -65 chromosomes/cellor DNA index > 1.16

– Trisomies 4, 10, 17– TEL/AML1 t(12;21)

• Poor Prognosis– Hypoploidy: < 44 chromosomes– Philadelphia chromosome– T(4;11) with MLL-AF4 fusion

Prognostic Variables

• Response to Initial Therapy:

– Day 7 and Day 14 BM responsesRapid response is favorableCurrent COG protocols

– Peripheral blood response to steroidsDay 7 (blasts< 1000/ul) GR is favorableBFM protocols

EARLY RESPONSE TO THERAPY

• Rapidity of response to initial chemotherapy is a significant predictor of long-term outcome

Treatment

• Induction of Remission (4 -6 weeks)

• Consolidation ( 4 -8 weeks)

• Interim Maintenance (8 weeks)

• Delayed Intensification (8 weeks)

• Maintenance (2 -3 years)

Treatment• Induction of Remission

Standard or Low RiskDexamethasoneVincristineL Asparaginase

High Risk Dexamethasone/Prednisone VincristineL AsparaginaseAnthracyclines (Daunomycin)

Treatment• Induction of Remission

Dexamethasone Low RiskLess CNS and BM relapsesBetter EFS

Use in Adolescents Aseptic Necrosis

Use in High Risk Infections

Treatment

• Consolidation:– Intensified CNS therapy

• Delayed Intensification:– improves outcome– Anthracyclines, Cyclophosphamide

Treatment

• Maintenance Therapy:– Daily oral 6MP and weekly oral MTX

– Severe hematopoietic toxicity with Thiopurine S Methyl Tranferase deficiency

– CNS prophylactic therapy

Treatment

Maintenance Therapy:– VCR + Prednisone/ Dexamethasone Pulses

1. VCR/Prednisone pulses improved EFS2. Dexamethasone in 1-9 yr SR patients showed fewer CNS

relapses and improved EFS compared to Prednisone3. Use of Dexamethasone in Adolescents: Risk of Aseptic

Necrosis and bone fractures

Treatment

• T-cell ALL:Intensified chemotherapy protocolsIntensified chemotherapy protocolsPilot trials with ARA-GPilot trials with ARA-G

• Infant ALL:Intensive chemotherapy protocols

• Philadelphia +ve ALL: BMT from matched related or MUDImatinib

Relapsed ALL

• Timing of Relapse:Early Relapse: Survival < 10-20% [ Relapse on therapy or 6 months off ]

Late Relapse: Survival 30-40% (chemotherapy)[ Relapse 12 months off therapy]

T-cell ALL: Survival < 20%

Treatment of Relapsed ALL

• Bone Marrow Transplantation:Early RelapseHigh Tumor Load (>10,000 blasts/ul)

• Chemotherapy

Conclusions

• ALL is the commonest leukemia of childhood• Minimal evaluation should include a good

H&P, peripheral smear and bone marrow exam

• Simple treatment protocols utilizing common agents used for ALL treatment should be used initially

• Treatment modifications should be based on institutional experience and results