Acute Lymphoblastic Leukemia An Overview Aziza Shad, MD.

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Acute Lymphoblastic Leukemia An Overview Aziza Shad, MD

Transcript of Acute Lymphoblastic Leukemia An Overview Aziza Shad, MD.

Page 1: Acute Lymphoblastic Leukemia An Overview Aziza Shad, MD.

Acute Lymphoblastic LeukemiaAn Overview

Aziza Shad, MD

Page 2: Acute Lymphoblastic Leukemia An 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

Page 3: Acute Lymphoblastic Leukemia An Overview Aziza Shad, MD.

Peripheral smear

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

Blasts with scant cytoplasm and prominent nucleoli

Page 4: Acute Lymphoblastic Leukemia An Overview Aziza Shad, MD.

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

Page 5: Acute Lymphoblastic Leukemia An Overview Aziza Shad, MD.

Diagnosis?

Acute Leukemia(most likely ALL)

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

Page 6: Acute Lymphoblastic Leukemia An Overview Aziza Shad, MD.

Making the diagnosis:

Morphology and Immunophenotype

Page 7: Acute Lymphoblastic Leukemia An Overview Aziza Shad, MD.

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

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Leukemia is a Bone Marrow Diagnosis!

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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

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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%

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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

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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

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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)

Page 14: Acute Lymphoblastic Leukemia An Overview Aziza Shad, MD.

• 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

Page 15: Acute Lymphoblastic Leukemia An Overview Aziza Shad, MD.

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

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Differential Diagnosis

• Non Malignant conditions:• Juvenile rheumatoid arthritis

• Infectious Mononucleosis

• ITP

• Pertussis and Parapertusis

• Aplastic Anemia

• Other viral illnesses

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Differential Diagnosis

• Malignancies:• Neuroblastoma

• Retinoblastoma

• Rhabomyosarcoma

• NHL

• Other small round blue cell tumors

• Hyper-eosinophilia, other aplastic presentations

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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

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Immunophenotype

CD138

CD

10

CD22

CD

19

Sid

e-s

catt

er

CD45

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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

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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?

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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

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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

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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

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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

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Prognostic Factors in Childhood ALL

• Clinical and Lab featuresClinical and Lab features

• Leukemia cells characteristics

• Response to initial therapy

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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

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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

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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

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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

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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

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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

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EARLY RESPONSE TO THERAPY

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

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Treatment

• Induction of Remission (4 -6 weeks)

• Consolidation ( 4 -8 weeks)

• Interim Maintenance (8 weeks)

• Delayed Intensification (8 weeks)

• Maintenance (2 -3 years)

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Treatment• Induction of Remission

Standard or Low RiskDexamethasoneVincristineL Asparaginase

High Risk Dexamethasone/Prednisone VincristineL AsparaginaseAnthracyclines (Daunomycin)

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Treatment• Induction of Remission

Dexamethasone Low RiskLess CNS and BM relapsesBetter EFS

Use in Adolescents Aseptic Necrosis

Use in High Risk Infections

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Treatment

• Consolidation:– Intensified CNS therapy

• Delayed Intensification:– improves outcome– Anthracyclines, Cyclophosphamide

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Treatment

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

– Severe hematopoietic toxicity with Thiopurine S Methyl Tranferase deficiency

– CNS prophylactic therapy

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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

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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

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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%

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Treatment of Relapsed ALL

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

• Chemotherapy

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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