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Childhood Acute Lymphoblastic Leukemia (ALL)

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Blood-Hematopoiesis-Lymphatics 2013 Childhood Acute Lymphoblastic Leukemia (ALL) Hanumantha R. Pokala, MD May 14, 2013 Overview of ALL Therapy Induction chemotherapy ... – PowerPoint PPT presentation

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Title: Childhood Acute Lymphoblastic Leukemia (ALL)


1
Childhood Acute Lymphoblastic Leukemia (ALL)
Blood-Hematopoiesis-Lymphatics 2013
  • Hanumantha R. Pokala, MD
  • May 14, 2013

2
Case Report
  • 3 year old boy brought to hospital with chief
    complaint of fever and leg pain for 3 weeks
  • ROS
  • fatigue manifested by increase in naps
  • reluctance to walk for 1 week
  • fevers up to 101-102F

3
Physical Exam
  • GENERAL
  • Mildly ill, consolable child
  • SKIN
  • Pallor, prominent petechial rash, ecchymoses
  • CV
  • III/VI systolic flow murmur radiating widely
  • Abdomen
  • Spleen palpable 1-2 cm below costal margin
  • Extremities
  • Mildly swollen right ankle

4
Laboratory Evaluation
  • CBC
  • WBC 15,000
  • 7 neutrophils, 27 lymphs, 63 other cells
  • Hemoglobin 7.2
  • Platelets 12,000
  • Other labs
  • Elevated creatinine, phosphorus and uric acid
  • Elevated lactate dehydrogenase

5
(No Transcript)
6
Leukemia Definition
  • Leukemia results from an event in a bone marrow
    precursor cell which gives rise to immature
    progeny that have lost the capacity to
    differentiate and proliferate in an uncontrolled
    manner
  • Immature progeny (blasts) expand in marrow and
    impair normal hematopoiesis

7
Childhood Leukemia
  • Leukemia is the most common form of cancer of
    childhood
  • Majority of childhood leukemias are acute
  • Acute Lymphoblastic Leukemia (ALL)
  • Acute Myeloid Leukemia (AML)
  • CBC in acute leukemia may demonstrate anemia,
    thrombocytopenia, leukocytosis or leukopenia with
    circulating blasts

8
Acute Leukemias Distribution by Age
9
Epidemiology of Childhood ALL
  • Most common pediatric cancer
  • 25 of all childhood cancer
  • 2500-3500 cases/year in USA
  • 3-4/100,000 in white children
  • 75 of pediatric leukemia
  • Peak age 2-5 years
  • 85 overall survival on modern therapy regimens

Pizzo and Poplack 4th Ed
10
Age at Diagnosis for ALL
11
Conditions Associated with Increased Risk of ALL
  • Ionizing radiation exposure
  • 5x increased risk for all childhood cancer if
    exposed in first trimester (leukemia accounts for
    50)
  • Down Syndrome
  • 20x greater lifetime risk of developing acute
    leukemia
  • Siblings
  • Increased risk by 2-4x
  • 25 concordance in monozygotic twins lt6yrs

Pizzo and Poplack 4th Ed
12
Conditions Associated with Increased Risk of ALL
  • Tumor suppressor mutations
  • Neurofibromatosis
  • Li-Fraumeni syndrome
  • Impaired DNA repair
  • Bloom Syndrome
  • Fanconis Anemia
  • Ataxia Telangictasia

Pizzo and Poplack 4th Ed
13
Common Presenting Signs and Symptoms
  • Expanding blast population in bone marrow causes
    bone and joint pain
  • Pallor and fatigue due to anemia
  • Bruising, petechiae and bleeding due to
    thrombocytopenia
  • Fever due to infection and cytokines from
    leukemia
  • Adenopathy, hepatomegaly and splenomegaly due to
    blasts migrating out of marrow

14
Differential Diagnosis Nonmalignant
  • Juvenile rheumatoid arthritis
  • Fever, Bone and joint pain
  • Infectious mononucleosis
  • Adenopathy, Splenomegaly, Fever, Fatigue
  • Idiopathic thrombocytopenic purpura
  • Thrombocytopenia, Bleeding, Bruising
  • Pertussis
  • Fever, Fatigue, Leukocytosis
  • Aplastic anemia/bone marrow failure syndromes
  • Pancytopenia

Pizzo and Poplack pg 425, 1997
15
Differential Diagnosis Malignancies
  • ALL
  • AML
  • Lymphoma
  • Adenopathy, Fatigue, Fever
  • Neuroblastoma, Rhabdomyosarcoma, Ewings sarcoma
  • Bone pain, Fatigue, Fever, Adenopathy

Pizzo and Poplack pg 425, 1997
16
Approaching New ALL Cases
  • Need to obtain diagnosis by flow cytometry on
    peripheral blood or marrow
  • Need bone marrow samples for cytogenetics
  • Need diagnostic LP to assess CNS status
  • For B precursor ALL will start Induction therapy
    based on NCI risk group

17
Bone Marrow Aspirate Or Biopsy Typically Obtained
From Pelvis
  • Aspiration obtains marrow blood for morphology,
    flow cytometry and cytogenetics
  • Biopsy can make diagnosis when aspirate is
    difficult due to packed marrow

18
Diagnosing ALL
  • Morphology
  • gt25 lymphoblasts in bone marrow or peripheral
    blood has gt1000 circulating blasts
  • Cannot differentiate B and T cells by morphology
  • Lymphoblasts and myeloblasts may also look
    similar
  • Flow cytometry
  • Identifies molecular surface markers on marrow or
    peripheral blood cells
  • More accurate than morphology in classifying
    leukemia
  • Can diagnose leukemia from peripheral blood in
    cases where marrow cant be safely performed

19
ALL Classification
  • B precursor ALL/pre B ALL
  • 80-90 of childhood ALL
  • Good prognosis with 85-90 survival
  • Mature B cell ALL/Burkitts leukemia
  • 2-3 of childhood ALL
  • 60-70 survival with intensive Burkitts lymphoma
    therapy
  • T precursor ALL/pre T ALL
  • 15-18 of childhood ALL
  • More CNS relapses
  • 70-75 survival with more intensive therapy and
    cranial radiation

20
FAB Classification of ALL
  • Classifies lymphoblasts according to morphology
  • L1 Most common
  • L3 Burkitts leukemia
  • Pre B and pre T cells look similar
  • No longer influences treatment or prognosis

L1
L3
L2
21
Flow Cytometry in ALL
  • Identifies molecular surface markers on marrow or
    peripheral blood cells
  • More accurate than morphology in classifying
    leukemia
  • Can diagnose leukemia in cases where marrow cant
    be safely performed
  • TdT is found on both B precursor and T cells
  • B cell ALL
  • CD10 (CALLA) 80 of pre B will express this
  • CD19, CD20, CD21, CD22, CD24
  • HLA-DR more intense in B precursor vs mature B
    cell ALL
  • T cell ALL
  • CD3, CD4, CD8

22
Reasons For Improved Outcomes in Childhood ALL
  • Multi-agent, risk-directed chemotherapy
  • Better definition of risk groups
  • Better use of chemotherapy agents
  • More effective treatment of sub-clinical CNS
    leukemia
  • Better supportive care

23
CNS Prophylaxis
  • lt 5 of children with ALL have CNS involvement at
    diagnosis
  • Incidence is increased in infants and in children
    with high WBC
  • In children not receiving prophylaxis, many will
    relapse in CNS after achieving bone marrow
    remission.
  • In 1970s CNS prophylaxis was introduced using
    radiation
  • Intrathecal therapy now preferred.
  • Radiation is added later for children with
    initial CNS disease and for all children with T
    cell ALL

24
Historical Perspective Treatment of Childhood ALL
100

75
EFS
50
25
Single agent 1950s
0
1
2
3
4
5
10
15
20
Time (Years)
25
Historical Perspective Treatment of Childhood ALL
100
75
EFS
50
25
Combination agent 1960s
Single agent 1950s
0
1
2
3
4
5
10
15
20
Time (Years)
26
Historical Perspective Treatment of Childhood ALL
100
75
EFS
50
CNS Prophylaxis 1970s
25
Combination agent 1960s
Single agent 1950s
0
1
2
3
4
5
10
15
20
Time (Years)
27
Historical Perspective Treatment of Childhood ALL
100
Intensive therapy 1980s
75
EFS
50
CNS Prophylaxis 1970s
25
Combination agent 1960s
Single agent 1950s
0
1
2
3
4
5
10
15
20
Time (Years)
28
(No Transcript)
29
Overview of ALL Therapy
  • Induction chemotherapy to obtain a bone marrow
    remission
  • Post-Induction will continue intensive therapy
    followed by a longer period of less intensive
    therapy
  • Majority of therapy is outpatient
  • Therapy lasts 2.5 years for girls and 3.5 years
    for boys
  • Bone marrow transplant (BMT) reserved only for
    certain very high risk patients and in relapse

30
NCI Risk Stratification for B Precursor ALL
  • Standard Risk (65patients)
  • Age 1.00-9.99 years
  • Initial WBC lt50K
  • High Risk (35patients)
  • Age lt1 yr or 10 yrs
  • Initial WBC 50K regardless of age
  • Testicular disease at diagnosis
  • CNS 3 at diagnosis

31
Induction Therapy is Based on NCI Risk Group
  • Standard risk patients receive 3 drug Induction
  • Dexamethasone x28 days
  • Vincristine weekly x4 doses
  • PEG Asparaginase x1 dose
  • High risk patients receive 4 drug Induction
  • Prednisone x28 days (Age gt10) or Dexamethasone
    x14 days (Age lt10)
  • Vincristine weekly x4 doses
  • PEG Asparaginase x1 dose
  • Daunorubicin weekly x4 doses

32
Post-Induction ALL Therapy
  • After Induction patients receive an additional
    7-8 months of intensive therapy
  • Weekly outpatient and several short inpatient
    chemotherapy visits
  • IV Methotrexate, Cytarabine, Vincristine,
    Doxorubicin, Cyclophosphamide, Asparaginase
  • Associated with periods of severe neutropenia and
    mucositis
  • Includes several lengthy courses of high-dose
    corticosteroids
  • Lumbar punctures on average every 2-3 weeks
  • Therapy is intensified for high risk patients

33
Post-Induction ALL Therapy
  • Remainder of therapy (Maintenance) lasts 2-3
    years
  • Outpatient therapy consisting of primarily oral
    chemotherapy
  • Daily Mercaptopurine, weekly Methotrexate,
    monthly Vincristine and steroids
  • Less myelosuppressive with shorter corticosteroid
    courses
  • Lumbar punctures every 12 weeks
  • Boys receive additional year of therapy to
    prevent testicular relapse

34
Response to Induction is An Important Tool in
Determining Post-Induction Therapy
  • Older studies used morphology on Day 15 marrow
    and minimal residual disease (MRD) on Day 29
    marrow to assess response
  • Rapid responder lt5 blasts on Day 15 and MRD
    lt0.1 on Day 29
  • Slow Responder gt5 blasts on Day 15 and/or MRD
    gt0.1 on Day 29
  • Intensified post-Induction therapy for slow
    responders
  • New studies use Day 8 peripheral blood MRD and
    Day 29 MRD of lt0.01 to determine post-Induction
    risk groups

35
Effect of Peripheral Blood MRD on Day 8 of
Induction
36
Effect of Bone Marrow MRD on Day 29 of Induction
37
Cytogenetics Play An Important Tool in
Determining Post-Induction Therapy
Anomaly Occurence Prognosis
Hyperdiploid (gt50) 25 Good
Trisomies 4 10 20-25 Good
t(1221) TEL AML1 16-22 Good
Hypodiploid (lt44) 1-2 Poor
t(411) 60 infant ALL 5 other ALL Poor
t(922) Ph-1 20 adult ALL 3-5 child ALL Poor
t(814) Mature B-cell ALL/Burkitts leukemia Improves with aggressive tx
38
Karyotype Hyperdiploid ALL
39
Double TEL/AML1 fusion
40
B Precursor ALL Risk Groups
Risk Group Low Average Average
Projected 5-yr EFS gt95 90-95 90-95
NCI Risk Group SR SR SR
Favorable genetics Yes Yes No
Day 8 PB MRD lt0.01 gt0.01 lt1
Day 29 BM MRD lt0.01 lt0.01 lt0.01
Patients/year 250 360 275
Total Accrual/year 250 635 635
Fraction of patients 14.7 37.3 37.3
Favorable Genetics - 4,10 OR ETV6-RUNX1 CNS2
included in Average Risk
41
B Precursor ALL Risk Groups
Risk Group High High High Very High Very High Very High
Projected 5-yr EFS 75-90 75-90 75-90 lt75 lt75 lt75
NCI Risk Group SR SR HR SR HR Any
Favorable genetics Yes No Any No Any No
Day 8 PB MRD Any gt1 Any Any Any Any
Day 29 BM MRD gt0.01 lt0.01 lt0.01 gt0.01 gt0.01 Any
Patients/year 70 91 435 86 74 61
Total Accrual/year 596 596 596 221 221 221
Fraction patients 35 35 35 13 13 13
CNS3 or testicular involvement assigned to HR VHR
includes hypodiploidy, induction failure, MLL
rearrangement
42
ALL in Down Syndrome Patients
Risk Group Standard DS High DS High DS
NCI Risk Group SR SR HR
Favorable genetics Any Any Any
Day 8 PB MRD Any Any Any
Day 29 BM MRD lt0.01 gt0.01 Any
  • Children with Down Syndrome have poorer outcomes
    due to excessive toxicity from therapy (60-70
    survival)
  • Cannot receive high dose Methotrexate
  • Receive less IT therapy and steroid pulses

43
Philadelphia ALL
  • 5 of pediatric ALL, associated with poor
    prognosis (lt40 survival)
  • Historically best matched BMT was best approach
    for cure
  • Recent studies have shown that adding Imatinib
    (Gleevec) to intensive chemotherapy backbone
    markedly improved survival to 70-80
  • Reserve BMT only for children with matched
    sibling

44
Infant ALL
  • ALL diagnosed in children lt365 days old
  • Majority of cases have absence of CD10 on flow
    cytometry
  • t(411) (MLL rearrangement) is seen in 75 of
    cases
  • MLL blasts express high levels of FLT3
  • FLT3 is a tyrosine kinase oncogene implicated in
    ALL and AML
  • Associated with poorer outcome
  • Age lt90 days also carries higher risk
  • Universally poor prognosis with EFS of 50 in
    past studies
  • Infants with without MLL rearrangement do better
    (5 year EFS 60-70)

45
T Cell ALL
  • Accounts for 15 of ALL
  • Poorer outcomes than B Precursor ALL (70-75 EFS)
  • Less sensitive to Methotrexate than B
    lymphoblasts
  • Increased risk of CNS relapse
  • Often older age at diagnosis (teenagers)
  • MalesgtFemales (41)
  • High WBC at diagnosis (often gt100,000) with
    associated tumor lysis syndrome
  • Require high risk therapy with cranial XRT for
    cure

46
T Cell ALL
  • Mediastinal mass is often present and can cause
    severe cardio-respiratory compromise
  • Often have to make diagnosis from peripheral
    blood or from biopsy done under minimal sedation

47
B-cell Leukemia (Burkitts Lymphoma/Leukemia)
  • gt25 marrow involvement with Burkitts Lymphoma
  • May see mass lesions on exam
  • Abdomen (U.S.)
  • Mandible/maxilla (Africa)
  • Rapidly growing disease
  • Cells divide every 24 hours
  • Potentially serious electrolyte disturbances at
    diagnosis from rapid cell turnover
  • Treat like Burkitts lymphoma
  • Poorer outcomes (60-70 survival)

48
Relapsed ALL
  • Approach to treatment depends on timing and
    location where relapse occurred
  • Must use high-dose chemotherapy to get into a 2nd
    remission
  • Some relapses require BMT for cure

49
Approach to Treating Relapsed ALL
  • Marrow Relapse
  • lt36 months from diagnosis (20-30 survival)
  • High dose chemotherapy followed by best matched
    BMT
  • gt36 months from diagnosis (40-50 survival)
  • High dose chemotherapy only unless sibling match
    is available for BMT
  • CNS Relapse
  • lt18 months from diagnosis (40-50 survival)
  • High dose chemotherapy cranial XRT unless
    sibling match is available for BMT
  • gt18 months from diagnosis (70-80 survival)
  • High dose chemotherapy cranial XRT

50
Common Complications of Therapy
  • Myelosuppression
  • Require blood product transfusions
  • Increased risk of infection when neutrophil count
    is low
  • GI symptoms
  • Nausea/Vomiting, Constipation, Mucositis
  • Alopecia
  • Difficulty ambulating
  • Myositis and neurotoxicity

51
Supportive Care
  • Anticipate electrolyte issues early in therapy
  • Anti-emetic medication
  • Monitoring of blood counts
  • Blood products if needed
  • Surveillance for infection especially when WBC is
    low
  • Psycho-social Support

52
Tumor Lysis Syndrome
  • Rapid death of large number of blasts during
    Induction triggers release of intracellular
    electrolytes
  • PO4 and uric acid are released and bind serum
    calcium
  • Stones can form that can impair renal function
    and cause increased creatinine
  • Ultimately renal failure can develop with fatal
    hyperkalemia

53
Tumor Lysis Syndrome
  • Prevent serious electrolytes issues with
    aggressive hydration with IV fluids without
    potassium
  • Allopurinol or urate oxidase to prevent
    hyperuricemia
  • Prompt recognition and treatment of hyperkalemia
  • Calcium to stabilize cardiac membranes
  • Decrease serum potassium--Kayexylate, diuretics,
    insulin, dialysis

54
Fever Neutropenia
  • Definitions
  • Fever Temperature greater than 38.3 C (101 F)
  • Severe neutropenia Absolute Neutrophil Count
    (ANC) lt500
  • Treatment
  • Immediate broad spectrum gram negative,
    anti-pseudomonal coverage and Gram positive
    coverage
  • Ex Ceftazadime, Cefepime, Zosyn, Timentin
  • Add Vancomycin for Strep viridans coverage in
    certain patients
  • Discharge criteria (before ANC gt500/mm3)
  • WBC and ANC rising to at least 100
  • Afebrile for gt24 hours
  • No significant or persistently positive cultures
  • Well appearing with reliable follow-up

55
Pneumocystis Pneumonia
  • Presentation
  • Fever
  • Tachypnea
  • Hypoxia
  • Ground glass appearance on CXR
  • Prophylaxis
  • Bactrim (Trimethoprim Sulfa) first line
    regimen
  • Dapsone
  • Pentamidine
  • Atovaquone

56
Late Effects of ALL Therapy
  • Long courses of steroids
  • Obesity
  • Low bone density
  • Osteonecrosis
  • Anthracyclines
  • Cardiomyopathy
  • CNS directed therapy
  • Slower processing speed

57
The Future of ALL Therapy
  • Safely decrease therapy for lower risk patients
  • Fewer steroid pulses and less Vincristine
  • Shorter Maintenance regimen
  • Add novel agents for higher risk ALL
  • T Cell ALL Nelarabine
  • Philadelphia ALL Imatinib, Dasatinib
  • Infants Lestaurtinib
  • High Day 29 MRD Clofarabine

58
AALL0932
Induction (4 weeks)
AR (Average Risk)-ALL
Consolidation (4 weeks)
Interim Maintenance I (8 weeks)
Delayed Intensification (8 weeks)
Interim Maintenance II (8 weeks)
Randomization
Maintenance (12-week cycles)lasts 2 years for
girls and 3 years for boys
Arm A VCR/DEX q 4 wk MTX 20 mg/m2/wk
Arm B VCR/DEX q 4 wk MTX 40 mg/m2/wk
Arm C VCR/DEX q 12 wk MTX 20 mg/m2/wk
Arm D VCR/DEX q 12 wk MTX 40 mg/m2/wk
59
Any Questions?
  • hanumantha-pokala_at_ouhsc.edu
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