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Acute Leukemias in Children

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Title: Acute Leukemias in Children


1
Acute Leukemias in Children
  • SOBOPE
  • Educação Continuada em Onco-Hematologia Pediátrica

2
Childhood Cancer
3
Epidemiology
3,250 new cases/year US 2,400 are ALL 32 of all
cancers 17 first year 46 between 2 and 3
years 9 in adolescence Leukemia is more common
in whites
4
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5
Predisposing Factors Genetic Syndromes
  • Down syndrome
  • 10-20 times increased incidence leukemia
  • 600 times in megakaryoblastic type
  • Fanconi Anemia
  • Bloom syndrome
  • Neurofibromatosis
  • Schwachman syndrome
  • Ataxia Telangiectasia
  • Klinefelter syndrome
  • Li-Fraumeni syndrome
  • Haplo-insufficiency of the AML-1 gene

6
Predisposing Factors
  • Familial aggregation
  • Concordance in Twins
  • High birth weight
  • Ionizing radiation
  • Non-ionizing radiation (EMF)
  • Alcohol consumption/cigarette smoking
  • Natural occurring flavanoids

7
M
G2
Nonproliferation Compartment G0
S
G1
Cell Death Loss
8
Transactivation
AML1
RHD
PST
NM
TA
WRPY-Grocho interaction domain
Repression
Repression
ETO
NHR1
PST
PST
NHR3
NHR4
PST
NHR2
Zn finger
hydrophobic heptad repeat
AML1-ETO t(821)(q22q22)
RHD
NHR1
PST
PST
NHR3
NHR4
PST
NHR2
9
Impaired Differentiation
X
HDAT
SinA3
N-CoR
p300
pCAF
CBF?
Ets myb C/EBP
AML-1
CBF?
AML-1
TGT/GGT
TGT/GGT
10
Multistep Origin of Leukemia
Normal cell, one genetic mutation may not impair
cell function
Normal cell, no mutation
Normal cell, no mutation
Malignant cell, resulting from accumulation of
several mutations
11
Pathogenesis
Proliferation
Kinases BCR-ABL c-KIT FLT3
Differentiation
Transcriptional Core Binding MLL RAR?
12
Leukemia
Birth
15 years
Greaves M. BMJ 324 283, 2002
13
Methods to Investigate Leukemia Heterogeneity
  • Conventional techniques
  • Morphology
  • Cytochemistry
  • Immunophenotyping
  • Conventional Cytogenetics
  • Molecular genetics
  • Gene expression
  • Protein expression

14
Diagnosis
  • Morphology, cytochemistry, immunophenotype and
    cytogenetic
  • Leukemia
  • Acute vs. Chronic
  • Lymphoid vs. Myeloid

15
Morphology/Cytochemistry
16
Blood Cells
Immunophenotype
17
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18
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19
Classification - ALL
20
Classification - ALL
21
Treatment Results of Selected Contemporary
Clinical Trials of Childhood ALL
Study
Year
No.
5-yr EFS (SE)
AIEOP 91 BFM 90 CCG 1800 COALL 92 DFCI
91-01 NOPHO III SJCRH XIIIB
1991-95 1990-95 1989-95 1992-97 1991-95 1992-98 19
94-98
1194 2178 5121 538 377 1143 247
71 (1) 78 (1) 75 (1) 77 (2) 83 (2) 78 (1) 81 (3)
22
Chemotherapy in ALL
  • Drugs Years approved in US
  • Mercaptopurine 1953
    Methotrexate 1953 Prednisone 1955
    Dexamethasone 1958 Cyclophosphamide 1959
    Vincristine 1964
    Cytarabine 1969 Asparaginase
    1978 Daunorubicin 1979
    Etoposide 1983 Teniposide 1990

23
Principles of Treatment in ALL
  • Risk-directed therapy
  • Early intensification of chemotherapy
  • Systemic and intrathecal
  • Consolidation/intensification
  • Early reinduction
  • Extended continuation treatment
  • Dose intensity of antimetabolites
  • Dexamethasone/vincristine pulses

24
Pui, Campana, Evans Lancet Oncology 2001
25
Risk-Directed Therapy in ALL
  • Proportion Risk Group of Patients Treatment
  • Low 45 Antimetabolite-based
  • Standard 50 Intensive multiagent
  • High 5 Allogeneic transplant

26
Remission Induction Rate With 2 Drugs
Combination CR () Study
Pred VCR 95 93 83 SJCRH VII CALGB-7111 SWOG 7420
Pred Dexa 83 CALGB-7111
27
Remission Induction Rate With 3 Drugs
Combination CR () Study
Pred VCR Asp 90 83 80 SJCRH VIII CCSG 101/143 CALGB-7111
Pred VCR Dauno 93 92 84 PARIS 06-LA-66 SJCRH IX GATLA 10-LAA-72
28
Remission Induction Rate With 4 Drugs
Combination CR () Study
Pred VCR Dauno Asp 96 BFM 70-76/76-79
Pred VCR Dauno Cyclo 91 CCSG 141
29
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30
Asparaginase Intolerance Conferred a Poor
Prognosis in DFC1 91-01 Protocol
Is L-Asparaginase necessary?
  • Asparaginase Doses No. 5-year EFS ? SE
  • ? 25 43 73 ? 7
  • gt 25 309 90 ? 2
  • weekly dosage of E Coli asparaginase at 25,000
    I.U./m2
  • P lt 0.01

31
Erwinia Asparaginase Is Less Efficacious Than E.
Coli Asparaginase Given at the Same Dose (10,000
U/m2 Twice a Week x 8) During Induction
Duval et al Blood 991134-9, 2002
32
Remission Induction Rates of Contemporary
Clinical Trials
Induction rates ()
Year
No.
Study
AIEOP/BFM 2000 COALL 92 DCLSG ALL 8 DFCI
91-01 EORTC 58881 NOPHO III SJCRH XIII TCCSG
L92-13 UKALL XI
2000- 1992-97 1991-96 1991-95 1989-98 1992-98 1991
-98 1992-95 1990-97
1774 538 467 386 2065 1143 412 347 2090
98.2 98.7 99 98 97.8 98.4 98.3 96 99
33
Consolidation
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High-Dose Methotrexate (5g/m2) Improves Outcome
of T-cell ALL in POG 9404 Study
  • 3-year EFS (No. of Patient)
  • No HDMTX With HDMTX
  • T-cell ALL 66 ? 8 (152) 85 ? 7 (149)
  • T-cell ALL 56 ? 10 (87) 84 ? 9
    (84)
  • WBCgt50x109/L
  • T-NHL 88 ? 12 (69) 87 ? 10 (71)
  • Backbone of DFCI protocol

35
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36
Double Reinduction (Intensification) Improved
Outcome of Intermediate-Risk ALL
Lange et al Blood 99825-33, 2002
37
Double Reinduction (Protocol II) Improved
Outcome of High-Risk ALL AIEOP ALL95 Study
PPR, delayed remission, t(922), t(411) in
infants
Aricó et al Blood 100420-6, 2002
38
Maintenance Chemotherapy Continuous
administration without extended rest periods
  • Abrogating repair and recovery of slowly
    proliferating endothelial cells (leukemia has
    angiogenic phase)
  • Effective regimens featuring continuous treatment
    (e.g. DFCI, CCG augmented BFM)
  • Ineffective regimens featuring interrupted
    therapy (e.g. Total XH, BFM90-HRG, POG-T3)

39
Metabolism and Elimination of MTX and MP
40
Genetic Polymorphism of TPMT
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41
Total XII Event-Free Survival According to TPMT
Status
42
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43
Dexamethasone Improves Outcome
  • Study No. CNS
    relapse 5-year EFS
  • Patients Dex Pred
    Dex Pred
  • CALBG 7111 493 14.3 25.6
  • (1971-74)
  • CCG 1922 1060 3.1 7.1
    85 81
  • (1993-95)

44
Can Continuation Treatment be Shortened?
  • Tokyo CCSG L92-13 Study (1992-1995)
  • Treatment duration 52 weeks
  • Treatment outcome 5-yr EFS
  • Overall (N347) 63.4 ? 2.7
  • B-lineage Standard-risk (N193) 67.8 ?
    3.4
  • High-risk (N94) 56.7 ?
    5.4
  • T-lineage Standard-risk (N10) 77.1 ?
    14.4
  • High-risk (N31) 53.6 ?
    10.1
  • Overall Survival 81.0 ? 2.1 at 5 yr

Toyoda Y et al. J Clin Oncol 181508, 2000
45
CNS Status According to CSF Findings in St. Jude
Study XI
  • Status Findings Patients
    ()
  • CNS 1 No blast 291(83)
  • CNS 2 lt5 WBC/mm3 with blasts 42(12)
  • CNS 3 5 WBC/mm3 with blasts 18(5)
  • Mahmoud et al. N Engl J Med, 329314-9, 1993

46
Study XI DFS by CSF Findings
1
0.8
CNS 1
75 4
Overall
72 4
0.6
CNS 2
53 15
Probability
CNS 3
49 14
0.4
0.2
0
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3
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6
7
1
5
Years From Complete Remission
47
CNS Relapse Rate According to CNS Status
  • Study Patient Group CNS1 CNS2
  • POG 8602 B-lineage 5.3 11.6
  • CCG 105 Intermediate-risk 6.5 11.8
  • BFM 95 All 3.5 10
  • EORTC 58881 All 8.1 15.7
  • CCG 1800/1900 All 3.9 7.7

48
Impact of Traumatic Lumbar Punctures
  • Traumatic LP defined as 10 RBCs/mm3
  • 546 children with ALL
  • 2 consecutive St. Jude trials (XI and XII)
  • 2 sequential LPs performed
  • First diagnosis
  • Second instillation of first intrathecal
    chemotherapy (1-2 days later)

Gajjar et al. Blood, 963381-4, 2000.
49
Studies XI and XII EFS According to CNS Status
100
80
CNS 1 (n 301)
p lt 0.001
60
Probability
Traumatic with blasts x 2 (n 26)
40
CNS 3 (n 16)
20
0
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Years From Diagnosis
50
Risk Factors for Traumatic/Bloody Lumbar Puncture
  • Traumatic LP defined as 10 RBCs/mm3
  • Platelet count lt100 x 109/L
  • Inexperienced practitioner
  • Lumbar puncture within 2 weeks of prior LP
  • Unmodifiable
  • Black race
  • Age lt 1 year
  • Early treatment era

Howard et al. JAMA, 2882001-7, 2002
51
Current St. Jude Approach to CNS-Directed Therapy
  • Transfuse thrombocytopenic patients at diagnosis
  • Deep sedation or anesthesia
  • Most experienced clinician to give IT therapy
  • Additional IT therapy for CNS 2, CNS 3 and
    traumatic with blast status
  • Elimination of cranial irradiation

52
Transplantation in Childhood ALL
Newly Diagnosed Relapse
Philadelphia Chromosome T-cell
t(411)/MLL-AF4 Very early marrow (lt18 mo)
High-risk T-cell Early marrow (gt18 mo, lt 6 mo off therapy)
Hypodiploidy lt45 Very early combined (lt18 mo)
53
Disease-free Survival of Complete Responders with
Ph ALL Chemotherapy vs Transplantation
  • No of Patients Hazard Ratio
  • Treatment Total Failed (95 CI)
    P-value
  • Chemotherapy 147 123 1.0
  • Autologous transplant 25 19
    1.1 (0.7-1.8) 0.66
  • MRD transplant 38 12
    0.3 (0.2-0.5) lt0.001
  • MUD transplant 21 13
    1.3 (0.7-2.4) 0.40
  • Other transplant 16 9
    0.8 (0.4-1.5) 0.45

54
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55
DFS of high-risk T-cell ALL BFM 90-95
1.0
0.9
0.8
678 Transplant (n37)
0.7
0.6
Proportion
0.5
344 Chemotherapy (n144)
0.4
0.3
0.2
0.1
P0.01
0.0
0
1
2
3
4
5
6
7
8
9
10
11
12
Years From Remission
56
Survival of Complete Responders with t(411)
Chemotherapy vs Transplantation
  • No. of Patients Hazard Ratio
  • Treatment Total Deaths (95
    CI) P value
  • Chemotherapy 174 104
    1.0 0.71
  • Autologous transplant 10
    4 0.83 (0,1.67) 0.26
  • MRD transplant 15
    9 1.48 (0.47, 2.48) 0.78
  • MUD transplant 14
    8 1.90 (0.11,3.27) 0.078
  • Other transplant 17
    14 2.54 (1.15, 3.92) 0.008
  • Any transplant 56
    35 1.76 (1.08, 2.45) 0.004

57
(No Transcript)
58
Summary - Transplant
  • Matched-related transplant is indicated for
    Philadelphia chromosome-positive ALL
  • Matched-related transplant or matched-unrelated
    transplant improves outcome of high risk T-cell
    ALL
  • Transplant does not appear to benefit t(411) ALL
  • Studies are needed to determine if transplant is
    effective for B-lineage late responders or those
    with severe hypodiploidy

59
Improving Cure Rates in Childhood Leukemia
  • Refinement of Current Therapy
  • Maximum Efficacy, Minimum Toxicity
  • Individualization of Dosage
  • Improving Risk Classification
  • Development of New Cancer Drugs
  • Understanding the Mechanism of Disease

60
Evans WE and Relling MV, Science 286487-91, 1999
61
SEER AML survival 5 years ()
http//seer.cancer.gov/Publications/CSR1973_1998/c
hild.pdf
Disease 83-85 86-88 89-91 92-97
Hodgkin 88.2 89.3 93.5 93.1
ALL 66.7 75.4 77.3 82.8
CNS Tumors 63.1 65.6 64.3 69.5
AML 34.4 31.7 38.5 41.1
62
Induction
Study No. Ara-C Dauno Other CR ()
MRC10 286 1,000 150 6-TG VP16 89 93
POG 8821 649 5,000 225 6-TG 85
CCG S 2891 I 294 295 800 1,600 80 60 VP/Dex/ 6-TG 74 78
BFM93 471 1,400 180 Idar 36 VP16 82
Aust/NZ 102 160 700 700 150 Idar 36 6-TG HD Ara-c 95 92
63
Induction - Summary
  • Intensive blocks of therapy
  • Cytarabine dosage of at least 1.0 g or 10 days of
    exposure
  • Daunomycin total dosage of at least 100 mg/m2/day
  • Minimum infusion time of at least 90 minutes
  • Etoposide benefit has not been established
  • No benefit of mitoxantrone or idarubicin over
    daunorubicin
  • Supportive care is of paramount importance (early
    mortality 1-2)

64
Post-Remission
  • Chemotherapy
  • Intensity
  • Number of courses
  • Maintenance
  • Stem Cell Transplantation
  • Autologous
  • Purged
  • Allogeneic
  • Related
  • Unrelated

65
Post-Remission - Summary
  • Consolidation is necessary
  • Intensive blocks
  • Drugs (?)
  • Number (?)
  • Maintenance is not necessary

66
Lessons from the Past Stem Cell Transplantation
  • Study CCG-2891
  • To compare two induction (intensified and
    standard) regimens
  • Woods et al. Blood 874979, 1996
  • To compare three strategies of post-remission
    therapy
  • Allogeneic HSCT
  • Autologous HSCT
  • Busulfan/Cyclophosphamide
  • Intensive Chemotherapy

Woods et al. Blood 9756, 2001
67
Allogeneic HSCT
Intensive Chemotherapy
Autologous HSCT
Woods W. Blood 9756-62, 2001
68
Estimates of Survival - 8 years
Woods W. Blood 9756-62, 2001
69
MRC 10
Preparative treatment for both allogeneic and
autologous HSCT was Cyclo 120 mg/kg and TBI
Burnett A et al. Lancet 351 700, 1998
70
MRC-10 Risk of relapse in all patients
Burnett A et al Lancet 351 700, 1998
71
MRC-10 Survival in all patients
Burnett A et al Lancet 351 700, 1998
72
Autologous Bone Marrow Transplantation
  • 31 consecutive patients with AML
  • 24 entered the autologous BMT
  • Preparatory regimen Melphalan 140 mg/m2/d

Tiedeman, K. Blood 823730-3738, 1993
73
HSC Transplantation - Summary
  • HLA-matched sibling donor HSCT is recommended for
    children with standard or high-risk AML
  • HLA-matched unrelated donor HSCT acceptable for
    high-risk patients
  • Alternative donors (haploidentical) and
    autologous should be investigated
  • TBI-free regimens should be considered

74
Central Nervous System-Directed Therapy
  • St. Jude Study AML-97
  • Triple IT MTX/HC/Ara-C x 4,
  • CNS at diagnosis triple IT every week until
    clear and then with each cycle (N8)
  • DFS 50
  • No isolated CNS relapse
  • BFM-93
  • IT Ara-C x 4
  • Cranial radiation 18 Gy (children gt 3 years)
  • No report on CNS relapses

75
Central Nervous System-Directed Therapy
  • UK MRC-10
  • Triple IT MTX/HC/Ara-C x 4
  • CNS at diagnosis triple IT every week until
    clear and then with each cycle (N8).
    Craniospinal radiotherapy (24Gy/12Gy)
  • No isolated CNS relapse 4 combined
  • Australian/NZ
  • IT MTX x 5
  • No radiation

76
CNS-directed therapy - Summary
  • No randomized studies
  • Type of drugs
  • Radiation
  • Chemotherapy likely to suffice
  • Radiotherapy
  • Overt CNS
  • Chloromas

77
Risk-directed therapy- AML
  • Intensive Chemotherapy
  • favorable cytogenetics
  • t(821), t(911), inv(16)
  • Down Syndrome
  • ATRA
  • Progranulocytic leukemia

78
Risk-directed therapy- AML
  • Bone Marrow Transplantation
  • High-risk groups
  • -7, -5q, trisomy 8
  • Failure to achieve remission after 1-2 courses of
    chemotherapy

79
AML in DOWN SYNDROME
  • Predominant form of leukemia in DS children under
    the age of 4 years
  • M7 is the most common FAB type
  • Favorable translocations are rare
  • Common history of myodysplasia
  • Adverse effect on survival by BMT
  • Excellent prognosis on standard AML treatment
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