Transcript Document

Acute Leukemias in
Children
SOBOPE
Educação Continuada em
Onco-Hematologia Pediátrica
Childhood Cancer
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
Predisposing Factors
Genetic Syndromes
• Down syndrome
– 10-20 times increased incidence leukemia
– 600 times in megakaryoblastic type
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Fanconi Anemia
Bloom syndrome
Neurofibromatosis
Schwachman syndrome
Ataxia Telangiectasia
Klinefelter syndrome
Li-Fraumeni syndrome
Haplo-insufficiency of the AML-1 gene
Predisposing
Factors
• Familial aggregation
– Concordance in Twins
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•
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High birth weight
Ionizing radiation
Non-ionizing radiation (EMF)
Alcohol consumption/cigarette
smoking
• Natural occurring flavanoids
M
G2
S
Nonproliferation
Compartment
G0
G1
Cell Death
Loss
Transactivation
RHD
PST
NM
Repression
PST
NHR1
PST
Repression
NHR3
NHR2
RHD
PST
NHR1
WRPY-Grocho
interaction domain
ETO
NHR4 PST
Zn
finger
hydrophobic
heptad repeat
AML1-ETO
AML1
TA
t(8;21)(q22;q22)
PST
NHR3
NHR2
NHR4 PST
Impaired Differentiation
X
CBF
N-CoR
p300
AML-1
TGT/GGT
Ets
myb
C/EBP
CBF
AML-1
TGT/GGT
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
Pathogenesis
Proliferation
Kinases
BCR-ABL
c-KIT
FLT3
Differentiation
Transcriptional
Core Binding
MLL
RAR
Leukemia
Birth
15 years
Greaves M. BMJ 324: 283, 2002
Methods to Investigate
Leukemia Heterogeneity
• Conventional techniques
– Morphology
– Cytochemistry
•
•
•
•
•
Immunophenotyping
Conventional Cytogenetics
Molecular genetics
Gene expression
Protein expression
Diagnosis
Morphology, cytochemistry,
immunophenotype and cytogenetic
Leukemia
Acute vs. Chronic
Lymphoid vs. Myeloid
Morphology/Cytochemistry
Lymph
Myelo
Mono
MPO
+
-
ANB
+
Megak
-
-
ANA
+,
diffuse
+,
granular
Blood
Cells
Immunophenotype
Classification - ALL
Immunophenotype
Frequency (%)
Early pre-B
57
Pre-B
25
Transitional
1
B-cell
2
T-cell
15
Classification - ALL
Ploidy
Hypodiploid
Diploid
Pseudodiploid
Hyperdiploid
Near tetraploid
Frequency (%)
7
8
42
42
1
Treatment Results of Selected Contemporary
Clinical Trials of Childhood ALL
Study
AIEOP 91
BFM 90
CCG 1800
COALL 92
DFCI 91-01
NOPHO III
SJCRH XIIIB
Year
1991-95
1990-95
1989-95
1992-97
1991-95
1992-98
1994-98
No.
1194
2178
5121
538
377
1143
247
% 5-yr EFS (SE)
71 (1)
78 (1)
75 (1)
77 (2)
83 (2)
78 (1)
81 (3)
Chemotherapy in ALL
Drugs
Mercaptopurine
Methotrexate
Prednisone
Dexamethasone
Cyclophosphamide
Vincristine
Cytarabine
Asparaginase
Daunorubicin
Etoposide
Teniposide
Years approved in US
1953
1953
1955
1958
1959
1964
1969
1978
1979
1983
1990
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
Total XV: Risk Classification Schema
T-lineage
B-lineage
t(9;22)/BCR-ABL
WBC <50 X 109/L
& age 1 to 9.9 years,
DNA index 1.16, or
TEL-AML1
WBC 50 X 109/L,
Age 10 years,
CNS leukemia,
Testicular leukemia,
MLL rearrangement,
t(1;19)/E2A-PBX1
<45 chromosomes
Minimal residual
leukemia detection
at remission date
1%
High-risk
~5%
<0.01%
Low-risk
~45%
Minimal residual
leukemia detection
at remission date
0.01% to 1%
1%
0.01% to <1%
Standard-risk
~50%
Pui, Campana, Evans Lancet Oncology 2001
Risk-Directed Therapy in ALL
Risk Group
Low
Standard
High
Proportion
of Patients
Treatment
45% Antimetabolite-based
50%
Intensive multiagent
5% Allogeneic transplant
Remission Induction Rate With 2 Drugs
Combination
CR (%)
Study
Pred + VCR
95
93
83
83
SJCRH VII
CALGB-7111
SWOG 7420
Pred +Dexa
CALGB-7111
Remission Induction Rate With 3 Drugs
Combination
CR (%)
Study
Pred + VCR + Asp
90
83
80
93
92
84
SJCRH VIII
CCSG 101/143
CALGB-7111
Pred + VCR + Dauno
PARIS 06-LA-66
SJCRH IX
GATLA 10-LAA-72
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
Delayed Intensification
(Not Intensive Induction)
Improved Outcome for Standard-Risk ALL
CCG 105 (1983-1988)
1.00
.80
.60
.40
Delayed Intensification (N = 312)
Intensive Induction/Consolidation/
Delayed Intensification (N = 318)
Intensive Induction/Consolidation (N = 314)
Standard (N = 313)
.20
P = .001
3
6
9
12
15
Time From Randomization (years)
Gaynon et al. Leukemia, 2000
Is L-Asparaginase necessary?
Asparaginase Doses* No. 5-year EFS  SE†
 25
> 25
43
309
73%  7%
90%  2%
* weekly dosage of E Coli asparaginase at 25,000
I.U./m2
† P < 0.01
Asparaginase Intolerance Conferred a
Poor Prognosis in DFC1 91-01 Protocol
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 99:1134-9, 2002
Remission Induction Rates of Contemporary
Clinical Trials
Study
Year
No.
Induction rates (%)
1774
98.2
AIEOP/BFM
2000-
2000
1992-97
538
98.7
COALL 92
1991-96
467
99
DCLSG ALL 8
1991-95
386
98
DFCI 91-01
1989-98
2065
97.8
EORTC 58881
1992-98
1143
98.4
NOPHO III
1991-98
412
98.3
SJCRH XIII
1992-95
347
96
TCCSG L92-13
1990-97
2090
99
UKALL XI
Consolidation
POG 9005: DFS According to Methotrexate Dosage
High-dose (n=349)
100
79% ± 7%
80
60
65% ± 8%
Low-dose (n=350)
40
P = 0.013
20
0
0
1
2
3
Years from CR Date
4
5
6
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
66  8 (152)
85  7 (149)
56  10 (87)
84  9 (84)
T-cell ALL
T-cell ALL +
WBC>50x109/L
T-NHL
88  12 (69)
* Backbone of DFCI protocol
87  10 (71)
Double Reinduction (Intensification)
Improved Outcome of Intermediate-Risk ALL
Lange et al Blood 99:825-33, 2002
Double Reinduction (Protocol II)
Improved Outcome of High-Risk ALL*
AIEOP ALL95 Study
*PPR, delayed remission, t(9;22), t(4;11) in
infants
Aricó et al Blood 100:420-6, 2002
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)
Metabolism and Elimination of MTX and MP
Genetic Polymorphism of TPMT
10
wt/wt
8
6
4
wt/m
6MP Dosage
2
500
TPMT Alleles
m/m
0
0
5
10
15
20
25
H1
30
ATG
TPMT Activity
250
H2
• Dose adjustments
to avoid toxicity
• Molecular
mechanisms
ATG
H 3A
ATG
25
0 m/m wt/m wt/wt
Wt/Mut
G460A A719C
H 3C
• Molecular diagnosis
Wt/Wt
G238C
ATG
A719G
[>6 additional alleles]
Mut/Mut
293 bp
207 bp
86 bp
ACCI:
–
+
–
+
–
+
Krynetski andEvans
AmJHumGen63(1):11-6, 1998
Total XII: Event-Free Survival According to TPMT Status
Dexamethasone Improves
Outcome
Study
CALBG 7111
(1971-74)
CCG 1922
(1993-95)
No.
% CNS relapse
Patients
Dex Pred
493
14.3 25.6
1060
3.1
7.1
%5-year EFS
Dex Pred
—
—
85
81
Can Continuation Treatment be Shortened?
• Tokyo CCSG L92-13 Study (1992-1995)
• Treatment duration 52 weeks
• Treatment outcome
Overall (N=347)
B-lineage Standard-risk (N=193)
High-risk
(N=94)
T-lineage
Standard-risk (N=10)
High-risk
(N=31)
• Overall Survival
81.0  2.1% at 5 yr
% 5-yr EFS
63.4  2.7
67.8  3.4
56.7  5.4
77.1  14.4
53.6  10.1
Toyoda Y et al. J Clin Oncol 18:1508, 2000
CNS Status According to CSF
Findings in St. Jude Study XI
Status
CNS 1
CNS 2
CNS 3
Findings
No blast
<5 WBC/mm3 with blasts
≥5 WBC/mm3 with blasts
Patients (%)
291(83)
42(12)
18(5)
Mahmoud et al. N Engl J Med, 329:314-9, 1993
Study XI: DFS by CSF Findings
Probability
1
0.8
CNS 1 75% ± 4%
0.6
Overall 72% ± 4%
CNS 2
53% ± 15%
CNS 3 49% ± 14%
0.4
0.2
0
0
1
2
3
4
5
Years From Complete Remission
6
7
CNS Relapse Rate According to CNS
Status
Study
Patient Group CNS1
POG 8602
B-lineage 5.3%
CCG 105 Intermediate-risk6.5%
BFM 95
All
3.5%
EORTC 58881
All
8.1%
CCG 1800/1900 All
3.9%
CNS2
11.6%
11.8%
10%
15.7%
7.7%
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, 96:3381-4, 2000.
Studies XI and XII: EFS According to CNS Status
100
Probability %
80
CNS 1 (n = 301)
p < 0.001
60
Traumatic with blasts x 2 (n = 26)
40
CNS 3 (n = 16)
20
0
2
4
6
8
10
Years From Diagnosis
12
14
16
Risk Factors for Traumatic/Bloody
Lumbar Puncture
• Traumatic LP defined as ≥10 RBCs/mm3
− Platelet count <100 x 109/L
− Inexperienced practitioner
− Lumbar puncture within 2 weeks of prior LP
• Unmodifiable
− Black race
− Age < 1 year
− Early treatment era
Howard et al. JAMA, 288:2001-7, 2002
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
Transplantation in Childhood ALL
Newly Diagnosed
Relapse
Philadelphia Chromosome
T-cell
t(4;11)/MLL-AF4
Very early marrow (<18 mo)
High-risk T-cell
Early marrow (>18 mo, < 6
mo off therapy)
Hypodiploidy <45
Very early combined (<18 mo)
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)
<0.001
MUD transplant
21
13
1.3 (0.7-2.4)
0.40
Other transplant
16
9
0.8 (0.4-1.5)
0.45
Proportion
DFS of high-risk T-cell ALL – BFM 90-95
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
P=0.01
0.0
0
1
2
67%±8%
34%±4%
3
4
5
6
Transplant (n=37)
Chemotherapy (n=144)
7
8
Years From Remission
9
10 11
12
Survival of Complete Responders with
t(4;11) Chemotherapy vs
Transplantation
Treatment
Chemotherapy
Autologous transplant
MRD transplant
MUD transplant
Other transplant
Any transplant
No. of Patients
Total Deaths
174
104
10
4
15
9
14
8
17
14
56
35
Hazard Ratio
(95% CI)
P value
1.0
0.71
0.83 (0,1.67)
0.26
1.48 (0.47, 2.48)
0.78
1.90 (0.11,3.27)
0.078
2.54 (1.15, 3.92)
0.008
1.76 (1.08, 2.45)
0.004
DFS and Survival in t(4;11) ALL
Chemotherapy vs MRD Transplantation
1
0.9
0.8
0.7
Survival
0.6
Chemotherapy
Transplantation
0.5
0.4
Chemotherapy
0.3
Transplantation
Disease-free survival
0.2
0.1
0
0
0.38
1
3
5
7
9
11
Years from Start of Therapy
13
15
17
Summary - Transplant
• Matched-related transplant is indicated for
Philadelphia chromosome-positive ALL
• Matched-related transplant or matchedunrelated transplant improves outcome of
high risk T-cell ALL
• Transplant does not appear to benefit
t(4;11) ALL
• Studies are needed to determine if
transplant is effective for B-lineage late
responders or those with severe
hypodiploidy
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
Evans WE and Relling MV, Science 286:487-91, 1999
SEER – AML survival – 5 years
(%)
http://seer.cancer.gov/Publications/CSR1973_1998/child.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
Induction
Study
No.
Ara-C
Dauno
Other
MRC10
286
1,000
150
POG 8821 649
5,000
225
6-TG
VP16
6-TG
CCG S
2891 I
BFM93
294
295
471
800
1,600
1,400
Aust/NZ
102
160
700
700
80
VP/Dex/
6-TG
60
180
VP16
Idar 36
150
6-TG
Idar 36 HD Ara-c
CR
(%)
89
93
85
74
78
82
95
92
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
Post-Remission
• Chemotherapy
– Intensity
– Number of courses
– Maintenance
• Stem Cell Transplantation
– Autologous
• Purged
– Allogeneic
• Related
• Unrelated
Post-Remission Summary
• Consolidation is necessary
–Intensive blocks
–Drugs (?)
–Number (?)
• Maintenance is not
necessary
Lessons from the Past
Stem Cell Transplantation
• Study CCG-2891
–To compare two induction
(intensified and standard)
regimens
Woods et al. Blood 87:4979, 1996
–To compare three strategies of
post-remission therapy
• Allogeneic HSCT
•Woods
Autologous
HSCT
et al. Blood 97:56, 2001
–Busulfan/Cyclophosphamide
Allogeneic HSCT
Intensive Chemotherapy
Autologous HSCT
Woods W. Blood 97:56-62, 2001
Estimates of Survival - 8
years
Allo HSCT Auto HSCT Int Chemo
No. (537)
181
177
179
DFS
55% ± 9%
42% ± 8%
47% ± 8%
Chemo (336)
113
115
108
DFS
66% ± 9%
48% ± 9%
53% ± 10%
Woods W. Blood 97:56-62, 2001
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
MRC-10: Risk of relapse in all patients
Burnett A et al Lancet 351: 700, 1998
MRC-10: Survival in all patients
Burnett A et al Lancet 351: 700, 1998
Autologous Bone Marrow Transplantation
• 31 consecutive patients with AML
• 24 entered the autologous BMT
• Preparatory regimen: Melphalan 140 mg/m2/d
Tiedeman, K. Blood 82:3730-3738, 1993
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
Central Nervous SystemDirected 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 (N=8)
– DFS ~ 50%
• No isolated CNS relapse
• BFM-93
– IT Ara-C x 4
– Cranial radiation 18 Gy (children > 3 years)
– No report on CNS relapses
Central Nervous SystemDirected 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 (N=8).
Craniospinal radiotherapy (24Gy/12Gy)
– No isolated CNS relapse; 4 combined
• Australian/NZ
– IT MTX x 5
– No radiation
CNS-directed therapy Summary
• No randomized studies
– Type of drugs
– Radiation
• Chemotherapy likely to
suffice
• Radiotherapy
– Overt CNS
– Chloromas
Risk-directed therapyAML
• Intensive Chemotherapy
–favorable cytogenetics
• t(8;21), t(9;11), inv(16)
• Down Syndrome
• ATRA
–Progranulocytic leukemia
Risk-directed therapy- AML
• Bone Marrow Transplantation
–High-risk groups
• -7, -5q, trisomy 8
• Failure to achieve
remission after 1-2
courses of chemotherapy
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