1. Advances in the Management of Pediatric Acute Leukemia

3. All leukemic cells have Clonal Genetic Abnormalities
B-lineage
Hyperdiploidy
>50 chromosomes
25%
Hypodiploidy
<45 chromosomes 1%
TEL-AML1
t(12;21)
22%
Others
22%
MYC
t(8;14), t(2;8),t(8;22) 2%
BCR-ABL
t(9;22) 3%
E2A-PBX1
t(1;19) 5%
TAL1
Ip32 7%
MLL rearrangements
e.g. t(4;11),t(11;19),
t(9;11) 8%
HOX11L2
5q35
2.5%
HOX11
10q24
0.7%
MLL-ENL
0.3%
LYL1
19p13
1.5%
Pui et al, NEJM, 350: ,2004
T-lineage

4. Genome-wide Analyses Identify Cooperative Mutations
Genes for class distinction (n=588)
HD>50
BCR-ABL
TEL-AML1
E2A-PBX1
T-ALL
MLL
Yeoh et al. Cancer Cell 1:133-43,2002.

5. Event-free Survival Relates to Genotype and Phenotype
Pui et al. Lancet 371: , 2008

6. Host Pharmacogenomics Affects Treatment Response
Same treatment
to all patients
+ Benefit
+ Toxicity
+ No Toxicity
Optimize treatment
With individualized dose
No Benefit
No Toxicity
+ Toxicity
Treat with alternative drug
Pui & Evans N Engl J Med 354:166-78,2006

7. Microenvironment Affects Leukemia Survival and Treatment Response
Mesenchymal cells support the growth of leukemia
Mesenchymal cells can protect leukemic cells from antileukemic treatment.
Iwamoto et al. J Clin Invest117: ,2007

8. Early Treatment Response is the Best Determinant of Clinical Outcome
Leukemic
cell
Micro-
environment
Tumor burden
Growth potential
Drug resistance
Drug resistance
Host
Therapy
Age
Drug dosage
Pharmacogenomics
Drug interactions
Treatment
response

9. Treatment Outcome According to Minimal Residual Disease After completion of Remission Induction
Level
No. Patients
5-year % EFS (SE)
<0.01%
0.01% to <1%
388 77
89(3)
81 (8)
1% to 5%
>5% 14 7
57 (27)
57 (37)
Pui et al. Total XV, unpublished data 9

10. Total XV (2000-2007): Principle of Therapy
Adopt effective treatment components of successful clinical trials Reinduction therapy including dexamethasone: BFM, CCG Intensive asparaginase: DFCI Intensive triple intrathecal therapy: POG, SJCRH Studies XIII
Individualized therapy Risk assessment based mainly on MRD Targeted HDMTX dose (Cpss:35µM in lower-risk, 65µM in higher-risk) Mercaptopurine dose based on TPMT, 6TGN and ANC
Limited use of treatment components associated with late complications Omit cranial irradiation in all patients anthracyclines (100 mg/m2 in lower-risk and 230 mg/m2 in higher-risk) etoposide used only in candidates for transplant (~5%)

11. Overall Treatment Results of Total XV
Event-free Survival
87 ± 3%
Isolated CNS Relapse
3% ± 1%
Survival
94% ± 2%
N=498
Pui et al. unpublished data 11

12. Genetic Subtypes of Childhood AML
Translocation not identified
22%
RMB15-MKL1
t(1;22) 1%
Monosomy 7
Random
25%
PML-RARa
PLZF-RARa
t(15;17) t(11;17) 8%
MLL-AF9
t(9;11)
DEK-CAN
t(6;9)
AML1-ETO
t(8;21)
12%
CBFb-MYH11
inv(16)
10%
NPM-MLF1
t(3;5)
EVl1
t(3;v) 2%
Other MLL
11q23 8%

13. St Jude AML02: Risk-directed Treatment

14. Prophylactic Antibiotics Reduce Infection Rates and Hospitalization
I.V. Cefepime I.V. Vancomycin +
PO Ciprofloxacin
Viridans Strept No infections % reduction
Any bacterial % reduction* % reduction
Hospitalization % reduction % reduction
Total cost-of-care 26% reduction % reduction
* Two breakthrough infections resistant to cefepime
Kurt et al Cancer 113:376-82, 2008

15. Improving Survival of AML by Treatment Era
Rubnitz et al. unpublished data

16. Conclusions
Contemporary risk-direct therapy, without the use of prophylactic central-nervous-system irradiation, can cure up to 90% children with acute lymphoblastic leukemia.
Improved supportive care including prophylactic antifungal and antibacterial treatment can cure 60% or more of children with acute myeloid leukemia.