Advances in the Management of Pediatric Acute Leukemia

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, 350:1535-48,2004 T-lineage

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.

Event-free Survival Relates to Genotype and Phenotype Pui et al. Lancet 371:1030-43, 2008

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

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 Invest117:1049-57,2007

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

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 Total XV, unpublished data 9

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%)

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

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%

St Jude AML02: Risk-directed Treatment

Prophylactic Antibiotics Reduce Infection Rates and Hospitalization I.V. Cefepime I.V. Vancomycin + PO Ciprofloxacin Viridans Strept No infections 97% reduction Any bacterial 91% reduction* 93% reduction Hospitalization 31% reduction 46% reduction Total cost-of-care 26% reduction 26% reduction * Two breakthrough infections resistant to cefepime Kurt et al Cancer 113:376-82, 2008

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 unpublished data

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.