The treatment outcome and the biological understanding of childhood acute lymphoblastic leukemia have improved substantially in the recent years. The advent of high-resolution genome-wide analyses of gene expression, DNA copy number alterations and loss-of-heterozygosity, sequence mutations, and epigenetic changes as well as whole genome sequencing have led to the detection of many novel genetic abnormalities. To date virtually all patients with ALL can be classified according to specific genetic abnormality. While primary somatic genetic abnormalities have important prognostic and therapeutic implications and play a critical role in leukemogenesis, experimental models have established that cooperative mutations are necessary to induce leukemia and contribute to the development of drug resistance. We have recently identified several novel high-risk subgroups of ALL: one with genetic profile similar to that of cases with Philadelphia chromosome and BCR-ABL1 fusion, characterized by IKZF1 deletion; one with JAK2 mutations; one with CRLF2 overexpression, and one with gene expression profile of normal early thymic precursor cells which we termed early T-cell precursor ALL. By studying host pharmacogenetics, we have identified germline polymorphisms of IKZF1 gene and ARID5B gene to be associated with an increased risk of childhood ALL. Interestingly, the risk alleles of ARID5B, a gene that encodes a member of a family of transcriptional factors important in embryonic development, cell type-specific gene expression and cell growth regulation, were specifically enriched in patients with hyperdiploid ALL, and were also associated with greater methotrexate polyglutamate accumulation. Thus, the same genetic variation of ARID5B that predisposes to the development of hyperdiploid ALL may also underlie the superior response of this subtype of ALL to chemotherapy. Future genome-wide studies promise to elucidate the full complement of germline alleles that contribute to leukemogenesis.

　　Parallel to the advances in biologic studies is the improved treatment outcome with the use of personalized treatment and meticulous supportive care. In our recently completed Total Therapy XV (2000 to 2007), emphasis was placed on the reduction of long-term sequelae by limiting the cumulative doses of anthracyclines and cyclophosphamide, and by omitting cranial irradiation in all patients. The intensity of postremissoin therapy was based on the level of minimal residual disease at the end of remission induction. The dose of high-dose methotrexate used in the consolidation therapy was individualized to achieve a steady-state concentration of 65 μM or 33 μM for standard-/high-risk and low-risk patients, respectively. Genotype and activity of thiopurine methyltransferase were determined prospectively so that the dosage of mercaptopurine was reduced in patients with low enzyme activity to avoid excessive hematopoietic toxicities and to decrease the risk of therapy-related leukemia. The 8-year event-free survival and overall survival rates (SE) for the 498 patients enrolled were 85.6 (13.2) % and 92.6 (8.0) %, respectively. The cumulative risk of isolated central-nervous-system relapse was only 2.7 (0.8) %; all 11 patients with the event are alive in remission after salvage therapy. We anticipate that 90% of all patients enrolled on the study will be cured. In our current Total Therapy study, we attempt to further improve the cure rate and the quality of life of the patients. We intensify intrathecal therapy in patients identified to have high risk of central-nervous-system relapse in Total XV, administer tyrosine kinase inhibitor (dasatinib) to patients with BCR-ABL1-positive ALL, and treat patients with early T-cell precursor ALL with high-dose dexamethasone. The early results for the first 140 patients enrolled are encouraging, with a remission induction rate of 100% and a 2-year event-free survival of 96 (11) %.