Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?

Abstract

Improved supportive care, more precise risk stratification, and personalized chemotherapy based on the characteristics of leukemic cells and hosts (eg, pharmacokinetics and pharmacogenetics) have pushed the cure rate of childhood acute lymphoblastic leukemia to near 90%. Further increase in cure rate can be expected from the discovery of additional recurrent molecular lesions, coupled with the development of novel targeted treatment through high-throughput genomics and innovative drug-screening systems. We discuss specific areas of research that promise to further refine current treatment and to improve the cure rate and quality of life of the patients.

Figure 1

Estimated frequency of specific genotypes in childhood ALL. Data were modified from Pui et al by including recently identified genotypes. The genetic lesions that are exclusively seen in cases of T-cell ALL are indicated in gold and those commonly associated with precursor B-cell ALL in blue. The darker gold or blue color indicates those subtypes generally associated with poor prognosis. BCR-ABL1–like cases can be separated into one group with CRLF2 dysregulation and the other with activating cytokine receptor and kinase signaling.

Figure 2

Use of germline variation to define ancestry (> 90% European ancestry for whites, > 10% Native American ancestry for Hispanics, > 70% African ancestry for blacks, and > 90% Asian ancestry for Asians). The population of children (n = 2534) with ALL in the United States (A) displays the ancestral diversity that is comparable to that observed in the entire United States population (B; based on self-declared status; United States Census Bureau, 2000), with a slightly lower proportion of blacks and a slightly higher proportion of Hispanics among patients with ALL (reflecting lower incidence of ALL in black children and higher incidence of ALL in Hispanic children).

Figure 3

At St Jude Children's Research Hospital, dosages of high-dose methotrexate are individualized based on the estimates of clearance to achieve a desired systemic exposure to the drug. As shown, in a patient estimated to have low clearance (40 mL/min per m²; A), the dosage should be lowered to achieve the desired steady-state plasma concentration to reduce potential toxicities (B). Those patients with high clearance have dosages increased.