A health-care system perspective on implementing genomic medicine: pediatric acute lymphoblastic leukemia as a paradigm

Abstract

The promise of genomic medicine has received great attention over the past decade, projecting how genomics will soon guide the prevention, diagnosis, and treatment of human diseases. However, this evolution has been slower than forecast, even where evidence is often strong (e.g., pharmacogenomics). Reasons include the requirement for institutional resources and the need for the will to push beyond barriers impeding health-care changes. Here, we illustrate how genomics has been deployed to advance the treatment of childhood leukemia.

Figure 1

A time line of discovery and clinical implementation of genomics to advance treatment of childhood ALL. A (orange): corresponds to time line for studies Total XI–XII in Figure 2; B (purple): corresponds to time line for studies Total XIII–XIV in Figure 2; C (blue): corresponds to time line for study Total XV in Figure 2; D (green): denotes future clinical use of genomics. ALL, acute lymphoblastic leukemia; SNP, single-nucleotide polymorphism; TPMT, thiopurine methyltransferase.

Figure 2

Kaplan–Meier analysis of treatment outcome (survival) for children enrolled in successive clinical trials at St Jude Children’s Research Hospital between 1962 and 2007. Advances in the cure rate of childhood ALL have occurred over this time period despite the introduction of only one new antileukemic agent (imatinib was developed for Philadelphia chromosome (BCR-ABL1)-positive ALL, which constitutes only 3% of childhood ALL cases). Better supportive care has been important (e.g., new antibiotics, new antifungals, and better diagnostics). However, genomics has played an important role in determining the optimal treatment based on both somatic and germline DNA variation. A: institution of use of chromosomal number (or DNA content) and translocations to guide therapy;B: implementation of TPMT genotype to dose mercaptopurine; C: institution of the use of the presence of Philadelphia chromosome (BCR-ABL1) to guide treatment, preemptive genotyping, and clinical decision support; D: use of next-generation sequencing for discovery (2010), clinical sequencing begins (2013). Numbers on the curves denote overall survival rates at 5 years. ALL, acute lymphoblastic leukemia; TPMT, thiopurine methyltransferase.