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. (Blood. 2012;120(6):1165-1174) IntroductionOptimal use of existing antileukemic agents and improved supportive care in contemporary clinical trials have improved the 5-year survival rate of childhood acute lymphoblastic leukemia (ALL) above 85% in developed countries (Table 1). [1][2][3][4][5][6][7][8] Further advances in survival and quality of life will require a better understanding of ALL pathobiology, the mechanisms of drug resistance, and drug disposition in the host, together with the development of innovative therapeutics. To this end, the advent of high-resolution genomewide analyses of gene expression, DNA copy number alterations, and epigenetic changes, and more recently, next-generation wholegenome and transcriptome sequencing have provided new insights into leukemogenesis, drug resistance, and host pharmacogenomics, identified novel subtypes of leukemia, and suggested potential targets for therapy. 9,10 Paralleling these advances has been the development of novel monoclonal antibodies, small molecule inhibitors, chemotherapeutics, and cell-based treatment strategies. 9 Here we discuss some of the current challenges and future directions in pediatric ALL research. Emerging leukemia subtypesTraditionally, ALL has been classified into precursor T (or T-cell), precursor B, and B-cell (Burkitt) phenotypes, which are then further subdivided according to recurrent karyotypic abnormalities, including aneuploidy and translocations. 9,11 Detailed profiling of submicroscopic alterations and mutational analyses have allowed refinement of these classification schema, identification of genetic alterations that coexist and cooperate with chromosomal alterations in leukemogenesis, and discovery of new ALL subtypes that lack alterations on cytogenetic analysis. Like acute myeloid leukemia, 12 many ALL subtypes are characterized by genetic alterations that perturb multiple key cellular pathways, including hematopoietic development, signaling or proliferation, and epigenetic regulation. Recent studies have identified a novel high-risk immature T-cell subtype, termed "early T-cell precursor" ALL, which is characterized by immunologic markers and a gene expression profile reminiscent of double-negative 1 thymocytes that retain the ability to differentiate into both T-cell and myeloid, but not B-cell, lineages. 13 Whole genome sequencing showed that the mutational spectru...

Protective effect of breastfeeding against childhood leukemia in Zhejiang Province, P. R. China: a retrospective case-control study

“…Its etiology and pathogenesis remain unknown, which may be linked to genetic factors and environmental factors including infection, radiation, and living conditions [3]. Impressive advancements in childhood leukemia treatment entail cure rates reaching 90% for ALL and 60–70% for AML [4,5]. As a result of improved cancer treatments, there has been a dramatic increase in the number of young survivors who are living well into adulthood, but many children have long-term complications because of radiotherapy and chemotherapy.…”

Risk assessment of relapse by lineage-specific monitoring of chimerism in children undergoing allogeneic stem cell transplantation for acute lymphoblastic leukemia

“…5,6 Potentially more sensitive detection of MRD can be achieved by real-time polymerase chain reaction (PCR) analysis of leukemia-specific fusion gene transcripts, but such markers are available only in a limited proportion of ALL patients. 7 In patients undergoing allogeneic HSCT for treatment of various types of leukemia, persistence or recurrence of autologous cells detectable in either whole peripheral blood (PB) samples or within specific leukocyte subsets expected to harbor the malignant cells, if present, was shown to be indicative of imminent disease relapse. 8,9 The identification of recipient-derived cells in whole PB specimens is hampered by the limited sensitivity offered by the most common approaches to chimerism analysis based on PCR amplification of microsatellite/short tandem repeat markers.…”

Cure trends in acute lymphoblastic leukemia: is it time for a revised concept of cure?

“…IKZF1-deletions and a 'BCR-ABL like' gene expression signature, do not directly provide druggable targets. 19,20 In conclusion, projected cure rates in ALL have improved significantly over time. Since the vast majority of children with ALL are nowadays cured, it is time to re-consider the concept of 'cure' for these patients and to take the long-term adverse effects into account when assessing cure.…”

“…19 However, the recent identification of two novel abnormalities underlying poor risk disease in pediatric ALL, i.e. IKZF1-deletions and a 'BCR-ABL like' gene expression signature, do not directly provide druggable targets.…”