title: Tyrosine kinase inhibitor use in pediatric Philadelphia chromosome-positive acute lymphoblastic anemia.
abstract: Until recently, pediatric Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) was associated with an extremely poor outcome when treated with chemotherapy alone, and only modest survival benefits were obtained with the widespread use of hematopoietic stem cell transplantation (HSCT). The development of first-generation (imatinib) and second-generation (dasatinib and nilotinib) tyrosine kinase inhibitors (TKIs) that target the BCR-ABL1 fusion protein produced by the Ph chromosome revolutionized the treatment of chronic myelogenous leukemia (CML). The Children's Oncology Group (COG) AALL0031 trial showed that the addition of imatinib to intensive chemotherapy did not cause increased toxicity and resulted in 3-year event-free survival rates that were more than double those of historical control data from the pre-imatinib era. These findings create a new paradigm for integrating molecularly targeted agents with conventional chemotherapy and call for a reassessment of the routine use of HSCT for children and adolescents with Ph(+) ALL. Second-generation TKIs have theoretical advantages over imatinib, and are now being tested in Ph(+) ALL. The focus of contemporary trials is to define the optimal use of chemotherapy, HSCT, and TKI in Ph(+) ALL. In the coming years, it is anticipated that additional agents will become available to potentiate TKI therapy and/or circumvent TKI resistance in Ph(+) ALL. Recent genomic studies have identified a subtype of high-risk pediatric B-cell-precursor ALL with a gene-expression profile similar to that of Ph(+) ALL, suggestive of active kinase signaling. Many of these Ph-like ALL cases harbor chromosome rearrangements and mutations that dysregulate cytokine receptor and kinase signaling, and these leukemias may also be candidates for TKI therapy.
authors.affiliation: Children's Hospital Colorado and Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA. hunger.stephen@tchden.org
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
mesh_terms: D002648:Child; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl