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Children's Oncology Group's 2013 blueprint for research: acute myeloid leukemia.

ABSTRACT: For the 365 children diagnosed with acute myeloid leukemia in the US annually, 5-year survival for patients on COG trials with low, intermediate, and high risk disease is 83%, 62%, and 23%, respectively. Recent advances include improved therapeutic stratification, improved survival with dose intensification, and further elucidation of the heterogeneity specific to childhood AML. These discoveries now guide current strategy incorporating targeted agents to pathways specific to childhood AML as well as evaluating methods to increase the sensitivity of the leukemic stem cell, first in Phase II feasibility trials followed by Phase III efficacy trials of the most promising agents. Acute myeloid leukemia in children, though with similar subgroups to adults, remains uniquely different based upon quite different prevalence of subtypes as well as overall response to therapy. The Children's Oncology Group's research agenda builds upon earlier efforts to better elucidate the leukemogenic steps distinct to childhood AML in order to more scientifically develop and test novel therapeutic approaches to the treatment and ultimate cure for children with this disorder. Pediatr Blood Cancer 2013; 60: 964-971. © 2012 Wiley Periodicals, Inc.

SUBMITTER: Gamis AS

PROVIDER: S-EPMC4605815 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Children's Oncology Group's 2013 blueprint for research: acute myeloid leukemia.

Gamis Alan S AS Alonzo Todd A TA Perentesis John P JP Meshinchi Soheil S

Pediatric blood & cancer 20121219 6

For the 365 children diagnosed with acute myeloid leukemia in the US annually, 5-year survival for patients on COG trials with low, intermediate, and high risk disease is 83%, 62%, and 23%, respectively. Recent advances include improved therapeutic stratification, improved survival with dose intensification, and further elucidation of the heterogeneity specific to childhood AML. These discoveries now guide current strategy incorporating targeted agents to pathways specific to childhood AML as we ...[more]

PMID: 23255301

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Project description:The US Food and Drug Administration recently announced reapproval of gemtuzumab ozogamicin (GO) for treatment of CD33-positive acute myeloid leukemia (AML), thus opening up opportunities to develop strategies for effective use of GO. In light of our recent report showing prognostic significance of CD33 splicing single nucleotide polymorphisms (SNPs), the objective of this study was to comprehensively evaluate CD33 SNPs for accurate prediction of patients with AML who are more or less likely to respond to GO. We investigated the five new CD33 SNPs (rs2455069, rs35112940, rs61736475, rs1803254, and rs201074739) for association with CD33 leukemic cell surface expression and clinical response in pediatric patients with AML enrolled in the Children's Oncology Group AAML0531 trial. We further developed a composite CD33 pharmacogenetics (PGx) score using six CD33 SNPs (CD33_PGx6_score) for association with clinical outcome. Four CD33 SNPs were associated with cell surface CD33 levels and clinical response in the GO versus no-GO arms. Therefore, the CD33_PGx6_score was built using directional genotype scores for the previously reported splicing SNP and five new SNPs. Patients with a CD33_PGx6_score of 0 or higher had higher CD33 expression levels compared with patients with a score of less than 0 (P < .001). In addition, patients with a score of 0 or higher demonstrated an improved disease-free survival in the GO versus no-GO arms (62.5% ± 7.8% v 46.8% ± 8.3%, respectively; P = .008) and a reduced risk of relapse (28.3% ± 7.2% v 49.9% ± 8.4%, respectively; P < .001). No improvement from GO was observed in patients with a CD33-PGx6_score of less than 0. Consistent results were observed across the risk groups. In this study, we report a composite CD33_PGx6_score using directional genotype scores of CD33 SNPs. Once validated, our findings hold promise for use of the CD33_PGx6_score to guide efficient use of GO in patients with AML. In addition, because the CD33_PGx6_score considers SNPs with varying abundance in different ethnic groups, it has potential for global application.

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Children's Oncology Group's 2013 blueprint for research: acute myeloid leukemia.

Publications

Children's Oncology Group's 2013 blueprint for research: acute myeloid leukemia.

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