Faculty Bibliography
Searched for:
person:carrow01
Total Results:
377
Association of intravenous (IV) and intramuscular (IM) pegaspargase (PEG) administration with rate of adverse events (AE) in standard risk (SR) Acute Lymphoblastic Leukemia (ALL) Children's Oncology Group (COG) trials. [Meeting Abstract]
ISI:000358036900041
ISSN: 1527-7755
CID: 1729792
Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia
There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.
PMCID:4377644
PMID: 25790293
ISSN: 2041-1723
CID: 1520792
Intensified chemotherapy without SCT in infant ALL: Results from COG P9407 (Cohort 3)
BACKGROUND: Infants with acute lymphoblastic leukemia (ALL) present with aggressive disease and a poor prognosis. Early relapse within 6-9 months of diagnosis is common. Approximately 75% of infants have MLL-rearranged (MLL-R) ALL with event free survival (EFS) ranging from 20% to 30%. Children's Oncology Group (COG) P9407 used shortened (46 weeks), intensified therapy to address early relapse and poor EFS. PROCEDURE: P9407 therapy was modified three times for induction toxicity resulting in three cohorts of therapy. One hundred forty-seven infants were enrolled in the third cohort. RESULTS: We report an overall 5-year EFS and OS of 42.3 +/- 6% and 52.9 +/- 6.5% respectively. Poor prognostic factors included age /=50,000/mul. For infants 90 days (P < 0.0001). Among infants >90 days of age, 5-year EFS rates were 43.8 +/- 8% for MLL-R versus 69.1 +/- 13.6% for MLL-germline ALL (P < 0.0001). CONCLUSIONS: Age
PMCID:5145261
PMID: 25399948
ISSN: 1545-5009
CID: 1477622
Decreased induction morbidity and mortality following modification to induction therapy in infants with acute lymphoblastic leukemia enrolled on AALL0631: a report from the Children's Oncology Group
BACKGROUND:Infants with acute lymphoblastic leukemia (ALL) have a poor prognosis. Intensification of therapy has resulted in fewer relapses but increased early deaths, resulting in failure to improve survival. PROCEDURE/METHODS:AALL0631 is a Phase 3 study for infants (<366 days of age) with newly diagnosed ALL. Induction initially (Cohort 1) consisted of 3 weeks of therapy based on COG P9407. Due to excessive early mortality, induction was amended to a less intensive 5 weeks of therapy based on Interfant-99. Additionally, enhanced supportive care guidelines were incorporated with hospitalization during induction until evidence of marrow recovery and recommendations for prevention/treatment of infections (Cohort 2). RESULTS:Induction mortality was significantly lower for patients in Cohort 2 (2/123, 1.6%) versus Cohort 1 (4/26, 15.4%; P = 0.009). All induction deaths were infection related except one due to progressive disease (Cohort 2). Sterile site infections were lower for patients in Cohort 2 (24/123, 19.5%) versus Cohort 1 (15/26, 57.7%; P = 0.0002), with a significantly lower rate of Gram positive infections during induction for patients in Cohort 2, P = 0.0002. No clinically significant differences in grades 3-5 non-infectious toxicities were observed between the two cohorts. Higher complete response rates were observed at end induction intensification for Cohort 2 (week 9, 94/100, 94%) versus Cohort 1 (week 7, 17/25, 68%; P = 0.0.0012). CONCLUSION/CONCLUSIONS:De-intensification of induction therapy and enhanced supportive care guidelines significantly decreased induction mortality and sterile site infections, without decreasing complete remission rates.
PMCID:4480675
PMID: 25407157
ISSN: 1545-5017
CID: 2927322
A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults
Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA: 16-39 years) is characterized by distinct presenting features and inferior prognosis compared to pediatric ALL. To better understand the disease etiology in this age group, we performed a genome-wide association study (GWAS) to comprehensively identify inherited genetic variants associated with susceptibility to AYA ALL. In the discovery GWAS, we compared genotype frequency at 635,297 SNPs in 308 AYA ALL cases and 6,661 non-ALL controls by using a logistic regression model with European, African and Native American genetic ancestries as a covariates. SNPs that reached association P
PMCID:4304112
PMID: 25468567
ISSN: 0006-4971
CID: 1371022
American Society of Clinical Oncology educational book. 2015:e601-7.DOI: 10.14694/EdBook_AM.2015.35.e601
State of the art discovery with tumor profiling in pediatric oncology
It is an exciting era in pediatric oncology with the advent of new technologies to comprehensively characterize cancer genomes in childhood tumors. Defining the genetic landscape of pediatric tumors has not only provided critical insight into tumor evolution, but it has also offered promise for more effective treatment in some cases, such as Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) and anaplastic lymphoma kinase (ALK)-mutated tumors. However, several challenges remain as the field of genomic tumor profiling emerges. This new technology is costly, and the overall impact on survival has yet to be determined. Tumor heterogeneity and clonal evolution have also presented challenges in the development of targeted therapy. In this article, we review breakthroughs in gene sequencing methodology and discuss examples where genomic discoveries have resulted in the recognition of tumor susceptibility as well as incorporation of targeted therapy. We also discuss how broad scale comprehensive tumor analyses have demonstrated the convergence of individual genetic alterations on common relevant pathways. Although the impact of tumor profiling is best studied within the context of rigorously designed clinical trials, there is promise that there will be growing opportunities for the adaption of precision medicine in pediatric oncology in the future.
PMID: 25993229
ISSN: 1548-8756
CID: 1863862
NT5C2 As a Major Contributor to Thiopurine Resistance at ALL Relapse Via Multiple Mechanisms [Meeting Abstract]
ISI:000368019001198
ISSN: 1528-0020
CID: 2019372
Mixed Lineage Leukemia Rearrangements (MLL-R) Are Determinants of High Risk Disease in Homeobox A (HOXA)-deregulated T-Lineage Acute Lymphoblastic Leukemia: A Children's Oncology Group Study [Meeting Abstract]
ISI:000368019002131
ISSN: 1528-0020
CID: 2019422
Capizzi-Style Methotrexate with Pegasparagase (C-MTX) Is Superior to High-Dose Methotrexate (HDMTX) in T-Lineage Acute Lymphoblastic Leukemia (T-ALL): Results from Children's Oncology Group (COG) AALL0434 [Meeting Abstract]
ISI:000368019002231
ISSN: 1528-0020
CID: 2019432
Genetic and Response-Based Risk Classification Identifies a Subgroup of NCI High Risk Childhood B-Lymphoblastic Leukemia (HR B-ALL) with Outstanding Outcomes: A Report from the Children's Oncology Group (COG) [Meeting Abstract]
ISI:000368019002244
ISSN: 1528-0020
CID: 2019442
