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Outcomes of dasatinib plus intensive chemotherapy or stem cell transplant (SCT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) on Children's Oncology Group AALL0622. [Meeting Abstract]
Slayton, William Birdsall; Kairalla, John A; Schultz, Kirk R; Devidas, Meenakshi; Helian, Shanjun; Pulsipher, Michael; Chang, Bill H; Carroll, William L; Borowitz, Michael J; Brown, Valerie I; Winick, Naomi J; Carroll, Andrew J; Heerema, Nyla A; Gastier-Foster, Julie M; Wood, Brent L; Mizrahy, Sherri L; Hunger, Stephen
ISI:000358036900009
ISSN: 1527-7755
CID: 1729432
Neurocognitive function of children treated for high-risk B-acute lymphoblastic leukemia (HR-ALL) randomized to Capizzi (CMTX) versus high-dose methotrexate (HDMTX): A report from the Children's Oncology Group (COG). [Meeting Abstract]
Winick, Naomi J; Embry, Leanne M; Hardy, Kristina K; Kairalla, John A; Devidas, Meenakshi; Armstrong, Daniel; Hunger, Stephen; Carroll, William L; Larsen, Eric; Raetz, Elizabeth A; Loh, Mignon L; Noll, Robert
ISI:000358036900005
ISSN: 1527-7755
CID: 1729422
Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia
Ma, Xiaotu; Edmonson, Michael; Yergeau, Donald; Muzny, Donna M; Hampton, Oliver A; Rusch, Michael; Song, Guangchun; Easton, John; Harvey, Richard C; Wheeler, David A; Ma, Jing; Doddapaneni, HarshaVardhan; Vadodaria, Bhavin; Wu, Gang; Nagahawatte, Panduka; Carroll, William L; Chen, I-Ming; Gastier-Foster, Julie M; Relling, Mary V; Smith, Malcolm A; Devidas, Meenakshi; Guidry Auvil, Jaime M; Downing, James R; Loh, Mignon L; Willman, Cheryl L; Gerhard, Daniela S; Mullighan, Charles G; Hunger, Stephen P; Zhang, Jinghui
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)
Dreyer, ZoAnn E; Hilden, Joanne M; Jones, Tamekia L; Devidas, Meenakshi; Winick, Naomi J; Willman, Cheryl L; Harvey, Richard C; Chen, I-Ming; Behm, Fred G; Pullen, Jeanette; Wood, Brent L; Carroll, Andrew J; Heerema, Nyla A; Felix, Carolyn A; Robinson, Blaine; Reaman, Gregory H; Salzer, Wanda L; Hunger, Stephen P; Carroll, William L; Camitta, Bruce M
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 =90 days at diagnosis, MLL-R ALL and white cell count >/=50,000/mul. For infants =90 days of age, the 5-year EFS was 15.5 +/- 10.1% and 48.5 +/- 6.7% for those >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 =90 days at diagnosis was the most important prognostic factor. Despite shortened therapy with early intensification, EFS remained less than 50% overall in MLL-R ALL. Pediatr Blood Cancer 2015;62:419-426. (c) 2014 Wiley Periodicals, Inc.
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
Salzer, Wanda L; Jones, Tamekia L; Devidas, Meenakshi; Dreyer, ZoAnn E; Gore, Lia; Winick, Naomi J; Sung, Lillian; Raetz, Elizabeth; Loh, Mignon L; Wang, Cindy Y; De Lorenzo, Paola; Valsecchi, Maria Grazia; Pieters, Rob; Carroll, William L; Hunger, Stephen P; Hilden, Joanne M; Brown, Patrick
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
Perez-Andreu, Virginia; Roberts, Kathryn G; Xu, Heng; Smith, Colton; Zhang, Hui; Yang, Wenjian; Harvey, Richard C; Payne-Turner, Debbie; Devidas, Meenakshi; Cheng, I-Ming; Carroll, William L; Heerema, Nyla A; Carroll, Andrew J; Raetz, Elizabeth A; Gastier-Foster, Julie M; Marcucci, Guido; Bloomfield, Clara D; Mrozek, Krzysztof; Kohlschmidt, Jessica; Stock, Wendy; Kornblau, Steven M; Konopleva, Marina; Paietta, Elisabeth; Rowe, Jacob M; Luger, Selina M; Tallman, Martin S; Dean, Michael; Burchard, Esteban G; Torgerson, Dara G; Yue, Feng; Wang, Yanli; Pui, Ching-Hon; Jeha, Sima; Relling, Mary V; Evans, William E; Gerhard, Daniela S; Loh, Mignon L; Willman, Cheryl L; Hunger, Stephen P; Mullighan, Charles G; Yang, Jun J
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=5x10-8 in the discovery GWAS were tested in an independent cohort of 162 AYA ALL cases and 5,755 non-ALL controls. We identified a single susceptibility locus on 10p14 signified by two SNPs within the GATA3 gene with genome-wide significant associations: rs3824662, P=2.8x10-10, odds ratio (OR)=1.77 and rs3781093, P=3.2x10-9, OR=1.73. These findings were validated in an independent replication cohort. The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non-Ph-like ALL in AYAs. In 1,827 non-selected ALL cases, the risk allele frequency at this SNP was positively correlated with age at diagnosis (P=6.29x10-11). As the first GWAS of ALL susceptibility in the AYA population, our results point to unique biology underlying leukemogenesis and potentially distinct disease etiology by age group.
PMCID:4304112
PMID: 25468567
ISSN: 0006-4971
CID: 1371022
NT5C2 As a Major Contributor to Thiopurine Resistance at ALL Relapse Via Multiple Mechanisms [Meeting Abstract]
Moriyama, Takaya; Meyer, Julia; Liu, Shuguang; Zhao, Xujie; Ying, Zhaohong; Carroll, William L; Yang, Jun J
ISI:000368019001198
ISSN: 1528-0020
CID: 2019372
6-Mercaptopurine (6MP) Intake during Maintenance for Childhood Acute Lymphoblastic Leukemia (ALL) - a Comparison of Self-Report and Electronic Monitoring: A Report from the Children's Oncology Group ( COG) Study AALL03N1 [Meeting Abstract]
Landier, Wendy; Chen, Yanjun; Hageman, Lindsey; Kim, Heeyoung; Bostrom, Bruce C; Casillas, Jacqueline; Dickens, David; Evans, William E; Maloney, Kelly W; Mascarenhas, Leo; Ritchey, Arthur K; Termuhlen, Amanda M; Carroll, William L; Wong, FLennie; Relling, Mary V; Bhatia, Smita
ISI:000368019000146
ISSN: 1528-0020
CID: 2019332
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]
Matlawska-Wasowska, Ksenia; Kang, Huining; Devidas, Meenakshi; Wen, Ji; Harvey, Richard C; Nickl, Christian C; Ness, Scott; Rusch, Michael; Li, Yongjin; Onozawa, Masahiro; Martinez, Carmen; Wood, Brent L; Asselin, Barbara; Chen, I-Ming L; Roberts, Kathryn G; Baruchel, Andre; Soulier, Jean; Dombret, Herve; Zhang, Jinghui; Larson, Richard S; Raetz, Elizabeth; Carroll, William L; Winick, Naomi J; Aplan, Peter D; Loh, Mignon L; Mullighan, Charles G; Hunger, Stephen P; Heerema, Nyla A; Carroll, Andrew J; Dunsmore, Kimberly P; Winter, Stuart S
ISI:000368019002131
ISSN: 1528-0020
CID: 2019422
Frequency of actionable gene fusions in patients with Philadelphia chromosome-like (Ph-like) B-acute lymphoblastic leukemia (ALL): A retrospective study from the Children's Oncology Group (COG) [Meeting Abstract]
Reshmi, Shalini C; Harvey, Richard C; Smith, Amy; Chen, I-Ming; Valentine, Marc; Liu, Yu; Li, Yongjin; Zhang, Jinghui; Roberts, Kathryn G; Shao, Ying; Easton, John; Payne-Turner, Debbie; Devidas, Meenakshi; Heerema, Nyla; Carroll, Andrew J; Raetz, Elizabeth A; Borowitz, Michael J; Wood, Brent L; Angiolillo, Anne L; Burke, Michael M; Salzer, Wanda L; Zweidler-McKay, Patrick A; Rabin, Karen R; Carroll, William L; Loh, Mignon L; Hunger, Stephen P; Mullighan, Charles G; Willman, Cheryl L; Gastier-Foster, Julie M
ISI:000371597104357
ISSN: 1538-7445
CID: 2064532