Early postinduction intensification therapy improves survival for children and adolescents with high risk acute lymphoblastic leukemia: a report from the Chilren’s Oncology Group

Hematology/Oncology, Children's National Medical Center and George Washington University School of Medicine and Public Health, 111 Michigan Avenue NW, Washington, DC 20010, USA.
Blood (Impact Factor: 10.45). 03/2008; 111(5):2548-55. DOI: 10.1182/blood-2007-02-070342
Source: PubMed


Longer and more intensive postinduction intensification (PII) improved the outcome of children and adolescents with "higher risk" acute lymphoblastic leukemia (ALL) and a slow marrow response to induction therapy. In the Children's Cancer Group study (CCG-1961), we tested longer versus more intensive PII, using a 2 x 2 factorial design for children with higher risk ALL and a rapid marrow response to induction therapy. Between November 1996 and May 2002, 2078 children and adolescents with newly diagnosed ALL (1 to 9 years old with white blood count 50 000/mm3 or more, or 10 years of age or older with any white blood count) were enrolled. After induction, 1299 patients with marrow blasts less than or equal to 25% on day 7 of induction (rapid early responders) were randomized to standard or longer duration (n = 651 + 648) and standard or increased intensity (n = 649 + 650) PII. Stronger intensity PII improved event-free survival (81% vs 72%, P < .001) and survival (89% vs 83%, P = .003) at 5 years. Differences were most apparent after 2 years from diagnosis. Longer duration PII provided no benefit. Stronger intensity but not prolonged duration PII improved outcome for patients with higher-risk ALL. This study is registered at as NCT00002812.

Download full-text


Available from: Charles M Rubin, Oct 13, 2015
31 Reads
  • Source
    • "7 Data Application: Children's Oncology Group Study 1961 7.1 Is there evidence of correlation between the survival times of patients within the same institution? We applied our method to a Children's Oncology Group (COG) study (protocol number 1961) (Seibel et al, 2008 "
    [Show abstract] [Hide abstract]
    ABSTRACT: We consider a Gaussian copula model for multivariate survival times. Estimation of the copula association parameter is easily implemented with existing software using a two-stage estimation procedure. Using the Gaussian copula, we are able to test whether the association parameter is equal to zero. When the association term is positive, the model can be extended to incorporate cluster-level frailty terms. Asymptotic properties are derived under the two-stage estimation scheme. Simulation studies verify finite sample utility. We apply the method to a Children's Oncology Group multi-center study of acute lymphoblastic leukemia. The analysis estimates marginal treatment effects and examines potential clustering within treatment institution.
    Statistics in Biosciences 12/2010; 2(2):154-179. DOI:10.1007/s12561-010-9026-x
  • Source
    • "It appeared that POG9411 consolidation helped achieve a greater reduction of leukemia. A recent study of CCG1961 indicated that longer post-induction intensification failed to prolong EFS, while an early aggressive post-induction intensification resulted in better EFS and OS for patients with newly diagnosed high-risk ALL [18]. Many studies have reported that the presence of minimal residual disease (MRD) prior to allogeneic transplantation is predictive of subsequent treatment failure [19, 20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite advances in chemotherapy, the prognosis of relapsed acute lymphoblastic leukemia (ALL) remains poor. Few studies on relapsed ALL have reported the importance of intensive consolidation followed with or without allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the post-relapse outcomes in 47 Korean children with a first marrow relapse, and analyzed the prognostic factors. A second complete remission (CR) was achieved in 40 patients (85.1%), and at the time of this study, second CR was maintained in 12 of these patients. The estimated 3-yr event-free survival (EFS) rate after the first marrow relapse was 29.8±6.7%, and the overall survival (OS) rate was 45.3±7.5%. We found that second remission, consolidation of pediatric oncology group chemotherapy regimen (POG 9411), and HSCT significantly affected the outcome of the disease after relapse (P<0.001; P=0.004; P=0.05). The results of our study revealed that an intensified POG 9411 consolidation chemotherapy regimen followed by HSCT can improve the outcome of patients with relapsed ALL.
    The Korean journal of hematology 06/2010; 45(2):109-14. DOI:10.5045/kjh.2010.45.2.109
  • Source
    • "We subsequently determined the expression levels of the genes in the 5-GC by qRT-PCR in diagnostic bone marrow specimens from 34 pediatric T-ALL patients from a completely independent Validation Cohort. Most of these patients were treated on COG 1882 or 1901, while the patients in the Training Cohort were treated on COG 1961 [4]. In the Validation Cohort the 5-GC yielded an overall prediction accuracy of 79% (Table 4). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Continuous complete clinical remission in T-cell acute lymphoblastic leukemia (T-ALL) is now approaching 80% due to the implementation of aggressive chemotherapy protocols but patients that relapse continue to have a poor prognosis. Such patients could benefit from augmented therapy if their clinical outcome could be more accurately predicted at the time of diagnosis. Gene expression profiling offers the potential to identify additional prognostic markers but has had limited success in generating robust signatures that predict outcome across multiple patient cohorts. This study aimed to identify robust gene classifiers that could be used for the accurate prediction of relapse in independent cohorts and across different experimental platforms. Using HG-U133Plus2 microarrays we modeled a five-gene classifier (5-GC) that accurately predicted clinical outcome in a cohort of 50 T-ALL patients. The 5-GC was further tested against three independent cohorts of T-ALL patients, using either qRT-PCR or microarray gene expression, and could predict patients with significantly adverse clinical outcome in each. The 5-GC featured the interleukin-7 receptor (IL-7R), low-expression of which was independently predictive of relapse in T-ALL patients. In T-ALL cell lines, low IL-7R expression was correlated with diminished growth response to IL-7 and enhanced glucocorticoid resistance. Analysis of biological pathways identified the NF-kappaB and Wnt pathways, and the cell adhesion receptor family (particularly integrins) as being predictive of relapse. Outcome modeling using genes from these pathways identified patients with significantly worse relapse-free survival in each T-ALL cohort. We have used two different approaches to identify, for the first time, robust gene signatures that can successfully discriminate relapse and CCR patients at the time of diagnosis across multiple patient cohorts and platforms. Such genes and pathways represent markers for improved patient risk stratification and potential targets for novel T-ALL therapies.
    Molecular Cancer 05/2010; 9(1):105. DOI:10.1186/1476-4598-9-105 · 4.26 Impact Factor
Show more