Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia.

Smith, Malcolm A.; Arthur, Diane C.; Camitta, Bruce M.; Carroll, Andrew J.; Crist, WM; Gaynon, Paul S.; Gelber, RD; Heerema, Nyla A.; Korn, Edward L.; Link, Michael P.; Murphy, Sharon B.; Pui, Ching Hon; Pullen, Jeanette; Reamon, G; Sallan, Stephen E.; Sather, Harland N.; Shuster, JJ; Simon, Réka; Trigg, Michael E.; Tubergen, David G.; Uckun, Fatih M.; Ungerleider, Richard S.

doi:10.1200/jco.1996.14.1.18

Cited by 809 publications

(531 citation statements)

References 33 publications

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“…Patients were studied at the time of initial diagnosis; were riskstratified according to the therapeutic protocol, which was always based on recognized prognostic features (including cytogenetics); and were entered in ALL protocols of the PETHEMA Spanish study group. For statistical analyses, children were also grouped according to the National Cancer Institute (NCI) risk-classification criteria (Smith et al, 1996). The specific PETHEMA ALL treatment protocols in which these patients entered included ALL-89 (between 1990 and1993;n ¼ 50) and ALL-93 (between 1993 and2002;n ¼ 130).…”

Section: Patients and Samplesmentioning

confidence: 99%

ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia

et al. 2006

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We have analyzed the regulation and expression of ASPP members, genes implicated in the regulation of the apoptotic function of the TP53 tumor-suppressor gene, in acute lymphoblastic leukemia (ALL). Expression of ASPP1 was significantly reduced in ALL and was dependent on hypermethylation of the ASPP1 gene promoter. Abnormal ASPP1 expression was associated with normal function of the tumor-suppressor gene TP53 in ALL. The analyses of 180 patients with ALL at diagnosis showed that the ASPP1 promoter was hypermethylated in 25% of cases with decreased mRNA expression. Methylation was significantly higher in adult ALL vs childhood ALL (32 vs 17%, P ¼ 0.03) and T-ALL vs B-ALL (50 vs 9%, P ¼ 0.001). Relapse rate (62 vs 44%, P ¼ 0.05) and mortality (59 vs 43%, P ¼ 0.05) were significantly higher in patients with methylated ASPP1. DFS and OS were 32.8 and 33.7% for patients with unmethylated ASPP1 and 6.1 and 9.9% for methylated patients (Po0.001 y Po0.02, respectively). On the multivariate analysis, methylation of the ASPP1 gene promoter was an independent poor prognosis factor in ALL patients. Our results demonstrate that decreased expression of ASPP1 in patients with ALL is due to an abnormal methylation of its promoter and is associated with a poor prognosis.Oncogene ( Mutations of TP53 may result in an inhibition of protein function, which is associated with tumor progression and genetic instability (Caron de Fromentel and Soussi, 1992;Hollstein et al., 1994;Soussi et al., 1994). Although 40-50% of human tumors have mutations on TP53, the percentage of mutations in patients with leukemia is significantly lower (less that 10%), suggesting that other mechanisms may be involved in the inability of p53 to induce apoptosis since p53 does not suppress tumor growth or induce apoptosis in tumors with wild-type TP53.The recently described ASPP family of proteins comprised of ASPP1, ASPP2 and iASPP has been implicated in the apoptotic function of TP53 and p53 family members TP73L (p63) and TP73 (Bergamaschi et al., 2004). Different studies have shown that ASPP1 and ASPP2 increase the apoptotic effect of p53 by inducing the transcription of proapoptotic genes such as BAX and PIG3 mediated by TP53, while they have no influence on the transcription of MDM2 and CDKN1A (p21, Cip1), which mediate p53-dependent cell cycle arrest (Samuels-Lev et al., 2001;Slee and Lu, 2003;Bergamaschi et al., 2004). Transactivation of TP53-mediated transcription of proapoptotic genes mediated by ASPP1 and ASPP2 is completely abolished by increased expression of the evolutionary conserved TP53 inhibitor and third member of the ASPP family, iASPP (Bergamaschi et al., 2003).It has been hypothesized that in wild-type TP53 tumors, alterations of ASPP1 and/or ASPP2, can produce a selective advantage due to the lack of stimulation of apoptosis (Samuels-Lev et al., 2001;Slee and Lu, 2003;Bergamaschi et al., 2004). Samuels-Lev et al. (2001) These two authors contributed equally to this work.

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Section: Patients and Samplesmentioning

confidence: 99%

ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia

et al. 2006

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“…Using the NCI consensus risk group designations for age and WBC defined prognostic groups, (ie age у10 years and/or WBC у50 000/ l confers poor prognosis), 8 outcome was compared between standard and poor risk patients with T-ALL, treated on the POG T3 regimens. Five year EFS was 56.9 ± 5.0% for the standard risk subgroup and 48.6 ± 3.0% for the poor risk subgroup (P = 0.11) (Figure 1).…”

Section: Prognostic Factor Analyses -Comparisons Between T-all and B-mentioning

confidence: 99%

“…Children with T cell acute lymphocytic leukemia (T-ALL) have been shown by many investigators to have an unfavorable prognosis, as compared to those with B-precursor ALL, [1][2][3][4][5][6][7][8][9] although significant improvement in outcome for patients with T-ALL has been reported from some studies employing intensive, rotating pulses of chemotherapy. [10][11][12][13][14] Some cooperative groups have placed any patient with the T-ALL immunophenotype in a higher risk group in treatment assignment, regardless of other commonly used prognostic determinants, such as age and WBC.…”

Section: Introductionmentioning

confidence: 99%

“…[10][11][12][13][14] Some cooperative groups have placed any patient with the T-ALL immunophenotype in a higher risk group in treatment assignment, regardless of other commonly used prognostic determinants, such as age and WBC. 8,9,[14][15][16][17] Other groups have used the same age and WBC-defined risk categories in designating intensity of treatment for both B-precursor and for T-ALL; 11,18,19 but some of these have assigned any patient with a mediastinal mass and the T immunophenotype to a higher risk category. 11,20,21 Furthermore, many groups have employed the identical risk-1697 Table 1 T3 treatment regimen Reprinted with permission from Amylon et al 12 effective in T cell disease.…”

Section: Introductionmentioning

confidence: 99%

“…These treatment regimens have been recently reported by Amylon et al 12 The prognostic factor analyses for the patients with T-ALL were compared to similar analyses for POG patients with newly diagnosed B-precursor ALL enrolled during the same time period. The previously reported prognostic factor analyses for patients with B-precursor ALL 6,8,26,27 have been updated to April 1997 for this paper. The patients with B-precursor ALL (n = 1933) were registered on the POG 8602, ALinC 14 protocol from February 1986 to January 1991, using the risk group stratified treatments previously described.…”

Section: Introductionmentioning

confidence: 99%

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1999

Leukemia

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Significance of commonly used prognostic factors differs for children with T cell acute lymphocytic leukemia (ALL), as compared to those with B-precursor ALL. A Pediatric Oncology Group (POG) studyT cell acute lymphocytic leukemia (T-ALL) and B-precursor ALL differ significantly in the clinical characteristics of the patients at presentation and in laboratory-defined characteristics of the leukemic cells. We assessed for pediatric patients with T-ALL the relative importance of prognostic factors previously demonstrated to predict outcome in B-precursor ALL. Presenting clinical and laboratory features were correlated with outcome for 441 children 12 months to 21 years of age with previously untreated T-ALL, registered on the Pediatric Oncology Group (POG) T3 protocol between 1986 and 1992. These T-ALL prognostic factor analyses were then compared to similar analyses for 1993 patients with B-precursor ALL enrolled during the same time period on the POG ALinC 14 protocol. Quantitative interaction between phenotype and each prognostic factor was studied to determine the relative importance of the prognostic factor for each of the two major immunophenotypes. We also analyzed the importance of maturational stage as a T-ALL prognostic factor, using a modified Ludwig definition of maturational stage. We conclude that several of the clinical and laboratory prognostic factors, which are used reliably for Bprecursor ALL, are much less predictive in T-ALL (ie age, WBC, consensus risk group, hyperdiploidy, presence of translocations and CALLA expression). There was no significant difference between the phenotypes in the prognostic importance of race or gender. Our data demonstrate a significant difference in outcome among the three maturational stages of Tcell ALL, with the intermediate group faring best. Using traditional risk group criteria to stratify patients with T-ALL for therapy may not be appropriate.

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No Evidence of a Trial Effect in Newly Diagnosed Pediatric Acute Lymphoblastic Leukemia

Koschmann

Thomson

Hawkins

2010

Arch Pediatr Adolesc Med

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Participants: Data were drawn from 322 patients with newly diagnosed acute lymphoblastic leukemia. Main Exposure: Enrollment in a Children's Oncology Group or Children's Cancer Group clinical trial. Main Outcome Measures: (1) Demographic variables associated with trial participation. (2) Event-free survival, which was defined as the time from initial diagnosis to either leukemia recurrence or death from any cause. Results: No outcome advantage was found for participants in a clinical trial compared with nonparticipants. Additionally, there were not demographic factors associated with increased clinical trial participation. Conclusions: Clinical trial participation does not, by itself, lead to improved outcome for pediatric patients with acute lymphoblastic leukemia in the current era. Discussions about participation in a clinical trial should focus on improvement of future therapy, not the direct benefit of the research participant.

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Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia.

Abstract: The more uniform approach to risk-based treatment assignment and to collection of specific prognostic factors should increase the efficiency of future ALL clinical research.

Cited by 809 publications

References 33 publications

ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia

ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia

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No Evidence of a Trial Effect in Newly Diagnosed Pediatric Acute Lymphoblastic Leukemia

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