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Second malignant neoplasms after treatment of 1487 children and adolescents with acute lymphoblastic leukemia-A population-based analysis of the Austrian ALL-BFM Study Group.

ABSTRACT: Second malignant neoplasms (SMN) after primary childhood acute lymphoblastic leukemia (ALL) are rare. Among 1487 ALL patients diagnosed between 1981 and 2010 in Austria, the 10-year cumulative incidence of an SMN was 1.1% ± 0.3%. There was no difference in the 10-year incidence of SMNs with regard to diagnostic-, response- and therapy-related ALL characteristics except for a significantly higher incidence in patients with leukocytes ≥50.0 G/L at ALL diagnosis (2.1% ± 1.0% vs. 0% for 20.0-50.0 G/L, and 1.0% ± 0.3% for < 20.0 G/L; p = 0.033). Notably, there was no significant difference in the incidence of SMNs between patients with or without cranial radiotherapy (1.2% ± 0.5% vs. 0.8% ± 0.3%; p = 0.295). Future strategies must decrease the incidence of SMNs, as this event still leads to death in one-third (7/19) of the patients.

SUBMITTER: Poyer F

PROVIDER: S-EPMC9421960 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Second malignant neoplasms after treatment of 1487 children and adolescents with acute lymphoblastic leukemia-A population-based analysis of the Austrian ALL-BFM Study Group.

Poyer Fiona F Dieckmann Karin K Dworzak Michael M Tamesberger Melanie M Haas Oskar O Jones Neil N Nebral Karin K Köhrer Stefan S Moser Reinhard R Kropshofer Gabriele G Peters Christina C Urban Christian C Mann Georg G Pötschger Ulrike U Attarbaschi Andishe A

EJHaem 20220612 3

Second malignant neoplasms (SMN) after primary childhood acute lymphoblastic leukemia (ALL) are rare. Among 1487 ALL patients diagnosed between 1981 and 2010 in Austria, the 10-year cumulative incidence of an SMN was 1.1% ± 0.3%. There was no difference in the 10-year incidence of SMNs with regard to diagnostic-, response- and therapy-related ALL characteristics except for a significantly higher incidence in patients with leukocytes ≥50.0 G/L at ALL diagnosis (2.1% ± 1.0% vs. 0% for 20.0-50.0 G/ ...[more]

PMID: 36051012

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Project description:BackgroundCharacterization of clinical phenotypes in context with tumor and host genomic information can aid in the development of more effective and less toxic risk-adapted and targeted treatment strategies. To analyze the impact of therapy-related hyperbilirubinemia on treatment outcome and to identify contributing genetic risk factors of this well-recognized adverse effect we evaluated serum bilirubin levels in 1547 pediatric patients with acute lymphoblastic leukemia (ALL) and conducted a genome-wide association study (GWAS).Patients and methodsPatients were treated in multicenter trial AIEOP-BFM ALL 2000 for pediatric ALL. Bilirubin toxicity was graded 0 to 4 according to the Common Toxicity Criteria (CTC) of the National Cancer Institute. In the GWAS discovery cohort, including 650 of the 1547 individuals, genotype frequencies of 745,895 single nucleotide variants were compared between 435 patients with hyperbilirubinemia (CTC grades 1-4) during induction/consolidation treatment and 215 patients without it (grade 0). Replication analyses included 224 patients from the same trial.ResultsCompared to patients with no (grade 0) or moderate hyperbilirubinemia (grades 1-2) during induction/consolidation, patients with grades 3-4 had a poorer 5-year event free survival (76.6 ± 3% versus 87.7 ± 1% for grades 1-2, P = 0.003; 85.2 ± 2% for grade 0, P < 0.001) and a higher cumulative incidence of relapse (15.6 ± 3% versus 9.0 ± 1% for grades 1-2, P = 0.08; 11.1 ± 1% for grade 0, P = 0.007). GWAS identified a strong association of the rs6744284 variant T allele in the UGT1A gene cluster with risk of hyperbilirubinemia (allelic odds ratio (OR) = 2.1, P = 7 × 10- 8). TT-homozygotes had a 6.5-fold increased risk of hyperbilirubinemia (grades 1-4; 95% confidence interval (CI) = 2.9-14.6, P = 7 × 10- 6) and a 16.4-fold higher risk of grade 3-4 hyperbilirubinemia (95% CI 6.1-43.8, P = 2 × 10- 8). Replication analyses confirmed these associations with joint analysis yielding genome-wide significance (allelic OR = 2.1, P = 6 × 10- 11; 95% CI 1.7-2.7). Moreover, rs6744284 genotypes were strongly linked to the Gilbert's syndrome-associated UGT1A1*28/*37 allele (r2 = 0.70), providing functional support for study findings. Of clinical importance, the rs6744284 TT genotype counterbalanced the adverse prognostic impact of high hyperbilirubinemia on therapy outcome.ConclusionsChemotherapy-related hyperbilirubinemia is a prognostic factor for treatment outcome in pediatric ALL and genetic variation in UGT1A aids in predicting the clinical impact of hyperbilirubinemia.Trial registrationhttp://www.Clinicaltrialsgov ; #NCT00430118.

Dataset Information

Second malignant neoplasms after treatment of 1487 children and adolescents with acute lymphoblastic leukemia-A population-based analysis of the Austrian ALL-BFM Study Group.

Publications

Second malignant neoplasms after treatment of 1487 children and adolescents with acute lymphoblastic leukemia-A population-based analysis of the Austrian ALL-BFM Study Group.

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