Outcome heterogeneity in childhood high-hyperdiploid acute lymphoblastic leukemia

Abstract

High hyperdiploidy (HeH) (51 to 65 chromosomes) is found in one third of children with acute lymphoblastic leukemia and is associated with a good prognosis. Cytogenetic features may further refine this prognosis and identify patients with a poor outcome. We examined the effect of sex, age, individual trisomies, modal number, and structural abnormalities on survival among 700 children with HeH. Univariate analysis showed that age. sex, +4, +10, +18, and a high modal number were associated with survival. Multivariate analysis however, revealed that only age, sex, +4, and +18 were independent indicators. Hazard scores for predicting relapse and mortality were constructed. Three risk groups with 5-year event-free survival (EFS) rates of 86%, 75%, and 50% (P <.0001) were identified. The high-risk group comprised boys older than 9 years, boys aged 1 through 9 years without +18, and girls older than 9 years without +18, while girls aged 1 through 9 years with +18 had the best EFS. In terms of mortality, those younger than age 10 years with both +4 and +18 had an improved survival (96% vs 84% at 5 years, P <.0001). These findings confirm that the outcome of children with HeH is heterogeneous and that specific trisomies can identify patients with the greatest and least risk of treatment failure.

Genome complexity in acute lymphoblastic leukemia is revealed by array-based comparative genomic hybridization

“…The detected abnormalities reflected previously published data, for example gain of chromosome 21 and deletions of 12p in ETV6-RUNX1 positive patients (Attarbaschi et al, 2004) and loss of 9p in patients with high hyperdiploidy (Pui et al, 1989;Moorman et al, 2003). In addition, further CNA were identified, including two patients with high hyperdiploidy and gain of a common genomic region on 3q.…”

“…In addition, further CNA were identified, including two patients with high hyperdiploidy and gain of a common genomic region on 3q. Previous reports suggest that approximately 15-20% of patients with a high-hyperdiploid karyotype relapse (Moorman et al, 2003), and thus it may be that as yet unidentified additional genomic alterations in these patients, such as gain of 3q, confer this adverse clinical outcome.…”

Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

“…Its main karyotypic feature is the nonrandom gain of chromosomes, resulting in a characteristic pattern of trisomies and tetrasomies that most frequently involves chromosomes X, 4, 6, 8, 10, 14, 17, 18, and 21 (Mitelman et al, 2007). High hyperdiploidy is associated with a CD10 1 BCP immunophenotype and favorable prognostic factors such as low white blood cell (WBC) count and a median age of 4 years, with an overall survival of 90% (Moorman et al, 2003;Johansson et al, 2004).…”

“…High hyperdiploidy (>50 chromosomes) is the largest cytogenetic subgroup in B-cell precursor (BCP) childhood acute lymphoblastic leukemia (ALL), comprising 20-30% of the cases (Forestier et al, 2000;Moorman et al, 2003). Its main karyotypic feature is the nonrandom gain of chromosomes, resulting in a characteristic pattern of trisomies and tetrasomies that most frequently involves chromosomes X, 4, 6, 8, 10, 14, 17, 18, and 21 (Mitelman et al, 2007).…”

“…Furthermore, it has been shown that a single abnormal mitosis underlies all chromosomal gains in most cases, indicating that the cell giving rise to the hyperdiploid clone harbored other genetic abnormalities, inducing the aberrant cell division and/or allowing it to survive such a drastic and sud-den aneuploidy (Onodera et al, 1992;Paulsson et al, 2003Paulsson et al, , 2005. G-banding, fluorescence in situ hybridization (FISH), conventional comparative genome hybridization (CGH), array-based CGH, and single nucleotide polymorphism array analyses only detect structural chromosomal changes in a subset of pediatric high hyperdiploid cases (Elghezal et al, 2001;Kristensen et al, 2003;Moorman et al, 2003;Paulsson et al, 2005Paulsson et al, , 2006Davidsson et al, 2006Davidsson et al, , 2007Mullighan et al, 2007;Strefford et al, 2007). Hence, on the chromosomal level, the tri-and tetrasomies seem to be the only consistent abnormal feature of high hyperdiploid childhood ALLs.…”