Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome

Abstract

To identify cytogenetic risk factors predicting outcome in children with advanced myelodysplastic syndrome, overall survival of 192 children prospectively enrolled in European Working Group of Myelodysplastic Syndrome in Childhood studies was evaluated with regard to karyotypic complexity. Structurally complex constitutes a new definition of complex karyotype characterized by more than or equal to 3 chromosomal aberrations, including at least one structural aberration. Five-year overall survival in patients with more than or equal to 3 clonal aberrations, which were not structurally complex, did not differ from that observed in patients with normal karyotype. Cox regression analysis revealed the presence of a monosomal and structurally complex karyotype to be strongly associated with poor prognosis (hazard ratio ‫؍‬ 4.6, P < .01). Notably, a structurally complex karyotype without a monosomy was associated with a very short 2-year overall survival probability of only 14% (hazard ratio ‫؍‬ 14.5; P < .01). The presence of a structurally complex karyotype was the strongest independent prognostic marker predicting poor outcome in children with advanced myelodysplastic syndrome. (Blood. 2010; 116(19):3766-3769) IntroductionKaryotypic complexity has been reported to be associated with a poor prognosis in myeloid neoplasia. [1][2][3] However, the definition of a complex karyotype remains a matter of debate. Most studies defined a complex karyotype as more than or equal to 3 independent abnormalities. 2,[4][5][6] In the Medical Research Council Acute Myeloid Leukemia 10 (MRC AML10) trial, more than or equal to 5 independent abnormalities were required 3 because acute myeloid leukemia (AML) patients with more than or equal to 5 abnormalities had a significantly worse 5-year overall survival (OS) than those with 3 or 4 abnormalities. 1 Increased numbers of chromosomal abnormalities were also found to adversely influence median survival in adult myelodysplastic syndrome (MDS) patients. 7 Breems et al recently investigated the prognostic value of different cytogenetic components of a complex karyotype in adult AML and identified a monosomal karyotype (ie, either one single autosomal monosomy in the presence of at least one structural aberration or at least 2 distinct autosomal monosomies) as a highly unfavorable risk category. 8 To better stratify children with advanced MDS, we evaluated the outcome in 192 children prospectively diagnosed and treated within the studies of the European Working Group of MDS in Childhood (EWOG-MDS) related to karyotypic complexity. This study is registered at www.clinicaltrials.gov as #NCT00047268 and #NCT00662090. MethodsAll patients younger than 18 years with adequate cytogenetic studies and advanced MDS (ie, refractory anemia with excess blasts or refractory anemia with excess blasts in transformation), 9,10 enrolled in studies EWOG-MDS 98 (www.clinicaltrials.gov; #NCT00047268) or EWOG-MDS 2006 (#NCT00662090) between July 1, 1998 and June 30, 2008 were included in this analysis. In both stud...

Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study

“…Other karyotypic features such as a structurally complex or monosomal karyotype have been reported as a strong negative prognostic indicator in overall MDS and AML. 10,[25][26][27]36,37 We found that these were also independent indicators of poor prognosis inv(3)/t(3;3) MDS and AML. Interestingly, t(9;22) was noted in 2 inv(3)/t(3;3) AML patients as secondary clonal evolution or part of complex karyotype in a de novo AML patient without history of CML.…”

“…25,26 A structurally complex karyotype is defined as a complex karyotype characterized by more than or equal to 3 chromosomal aberrations including at least one structural aberration. 27 Additional molecular studies related to EVI1 gene rearrangement were not performed in these cases because it was a retrospective analysis.…”

Response to treatment with azacitidine in children with advanced myelodysplastic syndrome prior to hematopoietic stem cell transplantation

“…Chromosome 7 or 7q abnormalities were not associated with poorer survival in pediatric MDS compared to other karyotypes in previous studies, which is in contrast to adult MDS. 38,39 Indeed, when we analyzed the differences in OS and EFS in controls with or without 7 or 7q abnormalities, we did not find significant differences. Normal cytogenetics were associated with better survival in one report from Japan 7 but not in a report from a European group.…”

RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)

“…In the father, loss of the Y chromosome was found, a cytogenetic abnormality associated with good prognosis. The daughter had a structurally complex karyotype including deletion of 5q, a very poor cytogenetic risk factor in childhood MDS [50]. In this family, the different secondary abnormalities may have had an impact on the age of onset and the clinical severity of the disease [46].…”