Acute leukemia in children with Down's syndrome: the importance of population based study.

The association between Down’s syndrome (DS) and acute leukemia is well documented. However, most information derives from retrospectively compiled patient series or treatment trials, which may not represent the general DS population. We report cases of acute leukemia and DS collected in the UK Childhood Cancer Study (UKCCS), a national population based case-control study. Data were gathered on all children aged 0-14 years diagnosed with acute leukemia between 1991 and 1996, irrespective of trial entry. Detailed diagnostic information on all cases was obtained from multiple sources, including: the Medical Research Council; UKCCSG; the National Registry of Childhood Tumours; the individual treating consultant; and hospital records. In addition, detailed cytogenetic information on trial and non-trial cases was obtained from the Leukaemia Research Cytogenetics Group. Molecular diagnostic information on patients with acute lymphoblastic leukemia (ALL) was provided by the central reference laboratory at the Leukaemia Research Fund Centre, Institute of Cancer Research. Details of the conduct and ethical approval of the UKCCS are described in full elsewhere. In total 1,709 children with acute leukemia enrolled in the UKCCS (Table 1). Of these, 14(6%) of the 248 with AML, and 34(2%) of the 1,461 with ALL, also had DS. Trial uptake was significantly lower for children with DS: 32/48 (67%) children with DS were in trials compared with 1,468/1,709 (86%) of non-DS cases (p<0.01). Entry was lowest for children with DS-AML: with only 8/14 (57%) in trials. We also report the striking finding that the increase in AML incidence in DS was confined to FAB M6 and M7 sub-types; no other FAB types were observed. Eleven (79%) of the DS-AML cases were M7 and 3 were M6. Importantly this was not apparent initially when the provisional diagnoses recorded by the treating hospital were considered. However, following panel review for the MRC AML 10 trial, 6 of the DS-AML cases initially diagnosed at the treating hospital and recorded for trial and study purposes as AML FAB M0 (4 cases), M1 (1 case) and M2 (1 case) were reclassified as AML FAB M7 (4 cases) and M6 (2 cases). The high number of reclassifications prompted review of the non-trial cases of DS-AML. These comprised 5 cases of AML FAB M7 and one case of AML FAB M6. All 6 diagnoses remained the same after review. In contrast, taken together, M6 and M7 accounted for only 18 (8%) of non-DS AML (p<0.001). The mean age at diagnosis of AML was significantly lower in DS children: 2.2 years (95% CI:1.5-3.0) compared with 6.7 years (95%CI:6.1-7.4; p<0.001). Interestingly, the average age at diagnosis of the 18 non-DS children with AML M6 or M7 was only 3.2 years (95% CI:1.1-5.4) comparable with DS-AML. Cytogenetic profiles in these DSAML cases were consistent with previous reports (3;5;6). Typically, the favorable translocations associated with non-DS AML, namely t(8;21), t(15;17), inv(16), and t(1;22) typically associated with AML FAB M7, were absent. Instead, a variety of unbalanced translocations were seen: +8 in 5/14(36%) DS-AML; del(6q) in 2/14(14%); +11 in 1/14(7%) and +21 in 1/14(7%) DSAML cases. Interestingly, both cases of del(6q) occurred in non-trial patients, emphasizing the importance of population based analysis. We confirm that B-cell precursor ALL (BCP-ALL) is the predominant form of leukemia observed in DS, occurring in 27/34 (79%) cases of DS-ALL compared with 1,067/1,427 (74%) cases of non-DS ALL. T-cell ALL, although reported, is extremely rare. There were no cases of proB or T-cell DS-ALL in our study. Age at diagnosis for DSALL and non-DS ALL were similar and the difference was not statistically significant. Whilst ML-DS is a specific entity, ALL in DS appears to be as heterogeneous as ALL in non-DS children. High hyperdiploidy (>50 chromosomes), a good-risk prognostic feature, appears underrepresented occurring in 1/27 (4%) cases. Testing for the most frequent chromosomal abnormality in childhood ALL, the ETV6-RUNX1 fusion resulting from t(12;21), was not standard in the study period. Specific chromosomal translocations associated with adverse outcomes in childhood ALL: 11q23/MLL translocations; t(9;22); and t(1;19) were absent in DS cases. However, the numbers are small. The finding of 5/27 (19%) cases with loss of 9p is interesting; it has been suggested elsewhere that it might play a significant role in the pathogenesis of DS-ALL. Two of these were in non-trial cases.