Comparison of the biology of Down syndrome (DS) acute lymphoblastic leukemia (ALL) and non-DS ALL: Children's Oncology Group (COG) study P9900.
10003 Background: DS ALL is a heterogeneous disorder with inferior survival compared to non-DS. Controversy exists regarding the relative frequencies of sentinel cytogenetic lesions in children with DS and ALL. METHODS: COG P9900 was a laboratory classification study for ALL therapeutic trials from 12/99 to 2/05. Flow cytometry for DNA index; molecular testing for TEL-AML1, E2A-PBX1, BCR-ABL and FISH testing for trisomies 4 and 10 and for MLL rearrangements were done centrally for risk group stratification in a prospective manner to assign continuing treatment. RESULTS: Eighty of 2811 (3%) consecutively enrolled eligible B-precursor ALL patients (pts) had DS. Age > or < than 10 years of age, gender, presenting white blood cell count (WBC) and NCI risk group were similar between ALL patients with/without DS. However, the genetic lesions present in DS-ALL patients and the event-free survival (EFS) and overall survival (OS) differed from those of non-DS patients. No BCR/ABL or MLL translocations were found in the DS pts. TEL-AML1 fusion was present in 2.5% (2/80) of DS-ALL pts vs. 24% (651/2710) (p<0.0001) of non-DS-ALL pts. Trisomies of chromosomes 4 and 10 were present in 7.7% (6/78) of DS-ALL pts vs. 24% (643/2689) (p=0.0004) of non-DS-ALL pts. Five-year EFS and OS were inferior in pts with DS-ALL; 70% vs. 76% (p=0.078), and 86% vs. 90% (p=0.0333). However, when pts with MLL, BCR/ABL, TEL-AML 1 and trisomies 4 and 10 were excluded, the EFS and OS for both groups were equivalent with EFS for DS 68% vs. 70% for non-DS (p=0.8174), and OS for DS 87% vs. 85% for non-DS (p=0.8519). CONCLUSIONS: The inferior outcome of patients with ALL and DS is related to a much lower incidence of favorable genetic features (TEL- AML 1 and trisomies of chromosomes 4 and 10). Further investigation into the distinct pathogenesis of DS ALL is warranted to improve treatment response. No significant financial relationships to disclose.
Maloney, K; Carroll, WL; Carroll, A; Devidas, M; Hunger, SP; Martin, PL; Willman, CL; Winick, N; Whitlock, J; Camitta, BM
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