A Swedish group has shown the over expression of a novel gene, BTG1, in DS-ALL patients. Lundin et al.15 analyzed 8 DS-AML and 17 DS-ALL patients with SNP assays. Genomic imbalances observed in DS-AML patients were predominantly gains, while those observed in DS-ALL patients were losses. Several recurrent gene deletions were identified, including BTG1 in five (29%) cases. The relevance of BTG1 was understood from the pro-apoptotic, negative regulation of cell proliferation. However, an alternate theory suggests only a subset of DS-ALL patients exhibit BTG1 deletion, since previous data have not identified BTG1 deletion in a large sample set of DS-ALL patients.15

Treatment strategies
Leukemogenesis resulting from an alternate pathway also suggests difference in response to standard drug therapy. Research is being conducted on altering drug regimens to lower toxicities.


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A recent report by the Children’s Oncology Group (COG A2971) has shown improved survival amongst DS-AML children treated with reduced-dose chemotherapy. The Children’s Cancer Group (CCG) conducted a trial (CCG 2891) in which children were treated intensively with timed cycles of a combination of dexamethasone, cytarabine, 6-thioguanine, etoposide and rubidomycin/daunomycin (DCTER). In the COG A2971 trial, dexamethasone and etoposide were removed from DCTER, and there was a shorter maintenance period. The trial analyzed 132 patients, with a median follow-up time of 4.8 years. There were no significant differences in toxicities and age-related remission rates observed between the two trials. The five-year survival rates for COG A2971 (84% +/-6%) were similar compared to (79% +/-7%) CCG 2891. The favorable survival rate was observed in children aged <4 years. Older children showed a lower survival rate. The study was the first to analyze the effect of reduced dosage of chemotherapy drugs.16

The effect of cytarabine on a patient with DS-AMKL was analyzed. A 25-bp deletion was detected in the splice acceptor site of the 3′ intron 1/exon boundary of the GATA1 gene. The patient was treated once each day for 12 days, with low-dose cytarabine (10mg/m2). Minimal residual disease levels were dependent on GATA1 expression levels. This study was the first to show the favorable effect of low-dose cytarabine therapy, which achieved complete remission for 23 months. However, a larger sample size is required to validate the result.17

Toxicities in 22 DS-ALL patients were compared with those of 44 non-DS-ALL patients during the first six months of therapy. Patients who were DS-ALL showed longer hospitalization periods with a mean of 34.1 vs. 24.9 days. There were significant grade 3 to 4 toxicities (2.5 vs. 1.4 per patient). Cellulitis and mucositis were increasingly observed in patients subjected to one of the treatment protocols. The increased prevalence of cutaneous infections was significant in DS-ALL (40.9%) compared to DS-AML patients (3.7%).18

A study by Reinhardt et al., in DS-AMKL patients (<5 years) with trisomy 21 and GATA1 mutation, indicates the requirement of a moderate treatment regimen to avoid overdose toxicity.19