Intrachromosomal Amplification of Chromosome 21 Associated With Poor Outcome in Children With ALL
Intrachromosomal amplification of a region of chromosome 21 (iAMP21; three or more extra copies of RUNX1 on an abnormal chromosome 21) is a recently identified recurrent genomic abnormality associated with poorer outcome in acute lymphoblastic leukemia (ALL). In a study reported in Journal of Clinical Oncology, Nyla A. Heerema, PhD, of The Ohio State University Wexner Medical Center, and colleagues in the Children’s Oncology Group (COG) assessed the frequency of this lesion and associated outcomes in a large cohort of children with B-cell precursor ALL treated in COG trials. They found that iAMP21 was present in 2% of children and that it was associated with poorer event-free survival and overall survival in those with National Cancer Institute standard-risk disease.
The study included 7,793 patients with B-cell precursor ALL aged 1 year or older treated in contemporary COG ALL trials. Fluorescent in situ hybridization for specific genetic aberrations was required at diagnosis. Minimal residual disease was measured by flow cytometry at the end of induction. Outcomes for the analysis were event-free survival and overall survival.
Frequency of iAMP21
Overall, iAMP21 was found in 158 patients (2%), including 74 (1.5%) of 5,057 standard-risk patients, and 84 (3.1%) of 2,736 high-risk patients. The presence of iAMP21 was associated with age ≥ 10 years, white blood cell count < 50,000/L, female sex, and detectable minimal residual disease at day 29. No patients with iAMP21 had trisomies of chromosomes 4 and 10, ETV6-RUNX1, MLL rearrangements, or BCR-ABL1.
Survival Outcomes
Among all patients, 4-year event-free survival (72.7% vs 88.1%, P < .001) and 4-year overall survival (87.6% vs 94.0%, P = .0184) were worse in those with iAMP21. Significant differences in 4-year event-free survival and overall survival were found among standard-risk patients (72.7% vs 92.0%, P < .001; 89.9% vs 96.9%, P < .001), but not among high-risk patients (72.5% vs 80.8%, P = .6670; 85.9% vs 88.6%, P = .9901).
Outcome comparisons examining iAMP21 status and end-induction minimal residual disease showed no interactions in any of the comparisons. Among standard-risk patients, iAMP21 status was significantly predictive of event-free survival and overall survival in minimal residual disease–positive and -negative subgroups. Minimal residual disease–positive patients with iAMP21 had significantly worse 4-year event-free survival than those without iAMP21 (59.6% vs 85.2%, P < .001), as did minimal residual disease–negative patients with iAMP21 compared with those without iAMP21 (82.2% vs 94.2%, P < .001).
Four-year overall survival was significantly poorer for minimal residual disease–negative patients with iAMP21 vs those without iAMP21 (93.0% vs 98.1%, P = .0094), but not for minimal residual disease-positive patients with iAMP21 vs those without (85.2% vs 93.8%, P = .082). Presence of iAMP21 was not significantly predictive of event-free survival or overall survival among high-risk minimal residual disease–negative or -positive patients.
The investigators concluded, “iAMP21 is associated with inferior outcome in pediatric [B-cell precursor ALL], particularly standard-risk patients who require more intensive therapy and are now treated on high-risk COG ALL protocols.”
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