In a study reported in The New England Journal of Medicine, Duncavage et al found that whole-genome sequencing in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) provided rapid genomic profiling that improved diagnostic yield vs conventional cytogenetic analysis, as well as improved risk stratification vs standard risk categories.
Study Details
The study involved the use of a streamlined whole-genome sequencing approach to obtain genomic profiles for 263 patients with either AML (n = 175), MDS (n = 81), or other hematologic cancers (n = 7) seen at the Washington University School of Medicine, including 235 who had undergone successful conventional cytogenetic analysis. Risk stratification based on whole-genome sequencing findings used existing European Leukemia Network guidelines.
Key Findings
Whole-genome sequencing detected each of the 40 recurrent translocations and 91 copy-number alterations identified on cytogenetic analysis in 235 patients.
In our study, we found that whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or MDS. Such sequencing also provided a greater diagnostic yield than conventional cytogenetic analysis and more efficient risk stratification on the basis of standard risk categories.— Duncavage et al
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Among the 235 patients, whole-genome sequencing identified new, cytogenetically cryptic, structural variants in 13 patients; found 21 new copy-number alterations in 14 patients with alterations identified on cytogenetic analysis; and definitively identified copy-number alterations in 13 patients with ambiguous or inconclusive results on cytogenetic analysis—yielding a total of 40 patients (17.0%) with findings not detected by conventional cytogenetic analysis.
In a prospective cohort, whole-genome sequencing of samples from 117 consecutive patients was performed in a median of 5 days. Compared with cytogenetic analysis and targeted sequencing in the same cohort, whole-genome sequencing provided new genetic information in 29 patients (24.8%), which resulted in a change in risk category for 19 (16.2%).
In analysis of 71 patients with AML treated with chemotherapy alone (none receiving hematopoietic stem cell transplantation [HSCT]), associations with overall survival were observed for both conventional testing (adjusted P = .09) and whole-genome sequencing (adjusted P = .01). Whole-genome sequencing was associated with somewhat better identification of patients with adverse risk and poor outcomes, yielding an adjusted hazard ratio (HR) for death of 0.32 (95% confidence interval [CI] = 0.11–0.92) vs 0.66 (95% CI = 0.17–1.05) on conventional risk-group analysis.
In analysis of 27 patients with AML (none receiving HSCT) with inconclusive results on cytogenetic analysis, whole-genome sequencing provided risk predictions that correlated with differing survival outcomes. Overall survival was significantly longer in 21 patients with intermediate or favorable risk on whole-genome sequencing (median = 20.5 months, 95% CI = 5.6–38.8 months) vs 6 patients with adverse risk (median = 3.3 months, 95% CI = 1.7–18.9 months; adjusted HR = 0.29, P = .03). The survival difference was superior to that observed with assignment of patients to risk groups on the basis of gene mutations alone.
The investigators concluded, “In our study, we found that whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or MDS. Such sequencing also provided a greater diagnostic yield than conventional cytogenetic analysis and more efficient risk stratification on the basis of standard risk categories.”
Disclosure: The study was funded by the Siteman Cancer Research Fund and others. For full disclosures of the study authors, visit nejm.org.
