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Measuring Minimal Residual Disease beyond 10-5 through IGHV leader-based NGS increases Prognostic Discrimination in Chronic Lymphocytic Leukemia

ABSTRACT: The sensitivity of conventional techniques for the quantification of minimal/measurable residual disease (MRD) in chronic lymphocytic leukemia (CLL) is limited to MRD 10-4. Measuring MRD <10-4 could help to further distinguish between CLL patients with durable remission and those at risk of early relapse. We here present a novel, academically developed IGHV leader-based next-generation sequencing (NGS) assay for the quantification of MRD in CLL. We demonstrate, based on measurements in contrived MRD samples, that the linear range of detection and quantification of our novel assay reaches beyond MRD 10-5. If provided with sufficient DNA input, MRD can even be detected down to MRD 10-6. There was high inter-assay concordance between measurements of the IGHV leader-based NGS assay and allele-specific oligonucleotide quantitative PCR (r=0.92, [95%CI 0.86-0.96]) and droplet digital PCR (r=0.93, [95%CI 0.88-0.96]) on contrived MRD samples. In a cohort of 37 patients from the CLL11 trial, using MRD 10-5 as a cut-off, MRD undetectability was associated with superior progression-free survival (PFS) and time to next treatment. Importantly, deeper MRD measurement allowed for additional stratification of patients with MRD <10-4 but ≥10‑5. Whereas the PFS of these patients was significantly shorter, compared to patients with MRD <10-5 (HR 4.9, [95%CI 1.3-17.9], P=0.017), their PFS was superior to those with MRD ≥10‑4 (HR 0.18, [95%CI 0.06-0.46], P<0.001). These results clearly demonstrate the clinical utility of the novel IGHV-leader based NGS assay.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188587 | GEO | 2021/11/13

REPOSITORIES: GEO

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Measuring Minimal Residual Disease beyond 10-5 through IGHV leader-based NGS increases Prognostic Discrimination in Chronic Lymphocytic Leukemia

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