Detecting measurable residual disease beyond 10−4 by an IGHV leader-based NGS approach improves prognostic stratification in CLL

Paul J. Hengeveld, Michèle Y. van der Klift, P. Martijn Kolijn, Frédéric Davi, François G. Kavelaars, Evert de Jonge, Sandra Robrecht, Jorn L.J.C. Assmann, Lina van der Straten, Matthias Ritgen, Peter E. Westerweel, Kirsten Fischer, Valentin Goede, Michael Hallek, Mark David Levin, Anton W. Langerak*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)


The sensitivity of conventional techniques for reliable 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 patients with CLL with durable remission and those at risk of early relapse. We herein present an academically developed immunoglobulin heavy-chain variable (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 assay reaches beyond MRD 10−5. If provided with sufficient DNA input, MRD can be detected down to MRD 10−6. There was high interassay concordance between measurements of the IGHV leader-based NGS assay and allele-specific oligonucleotide quantitative polymerase chain reaction (PCR) (r = 0.92 [95% confidence interval {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 67 patients from the CLL11 trial, using MRD 10−5 as a cutoff, undetectable MRD was associated with superior progression-free survival (PFS) and time to next treatment. More important, deeper MRD measurement allowed for additional stratification of patients with MRD <10−4 but ≥10−5. PFS of patients in this MRD range was significantly shorter, compared with patients with MRD <10−5 (hazard ratio [HR], 4.0 [95% CI, 1.6-10.3]; P = .004), but significantly longer, compared with patients with MRD ≥10−4 (HR, 0.44 [95% CI, 0.23-0.87]; P = .018). These results support the clinical utility of the IGHV leader-based NGS assay.

Original languageEnglish
Pages (from-to)519-528
Number of pages10
Issue number5
Publication statusPublished - 2 Feb 2023

Bibliographical note

This work was supported in part
by the Cancer Clinical Trials Office of Cedars-Sinai
Cancer (collection of data).

Publisher Copyright:
© 2023 The American Society of Hematology


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