Laboratory validation and clinical utility of next-generation sequencing-based IGH/TCR clonality testing for the monitoring of measurable residual disease in acute lymphoblastic leukaemia: real-world experience at Austin Pathology

Stephen B. Ma, Wendi Lin, Janine Campbell, Kerrie Clerici, Deborah White, David Yeung, Malgorzata Gorniak, Shaun Fleming, Chun Y. Fong, Rishu Agarwal

Research output: Contribution to journalArticlepeer-review

Abstract

Measurable residual disease (MRD) testing is an essential aspect of disease prognostication in acute lymphoblastic leukaemia (ALL) and informs clinical decisions. The depth of MRD clearance is highly relevant and requires assays with sufficient sensitivity. Austin Pathology is one of the few laboratories in Australia currently utilising a fully validated and National Association of Testing Authorities (NATA)-accredited ultrasensitive next-generation sequencing (NGS) platform for MRD monitoring in ALL. This technology is based on the detection of clonal rearrangement of immunoglobulin and T cell receptor genes in leukaemic cells, and is capable of achieving a limit of detection at least one to two logs below that of multiparametric flow cytometry (MFC). In this retrospective analysis, we report a clonotype detection rate of up to 85.7% at diagnosis, and a concordance rate of 78.7% in MRD results between NGS and MFC. Of the discordant samples, nearly all were NGS+/MFC, highlighting the superior sensitivity of NGS. The enhanced sensitivity is clinically relevant, as discordant MRD results often heralded fulminant relapse, and therefore offer clinicians additional lead time and a window of opportunity to initiate pre-emptive therapy. Notwithstanding a small and heterogeneous cohort, our real-world survival data indicate an intermediate relapse risk for NGS+/MFC patients. In light of recent approval of Medicare rebatable ALL MRD testing, we discuss how NGS can complement other techniques such as MFC in personalising management strategies. We recommend routine clonality testing by NGS at diagnosis and use a multi-modality approach for subsequent MRD monitoring.

Original languageEnglish
JournalPathology
DOIs
Publication statusAccepted/In press - 2024

Keywords

  • Acute lymphoblastic leukaemia
  • clonality
  • disease monitoring
  • immunoglobulin gene rearrangement
  • measurable residual disease
  • next generation sequencing
  • T cell receptor gene rearrangement

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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