Harmonising ctDNA Measurement in Haematological Malignancies: Traceability, Commutability and Reporting

Area of Science:

• * Hematology
• * Molecular Diagnostics
• * Cancer Genomics

Background:

• * Circulating tumor DNA (ctDNA) assays are vital for non-invasive monitoring in hematological malignancies, aiding genotyping, response assessment, and relapse detection.
• * Significant challenges exist in translating ctDNA results into comparable clinical decisions due to variations in measurand definitions, pre-analytical factors, workflow losses, and confounders like clonal hematopoiesis of indeterminate potential (CHIP).

Purpose of the Study:

• * To propose a harmonisation framework for ctDNA assays in hematological malignancies.
• * To address the need for standardized and comparable ctDNA measurements across different laboratories and platforms.

Main Methods:

• * Proposes a framework based on metrological traceability, ensuring reported ctDNA values are linked to reference systems with stated uncertainty.
• * Emphasizes commutability of reference materials across diverse workflows and the use of fit-for-purpose reference materials for calibration.
• * Incorporates quality control, external quality assessment, and harmonised CHIP-aware reporting rules.

Main Results:

• * The proposed framework aims to improve the comparability and reliability of ctDNA measurements in hematological cancers.
• * It provides strategies for calibration, quality control, and standardized reporting, including CHIP-aware rules.
• * Includes change-control and bridging strategies to maintain clinical decision thresholds during platform or pipeline evolution.

Conclusions:

• * A harmonised framework integrating metrological traceability, commutability, and fit-for-purpose reference materials is essential for reliable ctDNA testing in hematological malignancies.
• * Standardized reporting and quality control measures are critical for translating ctDNA findings into consistent clinical actions.
• * This approach will enhance the utility of ctDNA assays for patient management, reducing ambiguity and improving outcomes.