Conversion, Correction, and International Scale Standardization: Results From a Multicenter External Quality Assessment Study forBCR-ABL1Testing

Abstract

Context.-Monitoring BCR-ABL1 expression levels relative to clinically validated response criteria on the International Scale (IS) is vital in the optimal management of patients with chronic myeloid leukemia, yet significant variability remains across laboratories worldwide.Objective.-To assess method performance, interlaboratory precision, and different IS standardization modalities in representative laboratories performing routine BCR-ABL1 testing.Design.-Fifteen blinded test specimens with 5-level nominal BCR-ABL1 to ABL1 IS percentage ratios ranging from 5% to 0.0005% and 4-level secondary IS reference panels, the ARQ IS Calibrator Panels, were tested by relative quantitative polymerase chain reaction in 15 laboratories in 5 countries. Both raw and IS percentage ratios calculated by using local conversion factors (CFs) or analytic correction parameters (CPs) were collected and analyzed.Results.-A total of 670 valid positive results were generated. BCR-ABL1 detection was associated with variable ABL1 quality metric passing rates (P , .001) and reached at least 0.01% in 13 laboratories. Intralaboratory precision was within 2.5-fold for all sample levels combined with a relative mean difference greater than 5-fold across laboratories. International Scale accuracy was increased by using both the CF and CP standardization methods. Classification agreement for major molecular response status was 90% after CF conversion and 93% after CP correction, with precision improved by 3-fold for the CP method.Conclusions.-Despite preanalytic and analytic differences between laboratories, conversion and correction are effective IS standardization methods. Validated secondary reference materials can facilitate global diffusion of the IS without the need to perform sample exchange and improve the accuracy and precision of BCR-ABL1 quantitative measurements, including at low levels of residual disease.

A review of the challenge in measuring and standardizing BCR-ABL1

“…The validation and calibration to IS of the ARQ calibrator panels are based on the WHO primary materials, and this international research involving the assessment of linearity, sensitivity, and imprecision demonstrated that the panels enable analytical calibration of local RQ-PCR assay within the context of IS standardization and improve the accuracy and precision of BCR-ABL1 measurement [36]. The panels also have been evaluated in a multicenter external quality assessment study and confirmed that they can facilitate global diffusion of BCR-ABL1 IS standardization in laboratories not yet standardized [37]. The ARQ IS calibrator panels are commercially available and make it easy and convenient to implement IS standardization.…”

An Optimal Control Framework for the Automated Design of Personalized Cancer Treatments

“…We eventually selected 22 (out of 29) patients, for which the therapy led to a successful major molecular response (MMR), i.e., the ratio of cells with BCR-ABL mutation is ≤ 0.1 on the international scale (Griffiths et al, 2014).…”

Personalized Therapy Design for Liquid Tumors via Optimal Control Theory

“…We eventually selected 22 (out of 29) patients, for which the therapy led to a successful major molecular response (MMR), i.e., the ratio of cells with BCR-ABL mutation is ≤ 0.1 on the International Scale [54].…”