Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials

Abstract

An international basis for comparison of BCR-ABL mRNA levels is required for the common interpretation of data derived from individual laboratories. This will aid clinical decisions for individual patients with chronic myeloid leukemia (CML) and assist interpretation of results from clinical studies. We aligned BCR-ABL values generated by 38 laboratories to an international scale (IS) where a major molecular response (MMR) is 0.1% or less. Alignment was achieved by application of laboratory-specific conversion factors calculated by comparisons performed with patient samples against a reference method. A validation procedure was completed for 19 methods. We determined performance characteristics (bias and precision) for consistent interpretation of MMR after IS conversion. When methods achieved an average BCR-ABL difference of plus or minus 1.2-fold from the reference method and 95% limits of agreement within plus or minus 5-fold, the MMR concordance was 91%. These criteria were met by 58% of methods. When not met, the MMR concordance was 74% or less. However, irrespective of precision, when the bias was plus or minus 1.

Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia

“…27 An International program is now underway to harmonize the reporting of results according to the international scale in chronic myeloid leukemia. 15,16,28,29 In this regard, our study is reliable in that the measurement of BCR-ABL1 transcripts by RQ-PCR was performed at central laboratory and expressed results according to the concept of both international scale (for p210 BCR-ABL1 ) and log reduction from the standardized pooled baseline (for p190 BCR-ABL1 ) for the first time in Ph-positive ALL.…”

Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML

“…Hematologic, cytogenetic, and molecular responses during TKI treatment were determined according to published guidelines [22][23][24]. BCR/ABL levels were determined by quantitative PCR and were expressed as percent of ABL (reference gene) after adjustment according to the international scale (IS) [24].…”

Standardized definitions of molecular response in chronic myeloid leukemia

“…34,35 However, there are a number of obvious issues with CFs, for example, (i) the process is lengthy and costly; (ii) because of the requirement to involve an established reference laboratory, the process is only open to a limited number of laboratories at any given time; (iii) many centers struggle to accrue sufficient numbers of suitable samples; (iv) it is unclear as to how often CFs need to be revalidated; (v) it is unclear as to what happens to the 50% of laboratories who fail to achieve the defined performance criteria. 34 Some of these issues may be addressed by the recent commercial development of secondary reference reagents calibrated to the World Health Organization primary BCR-ABL standards. 36 With regard to definitions of MR, however, a new problem arises in how to define assay sensitivity in a standardized manner when BCR-ABL mRNA is undetectable.…”