Laboratory recommendations for scoring deep molecular responses following treatment for CML

Remarkably, some of these patients remain in sustained remission when treatment is withdrawn, suggesting that they may be at least operationally cured of their disease. Accurate definition of deep molecular responses (MRs) is therefore increasingly important for optimal patient management and comparison of independent data sets. We previously published proposals for broad standardized definitions of MR at different levels of sensitivity. Here we present detailed laboratory recommendations, developed as part of the European Treatment and Outcome Study for CML (EUTOS), to enable testing laboratories to score MR in a reproducible manner for CML patients expressing the most common BCR-ABL1 variants.

Introduction

Molecular monitoring provides important prognostic information for individual chronic myeloid leukemia (CML) patients undergoing therapy, and international treatment recommendations incorporate specific time-dependent molecular milestones to help determine whether a patient is responding optimally or not.1, 2 Molecular measurements are made by reverse transcriptase quantitative PCR (RT-qPCR) to estimate the amount of BCR-ABL1 mRNA relative to an internal reference gene, most commonly ABL1, GUSB or BCR.3, 4 The results are expressed on an International Scale (IS) as a percentage, with 100% BCR-ABLIS corresponding to the International Randomized Study of Interferon and STI571 (IRIS) study standardized baseline and 0.1% BCR-ABLIS being defined as a major molecular response (MMR or MR3; 3 log reduction from the standardized baseline).3 Expression of results on the IS depends on each testing laboratory either having obtained a laboratory-specific conversion factor (CF) by sample exchange with an established reference laboratory or by using kits and reagents that have been calibrated to the World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL1 mRNA.4, 5, 6, 7, 8, 9

Efforts to standardize molecular monitoring to the IS focused initially on detectable residual disease and in particular whether a patient had or had not achieved particular milestones, for example, 10% BCR-ABLIS or 0.1% BCR-ABLIS at various time points. However, with longer follow-up, it became apparent that many patients treated with imatinib achieved deeper levels of response, with BCR-ABL1 becoming undetectable in a minority of cases.10 This, along with the fact that second-generation tyrosine kinase inhibitors produce faster and deeper responses, compared with imatinib,11, 12 prompted the need for robust, standardized definitions of deep MR. Such definitions are particularly important in the context of studies that are enrolling patients with sustained deep responses into treatment-free protocols.13, 14

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