Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Deep molecular response in chronic myelogenous leukemia: ensuring accuracy and consistency

Leukemia volume 29, pages 1620–1621 (2015)Cite this article

Subjects

We read with interest the recent laboratory recommendations by European Treatment Outcome Study (EUTOS)1 on monitoring deep molecular response in chronic myelogenous leukemia (CML). The European LeukemiaNet recently adopted the concept of deep molecular response2 to clarify and re-define the previous obscure concept of ‘complete molecular response’. The EUTOS recommendations1 provide important and practical guidance on how to measure and categorize such deep molecular response (MR) in a standardized way in CML. In this correspondence, we raise three issues closely related to the discussion in the EUTOS recommendations that laboratories performing real-time reverse transcriptase PCR (RQ-PCR) for CML monitoring may encounter.

Determination of deep MR, that is, 4-log (MR4), 4.5-log (MR4.5) and 5-log (MR5) reduction from a standardized baseline, is relevant when comparing the treatment efficacy of tyrosine kinase inhibitors (TKI)3 and during the consideration of stopping TKI therapy for evaluation of treatment-free remission in the clinical trial settings.4 It has also been shown that deep MR is associated with a better outcome5 and may eventually become an important goal of TKI therapy.6 Given the clinical utility, the test performance of RQ-PCR assays, especially the analytical sensitivity at low range of BCR-ABL1 transcript level, is pivotal to accurate scoring of MR. EUTOS rightly recommends laboratories to specifically measure and optimize the limit of detection (LoD) of assays by established methods. Notwithstanding the incorporation of LoD as the lowest concentration of analyte that can be concluded as ‘detectable’ with confidence, laboratories should also take into account the limit of quantitation (LoQ) for quantitative measurements as RQ-PCR. LoQ is the lowest concentration of analyte that can be quantitatively determined with stated accuracy, in terms of bias and precision.7 To permit standardized and accurate scoring of MR, the determination of analytical sensitivity by means of LoQ verification or establishment is a crucial adjunct to LoD determination. We suggest that recommendation bodies may facilitate such process by defining the ‘stated accuracy’, or termed total allowable error,7 of RQ-PCR assays for BCR-ABL1 transcript. With the availability of plasmid, laboratories can obtain dilution(s) of BCR-ABL1 transcripts with known accurate concentration(s). This will allow bias at low level of BCR-ABL1 transcript be evaluated. Coupled with the evaluation of imprecision, the LoQ can then be determined and verified against the recommended total allowable error to evaluate the acceptability of assay performance.7

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

References

  1. Cross NC, White HE, Colomer D, Ehrencrona H, Foroni L, Gottardi E et al. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia 2015; 29: 999–1003.

    Article  CAS  Google Scholar 

  2. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122: 872–884.

    Article  CAS  Google Scholar 

  3. Hughes TP, Lipton JH, Spector N, Cervantes F, Pasquini R, Clementino NC et al. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood 2014; 124: 729–736.

    Article  CAS  Google Scholar 

  4. Ross DM, Hughes TP . How I determine if and when to recommend stopping tyrosine kinase inhibitor treatment for chronic myeloid leukaemia. Br J Haematol 2014; 166: 3–11.

    Article  CAS  Google Scholar 

  5. Etienne G, Dulucq S, Nicolini FE, Morisset S, Fort MP, Schmitt A et al. Achieving deeper molecular response is associated with a better clinical outcome in chronic myeloid leukemia patients on imatinib front-line therapy. Haematologica 2014; 99: 458–464.

    Article  CAS  Google Scholar 

  6. Mahon FX, Etienne G . Deep molecular response in chronic myeloid leukemia: the new goal of therapy? Clin Cancer Res 2014; 20: 310–322.

    Article  CAS  Google Scholar 

  7. CLSI Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - 2nd Edition (EP17-A2). Wayne, PA, USA: Clinical and Laboratory Standards Institute, 2012.

  8. Branford S, Cross NC, Hochhaus A, Radich J, Saglio G, Kaeda J et al. Rationale for the recommendations for harmonizing current methodology for detecting BCR-ABL transcripts in patients with chronic myeloid leukaemia. Leukemia 2006; 20: 1925–1930.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology and Clinical Biochemistry, Queen Mary Hospital, Hong Kong, Hong Kong

    H-W Ip

  2. Department of Pathology, Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong

    C-C So

Authors
  1. H-W Ip
    View author publications

    Search author on:PubMed Google Scholar

  2. C-C So
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to H-W Ip.

Ethics declarations

Competing interests

The authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ip, HW., So, CC. Deep molecular response in chronic myelogenous leukemia: ensuring accuracy and consistency. Leukemia 29, 1620–1621 (2015). https://doi.org/10.1038/leu.2015.93

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/leu.2015.93

This article is cited by

Search

Advanced search

Quick links