Abstract
Background
Real-time quantitative polymerase chain reaction (RQ-PCR) has been widely used for molecular monitoring for patients with chronic myeloid leukemia (CML). Currently, RQ-PCR is not based on the concept of international scale (IS) in Japan; mainly because none of the domestic laboratories have obtained their own conversion factor (CF) which makes it possible to convert locally scaled BCR-ABL (BCR-ABL L) value to the IS (BCR-ABL IS). To join the global trend of molecular assessment of BCR-ABL in CML patients, we have tried to obtain a CF in Japan.
Methods
Samples from 55 patients were exchanged between the Japanese laboratory and the reference laboratory in Adelaide, and BCR-ABL and internal control gene transcripts of the samples were measured using RQ-PCR. The patient bias conversion method was used to determine the CF for the IS using the Bland and Altman method.
Results
The local CF in the Japanese laboratory was determined to be 0.87. Based on this CF, 0.1% BCR-ABL IS, defined as major molecular response, becomes equivalent to 731 copy/μg RNA BCR-ABL L.
Conclusion
This study is the first to introduce a laboratory-specific CF for harmonizing RQ-PCR methodology for detecting BCR-ABL transcripts to Japan, which may open new windows for molecular assessment of CML patients in Japan.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10147-011-0328-x/MediaObjects/10147_2011_328_Fig1_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10147-011-0328-x/MediaObjects/10147_2011_328_Fig2_HTML.gif)
Similar content being viewed by others
References
Goldman JM, Melo JV (2003) Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med 349:1451–1464
Baccarani M, Cortes J, Pane F et al (2009) Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 27:6041–6051
Deininger M, O’Brien SG, Guilhot F et al (2009) International Randomized Study of Interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. ASH annual meeting abstracts 114:1126
Hughes TP, Kaeda J, Branford S et al (2003) Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349:1423–1432
Hughes TP, Hochhaus A, Branford S et al (2010) Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood 116:3758–3765
Mensink E, van de Locht A, Schattenberg A et al (1998) Quantitation of minimal residual disease in Philadelphia chromosome positive chronic myeloid leukaemia patients using real-time quantitative RT-PCR. Br J Haematol 102:768–774
Branford S, Hughes TP, Rudzki Z (1999) Monitoring chronic myeloid leukaemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics. Br J Haematol 107:587–599
Zhang T, Grenier S, Nwachukwu B et al (2007) Inter-laboratory comparison of chronic myeloid leukemia minimal residual disease monitoring: summary and recommendations. J Mol Diagn 9:421–430
Hughes T, Deininger M, Hochhaus A et al (2006) Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 108:28–37
Paschka P, Branford S, Lorentz C et al (2004) Comparison of “log reduction from median pretherapeutic value” vs ratio BCR-ABL/ABL to express the therapeutic response in CML patients. ASH annual meeting abstracts 104:1013
Branford S, Fletcher L, Cross NC et al (2008) 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. Blood 112:3330–3338
Rulcova J, Zmekova V, Zemanova Z et al (2007) The effect of total-ABL, GUS and B2M control genes on BCR-ABL monitoring by real-time RT-PCR. Leuk Res 31:483–491
Bland JM, Altman DG (1986) Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1:307–310
Langabeer SE, Gale RE, Harvey RC et al (2002) Transcription-mediated amplification and hybridisation protection assay to determine BCR-ABL transcript levels in patients with chronic myeloid leukaemia. Leukemia 16:393–399
Yagasaki F, Niwa T, Abe A et al (2009) Correlation of quantification of major bcr-abl mRNA between TMA (transcription mediated amplification) method and real-time quantitative PCR. Rinsho Ketsueki 50:481–487
Marin D, Milojkovic D, Olavarria E et al (2008) European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood 112:4437–4444
Mahon FX, Rea D, Guilhot J et al (2010) Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11:1029–1035
Cross NC, Hughes TP, Hochhaus A et al (2008) International standardisation of quantitative real-time RT-PCR for BCR-ABL. Leuk Res 32:505–506
Müller MC, Munjal U, Erben P et al Stability of conversion factors for BCR-ABL monitoring—implications for the frequency of validation rounds. ASH annual meeting abstracts 116:893
White HE, Matejtschuk P, Rigsby P et al (2010) Establishment of the first World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL mRNA. Blood 116:e111–e117
Acknowledgments
This study was supported by the Epidemiological and Clinical Research Information Network (ECRIN). The following investigators in the Kanto CML study group participated in this study: Nobuyuki Aotsuka (Japanese Red Cross Soc., Narita Red Cross Hospital), Yokitaka Katsura (National Hospital Organization Mito Medical Center), Toshiko Motoji (Tokyo Women’s Medical University Hospital), Kentaro Yoshinaga (Tokyo Women’s Medical University Hospital), Masayuki Yamakura (Kameda General Hospital), Masami Takeuchi (Kameda General Hospital), Atsushi Wake (Toranomon Hospital), Hiroaki Tanaka (Oami Hospital), Naoshi Obara (University of Tsukuba), and Akihiro Nakajima (Tokyo Medical University Hachioji Medical Center).
Conflict of interest
Susan Branford received honoraria and research funding from Bristol Myers Squibb and Novartis. Chikashi Yoshida, Linda Fletcher, Kazuteru Ohashi, Hisashi Wakita, Takashi Kumagai, Masayuki Shiseki, Kousei Matsuei, Koiti Inokutchi, Yoshihiro Hatta, Yukari Shirasugi, Toshikazu Yamaguchi, Junichi Sakamoto, and Hisashi Sakamaki have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
for the Kanto CML Study Group.
About this article
Cite this article
Yoshida, C., Fletcher, L., Ohashi, K. et al. Harmonization of molecular monitoring of chronic myeloid leukemia therapy in Japan. Int J Clin Oncol 17, 584–589 (2012). https://doi.org/10.1007/s10147-011-0328-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10147-011-0328-x