Laboratory Monitoring of Chronic Myeloid Leukemia in Patients on Tyrosine Kinase Inhibitors
Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by translocation of genetic material from chromosome 9 to chromosome 22 to form a fusion gene (BCR-ABL1) that is responsible for abnormal tyrosine kinase activity and alteration of various downstream signaling pathways. In addition to morphological diagnosis of CML phase, it is essential to detect BCR-ABL1 fusion by either metaphase cytogenetics or reverse transcriptase polymerase chain reaction that also determines type of mRNA transcript. Once treatment begins, monitoring the response to Tyrosine Kinase Inhibitor (TKI) using standardized techniques and guidelines is important to check for failure of response and thus, plan timely intervention by increasing the dose of TKI or opting for second line TKIs. The goal is to stop evolution of CML to accelerated phase or blast crisis that has poor response to treatment. Also, it is desirable to achieve good outcomes and even treatment free remission in patients of CML on TKI. Thus, molecular monitoring by reverse transcriptase quantitative PCR (RT-qPCR) is done at regular intervals. There are international recommendations and quality control measures to standardize the reporting of fusion gene transcript levels by quantitative PCR (RT-qPCR) in CML to achieve and maintain sensitivity in molecular detection of CML disease burden. Various state-of-the-art molecular techniques have emerged to accurately determine the number of fusion-gene transcript levels. This review highlights various methodologies and their practical implications in management of CML patients on TKI.
keywordsChronic Myeloid Leukemia Monitoring Tyrosine kinase inhibitors Reverse transcriptase quantitative polymerase chain reaction
We would like to acknowledge Dr. Rekha Chaubey Ph.D scientist, Dr. Kanwaljeet Singh, M.D and the technical staff of molecular laboratory at department of hematology, AIIMS for their dedicated work and support.
Compliance with Ethical Standards
Conflict of interest
All authors declare that they have no conflict of interest.
Research Involving Human and/or Animals
This article does not contain any studies with human participants or animals performed by any of the authors.
- 6.Oehler VG (2013) Update on current monitoring recommendations in chronic myeloid leukemia: practical points for clinical practice. Hematol Am Soc Hematol Educ Program 2013:176–183Google Scholar
- 14.Testoni N, Marzocchi G, Luatti S, Amabile M, Baldazzi C, Stacchini M et al (2009) Chronic myeloid leukemia: a prospective comparison of interphase fluorescence in situ hybridization and chromosome banding analysis for the definition of complete cytogenetic response: a study of the GIMEMA CML WP. Blood 114(24):4939–4943CrossRefPubMedGoogle Scholar
- 15.Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J 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(1):28–37CrossRefPubMedPubMedCentralGoogle Scholar
- 19.National Comprehensive Cancer Network®, NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®); Chronic Myelogenous Leukemia, Version 4.2018Google Scholar
- 22.Mahon F-X (2017) Treatment-free remission in CML: who, how, and why? Hematol Am Soc Hematol Educ Program 2017(1):102–109Google Scholar
- 26.Deininger MW (2015) Molecular monitoring in CML and the prospects for treatment-free remissions. ASH Educ Program Book 2015(1):257–263Google Scholar
- 27.Branford S, Fletcher L, Cross NCP, Müller Martin C, Hochhaus A, Kim D-W 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(8):3330–3338CrossRefPubMedGoogle Scholar
- 29.Beillard E, Pallisgaard N, van der Velden VHJ, Bi W, Dee R, van der Schoot E et al (2003) Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using “real-time” quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR)—a Europe against cancer program. Leukemia 17(12):2474–2486CrossRefPubMedGoogle Scholar
- 33.Gabert J, Beillard E, van der Velden VHJ, Bi W, Grimwade D, Pallisgaard N et al (2003) Standardization and quality control studies of “real-time” quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia—a Europe against cancer program. Leukemia 17(12):2318–2357CrossRefPubMedGoogle Scholar
- 37.Enjeti A, Granter N, Ashraf A, Fletcher L, Branford S, Rowlings P et al (2015) A longitudinal evaluation of performance of automated BCR-ABL1 quantitation using cartridge-based detection system. Pathology (Phila) 47(6):570Google Scholar