Clinical implications of conventional cytogenetics, fluorescence in situ hybridization (FISH) and molecular testing in chronic myeloid leukaemia patients in the tyrosine kinase inhibitor era – A review
- Author:
Ravindran Ankathil
1
Author Information
1. Human Genome Centre, School of Medical Sciences, Health campus, Universiti Sains Malaysia, 16150 Kubang kerian, Kelantan
- Collective Name:Siti Mariam Ismail; Nazihah Mohd Yunus; Sarina Sulong; Azlan Husin; Abu Dzarr Abdullah; Rosline Hassan
- Publication Type:Review
- Keywords:
CML;
Cytogenetics;
Fish;
Molecular Testing;
Tyrosine Kinase Inhibitors
- From:The Malaysian Journal of Pathology
2020;42(3):307-321
- CountryMalaysia
- Language:English
-
Abstract:
Chronic myeloid leukaemia (CML) provides an illustrative disease model for both molecular
pathogenesis of cancer and rational drug therapy. Imatinib mesylate (IM), a BCR-ABL1 targeted tyrosine
kinase inhibitor (TKI) drug, is the first line gold standard drug for CML treatment. Conventional
cytogenetic analysis (CCA) can identify the standard and variant Philadelphia (Ph) chromosome, and
any additional complex chromosome abnormalities at diagnosis as well as during treatment course.
Fluorescence in situ hybridization (FISH) is especially important for cells of CML patients with
inadequate or inferior quality metaphases or those with variant Ph translocations. CCA in conjunction
with FISH can serve as powerful tools in all phases of CML including the diagnosis, prognosis, risk
stratification and monitoring of cytogenetic responses to treatment. Molecular techniques such as
reverse transcriptase-polymerase chain reaction (RT-PCR) is used for the detection of BCR-ABL1
transcripts at diagnosis whereas quantitative reverse transcriptase-polymerase chain reaction (qRTPCR) is used at the time of diagnosis as well as during TKI therapy for the quantitation of BCR-ABL1
transcripts to evaluate the molecular response and minimal residual disease (MRD). Despite the
excellent treatment results obtained after the introduction of TKI drugs, especially Imatinib mesylate
(IM), resistance to TKIs develops in approximately 35% - 40% of CML patients on TKI therapy.
Since point mutations in BCR-ABL1 are a common cause of IM resistance, mutation analysis is
important in IM resistant patients. Mutations are reliably detected by nested PCR amplification of
the translocated ABL1 kinase domain followed by direct sequencing of the entire amplified kinase
domain. The objective of this review is to highlight the importance of regular and timely CCA,
FISH analysis and molecular testing in the diagnosis, prognosis, assessment of therapeutic efficacy,
evaluation of MRD and in the detection of BCR-ABL1 kinase mutations which cause therapeutic
resistance in adult CML patients.
- Full text:5.2020my01078.pdf
