Tyrosine kinase domain mutations in chronic myelogenous leukemia patients: Indian perspective
Fmr. Director, National Institute of Immunohaematology, KEM Hospital, Parel, Mumbai, Maharashtra, India
Fmr. Director, National Institute of Immunohaematology, KEM Hospital, Parel, Mumbai, Maharashtra
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Ghosh K. Tyrosine kinase domain mutations in chronic myelogenous leukemia patients: Indian perspective.J Postgrad Med 2022;68:70-71
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Ghosh K. Tyrosine kinase domain mutations in chronic myelogenous leukemia patients: Indian perspective. J Postgrad Med [serial online] 2022 [cited 2022 Jun 30 ];68:70-71
Available from: https://www.jpgmonline.com/text.asp?2022/68/2/70/343150
Discovery of tyrosine kinase inhibitor, imatinib, and its application in therapy of chronic myeloid leukemia (CML) is a milestone in the history of medicine. This discovery changed the outlook of CML patients from almost an universally fatal disease without allogenic bone marrow transplantation to an eminently treatable disease. In addition, following the route of synthesis of imatininb, hundreds of other tyrosine kinase inhibitors have entered the market with equally diverse applications in various disorders.
However, within a short time of its discovery and widespread applications, resistance to treatment of CML with imatinib started getting reported, as also various mechanisms of its resistance. Some of these mechanisms like differential biotransformation, gene amplifications [double Ph (Philadelphia) chromosomes, etc.], amplification and polymorphisms of drug pumping protein genes, and development of alternative pathways of maintaining the malignant clones could be expected to occur and some of them could be overcome by increasing the dose of imatinib., However, a common cause of imatinib resistance in the disease comes from tyrosine kinase domain mutations in the BCR-ABL1 kinase hybrid gene.
This enzyme has several domains of which imatinib binding domain and catalytic domain of the oncogene contribute maximum mutations to imatinib resistance with some contribution from P loop domain and myristate binding site of the ABL1 gene. In this issue of the journal, Bommannan et al. report that six common tyrosine kinase domain (TKD) mutations E255K, T315I, G250E, M244V, M351T, and Y253F were analyzed in 83 CML patients in different stages of the disease using sensitive allele specific oligonucleotide -polymerase chain reaction (ASO-PCR)technique. The patients were resistant to the standard dose of imatinib therapy. Before this report, four other Indian reports between 2009 till today have already been published.,,, Techniques used in most of these studies involved amplification of whole kinase domain of the affected gene followed by Sanger's sequencing technique. This technique is only 20% sensitive, but detects many other mutations than is specifically looked for as with ASO-PCR technique.
In the present study under discussion, more than 50% patients selected on the basis of imatinib resistance revealed TKD mutations, of which E255K and T315I were the commonest. They also found that 14% patients had two mutations and 4% had three mutations. The authors could have missed other mutations, which they could not look for, due to technical restrictions.
TKD mutation(s) accumulates in CML patients under continued pressure exerted by the tyrosine kinase inhibitor drug, with clonal evolution of the disease leading to loss and gain of many chromosomes and genes (insertions and deletions) over time., Downregulation of certain microRNA like miR199b also contribute,, detection of which requires a different technique like next generation sequencing. Apart from common mutations like T315I, five known mutations have also been described in the present brief report. How does one know that a particular mutation is not just a passenger mutation but the cause of imatinib resistance? This can be done by detecting 50% inhibitory concentration (IC50) value of the amount of a particular tyrosine kinase required in an in vitro cellular or biochemical assay. The most potent inhibitor of BCR-ABL1 is ponatinib, with a IC50 value of 0.5 nmol/L; followed by dasatinib (0.8–1.8 nmol/L), nilotinib (10–25 nmol/L), bosutinib (42 nmol/L), and imatinib (260–678 nmol/L).
Combining this value, clinical progress and molecular remission status, a suitable drug can be chosen. Nowadays, CML patients after initial work up are started on a tyrosine kinase inhibitor, usually imatinib, at 400 mg per day. CML patients should be regularly followed up with peripheral blood analysis for major molecular remission, i.e., 3 log reduction of BCR-ABL transcript load on QR–PCR against a standard house keeping gene at various intervals. From a clinician's point of view, the goal of CML treatment is to obtain sustained complete cytogentic response associated with survival benefit and also to achieve major molecular remission at 3 log level. Better still is to achieve deeper remission at 4, 4.5, or even 5 log reduction of the transcript with an idea to assess treatment-free remission under clinical trial. At anytime, if there is a suggestion that the two closely determined transcript values are showing an upward trend (0.5 log i.e., 2–6% difference is within laboratory error), then one should look for kinase domain mutation provided compliance and intolerance issues are ruled out. T315 I remains the most difficult mutation to treat and is responsible for 20–30% of all the mutations, and this mutation at present responds to ponatinib.
Studies on TKD mutation from India,,,, show similar common mutation pattern with a plethora of newer and novel mutations of unknown significance. Sometimes more than one mutation may be associated with a single gene on the affected cells or they may be on different cells (different clones); the significance of this has already been discussed. Baccarani et al. have reported a very comprehensive way of detecting mutations and management of CML patients and this report is recommended for further reading.
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