The use of Imatinib resistance mutation analysis to direct therapy in Philadelphia chromosome/BCR‐ABL1 positive chronic myeloid leukaemia patients failing Imatinib treatment, in Patan Hospital, Nepal

Abstract

Summary Philadelphia chromosome/BCR‐ABL1 positive chronic myeloid leukaemia (CML) can be successfully treated with Glivec (Imatinib), which is available free of cost through the Glivec International Patient Assistance programme (GIPAP) to patients with proven CML without means to pay for the drug. We review the acquired mutations in the tyrosine kinase encoded by the BCR‐ABL1 gene underlying Glivec failure or resistance in a cohort of 388 imatinib‐treated CML patients (149 Female and 239 male) registered between February 2003 and June 2016 in Nepal. Forty‐five patients (11 female 34 male) were studied; 18 different BCR‐ABL1 mutations were seen in 33 patients. P‐loop mutation, Kinase domain and A‐loop mutations were seen in 9, 16 and 4 patients respectively. Other mutations were seen in five patients. A T315I mutation was the most common mutation, followed by F359V and M244V. Sixteen mutations showed intermediate activity to complete resistance to Glivec. Among the 45 patients evaluated for BCR‐ABL1 mutations, 4 were lost to follow‐up, 14 died and 27 are still alive. Among the surviving patients, 16 are receiving Nilotinib, 5 Dasatinib and 3 Ponatinib, while 3 patients were referred to India, one of who received allogenic bone marrow transplantation. Understanding the spectrum of further acquired mutations in BCR‐ABL1 may help to choose more specific targeted tyrosine kinase inhibitors that can be provided by GIPAP.

Outcomes of 219 chronic myeloid leukaemia patients with additional chromosomal abnormalities and/or tyrosine kinase domain mutations

“…Thus, this ratio was slightly lower than the ratios in other reports. The most common KD mutation subtype was p.(Y253H) (n = 3; 23.07%), followed by p.(F359V) and p.(T315I) (n = 2; 15.38%), results that are similar to the study by Kayastha …”

“…In our study, KD mutations were identified in 13 of the 53 patients (24.5%) diagnosed with imatinib resistance. However, in other studies, the occurrence rate of KD mutations fluctuated between 22.4% and 73% . Thus, this ratio was slightly lower than the ratios in other reports.…”

“…However, the occurrence of resistance is more frequent. Many studies have shown that kinase domain (KD) mutations are the main mechanism of CML resistance to TKIs . Currently, more than 100 different KD mutations have been found since the discovery of the p.(T315I) mutation .…”

“…The most common mutations are the P‐loop mutations and the p.(T315I) mutation. Different types of mutations have been divided according to their roles in imatinib resistance: strong resistance (p.(T315I), p.(E255V), p.(Y253H), p.(L248V), p.(E279K) and p.(G250E)) and intermediate resistance (p.(H396R), p.(F359V), p.(F317L), p.(Q252H), p.(L387M), p.(F359C), p.(M351T), p.(M244V), p.(E355G) and p.(V379I)) . With the widespread application of TKIs and sequencing technology innovations, more complex and deeper types of mutations have been detected .…”

“…11,15 The most common mutations are the P-loop muta- V379I)). 8 With the widespread application of TKIs and sequencing technology innovations, more complex and deeper types of mutations have been detected. 10 Simultaneously, different KD mutations subtypes have been found to confer different degrees of resistance to TKIs.…”