Significance of pretherapeutic genetic testing in patient-tailored therapy of leukaemia as manifested by correlation of pre-Imatinib BCR-ABL ATP-binding domain mutations and natural Imatinib resistance in CML patients
Authors: Zafar Iqbal, Zhao LiJuan, Shahid Baig, Zeba Aziz, Mudassar Iqbal, Ahmad Khalid, Tanveer Akhtar
Journal: Clinical Cancer Research (2008)

AACR Centennial Conference: Translational Cancer Medicine-- July 20-23, 2008; Monterey, CA

B25     Introduction : Novel targeted anti-cancer therapies like Imatinib, Dasatinib etc. are the hot favorite drugs for treatment of BCR-ABL positive Leukaemia. However, resistance to these drugs is a major obstacle to their curative use. This resistance is mostly due to BCR-ABL ATP-binding domain mutations. Successful management of this resistance is a big challenge in the field of Pharmacogenomics. In case of Imatinib resistance, these mutations can exist before the start of treatment in very small number, proliferate under selective pressure of this drug and lead to resistance(1). It has been established that different mutations vary in degree of Imatinib resistance and their sensitivity to Imatinib dose escalation and/or other targeted therapies like Dasatinib, detection of pre-existing mutations can be extremely valuable in tailoring the treatment to individualize the patients’ needs(2). However, a large-scale study of Imatinib resistance in CML patients due to pre-existing BCR-ABL mutations was needed to assess the role of pre-Imatinib genetic testing and its potential implication in patient-tailored therapy. However, previous studies on this subject in CML were limited to few patients(3). We hereby report our studies involving a large number of patients.    Methods : One 100 chronic phase newly diagnosed CML patients were analyzed for BCR-ABL mutations before and after 400mg/day of Imatinib, using ASO-PCR, as reported by Roche-Lestienne et al.(3). Frequencies of Imatinib-resistance due to pre-existing mutations and that of acquired resistance were subjected to statistical analysis using χ2 test.    Results : Mutations were detected in 32 patients before Imatinib treatment and these patients showed Imatinib resistance after 6-9 months of treatment (32/32, 100%). 24 patients with no pre-existing mutations manifested Imatinib resistance (24/68, 35.3%). χ2 test showed significant difference between frequencies of Imatinib resistance in two groups (p=0.01). All 32 patients with pre-existing mutations persisted with same mutations after manifestation of resistance. It shows that BCR-ABL kinase domain mutations are present in a considerable number of CML patients prior to Imatinib treatment and lead to Natural Imatinib Resistance (NImR).    Conclusions : Pre-existing BCR-ABL mutations have a significant impact on Imatinib therapy . Pre-treatment genetic testing for these mutations and adjustment of Imatinib therapy according to type of mutation(s) can be very valuable strategy not only in management of Imatinib resistance but to other targeted therapies like Dasatinib, Nilotinib etc., which are currently the gold-standard for treatment of Imatinib-resistant Leukaemia(2,4). Thus, study opens new dimensions for the use of patient-tailored treatment strategies to effectively treat Leukaemia and encourages the more practical use of Cancer Pharmacogenomics in Clinics.    1: Bocchia M, Forconi F, Lauria F.Expert Opin Emerg Drugs. 2006 Nov;11(4):651-64.    2: Marshall HM, Hammond JM. Ann Pharmacother. 2008 Jan 22; [Epub ahead of print].    3: Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, Lai JL, Philippe N, Facon T et al. Blood. 2002 Aug 1;100(3):1014-8. 4: Nardi V, Raz T, Cao X, Wu CJ, Stone RM, Cortes J et al. Oncogene. 2008 Jan 31;27(6):775-82.