Nilotinib rapidly reverses breakpoint cluster region-Abelson oncogene fusion gene and M244V mutations in a patient with chronic myelogenous leukemia: A case report

Abstract

Abstract. Chronic myelogenous leukemia (CML) is a condition characterized by a balanced genetic translocation, t (9;22) (q34;q11.2), which leads to a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is referred to as the Philadelphia chromosome. At a molecular level, this translocation results in the formation of the BCR-ABL fusion oncogene, which translates into a BCR-ABL oncoprotein. Imatinib, nilotinib and dasatinib are three tyrosine kinase inhibitors that have been approved by the US Food and Drug Administration for the treatment of patients diagnosed with CML in the chronic phase (CML-CP). The present study describes the case of a patient with imatinib-resistant CML who, following two months of treatment with nilotinib, no longer exhibited detectable BCR-ABL fusion genes or M244V mutations. This suggests that nilotinib may be effective for treating CML cases in which the BCR-ABL fusion protein has an M244V mutation. IntroductionChronic myelogenous leukemia (CML) is a cancer of the white blood cells characterized by a balanced genetic translocation, t (9;22) (q34;q11.2), which leads to a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This chromosomal translocation is known as the Philadelphia chromosome. At a molecular level, the rearrangement results in the formation of the BCR-ABL fusion oncogene, which translates into a BCR-ABL oncoprotein (1).The US Food and Drug Administration has approved three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib and dasatinib, as first-line treatments for patients diagnosed with CML in the chronic phase (CML-CP) (2-5). Imatinib mesylate, otherwise known as Gleevec ® (Novartis Pharmaceuticals Corp., East Hanover, NJ, USA), was the first of the TKIs to receive approval; however, 20-40% of patients receiving imatinib as a first-line therapy are likely to eventually require an alternative treatment, due to intolerance or resistance to imatinib (5). It is recommended that, upon failure of imatinib treatment, patients with CML should be assessed for BCR-ABL kinase domain mutations, as this can indicate which TKI should be selected for continued therapy. Dasatinib and nilotinib have been demonstrated to retain efficacy against several of the mutations known to confer resistance to imatinib (6). Notably, a number of distinct mutations leading to decreased sensitivity to dasatinib and nilotinib have been found in in vitro and in vivo studies (7,8). Dasatinib is favored when patients have Y253H, E255K/V or F359C/V mutations in BCR-ABL. By contrast, nilotinib is more effective when V299L or F317L mutations are present (2). Despite this evidence, it remains unclear how the M244V mutation to the BCR-ABL fusion protein should affect the choice of treatment. The present study describes the effect of nilotinib therapy in a patient with imatinib-resistant CML. Case reportThis study was conducted in accordanc...