Role of ABL Gene Mutations in Chronic Myeloid Leukemia Patients Resistant to Imatinib and Results of Treatment Shift to Second-Generation Tyrosine Kinase Inhibitors

Abstract

Abstract 4442 Introduction:Chronic myeloid leukemia (CML) is a model of disease in the development of targeted therapies. Tyrosine kinase inhibitors (TKIs) have transformed the approach to management of CML and have dramatically improved patients' outcome. Clinical response is obtained in the majority of patients. However, a significant proportion of patients do not achieve the optimal desirable outcome or are completely resistant to this treatment. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance. Treatment with second-generation TKIs has produced high rates of hematologic and cytogenetic response in mutated ABL patients.The aim of this study was analyzed the presence of ABL mutations in imatinib resistant patients and determine the importance of changing to second-generation TKIs treatment as soon as failure or suboptimal response is recognized. Patients and methods:From 420 CML patients diagnosed in 6 centers between 2004 and 2010, we have amplified and sequenced the ABL1 domain from BCR-ABL1 amplicon of 45 imatinib resistant patients (23 patients with suboptimal response, 14 with treatment failure, 4 who lost the molecular response and 4 patients who progressed to blast phase). The obtained sequences were compared with the published ABL1 sequence, GenBank U07563, using BLAST 2 software. Results:We have detected mutations in 15 of 45 patients (33%), some of them with more than one mutation (Table 1). Seven of these patients were treated with second-generation TKIs as a single treatment. Three of them achieve a major molecular response (MMR), one patient is in complete cytogenetic response (CCyR) and the other two patients are in major (MCyR) and partial (PCyR) cytogenetic response. Another patient received nilotinib followed by hematological stem cell transplantation (HSCT) and is in MMR. Two patients were submitted to a HSCT and achieve MMR. Only one patient treated with nilotinib as second option has not reach a cytogenetic response one year after detection of the mutation.Two of the patients with the T315I mutation were treated with IFN and nilotinib achieving PCyR and MCyR, respectively, and are still alive. The other T315I patient, and two patients in blast-crisis (BC) disease with the F317L mutation who received dasatinib prior to the study of ABL mutations, died before a change of treatment could have been performed. Conclusions:1.In our series, 10 out of the 15 patients who carried an ABL mutation benefit of treatment shift, suggesting that change of therapy as soon as either failure or suboptimal response is recognized seems to be better than waiting until hematologic response is also lost.2.F317L mutation in the two patients in BC appeared, probably, as a consequence of dasatinib treatment.3.We could identify the T315I mutation by early study of the ABL mutational status in patients with suboptimal response or failure to treatment in chronic-phase CML before their transformation to an advanced-phase disease.Table 1Characteristics of the 15 analyzed patients harboring ABL mutations.UPNFASEINITIAL TREATMENTRESPONSEMUTATIONSECOND LINE TREATMENTRESPONSE1APIM 400mg/24h - DA 70mg/12hFailureM351T and Y253HNI 400mg/48hCCyR2CPIM 400mg/24h – DA 70mg/12hSuboptimal ResponseM244VNI 800mg/12hHR3CPIM 400mg/24hSuboptimal ResponseS417YIM 400mg/24hMMR4CPIM (400-600-800mg/24h)Suboptimal ResponseL340LDA 70mg/12hMMR5BCIM 400mg/24hOtherdel exon 7DA 70mg/12hMMR6BCIM (400-600-800mg/24h)FailureT277AHSCTMMR7CPIM 400mg/24h - NI 200mg/12hFailureV379IHSCTMMR8CPIM 400mg/24hSuboptimal ResponseT315IIFNPCyR9BCIM 400mg/24h -DA 70mg/12hFailureF317LNoneExitus10BCIM 400mg/24h - DA 70mg/12hFailureT315INoneExitus11CPIFN – IM 400mg/24hSuboptimal ResponseD276ADA 50mg/48hPCyR12CPIM 400mg/24hSuboptimal ResponseT315I and F359VNI 200mg/12hMCyR13CPIM – NI - DAProgression to BCF317LNoneExitus14CPIM 400mg/24hTransformation to LAL-BCG250E and F311LNI + HSCTMMR15CPIM 400mg/24hSuboptimal ResponseLoss of 1 nucleotideNI 400mg/12hMMRAbbreviations: AP, Accelerated phase; CP, Chronic phase; BC, Blast crisis, IM, imatinib; DA, dasatinib; NI, nilotinib; del, deletion; HSCT, hematopoietic stem cell transplantation; IFN, interferon; MMR, major molecular response; CCyR, complete cytogenetic response; MCyR, major cytogenetic response; PCyR, partial cytogenetic response; HR, hematologic response. Disclosures:No relevant conflicts of interest to declare.