Dasatinib May Override F317L BCR-ABL Kinase Domain Mutation in Patients with Chronic Myeloid Leukemia

The most common mechanisms for resistance in patients with chronic myeloid leukemia (CML) receiving imatinib mesylate are BCR-ABL kinase domain (KD) mutations. The mutations are stratifi ed according to in vitro 50% inhibitory concentration (IC 50) values. The F317L KD mutation has been shown to induce a 9-to 13.5-fold increase of dasatinib IC 50 with respect to wild-type BCR-ABL in cellular assays [1]. The pharmacokinetic data showed that F317L is predicted to be moderately sensitive to dasatinib [2]. Jabbour et al. [3] published data on a cohort of 20 CML patients with F317L mutation and evaluated the characteristics and outcomes of these patients with tyrosine-kinase inhibitor (TKI) therapy. Among these 20 patients, F317L was detected in 12 after imatinib failure and in 8 after dasatinib failure. In the post-imatinib failure group, 3 patients received dasatinib. The best achieved response was partial hematologic response in 1 and complete hematologic response (CHR) in 2. Müller et al. [4] also reported the results of analysis of original dasatinib phase 2/3 trial data according to pre-existing mutations. Of the 402 patients with baseline KD mutations, 14 had F317L mutations; 13 (93%), 2 (14%), and 1 (7%) achieved CHR, major cytogenetic response (MCyR), and complete cytogenetic response (CCyR), respectively. None of the patients achieved major molecular response (MMR). Among our CML cohort, we identifi ed KD mutations by the denaturing high performance liquid chromatography sequencing method as described before [5]. In the literature, it has been recently demonstrated by our group as well as by some others that there are CML patients with F317L mutation who achieved and maintained both CCyR and MMR with dasatinib after imatinib failure (Table 1) [6,7,8,9]. Dasatinib is known to have signifi cant therapeutic activity against the Src kinases, and this is responsible for several of its " off-target effects ". Pulmonary toxicity [i.e. pleural effusion (PE)] following dasatinib use can be observed in CML patients [10]. Lymphocytosis in CML patients receiving dasatinib might have contributed to therapeutic effi cacy, and Mustjoki et al. [11] showed a strong association between clonal T/NK cell expansion and lymphocytic PE under dasatinib therapy and prolonged stable responses in patients with advanced Ph-positive leukemias. Among the 4 CML cases described in the literature with F317L in which MMR was achieved with dasatinib, 3 had episodes of reversible dasatinib-induced PEs and modest lymphocytosis was seen in 1 (Table 1). These clinical and laboratory fi ndings …