Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain

Abstract

T he striking efficacy of imatinib mesylate in chronic myeloid leukemia (CML) 1,2 has established this therapy as the new standard of care for the disease. However, resistance is an emerging problem which has prompted the design of several second-generation Bcr-Abl inhibitors. One of these, dasatinib , is now in advanced clinical development. 4 In vitro assays 5,6 and crystallographic studies 7 have suggested that the less stringent conformational requirements for Bcr-Abl binding are likely to render dasatinib active against many of the kinase domain mutants responsible for imatinib resistance. One remarkable exception appears to be the T315I, which has been shown to disrupt a hydrogen bond critical for dasatinib binding and to create steric hindrance which interferes with the entrance of the inhibitor into the ATP-binding site. In order to assess which pre-existent or emerging mutations are associated with decreased clinical efficacy of dasatinib, we analyzed BCR-ABL kinase domain sequences before and during treatment in Philadelphia chromosome-positive (Ph + ) leukemia patients who failed to respond to or relapsed during dasatinib therapy. Design and MethodsIn a phase II program (sponsored by Bristol-Myers Squibb) we treated with dasatinib 70 mg twice daily a total of 45 patients with either CML (n=35) or Ph + acute lymphoblastic leukemia (ALL) (n=10) who were resistant to or intolerant of imatinib. Their median age was 50 years (range, 18-74), the median duration since the diagnosis of CML was 32 months (range, 4-158); and the median duration of imatinib treatment was 17 months (2-57). At the time of writing, with a median follow-up of 12 months (range, 1-19), 21 patients have shown evidence of either primary or acquired resistance, defined as a failure to achieve a hematologic response or loss of hematologic response during treatment, respectively. All the patients provided written informed consent to their participation in this study. Hematologic response was assessed according to the criteria already described for the phase I study.4 Cytogenetic ABSTRACT Brief ReportThe emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelphia chromosome-positive (Ph + ) leukemia has prompted the development of second-generation compounds active against several imatinib-insensitive mutant forms of Bcr-Abl, including dasatinib (BMS-354825; Bristol-Myers Squibb). In order to assess which pre-existent or emerging kinase domain mutations are associated with decreased clinical efficacy of desatinib, we analyzed BCR-ABL kinase sequences before and during treatment in 21 Ph + patients who failed to respond to or relapsed during dasatinib therapy. In all patients but one, resistance to dasatinib was invariably found to be associated with mutations at residue 315 and/or at residue 317. Hematology and Medical Oncology "L. e A. Seràgnoli", S. OrsolaMalpighi Hospital, Massarenti 9, 40138 Bologna, Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selec...

SGX393 inhibits the CML mutant Bcr-Abl T315I and preempts in vitro resistance when combined with nilotinib or dasatinib

“…Emerging clinical data confirms that patients harboring Bcr-Abl T315I are resistant to nilotinib (14) and dasatinib (15), and Bcr-Abl T315I is frequently detected in patients with resistance to these inhibitors (14)(15)(16). Thus, an inhibitor of Bcr-Abl T315I will be essential to circumvent resistance to Abl kinase inhibitor therapy for CML.…”

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

“…41 Dasatinib inhibits all imatinib-resistant BCR-ABL mutants except T315I 41 and possibly F317L. 67,68 It inhibits PDGFRs and KIT more potently than imatinib or nilotinib and also inhibits the ephrin receptor tyrosine kinases 68 and the Src family kinases. 69 Results from phase 2 trials led to the approval of dasatinib in the United States, the European Union, and other regions for use in imatinib-resistant CML.…”

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

“…113 Six manuscripts have described the outgrowth of new Abl mutations in imatinib-resistant patients receiving second-line dasatinib. 109,[114][115][116][117][118] Specifically, Cortes and colleagues 109 detailed the evolution of Abl mutations in patients receiving second and third-line TKI therapy, noting the appearance and disappearance of specific mutations after therapeutic adjustments. As previously emphasized, the etiology of dasatinib resistance in patients failing second-line therapy is potentially independent of the mutations identified and likely reflects activation of alternative survival pathways.…”