Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations

Müller, Martin C.; Cortes, Jorge; Kim, Dong Wook; Druker, Brian J.; Erben, Philipp; Pasqüini, Ricardo; Branford, Susan; Hughes, Timothy P.; Radich, Jerald P.; Ploughman, Lynn; Mukhopadhyay, Jaydip; Hochhaus, Andreas

doi:10.1182/blood-2009-04-214221

Cited by 262 publications

(216 citation statements)

References 37 publications

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“…Dasatinib and nilotinib retain activity against most of the known mutations that confer resistance to imatinib [65,66]. When selecting between dasatinib and nilotinib, in vitro and in vivo data have identified distinct mutations that exhibit decreased sensitivity to each of the agents [67,68]. The clinician may tend to favor dasatinib if the patient has the following mutations at the time of disease progression: Y253H, E255K/V, or F359C/V.…”

Section: How To Select a Second Or Third Line Optionmentioning

confidence: 99%

Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management

2014

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Disease overview: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1–2 cases per 100,000 adults, and accounts for ∼15% of newly diagnosed cases of leukemia in adults. Diagnosis: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR‐ABL fusion oncogene, which in turn translates into a Bcr‐Abl oncoprotein. Frontline therapy: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib have been approved by the US Food and Drug Administration for the first‐line treatment of patients with newly diagnosed CML in chronic phase (CML‐CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses; their impact on long‐term survival remains to be determined. Salvage therapy: For patients who fail frontline therapy, second‐line options include second and third generation TKIs. Although second and third generation TKIs are potent and specific BCR‐ABL TKIs, they exhibit unique pharmacological profiles and response patterns relative to different patient characteristics, such as patients comorbidities, disease stage, and BCR‐ABL mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib. Allogeneic transplantation remains an important therapeutic option for CML‐CP who have failed at least 2 TKIs, and for all patients in advanced phase disease. Am. J. Hematol. 89:547–556, 2014. © 2014 Wiley Periodicals, Inc.

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Section: How To Select a Second Or Third Line Optionmentioning

confidence: 99%

Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management

2014

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“…5 Although preclinical data may be used to identify candidate resistance mutations for a particular TKI, 7,8 it is the lack of substantial and durable responses in patients who present with particular BCR-ABL1 mutations (primary resistance), coupled with the frequent emergence of those mutations at the time of treatment failure (secondary resistance), that ultimately define such vulnerabilities. 9,10 Historically, Sanger sequencing (SS) has been used clinically to identify BCR-ABL1 mutations associated with TKI resistance. However, SS is unable to detect mutations present in less than 10% to 20% of There is an Inside Blood Commentary on this article in this issue.…”

Section: Introductionmentioning

confidence: 99%

Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients

Deininger

Hodgson

Shah

et al. 2016

Blood

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“…77 Across several studies, newly arising mutations associated with the development of clinical resistance to next-generation agents have included V299L, T315I/A and F317I/L for dasatinib and Y253F/H, E255K/V, T315I and F359C/V for nilotinib. 69,74,75,[78][79][80][81] Because imatinib-treated patients may have multiple low-level BCR-ABL mutations detectable only using highly sensitive detection methods, mutations that arise within the first few months of treatment with second-line agents are likely to represent preexisting clones. 45 Mutations arising at later time points are more likely to reflect newly emerging and selected clones during second-line BCR-ABL inhibitor treatment.…”

confidence: 99%

“…17 In vitro data have suggested that some other mutations may have reduced sensitivity to dasatinib or nilotinib, patients with or without any mutation (43% vs. 47%) whereas rates of event-free survival (EFS) at 2 years seemed slightly lower for patients with mutations (70% vs. 80%). 74 Analyses were also performed to determine if clinical responses correlated with in vitro IC 50 values of different mutants for dasatinib. Among 21 patients who had a T315I mutation (highly resistant to dasatinib), 0% achieved a CCyR.…”

confidence: 99%