Activity of Bosutinib, Dasatinib, and Nilotinib Against 18 Imatinib-Resistant BCR/ABL Mutants

Redaelli, Sara; Piazza, Rocco; Rostagno, Roberta; Magistroni, Vera; Perini, Pietro; Marega, M; Gambacorti‐Passerini, Carlo; Boschelli, Frank

doi:10.1200/jco.2008.19.8853

Cited by 359 publications

(342 citation statements)

References 23 publications

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“…These patients are probably less likely to have ABL kinase domain mutations. In accordance with the recently reported clinical results in chronic phase patients, 21 and with a cutoff of IC 50 150 nM for mutations with a higher chance of clinical responses to nilotinib recently described by Hughes et al, 15 we found that patients harboring mutations with an in vitro moderate or high resistance to nilotinib, including E255K, Y253H, and F359V, [22][23][24][25] were less likely to respond to nilotinib, and none of the 3 T315I-positive patients responded. These mutations were also the most commonly newly acquired mutations in patients who did not respond to nilotinib or progressed during therapy.…”

Section: Discussionsupporting

confidence: 92%

Activity and tolerability of nilotinib

Koren‐Michowitz

Coutre

Duyster

et al. 2010

Cancer

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BACKGROUND: Nilotinib is active in imatinib-resistant and -intolerant chronic myeloid leukemia patients and was recently approved for these indications. METHODS: Data on the efficacy and safety of nilotinib treatment were collected from 2 phase 2 expanded access clinical trials with similar designs (CAMN107AIL01 and ENACT). RESULTS: Of 88 study patients (58 chronic, 11 accelerated, 19 blast crisis), the best responses to nilotinib were complete hematologic response (CHR) in 27%, partial cytogenetic response in 12%, complete cytogenetic response in 14%, and major molecular response in 19%. Patients achieving at least a CHR during imatinib therapy were more likely to respond to nilotinib, and failure to achieve at least a CHR on imatinib therapy was predictive of progression or lack of response to nilotinib (P ¼ .0021). Responses were not statistically different in subgroup analysis, including that of imatinib intolerance compared with imatinib resistance, presence of ABL kinase domain mutations compared with absence of mutations, and previous treatment with another second-generation tyrosine kinase inhibitor compared no prior treatment. The overall survival and progression-free survival rates at 1 year were 83% and 48% for the entire cohort, 93% and 66% in chronic phase, and 64% and 19% in advanced phase. Adverse hematological events included thrombocytopenia (all events, 27%; grade 3-4, 13%) and leukopenia (all events, 18%; grade 3-4, 10%). The majority of the nonhematological events were mild, the most common being rash, infection, bone pain, headache, nausea, and vomiting. CONCLUSIONS: Nilotinib treatment is an efficient and safe therapy for imatinib-resistant or -intolerant patients. Prior response to imatinib therapy is a predictor for the response to nilotinib. Cancer 2010;116:4564-72.

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Section: Discussionsupporting

confidence: 92%

Activity and tolerability of nilotinib

Koren‐Michowitz

Coutre

Duyster

et al. 2010

Cancer

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“…P-ALK value is normalized both on the untreated sample and on the total ALK level: (P-ALK treated/ P-ALK untreated) divided by (ALK treated/ALK untreated). Relative resistance (RR) index was calculated as the ratio between mutant and WT IC 50 values (32). qPCR data were analyzed using the DDCt method, normalized on the proper housekeeping gene.…”

Section: Software and Statistical Analysismentioning

confidence: 99%

Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK–Positive Anaplastic Large Cell Lymphoma

Ceccon

Mologni

Giudici

et al. 2015

Molecular Cancer Research

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ALK is a tyrosine kinase receptor involved in a broad range of solid and hematologic tumors. Among 70% to 80% of ALK þ anaplastic large cell lymphomas (ALCL) are caused by the aberrant oncogenic fusion protein NPM-ALK. Crizotinib was the first clinically relevant ALK inhibitor, now approved for the treatment of late-stage and metastatic cases of lung cancer. However, patients frequently develop drug resistance to Crizotinib, mainly due to the appearance of point mutations located in the ALK kinase domain. Fortunately, other inhibitors are available and in clinical trial, suggesting the potential for second-line therapies to overcome Crizotinib resistance. This study focuses on the ongoing phase I/II trial small-molecule tyrosine kinase inhibitor (TKI) AP26113, by Ariad Pharmaceuticals, which targets both ALK and EGFR. Two NPM-ALK þ human cell lines, KARPAS-299 and SUP-M2, were grown in the presence of increasing concentrations of AP26113, and eight lines were selected that demonstrated resistance. All lines show IC 50 values higher (130 to 1,000-fold) than the parental line. Mechanistically, KARPAS-299 populations resistant to AP26113 show NPM-ALK overexpression, whereas SUP-M2-resistant cells harbor several point mutations spanning the entire ALK kinase domain. In particular, amino acid substitutions: L1196M, S1206C, the double F1174VþL1198F and L1122VþL1196M mutations were identified. The knowledge of the possible appearance of new clinically relevant mechanisms of drug resistance is a useful tool for the management of new TKI-resistant cases.Implications: This work defines reliable ALCL model systems of AP26113 resistance and provides a valuable tool in the management of all cases of relapse upon NPM-ALK-targeted therapy. Mol Cancer Res; 13(4); 775-83. Ó2014 AACR.

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“…Second-TKIs are generally well tolerated, with occurrence of grade 3/4 drug-related adverse events being less and hematological adverse event profiles being more favorable than those of imatinib. Second-TKIs also exhibit increased inhibitory potency against BCR-ABL1 kinase and efficacy in the treatment of patients with many BCR-ABL1 KD mutations that develop from imatinib use [16,24]; the T315I mutation confers resistance to both imatinib and 2nd-TKIs. Although excellent results have been reported with 2nd-TKIs, most of these were from prospective clinical trials, indicating that the data is from a selected group of patients.…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis of the BCR-ABL1 kinase domain in chronic-phase chronic myelogenous leukemia treated with tyrosine kinase inhibitors in practice: Study by the Nagasaki CML Study Group

Itonaga

Tsushima²,

Imanishi

et al. 2014

Leukemia Research

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An appropriate trigger for BCR-ABL1 mutation analysis has not yet been established in unselected cohorts of chronic-phase chronic myelogenous leukemia patients. We examined 92 patients after 12 months of tyrosine kinase inhibitor (TKI) treatment in Nagasaki Prefecture, Japan. Univariate analysis revealed that significant factors associated with not attaining a major molecular response (MMR) were the presence of the minor BCR-ABL1 fusion gene, a low daily dose of TKI, and the emergence of BCR-ABL1 kinase domain mutations conferring resistance to imatinib. Factors associated with the loss of sustained MMR were a low daily dose of TKI and the emergence of alternatively spliced BCR-ABL1 mRNA with a 35-nucleotide insertion. Taken together, our results suggest that the search for BCR-ABL1 mutations should be initiated if patients have not achieved MMR following 12 months of TKI treatment.

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Activity of Bosutinib, Dasatinib, and Nilotinib Against 18 Imatinib-Resistant BCR/ABL Mutants

Cited by 359 publications

References 23 publications

Activity and tolerability of nilotinib

Activity and tolerability of nilotinib

Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK–Positive Anaplastic Large Cell Lymphoma

Molecular analysis of the BCR-ABL1 kinase domain in chronic-phase chronic myelogenous leukemia treated with tyrosine kinase inhibitors in practice: Study by the Nagasaki CML Study Group

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