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Andreas Hochhaus - One of the best experts on this subject based on the ideXlab platform.
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treatment free remission following frontline Nilotinib in patients with chronic myeloid leukemia in chronic phase results from the enestfreedom study
Leukemia, 2017Co-Authors: Andreas Hochhaus, Francis J Giles, Tamas Masszi, J Radich, David M Ross, M Gomez T Casares, Andrzej Hellmann, Jesper Stentoft, Eibhlin Conneally, Valentin GarciagutierrezAbstract:The single-arm, phase 2 ENESTfreedom trial assessed the potential for treatment-free remission (TFR; i.e., the ability to maintain a molecular response after stopping therapy) following frontline Nilotinib treatment. Patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase with MR4.5 (BCR-ABL1⩽0.0032% on the International Scale (BCR-ABL1IS)) and ⩾2 years of frontline Nilotinib therapy were enrolled. Patients with sustained deep molecular response during the 1-year Nilotinib consolidation phase were eligible to stop treatment and enter the TFR phase. Patients with loss of major molecular response (MMR; BCR-ABL1IS⩽0.1%) during the TFR phase reinitiated Nilotinib. In total, 215 patients entered the consolidation phase, of whom 190 entered the TFR phase. The median duration of Nilotinib before stopping treatment was 43.5 months. At 48 weeks after stopping Nilotinib, 98 patients (51.6%; 95% confidence interval, 44.2-58.9%) remained in MMR or better (primary end point). Of the 86 patients who restarted Nilotinib in the treatment reinitiation phase after loss of MMR, 98.8% and 88.4%, respectively, regained MMR and MR4.5 by the data cutoff date. Consistent with prior reports of imatinib-treated patients, musculoskeletal pain-related events were reported in 24.7% of patients in the TFR phase (consolidation phase, 16.3%).
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long term benefits and risks of frontline Nilotinib vs imatinib for chronic myeloid leukemia in chronic phase 5 year update of the randomized enestnd trial
Leukemia, 2016Co-Authors: Andreas Hochhaus, Timothy P Hughes, Richard A Larson, Gabriel Etienne, D W Kim, Giuseppe Saglio, Le P Coutre, Surapol Issaragrisil, Pedro Enrique Dorlhiacllacer, Richard E ClarkAbstract:In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, Nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each Nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR(4.5); BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of Nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving Nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with Nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline Nilotinib 300 mg twice daily in patients with CML-CP.
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Nilotinib in patients with systemic mastocytosis analysis of the phase 2 open label single arm Nilotinib registration study
Journal of Cancer Research and Clinical Oncology, 2015Co-Authors: Andreas Hochhaus, Steven Novick, Philipp Le Coutre, Francis J Giles, Michele Baccarani, Martin C Muller, Andreas Reiter, Helene Santanastasio, Mimi Leung, Hagop M KantarjianAbstract:Purpose Activating KIT mutations are part of the pathogenesis of systemic mastocytosis (SM). Nilotinib is a tyrosine kinase inhibitor that potently inhibits activated forms of KIT. This phase 2, open-label, single-arm study (CAMN107A2101; www.clinicaltrials.gov NCT00109707) evaluated Nilotinib in patients with SM.
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safety and efficacy of switching to Nilotinib 400 mg twice daily for patients with chronic myeloid leukemia in chronic phase with suboptimal response or failure on front line imatinib or Nilotinib 300 mg twice daily
Haematologica, 2014Co-Authors: Timothy P Hughes, Andreas Hochhaus, Hagop M Kantarjian, Gianantonio Rosti, G J Ossenkoppele, Francisco Cervantes, Francois Guilhot, Dietger Niederwieser, Philipp Le Coutre, Clarisse LoboAbstract:In a randomized, phase III trial of Nilotinib versus imatinib in patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, more patients had suboptimal response or treatment failure on front-line imatinib than on Nilotinib. Patients with suboptimal response/treatment failure on imatinib 400 mg once or twice daily or Nilotinib 300 mg twice daily could enter an extension study to receive Nilotinib 400 mg twice daily. After a 19-month median follow up, the safety profile of Nilotinib 400 mg twice daily in patients switching from imatinib (n=35) was consistent with previous reports, and few new adverse events occurred in patients escalating from Nilotinib 300 mg twice daily (n=19). Of patients previously treated with imatinib or Nilotinib 300 mg twice daily, respectively, 15 of 26 (58%) and 2 of 6 (33%) without complete cytogenetic response at extension study entry, and 11 of 34 (32%) and 7 of 18 (39%) without major molecular response at extension study entry, achieved these responses at any time on Nilotinib 400 mg twice daily. Estimated 18-month rates of freedom from progression and overall survival after entering the extension study were lower for patients switched from imatinib (85% and 87%, respectively) versus Nilotinib 300 mg twice daily (95% and 94%, respectively). Nilotinib dose escalation was generally well tolerated and improved responses in about one-third of patients with suboptimal response/treatment failure. Switch to Nilotinib improved responses in some patients with suboptimal response/treatment failure on imatinib, but many did not achieve complete cytogenetic response (clinicaltrials.gov identifiers:00718263, 00471497 - extension).
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Nilotinib is associated with a reduced incidence of bcr abl mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase
Blood, 2013Co-Authors: Andreas Hochhaus, Carmino Antonio De Souza, Richard A Larson, Gabriel Etienne, Mineo Kurokawa, Giuseppe Saglio, Gianantonio Rosti, Dongwook Kim, Matt Kalaycio, Albert HoenekoppAbstract:In patients with chronic myeloid leukemia, BCR-ABL mutations contribute to resistance to tyrosine kinase inhibitor therapy. We examined the occurrence of treatment-emergent mutations and their impact on response in patients from the ENESTnd phase 3 trial. At the 3-year data cutoff, mutations were detected in approximately twice as many patients (21) on imatinib 400 mg once daily as on Nilotinib (11 patients each on Nilotinib 300 mg twice daily and Nilotinib 400 mg twice daily). The majority of mutations occurred in patients with intermediate or high Sokal scores. Most mutations (14 [66.7%]) emerging during imatinib treatment were imatinib-resistant and Nilotinib-sensitive. Incidence of the T315I mutation was low (found in 3, 2, and 3 patients on Nilotinib 300 mg twice daily, Nilotinib 400 mg twice daily, and imatinib, respectively) and mostly occurred in patients with high Sokal scores. Of the patients with emergent mutations, 1 of 11, 2 of 11, and 7 of 21 patients on Nilotinib 300 mg twice daily, Nilotinib 400 mg twice daily, and imatinib, respectively, progressed to accelerated phase/blast crisis (AP/BC) on treatment. Overall, Nilotinib led to fewer treatment-emergent BCR-ABL mutations than imatinib and reduced rates of progression to AP/BC in patients with these mutations. (Clinicaltrials.gov NCT00471497).
Hagop M Kantarjian - One of the best experts on this subject based on the ideXlab platform.
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a propensity score matching analysis of dasatinib and Nilotinib as a frontline therapy for patients with chronic myeloid leukemia in chronic phase
Cancer, 2016Co-Authors: Koichi Takahashi, Hagop M Kantarjian, Yulong Yang, Koji Sasaki, Preetesh Jain, Sara Dellasala, Farhad Ravandi, Tapan M Kadia, Naveen Pemmaraju, Naval DaverAbstract:BACKGROUND Both dasatinib and Nilotinib are approved frontline therapy for chronic myeloid leukemia in chronic phase (CML-CP) based on randomized trials compared with imatinib. However, no head-to-head comparison of dasatinib and Nilotinib has been conducted in patients with newly diagnosed CML-CP. METHODS The authors conducted a propensity score (PS) matched comparison of patients with CML-CP who received frontline therapy with either dasatinib (N = 102) or Nilotinib (N = 104) under the respective phase 2 trials conducted in parallel. RESULTS PS matching resulted in 87 patients from each trial being matched for pretreatment characteristics. The 3-month BCR-ABL1/ABL1 ratio <10% rate was 93% with dasatinib and 94% with Nilotinib (P = .25); the rates of major molecular response at 12 months were 77% and 85%, respectively (P = .13); and the rates of molecular response with 4.5-log reduction in the ratio at 36 months were 66% and 64%, respectively (P = .96). All other clinically relevant responses were similar between the 2 treatment cohorts. The 3-year probability of event-free survival was 89% among the patients who received dasatinib and 87% among those who received Nilotinib (P = .99), and the corresponding 3-year overall survival probabilities were 99% and 93%, respectively (P = .95). No statistical difference was observed between the dasatinib and Nilotinib groups in any of the other survival endpoints. The treatment discontinuation rate also was similar between the 2 cohorts (dasatinib group, 18%; Nilotinib group, 19%; P = .82). CONCLUSIONS In a PS-matched cohort of patients with newly diagnosed CML-CP, dasatinib and Nilotinib offer similar response and survival outcomes. Both drugs can be considered reasonable standard-of-care options as first-line therapy for patients with CML-CP. Cancer 2016;122:3336–3343. © 2016 American Cancer Society.
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Nilotinib in patients with systemic mastocytosis analysis of the phase 2 open label single arm Nilotinib registration study
Journal of Cancer Research and Clinical Oncology, 2015Co-Authors: Andreas Hochhaus, Steven Novick, Philipp Le Coutre, Francis J Giles, Michele Baccarani, Martin C Muller, Andreas Reiter, Helene Santanastasio, Mimi Leung, Hagop M KantarjianAbstract:Purpose Activating KIT mutations are part of the pathogenesis of systemic mastocytosis (SM). Nilotinib is a tyrosine kinase inhibitor that potently inhibits activated forms of KIT. This phase 2, open-label, single-arm study (CAMN107A2101; www.clinicaltrials.gov NCT00109707) evaluated Nilotinib in patients with SM.
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safety and efficacy of switching to Nilotinib 400 mg twice daily for patients with chronic myeloid leukemia in chronic phase with suboptimal response or failure on front line imatinib or Nilotinib 300 mg twice daily
Haematologica, 2014Co-Authors: Timothy P Hughes, Andreas Hochhaus, Hagop M Kantarjian, Gianantonio Rosti, G J Ossenkoppele, Francisco Cervantes, Francois Guilhot, Dietger Niederwieser, Philipp Le Coutre, Clarisse LoboAbstract:In a randomized, phase III trial of Nilotinib versus imatinib in patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, more patients had suboptimal response or treatment failure on front-line imatinib than on Nilotinib. Patients with suboptimal response/treatment failure on imatinib 400 mg once or twice daily or Nilotinib 300 mg twice daily could enter an extension study to receive Nilotinib 400 mg twice daily. After a 19-month median follow up, the safety profile of Nilotinib 400 mg twice daily in patients switching from imatinib (n=35) was consistent with previous reports, and few new adverse events occurred in patients escalating from Nilotinib 300 mg twice daily (n=19). Of patients previously treated with imatinib or Nilotinib 300 mg twice daily, respectively, 15 of 26 (58%) and 2 of 6 (33%) without complete cytogenetic response at extension study entry, and 11 of 34 (32%) and 7 of 18 (39%) without major molecular response at extension study entry, achieved these responses at any time on Nilotinib 400 mg twice daily. Estimated 18-month rates of freedom from progression and overall survival after entering the extension study were lower for patients switched from imatinib (85% and 87%, respectively) versus Nilotinib 300 mg twice daily (95% and 94%, respectively). Nilotinib dose escalation was generally well tolerated and improved responses in about one-third of patients with suboptimal response/treatment failure. Switch to Nilotinib improved responses in some patients with suboptimal response/treatment failure on imatinib, but many did not achieve complete cytogenetic response (clinicaltrials.gov identifiers:00718263, 00471497 - extension).
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early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline Nilotinib or imatinib
Blood, 2014Co-Authors: Timothy P Hughes, Carmino Antonio De Souza, Hagop M Kantarjian, Giuseppe Saglio, Gianantonio Rosti, Francois Guilhot, Dietger Niederwieser, Matt Kalaycio, Chiaki Nakaseko, Stephan MeierAbstract:We explored the impact of early molecular response (EMR; BCR-ABL ≤10% on the international scale [BCR-ABL(IS)] at 3 or 6 months) on outcomes in patients with newly diagnosed chronic myeloid leukemia in chronic phase treated with Nilotinib or imatinib based on 4 years of follow up in Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients. Patients (n = 846) received Nilotinib 300 mg twice daily, Nilotinib 400 mg twice daily, or imatinib 400 mg once daily. At 3 months, more patients had EMR failure (ie, BCR-ABL(IS) >10%) on imatinib (33%) than on Nilotinib (9%-11%); similarly at 6 months, 16% of patients in the imatinib arm vs 3% and 7% in the Nilotinib arms had EMR failure. In all arms, EMR failure was associated with lower rates of molecular response, an increased risk of progression, and lower overall survival compared with EMR achievement. We also analyzed patient and treatment characteristics associated with EMR and found distinct patterns in the Nilotinib arms vs the imatinib arm. High Sokal risk score was associated with a high rate of EMR failure on imatinib, but not on Nilotinib. In contrast, reduced dose intensity and dose interruptions were strongly associated with EMR failure in Nilotinib-treated, but not imatinib-treated, patients. This study is registered at www.clinicaltrials.gov as #NCT00471497.
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enestnd 4 year y update continued superiority of Nilotinib vs imatinib in patients pts with newly diagnosed philadelphia chromosome positive ph chronic myeloid leukemia in chronic phase cml cp
Blood, 2012Co-Authors: Hagop M Kantarjian, Timothy P Hughes, Andreas Hochhaus, Richard E Clark, J Reiffers, Matt Kalaycio, Ricardo Pasquini, Surapol Issaragrisil, Franck E Nicolini, Charisse KempAbstract:Abstract 1676 Background: Pts treated with Nilotinib in the ENESTnd phase 3 trial achieved higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular responses (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), significantly lower rates of progression to accelerated phase/blast crisis (AP/BC), and fewer CML-related deaths compared with imatinib by 1, 2, and 3 y. Here, we report data with a minimum follow-up of 3 y; efficacy and safety data based on longer follow-up of 4 y will be presented to further assess the impact of Nilotinib vs imatinib in pts with newly diagnosed Ph+ CML-CP. Methods: Adult pts (N = 846) with newly-diagnosed Ph+ CML-CP were randomized to Nilotinib 300 mg twice daily (BID; n = 282), Nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD; n = 283). MMR, MR4, MR4.5, time to progression to AP/BC, progression-free survival (PFS), and overall survival (OS) were evaluated. Results: Significantly higher rates of MMR, MR4, and MR4.5 by 3 y were achieved in Nilotinib- vs imatinib-treated pts (Table). Nilotinib led to the achievement of higher rates of molecular responses regardless of Sokal risk group or age. The difference in the rates of both MR4 and MR4.5 continued to be significantly higher for Nilotinib, with the difference in favor of Nilotinib increasing from 1 to 3 y (MR4: 9%-14% difference by 1 y, 18%-24% difference by 3 y; MR4.5: 6%-10% difference by 1 y, 13%-17% difference by 3 y). Among patients who achieved MMR, more pts achieved MR4 or MR4.5 on Nilotinib 300 mg BID (68%) and Nilotinib 400 mg BID (62%) compared with imatinib (49%). No pt in any arm progressed after achieving MR4.5. Significantly fewer pts progressed to AP/BC on Nilotinib vs imatinib (Table). No new progressions occurred on core treatment between the 2-y and 3-y analyses. When events occurring after treatment discontinuation were included, the rates of progression to AP/BC were also significantly lower with Nilotinib vs imatinib (Table). Nearly twice as many pts had emergent mutations on imatinib (n = 21) vs either Nilotinib arm (n = 11 in each arm), with 5 pts overall developing mutations between 2 and 3 y. OS remained similar in all groups at 3 y, but fewer CML-related deaths occurred in both the Nilotinib 300 mg BID (n = 5) and 400 mg BID (n = 4) arms vs imatinib (n = 14). Both drugs were well tolerated. Few new adverse events (AEs) and laboratory abnormalities were observed between 2 and 3 y. Rates of discontinuation due to AEs were 10%, 14%, and 11% in the Nilotinib 300 mg BID, Nilotinib 400 mg BID, and imatinib arms, respectively. Conclusions: Nilotinib continues to demonstrate superiority vs imatinib, yielding faster and deeper molecular responses and a significantly decreased risk of progression. Results of ENESTnd support the use of Nilotinib as a standard of care option in newly diagnosed adult pts with Ph+ CML-CP and should be considered to replace imatinib as the standard-of-care frontline therapy for patients with Ph+ CML-CP. Disclosures: Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Kim:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding; II-Yang: Research Funding. Clark:Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Reiffers:BMS: Expense reimbursement for travel expenses Other; Novartis: Expense reimbursement for travel expenses, Expense reimbursement for travel expenses Other. Nicolini:Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria. Hughes:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Hochhaus:BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Kemp:Novartis Pharmaceuticals Corp: Employment. Fan:Novartis Pharmaceuticals Corp: Employment. Waltzman:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Larson:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding.
Neil Gallagher - One of the best experts on this subject based on the ideXlab platform.
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Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase philadelphia chromosome positive chronic myeloid leukaemia 24 month minimum follow up of the phase 3 randomised enestnd trial
Lancet Oncology, 2011Co-Authors: Hagop M Kantarjian, Andreas Hochhaus, Carmino Antonio De Souza, Ian W Flinn, Giuseppe Saglio, Leif Stenke, Gianantonio Rosti, Hirohisa Nakamae, Neil GallagherAbstract:Summary Background Nilotinib has shown greater efficacy than imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (CML) in chronic phase after a minimum follow-up of 12 months. We present data from the Evaluating Nilotinib Efficacy and Safety in clinical Trials–newly diagnosed patients (ENESTnd) study after a minimum follow-up of 24 months. Methods ENESTnd was a phase 3, multicentre, open-label, randomised study. Adult patients were eligible if they had been diagnosed with chronic phase, Philadelphia chromosome-positive CML within the previous 6 months. Patients were randomly assigned (1:1:1) to receive Nilotinib 300 mg twice a day, Nilotinib 400 mg twice a day, or imatinib 400 mg once a day, all administered orally, by use of a computer-generated randomisation schedule, using permuted blocks, and stratified according to Sokal score. Efficacy results are reported for the intention-to-treat population. The primary endpoint was major molecular response at 12 months, defined as BCR–ABL transcript levels on the International Scale (BCR–ABL IS ) of 0·1% or less by real-time quantitative PCR in peripheral blood. This study is registered with ClinicalTrials.gov, number NCT00471497. Findings 282 patients were randomly assigned to receive Nilotinib 300 mg twice daily, 281 to receive Nilotinib 400 mg twice daily, and 283 to receive imatinib. By 24 months, significantly more patients had a major molecular response with Nilotinib than with imatinib (201 [71%] with Nilotinib 300 mg twice daily, 187 [67%] with Nilotinib 400 mg twice daily, and 124 [44%] with imatinib; p IS levels to ≤0·0032%) at any time than did those in the imatinib group (74 [26%] with Nilotinib 300 mg twice daily, 59 [21%] with Nilotinib 400 mg twice daily, and 29 [10%] with imatinib; p vs imatinib, p=0·0004 for Nilotinib 400 mg twice daily vs imatinib). There were fewer progressions to accelerated or blast phase on treatment, including clonal evolution, in the Nilotinib groups than in the imatinib group (two with Nilotinib 300 mg twice daily, five with Nilotinib 400 mg twice daily, and 17 with imatinib; p=0·0003 for Nilotinib 300 mg twice daily vs imatinib, p=0·0089 for Nilotinib 400 mg twice daily vs imatinib). At 24 months, survival was comparable in all treatment groups, but fewer CML-related deaths had occurred in both the Nilotinib groups than in the imatinib group (five with Nilotinib 300 mg twice daily, three with Nilotinib 400 mg twice daily, and ten with imatinib). Overall, the only grade 3 or 4 non-haematological adverse events that occurred in at least 2·5% of patients were headache (eight [3%] with Nilotinib 300 mg twice daily, four [1%] with Nilotinib 400 mg twice daily, and two [ Interpretation Nilotinib continues to show better efficacy than imatinib for the treatment of patients with newly diagnosed CML in chronic phase. These results support Nilotinib as a first-line treatment option for patients with newly diagnosed disease. Funding Novartis.
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structural resemblances and comparisons of the relative pharmacological properties of imatinib and Nilotinib
Bioorganic & Medicinal Chemistry, 2010Co-Authors: Paul W Manley, Jurgen Mestan, Markus Wartmann, Richard C Woodman, Nikolaus Stiefl, Sandra W Cowanjacob, Susan Kaufman, Marion Wiesmann, Neil GallagherAbstract:Although orphan drug applications required by the EMEA must include assessments of similarity to pre-existing products, these can be difficult to quantify. Here we illustrate a paradigm in comparing Nilotinib to the prototype kinase inhibitor imatinib, and equate the degree of structural similarity to differences in properties. Nilotinib was discovered following re-engineering of imatinib, employing structural biology and medicinal chemistry strategies to optimise cellular potency and selectivity towards BCR-ABL1. Through evolving only to conserve these properties, this resulted in significant structural differences between Nilotinib and imatinib, quantified by a Daylight-fingerprint-Tanimoto similarity coefficient of 0.6, with the meaning of this absolute measure being supported by an analysis of similarity distributions of similar drug-like molecules. This dissimilarity is reflected in the drugs having substantially different preclinical pharmacology and a lack of cross-intolerance in CML patients, which translates into Nilotinib being an efficacious treatment for CML, with a favourable side-effect profile.
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effect of the proton pump inhibitor esomeprazole on the oral absorption and pharmacokinetics of Nilotinib
The Journal of Clinical Pharmacology, 2010Co-Authors: Ophelia Q P Yin, Neil Gallagher, Deirdre Fischer, Eren Demirhan, Wei Zhou, Georg Golor, Horst SchranAbstract:Nilotinib (Tasigna), a highly selective and potent BCR-ABL tyrosine kinase inhibitor (TKI), is administered orally and has pH-dependent aqueous solubility, with lower dissolution at higher pH. This study evaluated the effect of esomeprazole on the pharmacokinetics of Nilotinib in healthy participants. Twenty-two participants (6 women, 16 men, mean age of 44.9 +/- 12.9 years) were enrolled to receive Nilotinib as a single oral 400-mg dose on days 1 and 13 and esomeprazole as 40 mg once daily on days 8 to 13. Serial blood samples were collected up to 72 hours after Nilotinib dosing, and Nilotinib serum concentrations were determined by a validated liquid chromatography/tandem mass spectrometry assay. Gastric pH was also monitored in all participants. When coadministered with esomeprazole, Nilotinib C(max) was decreased by 27% and AUC(0-infinity) decreased by 34%. Nilotinib t(max) was prolonged from 4.0 to 6.0 hours, but t(1/2) was not altered. Mean gastric pH was 1.0 +/- 0.5 at baseline and increased to 2.79 +/- 2.50, 3.98 +/- 2.27, 5.30 +/- 1.70, 5.38 +/- 1.26, and 5.31 +/- 1.42 at predose and 1, 2, 3, and 4 hours after the fifth esomeprazole dose, respectively. These results suggested a modest reduction in the rate and extent of Nilotinib absorption by esomeprazole. Nilotinib is a TKI that may be used concurrently with esomeprazole or other proton pump inhibitors.
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Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia
The New England Journal of Medicine, 2010Co-Authors: Giuseppe Saglio, Timothy P Hughes, Andreas Hochhaus, Richard E Clark, Gabriel Etienne, Clarisse Lobo, Dongwook Kim, Ricardo Pasquini, Surapol Issaragrisil, Neil GallagherAbstract:Background Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of Nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (CML) in the chronic phase. Methods In this phase 3, randomized, open-label, multicenter study, we assigned 846 patients with chronic-phase Philadelphia chromosome–positive CML in a 1:1:1 ratio to receive Nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily). The primary end point was the rate of major molecular response at 12 months. Results At 12 months, the rates of major molecular response for Nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P<0.001 for both comparisons). The rates of complete cytogenetic response by 12 months were significantly higher for Nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than for imatinib (65%) (P<0.001 for both comparisons). Patients receiving either the 300-mg dose or the 400-mg dose of Nilotinib twice daily had a significant improvement in the time to progression to the accelerated phase or blast crisis, as compared with those receiving imatinib (P = 0.01 and P = 0.004, respectively). No patient with progression to the accelerated phase or blast crisis had a major molecular response. Gastrointestinal and fluid-retention events were more frequent among patients receiving imatinib, whereas dermatologic events and headache were more frequent in those receiving Nilotinib. Discontinuations due to aminotransferase and bilirubin elevations were low in all three study groups. Conclusions Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome–positive CML. (ClinicalTrials.gov number, NCT00471497.)
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comparison of Nilotinib and imatinib in patients pts with newly diagnosed chronic myeloid leukemia in chronic phase cml cp enestnd beyond one year
Journal of Clinical Oncology, 2010Co-Authors: Richard A Larson, Timothy P Hughes, Neil Gallagher, Hagop M Kantarjian, Giuseppe Saglio, Le P Coutre, J Reiffers, P Edrich, Albert Hoenekopp, Andreas HochhausAbstract:6501 Background: Study results of ENESTnd at 12 month (mo) demonstrated superior efficacy of Nilotinib 300 and 400 mg bid over imatinib. Methods: 846 CML-CP pts were randomized to Nilotinib 300 mg bid (n=282), Nilotinib 400 mg bid (n=281), and imatinib 400 mg qd (n=283). Primary endpoint was major molecular response (MMR, ≤ 0.1% BCR-ABLIS) rate at 12 mo. Results: Rates of MMR and CCyR were superior for Nilotinib 300 and 400 mg bid compared with imatinib and deeper molecular responses were also achieved with Nilotinib at both doses (Table). Suboptimal responses and treatment failure (based on cytogenetic criteria) were less frequent on the Nilotinib arms. Progression to advanced disease was lower for Nilotinib at both doses compared with imatinib (Table); no pt who achieved MMR progressed; 3 pts who achieved CCyR on imatinib progressed. There were no unexpected safety events. Discontinuations due to adverse events or abnormal laboratory values were lowest for Nilotinib 300 mg bid (7%). Overall, 1% of pts d...
Giuseppe Saglio - One of the best experts on this subject based on the ideXlab platform.
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long term benefits and risks of frontline Nilotinib vs imatinib for chronic myeloid leukemia in chronic phase 5 year update of the randomized enestnd trial
Leukemia, 2016Co-Authors: Andreas Hochhaus, Timothy P Hughes, Richard A Larson, Gabriel Etienne, D W Kim, Giuseppe Saglio, Le P Coutre, Surapol Issaragrisil, Pedro Enrique Dorlhiacllacer, Richard E ClarkAbstract:In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, Nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each Nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR(4.5); BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of Nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving Nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with Nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline Nilotinib 300 mg twice daily in patients with CML-CP.
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phase 3 study of Nilotinib vs imatinib in chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase enestchina
Blood, 2015Co-Authors: Jianxiang Wang, Giuseppe Saglio, Z X Shen, Jie Jin, He Huang, Fanyi Meng, Huanling Zhu, Jianmin Wang, Ming Hou, Sabine HertleAbstract:Treatment with a tyrosine kinase inhibitor (TKI) targeting BCR-ABL1 is currently the standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP). In this study, we present results of the ENESTchina (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-China) that was conducted to investigate Nilotinib 300 mg twice daily vs imatinib 400 mg once daily in a Chinese population. ENESTchina met its primary end point with a statistically significant higher rate of major molecular response (MMR; BCR-ABL1 ≤0.1% on the International Scale) at 12 months in the Nilotinib arm vs the imatinib arm (52.2% vs 27.8%; P < .0001), and MMR rates remained higher with Nilotinib vs imatinib throughout the follow-up period. Rates of complete cytogenetic response (0% Philadelphia chromosome-positive [Ph+] metaphases by standard cytogenetics) were comparable and ≥80% by 24 months in both arms. The estimated rate of freedom from progression to accelerated phase/blast crisis at 24 months was 95.4% in each arm. The safety profiles of both drugs were similar to those from previous studies. In conclusion, rates of MMR at 12 months were superior with Nilotinib vs imatinib in Chinese patients with newly diagnosed Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01275196.
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early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline Nilotinib or imatinib
Blood, 2014Co-Authors: Timothy P Hughes, Carmino Antonio De Souza, Hagop M Kantarjian, Giuseppe Saglio, Gianantonio Rosti, Francois Guilhot, Dietger Niederwieser, Matt Kalaycio, Chiaki Nakaseko, Stephan MeierAbstract:We explored the impact of early molecular response (EMR; BCR-ABL ≤10% on the international scale [BCR-ABL(IS)] at 3 or 6 months) on outcomes in patients with newly diagnosed chronic myeloid leukemia in chronic phase treated with Nilotinib or imatinib based on 4 years of follow up in Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients. Patients (n = 846) received Nilotinib 300 mg twice daily, Nilotinib 400 mg twice daily, or imatinib 400 mg once daily. At 3 months, more patients had EMR failure (ie, BCR-ABL(IS) >10%) on imatinib (33%) than on Nilotinib (9%-11%); similarly at 6 months, 16% of patients in the imatinib arm vs 3% and 7% in the Nilotinib arms had EMR failure. In all arms, EMR failure was associated with lower rates of molecular response, an increased risk of progression, and lower overall survival compared with EMR achievement. We also analyzed patient and treatment characteristics associated with EMR and found distinct patterns in the Nilotinib arms vs the imatinib arm. High Sokal risk score was associated with a high rate of EMR failure on imatinib, but not on Nilotinib. In contrast, reduced dose intensity and dose interruptions were strongly associated with EMR failure in Nilotinib-treated, but not imatinib-treated, patients. This study is registered at www.clinicaltrials.gov as #NCT00471497.
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Nilotinib is associated with a reduced incidence of bcr abl mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase
Blood, 2013Co-Authors: Andreas Hochhaus, Carmino Antonio De Souza, Richard A Larson, Gabriel Etienne, Mineo Kurokawa, Giuseppe Saglio, Gianantonio Rosti, Dongwook Kim, Matt Kalaycio, Albert HoenekoppAbstract:In patients with chronic myeloid leukemia, BCR-ABL mutations contribute to resistance to tyrosine kinase inhibitor therapy. We examined the occurrence of treatment-emergent mutations and their impact on response in patients from the ENESTnd phase 3 trial. At the 3-year data cutoff, mutations were detected in approximately twice as many patients (21) on imatinib 400 mg once daily as on Nilotinib (11 patients each on Nilotinib 300 mg twice daily and Nilotinib 400 mg twice daily). The majority of mutations occurred in patients with intermediate or high Sokal scores. Most mutations (14 [66.7%]) emerging during imatinib treatment were imatinib-resistant and Nilotinib-sensitive. Incidence of the T315I mutation was low (found in 3, 2, and 3 patients on Nilotinib 300 mg twice daily, Nilotinib 400 mg twice daily, and imatinib, respectively) and mostly occurred in patients with high Sokal scores. Of the patients with emergent mutations, 1 of 11, 2 of 11, and 7 of 21 patients on Nilotinib 300 mg twice daily, Nilotinib 400 mg twice daily, and imatinib, respectively, progressed to accelerated phase/blast crisis (AP/BC) on treatment. Overall, Nilotinib led to fewer treatment-emergent BCR-ABL mutations than imatinib and reduced rates of progression to AP/BC in patients with these mutations. (Clinicaltrials.gov NCT00471497).
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Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase philadelphia chromosome positive chronic myeloid leukaemia 24 month minimum follow up of the phase 3 randomised enestnd trial
Lancet Oncology, 2011Co-Authors: Hagop M Kantarjian, Andreas Hochhaus, Carmino Antonio De Souza, Ian W Flinn, Giuseppe Saglio, Leif Stenke, Yeow Tee Goh, Gianantonio Rosti, Hirohisa NakamaeAbstract:Summary Background Nilotinib has shown greater efficacy than imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (CML) in chronic phase after a minimum follow-up of 12 months. We present data from the Evaluating Nilotinib Efficacy and Safety in clinical Trials–newly diagnosed patients (ENESTnd) study after a minimum follow-up of 24 months. Methods ENESTnd was a phase 3, multicentre, open-label, randomised study. Adult patients were eligible if they had been diagnosed with chronic phase, Philadelphia chromosome-positive CML within the previous 6 months. Patients were randomly assigned (1:1:1) to receive Nilotinib 300 mg twice a day, Nilotinib 400 mg twice a day, or imatinib 400 mg once a day, all administered orally, by use of a computer-generated randomisation schedule, using permuted blocks, and stratified according to Sokal score. Efficacy results are reported for the intention-to-treat population. The primary endpoint was major molecular response at 12 months, defined as BCR–ABL transcript levels on the International Scale (BCR–ABL IS ) of 0·1% or less by real-time quantitative PCR in peripheral blood. This study is registered with ClinicalTrials.gov, number NCT00471497. Findings 282 patients were randomly assigned to receive Nilotinib 300 mg twice daily, 281 to receive Nilotinib 400 mg twice daily, and 283 to receive imatinib. By 24 months, significantly more patients had a major molecular response with Nilotinib than with imatinib (201 [71%] with Nilotinib 300 mg twice daily, 187 [67%] with Nilotinib 400 mg twice daily, and 124 [44%] with imatinib; p IS levels to ≤0·0032%) at any time than did those in the imatinib group (74 [26%] with Nilotinib 300 mg twice daily, 59 [21%] with Nilotinib 400 mg twice daily, and 29 [10%] with imatinib; p vs imatinib, p=0·0004 for Nilotinib 400 mg twice daily vs imatinib). There were fewer progressions to accelerated or blast phase on treatment, including clonal evolution, in the Nilotinib groups than in the imatinib group (two with Nilotinib 300 mg twice daily, five with Nilotinib 400 mg twice daily, and 17 with imatinib; p=0·0003 for Nilotinib 300 mg twice daily vs imatinib, p=0·0089 for Nilotinib 400 mg twice daily vs imatinib). At 24 months, survival was comparable in all treatment groups, but fewer CML-related deaths had occurred in both the Nilotinib groups than in the imatinib group (five with Nilotinib 300 mg twice daily, three with Nilotinib 400 mg twice daily, and ten with imatinib). Overall, the only grade 3 or 4 non-haematological adverse events that occurred in at least 2·5% of patients were headache (eight [3%] with Nilotinib 300 mg twice daily, four [1%] with Nilotinib 400 mg twice daily, and two [ Interpretation Nilotinib continues to show better efficacy than imatinib for the treatment of patients with newly diagnosed CML in chronic phase. These results support Nilotinib as a first-line treatment option for patients with newly diagnosed disease. Funding Novartis.
Timothy P Hughes - One of the best experts on this subject based on the ideXlab platform.
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ABCC6 plays a significant role in the transport of Nilotinib and dasatinib, and contributes to TKI resistance in vitro, in both cell lines and primary patient mononuclear cells
PloS one, 2018Co-Authors: Laura N Eadie, Timothy P Hughes, Phuong Dang, Jarrad M. Goyne, Deborah L. WhiteAbstract:ATP Binding Cassette family efflux proteins ABCB1 and ABCG2 have previously been demonstrated to interact with Tyrosine Kinase Inhibitors (TKIs); however, evidence for the interaction of other potentially relevant drug transporters with TKIs is lacking. Through Taqman transporter array technology we assessed the impact of Nilotinib on mRNA expression of ABC transporters, with ABCC6 identified as a transporter of interest. Additionally, increased expression of ABCC6 mRNA was observed during in vitro development of Nilotinib resistance in BCR-ABL1-expressing cell lines. K562 cells exposed to gradually increasing concentrations of Nilotinib (to 2 μM) expressed up to 57-fold higher levels of ABCC6 mRNA when compared with control cells (p = 0.002). Analogous results were observed in Nilotinib resistant K562-Dox cells (up to 33-fold higher levels of ABCC6, p = 0.002). IC50 experiments were conducted on patient mononuclear cells in the absence and presence of three ABCC6 inhibitors: indomethacin, probenecid and pantoprazole. Results demonstrated that all three inhibitors significantly reduced Nilotinib IC50 (p
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abcc6 plays a significant role in the transport of Nilotinib and dasatinib and contributes to tki resistance in vitro in both cell lines and primary patient mononuclear cells
PLOS ONE, 2018Co-Authors: Laura N Eadie, Timothy P Hughes, Phuong Dang, Jarrad M. Goyne, Deborah L. WhiteAbstract:ATP Binding Cassette family efflux proteins ABCB1 and ABCG2 have previously been demonstrated to interact with Tyrosine Kinase Inhibitors (TKIs); however, evidence for the interaction of other potentially relevant drug transporters with TKIs is lacking. Through Taqman transporter array technology we assessed the impact of Nilotinib on mRNA expression of ABC transporters, with ABCC6 identified as a transporter of interest. Additionally, increased expression of ABCC6 mRNA was observed during in vitro development of Nilotinib resistance in BCR-ABL1-expressing cell lines. K562 cells exposed to gradually increasing concentrations of Nilotinib (to 2 μM) expressed up to 57-fold higher levels of ABCC6 mRNA when compared with control cells (p = 0.002). Analogous results were observed in Nilotinib resistant K562-Dox cells (up to 33-fold higher levels of ABCC6, p = 0.002). IC50 experiments were conducted on patient mononuclear cells in the absence and presence of three ABCC6 inhibitors: indomethacin, probenecid and pantoprazole. Results demonstrated that all three inhibitors significantly reduced Nilotinib IC50 (p<0.001) indicating ABCC6 is likely involved in Nilotinib transport. Cell line data confirmed these findings. Similar results were obtained for dasatinib, but not imatinib. Combined, these studies suggest that Nilotinib and dasatinib are likely substrates of ABCC6 and to our knowledge, this is the first report of ABCC6 involvement in TKI transport. In addition, ABCC6 overexpression may also contribute to Nilotinib and dasatinib resistance in vitro. With Nilotinib and dasatinib now front line therapy options in the treatment of CML, concomitant administration of ABCC6 inhibitors may present an attractive option to enhance TKI efficacy.
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long term benefits and risks of frontline Nilotinib vs imatinib for chronic myeloid leukemia in chronic phase 5 year update of the randomized enestnd trial
Leukemia, 2016Co-Authors: Andreas Hochhaus, Timothy P Hughes, Richard A Larson, Gabriel Etienne, D W Kim, Giuseppe Saglio, Le P Coutre, Surapol Issaragrisil, Pedro Enrique Dorlhiacllacer, Richard E ClarkAbstract:In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, Nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each Nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR(4.5); BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of Nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving Nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with Nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline Nilotinib 300 mg twice daily in patients with CML-CP.
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deep molecular responses achieved in patients with cml cp who are switched to Nilotinib after long term imatinib
Blood, 2014Co-Authors: Timothy P Hughes, Anthony P Schwarer, Francisco Cervantes, Francoisxavier Mahon, Jeffrey H Lipton, Nelson Spector, Ricardo Pasquini, Nelma Cristina D Clementino, Pedro Enrique Dorlhiac Llacer, Delphine ReaAbstract:Patients in complete cytogenetic response (CCyR) with detectable BCR-ABL1 after ≥2 years on imatinib were randomized to Nilotinib (400 mg twice daily, n = 104) or continued imatinib (n = 103) in the Evaluating Nilotinib Efficacy and Safety in clinical Trials-Complete Molecular Response (ENESTcmr) trial. By 1 and 2 years, confirmed undetectable BCR-ABL1 was achieved by 12.5% vs 5.8% (P = .108) and 22.1% vs 8.7% of patients in the Nilotinib and imatinib arms, respectively (P = .0087). Among patients without molecular response 4.5 (BCR-ABL1(IS) ≤0.0032%; MR(4.5)) and those without major molecular response at study start, MR(4.5) by 2 years was achieved by 42.9% vs 20.8% and 29.2% vs 3.6% of patients in the Nilotinib and imatinib arms, respectively. No patient in the Nilotinib arm lost CCyR, vs 3 in the imatinib arm. Adverse events were more common in the Nilotinib arm, as expected with the introduction of a new drug vs remaining on a well-tolerated drug. The safety profile of Nilotinib was consistent with other reported studies. In summary, switching to Nilotinib enabled more patients with chronic myeloid leukemia in chronic phase (CML-CP) to sustain lower levels of disease burden vs remaining on imatinib. This trial was registered at www.clinicaltrials.gov as #NCT00760877.
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safety and efficacy of switching to Nilotinib 400 mg twice daily for patients with chronic myeloid leukemia in chronic phase with suboptimal response or failure on front line imatinib or Nilotinib 300 mg twice daily
Haematologica, 2014Co-Authors: Timothy P Hughes, Andreas Hochhaus, Hagop M Kantarjian, Gianantonio Rosti, G J Ossenkoppele, Francisco Cervantes, Francois Guilhot, Dietger Niederwieser, Philipp Le Coutre, Clarisse LoboAbstract:In a randomized, phase III trial of Nilotinib versus imatinib in patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, more patients had suboptimal response or treatment failure on front-line imatinib than on Nilotinib. Patients with suboptimal response/treatment failure on imatinib 400 mg once or twice daily or Nilotinib 300 mg twice daily could enter an extension study to receive Nilotinib 400 mg twice daily. After a 19-month median follow up, the safety profile of Nilotinib 400 mg twice daily in patients switching from imatinib (n=35) was consistent with previous reports, and few new adverse events occurred in patients escalating from Nilotinib 300 mg twice daily (n=19). Of patients previously treated with imatinib or Nilotinib 300 mg twice daily, respectively, 15 of 26 (58%) and 2 of 6 (33%) without complete cytogenetic response at extension study entry, and 11 of 34 (32%) and 7 of 18 (39%) without major molecular response at extension study entry, achieved these responses at any time on Nilotinib 400 mg twice daily. Estimated 18-month rates of freedom from progression and overall survival after entering the extension study were lower for patients switched from imatinib (85% and 87%, respectively) versus Nilotinib 300 mg twice daily (95% and 94%, respectively). Nilotinib dose escalation was generally well tolerated and improved responses in about one-third of patients with suboptimal response/treatment failure. Switch to Nilotinib improved responses in some patients with suboptimal response/treatment failure on imatinib, but many did not achieve complete cytogenetic response (clinicaltrials.gov identifiers:00718263, 00471497 - extension).
