Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance

Hagop M. Kantarjian, Francis Giles, Norbert Gattermann, Kapil Bhalla, Giuliana Alimena, Francesca Palandri, Gert J. Ossenkoppele, Franck-Emmanuel Nicolini, Stephen G. O'Brien, Mark Litzow, Ravi Bhatia, Francisco Cervantes, Ariful Haque, Yaping Shou, Debra J. Resta, Aaron Weitzman, Andreas Hochhaus and Philipp le Coutre


Nilotinib, an orally bioavailable, selective Bcr-Abl tyrosine kinase inhibitor, is 30-fold more potent than imatinib in pre-clinical models, and overcomes most imatinib resistant BCR-ABL mutations. In this phase 2 open-label study, 400 mg nilotinib was administered orally twice daily to 280 patients with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) after imatinib failure or intolerance. Patients had at least 6 months of follow-up and were evaluated for hematologic and cytogenetic responses, as well as for safety and overall survival. At 6 months, the rate of major cytogenetic response (Ph ≤ 35%) was 48%: complete (Ph = 0%) in 31%, and partial (Ph = 1%-35%) in 16%. The estimated survival at 12 months was 95%. Nilotinib was effective in patients harboring BCR-ABL mutations associated with imatinib resistance (except T315I), and also in patients with a resistance mechanism independent of BCR-ABL mutations. Adverse events were mostly mild to moderate, and there was minimal cross-intolerance with imatinib. Grades 3 to 4 neutropenia and thrombocytopenia were observed in 29% of patients; pleural or pericardial effusions were observed in 1% (none were severe). In summary, nilotinib is highly active and safe in patients with CML-CP after imatinib failure or intolerance. This clinical trial is registered at as ID no. NCT00109707.


Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the expansion of hematopoietic cells carrying the Philadelphia chromosome (Ph), resulting from a reciprocal translocation of the long arms of chromosomes 9 and 22. A novel fusion gene is formed, BCR-ABL, which encodes a constitutively active protein tyrosine kinase.1,2

Imatinib (Gleevec, Glivec; Novartis Pharmaceuticals, Florham Park, NJ), a Bcr-Abl tyrosine kinase inhibitor, has dramatically improved outcome in CML.36 In newly diagnosed patients with CML, imatinib is associated with a complete cytogenetic response rate of 87%, a progression rate to accelerated or blastic phase of 7%, and an estimated 5-year survival rate of 89%.3,6

Resistance to imatinib occurs annually in 3% to 4% of patients with CML in chronic phase (CML-CP), and is defined as failure to achieve complete hematologic response (CHR) within 3 months of therapy, any cytogenetic response within 6 months, or major cytogenetic response (Ph+ ≤ 35%) within 12 months, or the development of cytogenetic or hematologic relapse.7 Resistance can be mediated through BCR-ABL–dependent mechanisms, often through mutations in the ABL kinase domain (40%–50%), or by mechanisms independent of BCR-ABL.8 In patients with CML and resistance or intolerance to imatinib, alternative treatments are needed.810 Dasatinib, which inhibits Bcr-Abl as well as the Src-family kinases, has produced major cytogenetic responses in 52% of patients with CML-CP following resistance or intolerance to imatinib.11,12

Nilotinib (Tasigna; N-[3-[3-(1H-imidazolyl)propoxy] phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino] benzamide; Novartis Pharmaceuticals), a novel orally bioavailable derivative of imatinib, is a tyrosine kinase inhibitor with improved target specificity.13,14 Based on an understanding of the molecular mechanism of imatinib activity, structural modifications led to the development of nilotinib.15 Like imatinib, nilotinib inhibits Bcr-Abl by binding to an inactive, DFG-out conformation of the ABL kinase domain, thus preventing the enzyme from adopting the catalytically active conformation and blocking the tyrosine phosphorylation of proteins involved in Bcr-Abl signal transduction.16 The improved binding of nilotinib results in greater potency and selectivity over the KIT and PDGF receptor kinases and has no activity against targets such as the Src-family of tyrosine kinases.17 In preclinical models, nilotinib was 30 times more potent than imatinib in imatinib-sensitive CML cell lines, and maintained activity in 32 of 33 imatinib-resistant BCR-ABL mutant cell lines, encouraging its development in CML.18 Results from a phase 1 dose escalation study performed in patients with imatinib-resistant CML and Ph+ acute lymphoblastic leukemia (ALL) indicated that nilotinib produced significant hematologic and cytogenetic responses in all phases of CML.19 Side effects potentially related to nilotinib included grade 3 or 4 hematologic toxicity, with cytopenias in 6% to 20% of patients, as well as transient indirect hyperbilirubinemia and skin rash.

The primary objective of this phase 2 study was to determine the rate of major cytogenetic response in patients with CML-CP following resistance or intolerance to imatinib. The results presented are from an interim analysis conducted on the first 280 consecutively enrolled patients with at least 6 months of follow-up.

Patients, materials, and methods

Patients and study design

Patients with Ph+ CML-CP who were at least 18 years of age were eligible if they had imatinib resistance or intolerance, adequate performance status (World Health Organization Performance Score ≤ 2), and normal hepatic, renal, and cardiac functions. Patients with imatinib resistance had to have been treated with a dose of at least 600 mg daily for 3 months. Patients in accelerated or blastic phases,20,21 or patients who received treatment with imatinib for 7 days and with hydroxyurea for 2 days prior to nilotinib, were excluded. Potassium and magnesium levels had to be greater than or equal to the lower limit of normal or corrected to within normal range. For safety, patients receiving concomitant medications known to prolong the QT interval or inhibit CYP3A4 were excluded if alternative treatments were not possible. Imatinib resistance was defined as failure to achieve CHR after 3 months, cytogenetic response after 6 months, major cytogenetic response after 12 months, or loss of a hematologic or cytogenetic response at any time during treatment with imatinib. Entry criteria for imatinib intolerance included patients with intolerant symptoms, but who also had never achieved a major cytogenetic response with imatinib. Intolerant symptoms were defined as any nonhematologic toxicity of grade 3 or higher severity, or of grade 2 or higher severity lasting more than 1 month or recurring more than 3 times despite dose reduction and maximal supportive care. The definition of intolerance also included hematologic toxicity of grade 4 severity persisting for more than 7 days. Imatinib-intolerant patients who had previously demonstrated sensitivity to imatinib, as evidenced by a prior major cytogenetic response, were to be excluded from participation in the study.

Nilotinib at a dose of 400 mg twice daily (800 mg/day) was administered to all patients based on safety, tolerability, and pharmacokinetic data from the phase 1 study.19 Patients were instructed to fast for at least 2 hours prior to and 1 hour after taking nilotinib. In the absence of safety concerns, nilotinib could be escalated to 600 mg twice daily (1200 mg/day) if patients had not obtained a hematologic response at 3 months, a cytogenetic response at 6 months, a major cytogenetic response at 12 months, or if they showed loss of hematologic or cytogenetic response or disease progression at any time. Hematologic and cytogenetic response criteria have been described previously.22 Cytogenetic responses are as follows: complete, Ph positivity of 0%; partial, Ph positivity of 1% to 35%; minor, Ph positivity of 36% to 65%; and minimal, Ph positivity of 66% to 95%. A major cytogenetic response includes complete and partial cytogenetic responses. Cytogenetic responses were based on the percentage of Ph+ metaphases among 20 or more metaphase cells in each bone marrow sample. Fluorescent in situ hybridization (FISH) studies to document cytogenetic response were accepted if routine cytogenetic studies were not successful or not available at a particular analysis time. Complete blood counts and biochemistries were obtained weekly for the first 8 weeks, and thereafter every 2 weeks. Bone marrow assessments were done on day 28 of cycle 1 and every 3 months. Cytogenetic studies on bone marrow samples were performed at baseline and repeated every 3 months in responding patients. Safety assessments included evaluation of adverse events, hematologic assessment, biochemical testing, urinalysis, cardiac enzyme assessment, serial electrocardiogram evaluation, and physical examination. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. Survival was dated from start of nilotinib therapy until death from any cause and censored at last follow-up for patients who were alive. Duration of major cytogenetic response was measured from date of response until the date treatment was discontinued for progression or death. Patients who discontinued for other reasons were censored at date of last treatment and patients still on treatment at data cut-off date.

The study was conducted in accordance with the Declaration of Helsinki. The study protocol was reviewed and approved by the ethics committees or institutional review boards of all participating centers. All patients gave written informed consent according to institutional guidelines.

Assessment of BCR-ABL mutation status

Peripheral blood samples were obtained prior to the first dose of nilotinib. The total blood RNA was reversely transcribed and amplified by nested polymerase chain reaction (PCR) using primers located in the BCR and ABL regions of the BCR-ABL gene. The amplicons that extend over the entire Bcr-Abl tyrosine kinase domain (ranging from amino acid 230-490; GenBank accession no. M14752) and the surrounding regions, were then screened for mutations by direct sequencing technology. This BCR-ABL mutation analysis was performed by 5 regional academic laboratories. All 5 laboratories reported reliable detection of mutant clones present at a frequency of 20% or higher.

Statistical considerations

The primary efficacy variable of this study was the overall major cytogenetic response. Secondary efficacy variables included time to major cytogenetic response, duration of major cytogenetic response, CHR, time to and duration of CHR, and overall survival. Response rates were calculated as percentages relative to the respective patient populations. For major cytogenetic response and CHR, 95% confidence intervals (CIs) using Clopper-Pearson limits were determined. Time-to-event variables were summarized and are presented using the Kaplan-Meier method. A Fleming single-stage design was used to test the null hypothesis that the rate of major (complete + partial) cytogenetic response was 10% or less, versus the alternative hypothesis that the true response rate was 20% or more. A minimum of 132 patients were required (assuming a one-sided P = .025; power 0.90). A response rate of 21 or more out of 132 would be sufficient to reject the null hypothesis. Because of the activity of the agent, overenrollment on the study was allowed to offer more patients in need of alternative options after imatinib failure access to nilotinib therapy.


A total of 318 patients were enrolled in the study between April 2005 and August 2006, and were treated at 63 centers from 15 countries. Results are presented for the initial cohort of 280 patients with at least 6 months of follow-up or those who prematurely discontinued study treatment. Patient characteristics are shown in Table 1. Their median age was 58 years (range, 21 to 85 years). Patients had received extensive prior therapy: 66% had received interferon-α, 83% had received hydroxyurea, and 25% had received cytarabine. The median duration of CML was 57 months; the median duration of prior imatinib therapy was 32 months. A total of 194 (69%) patients had imatinib resistance, and 86 (31%) patients had imatinib intolerance.

Table 1

Characteristics of the study group

The median cumulative duration of nilotinib dose interruptions was low (18 days; range, 1-185 days) relative to the median duration of therapy (261 days; range, 1-502 days). The median duration of exposure for the 318 patients enrolled was 245 days. The median dose intensity of nilotinib was 797 mg/day (range, 151-1112 mg/day), very close to the intended total daily nilotinib dose of 800 mg per day.

As of September 2006, 183 (65%) patients remain on study. Reasons for discontinuation, regardless of causality, included adverse events in 42 (15%) patients, disease progression in 32 (11%) patients, consent withdrawal in 10 (4%) patients, and other reasons in 4% (including abnormal laboratory test [n = 5], death [n = 2], administrative problems [n = 3], loss of follow-up [n = 1], and protocol violations [n = 3]). A total of 17 (6%) patients required discontinuation from study for cytopenia (neutropenia in 9 patients, thrombocytopenia in 8 patients).


Overall, a major cytogenetic response was achieved in 134 of 280 patients (48%; 95% CI, 41.9%-53.9%). Table 2 details the response rates. Rates of major cytogenetic response were 48% (95% CI, 41.2%-55.7%) in patients with imatinib intolerance and 47% (95% CI, 35.7%-57.6%) in patients with imatinib resistance. Complete cytogenetic response was achieved in 88 patients (31%; 95% CI, 26.0%-37.2%). A total of 30 of the 134 patients with major cytogenetic response were categorized based only on FISH evaluations (12 complete cytogenetic responses, 18 partial cytogenetic responses). While there is excellent concordance between conventional and FISH analyses in patients achieving complete cytogenetic response, the concordance rate for partial cytogenetic response is good. If the 18 partial cytogenetic responses are not considered, 116 (41%) of 280 patients would be considered to have achieved a major cytogenetic response with nilotinib therapy. In addition, 5 patients entered the study with a complete cytogenetic response and maintained their response in the study; another 3 patients entered the study in partial cytogenetic response and also maintained their response in the study; and 3 patients had missing baseline assessment but achieved complete cytogenetic response during the study. Therefore, another 11 (4%) patients had documentation of major cytogenetic response during the study. The median time to major cytogenetic response was 2.8 months. Among patients achieving major cytogenetic response, 96% continued on nilotinib without progression or death for at least 6 months from the date of achieving their response (Figure 1). Only 5 (4%) patients in major cytogenetic response discontinued nilotinib due to progression or death (Figure 1). A further 16 (12%) patients in major cytogenetic response lost their major cytogenetic response but were still on treatment at data cut-off. The estimated 12-month overall survival rate was 95% (Figure 2). A CHR, assessable in 185 patients without CHR at baseline, occurred in 74% (95% CI, 67.1%-80.2%) of patients. Complete hematologic responses occurred early (median time to CHR, 1 month). Only 11 (8%) of the 137 patients who had achieved CHR discontinued due to progression or death.

Table 2

Clinical responses (N=280)

Figure 1

Duration of major cytogenetic response with nilotinib. Only 5 (4%) of the 134 patients who had achieved major cytogenetic response discontinued due to progression or death.

Figure 2

Overall survival in the 280 patients treated with nilotinib. A total of 10 (4%) patients died; 2 during treatment, 8 during long-term follow-up.

Baseline assessment for the BCR-ABL mutation status was available in 182 patients at the time of analysis. A total of 28 different BCR-ABL mutations involving 23 amino acids were detected in 42% of the patients (77 of 182 patients), 8% of whom (6 of 77 patients) showed more than 1 mutation. After 6 months of therapy, major cytogenetic response was achieved in 42% of patients and complete cytogenetic response was achieved in 23% of patients with baseline mutations, versus in 51% and 35% of patients without baseline mutations (Table 3). Among patients who did not have CHR at baseline, the rate of CHR at 6 months was 61% and 83% in patients with or without baseline mutations, respectively. Major cytogenetic response and CHR were observed across all BCR-ABL genotypes, with the exception of the T315I mutation identified in 4 (2.2%) of 182 patients, and the E255V and E274K mutation each identified in 1 (0.6%) of 182 patients (Table 3). However, both the E255V and E274K mutations coexisted with a T315I mutation at baseline in these 2 patients. There were 2 patients with a L248V mutation who were not assessable for hematologic and cytogenetic responses.

Table 3

Baseline BCR-ABL mutation status and response to nilotinib

Although responses were observed broadly across the mutation spectrum, the rate of responses appeared to be affected by the types of mutations identified in patients and their sensitivity to nilotinib as assessed in vitro. Major cytogenetic response and CHR were achieved in 53% (16 of 30) and 77% (17 of 22) of patients with mutations associated with preclinical IC50 to nilotinib of less than 100 nM18 (Table 3; mutation group 1), in 43% (6 of 14) and 50% (6 of 12) of patients with IC50 of 101 to 200 nM (Table 3; mutation group 2), and in 15% (2 of 13) and 18% (2 of 11) of patients with IC50 of 201 to 800 nM (Table 3; mutation group 3), respectively. Mutation group 4 (IC50 > 800 nM), which only includes T315I in 4 patients, showed no hematologic and cytogenetic responses.

Safety profile

Adverse events with a suspected relationship to nilotinib are summarized in Table 4. These were generally mild to moderate in severity. The most commonly reported nonhematologic events considered possibly related to nilotinib, and of any grade severity, were rash (28%), nausea and pruritus (24% each), and headache and fatigue (19% each). Grade 3 or 4 toxicities were noted in 3% or less of patients (Table 4). Clinically notable adverse events reported with other Bcr-Abl inhibitors, such as pleural effusions, pericardial effusions, pulmonary edema, and left ventricular dysfunction,23 were rarely observed with nilotinib (3 [1.1%] patients, all grades 1–2).

Table 4

Most frequent (5% or more) nonhematologic adverse events associated with nilotinib

The most commonly reported grade 3 or 4 hematologic abnormalities were neutropenia (29%) and thrombocytopenia (29%), with median durations of 15 and 22 days, respectively. Neutropenia and thrombocytopenia were generally manageable with dose interruptions and reductions, which were necessitated in 10% and 19% of patients, respectively. Patients only occasionally required support with hematopoietic growth factors (5%) or platelet transfusions (10%).

The majority of serum biochemistry abnormalities observed with nilotinib were mild to moderate in severity. Grade 3 or 4 elevations in AST and ALT occurred in 1% and 4% of patients, respectively. Grade 3 or 4 bilirubin and lipase elevations occurred in 9% and 14% of patients, respectively. These were self-limited and resolved spontaneously, with continuation of nilotinib at the same dose, within 1 to 2 weeks. Pancreatitis was reported in 3 (1%) patients.

The nonhematologic reasons for imatinib intolerance are presented in Table 5. Cross-intolerance, defined as the occurrence of any grade 3 or higher nilotinib-induced toxicity previously reported in the same patient receiving imatinib, was infrequent, occurring in only 2 (2%) of 86 patients. Almost all imatinib-intolerant patients were able to tolerate therapy with nilotinib. Because of a preclinical signal indicating that nilotinib could potentially prolong the QT interval, frequent electrocardiograms were obtained during this study and analyzed centrally. The effect of nilotinib at steady-state (day 8) on the QTcF interval, measured as a time-averaged mean change from baseline in QTcF (Fridericia15 correction), was 5 milliseconds. Categoric, or outlier analysis of serial electrocardiograms, measuring the number of absolute QTcF intervals exceeding 500 milliseconds, showed an incidence of 1% (3 of 280 patients).

Table 5

Comparison of nonhematologic adverse events observed in imatinib-intolerant patients treated with nilotinib

A total of 4 deaths occurred in the study, or within 28 days of discontinuing nilotinib; 1 patient had a myocardial infarction, another died of coronary artery disease, and 2 patients died of sepsis.

Overall, nilotinib was well tolerated as demonstrated by the high dose intensity achieved.


Nilotinib, a highly selective and potent Bcr-Abl inhibitor, was very active and safe in this phase 2 study of patients with CML-CP post-imatinib resistance and intolerance. Major cytogenetic response, which correlated with long-term survival and clinical benefit,5,6 was observed in 48% of patients. Complete cytogenetic responses were noted in 31% of patients. Dasatinib given to patients with CML-CP post-imatinib failure produced a major cytogenetic response rate of 45% at 6 months, and a complete cytogenetic response rate of 33%.11 With nilotinib, the estimated 1-year overall survival rate was 95% (Figure 1). The estimated percent of patients who achieved a major cytogenetic response and who did not discontinue nilotinib due to progression or death for at least 6 months after achievement of response was 96% (Figure 2). Similar rates of major cytogenetic response were observed in imatinib-resistant and -intolerant patients. This is likely due to the rigorous definition of imatinib intolerance, which excluded imatinib-intolerant patients who had achieved a prior major cytogenetic response (thus, the imatinib-intolerant patients had also relatively less sensitive disease). Among the 134 of 280 patients who achieved a major cytogenetic response, the response was documented only by FISH analysis in 30 patients (12 complete cytogenetic responses, 18 partial cytogenetic responses). Excluding the 18 partial cytogenetic responses documented by FISH, the major cytogenetic response rate with nilotinib would be 41%.

Mutations in BCR-ABL are a known mechanism of resistance to imatinib. In this study, 28 different BCR-ABL mutations affecting 23 amino acids were noted in 42% of patients prior to nilotinib therapy. CHR and/or cytogenetic response (major, complete) were observed in patients harboring a variety of BCR-ABL mutations associated with imatinib resistance as well as in imatinib-resistant patients without BCR-ABL mutation. The rates of major cytogenetic response at 6 months were 42% and 51% in patients with and without baseline mutations, respectively. As predicted by preclinical data,18 none of the 4 patients with baseline T315I mutation had either CHR or major cytogenetic response during the nilotinib therapy. Thus, nilotinib was effective in patients with BCR-ABL mutations, except T315I, as well as in patients with other mechanisms of resistance independent of BCR-ABL mutations, demonstrating its clear therapeutic role in patients with imatinib resistance.

Although responses were observed in all genotypes except T315I, patients with BCR-ABL mutations that showed higher in vitro sensitivity against nilotinib (cellular IC50 ≤ 200 nM)18 appeared to have better rates of response than patients with less sensitive mutations (cellular IC50 of 201–800 nM; Table 3). These less sensitive mutant clones (described by Weisberg et al18 as having IC50 values of ≥ 200 nM) showed complete in vitro suppression with increased exposure of nilotinib. With nilotinib plasma peak-trough levels of 3600 to 1700 nM at a 400-mg twice-daily dose, it is possible that longer treatment duration may result in further improvement in clinical responses in patients with less sensitive mutations.

In this study, nilotinib was rarely associated with the common toxicities seen with imatinib (eg, fluid retention, edema, cramps, periorbital edema, and weight gain). Commonly noted side effects included mild skin rash, headache, and nausea. Serious grades 3 to 4 nonhematologic side effects were uncommon. Pleural effusions, observed in 10% to 35% of patients on dasatinib11,23 were observed in only 1% of patients with nilotinib therapy. Peripheral edema, reported in 20% to 30% of patients on imatinib3,6 and in 18% of patients on dasatinib,11 was rarely observed in patients on nilotinib. Although nilotinib and imatinib are chemically similar, the minimal occurrence of cross-intolerance between the 2 agents represents also an interesting and important therapeutic advantage (Table 5).

With nilotinib therapy, neutropenia and thrombocytopenia were modest in severity and infrequently required growth factor support or platelet transfusions. Grades 3 to 4 neutropenia and thrombocytopenia were each reported in 29% of patients. Myelosuppression was the most common adverse event (4%) leading to permanent nilotinib discontinuation. With dasatinib, the rates of grades 3 to 4 neutropenia (49%) and thrombocytopenia (47%) patients with CML-CP after imatinib intolerance and resistance were higher.11 It has been postulated that a more potent inhibitor of Bcr-Abl may contribute to increased myelosuppression from rapid clearance of BCR-ABL expressing malignant hematopoietic cells. Interestingly, despite the greater potency of nilotinib relative to imatinib, the rates of grades 3 to 4 neutropenia and thrombocytopenia in this heavily pretreated population were comparable with those reported in imatinib-treated patients with late CML-CP who were previously treated with interferon-α. Thus, the selectivity of nilotinib against Bcr-Abl (relative to other targets, such as Src-family or c-Kit kinases) may account for the high level of efficacy unaccompanied by higher rates of severe myelosuppression. Nilotinib was well tolerated in this study as demonstrated by the high dose intensity achieved. In contrast, the median dose delivered in the dasatinib studies was about two-thirds of the intended dose (median daily dose delivered was 101 mg; the intended daily dose was 140 mg).11

Drug-induced effects on the QT interval are often difficult to accurately assess in patients given the inherent variability around this parameter and the lack of available age- and disease-matched controls providing information on the background incidence of these findings in similar populations. The QT interval results observed in this study were consistent with those observed in similar imatinib-resistant and -intolerant patients with CML treated with dasatinib (pooled analysis of 5 CML studies showed a mean change from baseline in QTcF of 3 to 6 milliseconds; QTcF interval of more than 500 milliseconds observed in 0.7% of patients).

Clinically significant abnormalities in nonhematologic laboratory parameters were infrequent. The most commonly observed biochemical abnormality was hyperbilirubinemia, followed by transient elevations in ALT, AST, and serum lipase. Indirect hyperbilirubinemia, mostly grade 2 or lower severity, was self-limited and reversed spontaneously with continued nilotinib therapy at the same dose. The etiology of hyperbilirubinemia was explored by examining polymorphisms in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in 62 patients in the study. Results suggested that the TA repeat polymorphism in UGT1A1, which predisposes to Gilbert syndrome, predicted for the susceptibility to nilotinib-induced hyperbilirubinemia. Therefore, it appears that the administration of nilotinib unmasked a clinically benign form of indirect hyperbilirubinemia, which was self-limited, resolving with continued therapy.

In summary, nilotinib is highly active and safe, and provides an alternative effective treatment for patients whose disease becomes resistant or intolerant to imatinib. Nilotinib is also being studied in newly diagnosed CML, where the goal is to prevent the emergence of mutant clones, which may confer clinical benefit over that of the current standard of care, imatinib.


Contribution: H.K. designed research, performed research, analyzed data, and wrote the paper. F.G., N.G., K.B., G.A., F.P., G.J.O, F.-E.N., S.G.O'B., M.L., R.B., F.C., and P.le.C. performed research. A. Hochhaus performed research and conducted mutation analysis. A. Haque analyzed data. Y.S. conducted mutation data analysis. D.J.R. wrote paper. A.W. analyzed data and wrote the paper.

Conflict-of-interest disclosure: P.le.C., received a research grant and honoraria from Novartis. F.-E.N. received lecture fees from Novartis; F.G. received research support from Novartis and Bristol-Meyers-Squibb (BMS); H.K. received research support from Novartis and BMS; F.C. received research support from Novartis and the Novartis Advisory Board; A. Hochhaus received research support from Novartis and BMS; N.G. received research support from Novartis; K.B. received research support and a research grant from Novartis; S.G.O'B. received research funding from Novartis, BMS, and Roche; R.B. received research support from Novartis; A. Haque, Y.S., D.J.R., and A.W. are employed by Novartis.

Correspondence: Hagop Kantarjian, Department of Leukemia, Unit 428, The University of Texas M. D. Anderson Cancer Center, P. O. Box 301402, Houston, TX 77230-1402; e-mail: hkantarj{at}


This work was supported by research funding from Novartis Pharmaceuticals.


  • The online version of this article contains a data supplement.

  • The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

  • Submitted March 19, 2007.
  • Accepted July 27, 2007.


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