Background Resistance to imatinib mesylate can occur in chronicmyelogenous leukemia (CML). Preclinical in vitro studies haveshown that nilotinib (AMN107), a new BCR-ABL tyrosine kinaseinhibitor, is more potent than imatinib against CML cells bya factor of 20 to 50.
Methods In a phase 1 dose-escalation study, we assigned 119patients with imatinib-resistant CML or acute lymphoblasticleukemia (ALL) to receive nilotinib orally at doses of 50 mg,100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg once dailyand at 400 mg and 600 mg twice daily.
Results Common adverse events were myelosuppression, transientindirect hyperbilirubinemia, and rashes. Of 33 patients withthe blastic phase of disease, 13 had a hematologic responseand 9 had a cytogenetic response; of 46 patients with the acceleratedphase, 33 had a hematologic response and 22 had a cytogeneticresponse; 11 of 12 patients with the chronic phase had a completehematologic remission.
Conclusions Nilotinib has a relatively favorable safety profileand is active in imatinib-resistant CML. (ClinicalTrials.govnumber, NCT00109707
[ClinicalTrials.gov]
.)
The chimeric BCR-ABL gene, created by the formation of the Philadelphiachromosome (Ph), encodes a fusion protein, BCR-ABL. The unregulatedactivity of the ABL tyrosine kinase in BCR-ABL is the causeof chronic myeloid leukemia (CML). Imatinib mesylate, an inhibitorof the BCR-ABL tyrosine kinase, improves the outcome in CML.1,2However, the annual progression rate during treatment of chronic-phaseCML with imatinib is 4 percent.3 Imatinib is active alone orin combination in newly diagnosed Ph-positive acute lymphoblasticleukemia (ALL).4,5,6,7
Nilotinib (AMN107, Novartis) is a new, orally active, aminopyrimidine-derivativetyrosine kinase inhibitor that is more potent against CML cellsin vitro than is imatinib.8,9,10,11,12 Like imatinib, nilotinibfunctions through competitive inhibition at the ATP-bindingsite of BCR-ABL, leading to the inhibition of tyrosine phosphorylationof proteins that are involved in the intracellular signal transductionthat BCR-ABL mediates. Nilotinib has a higher binding affinityand selectivity for the ABL kinase than does imatinib. It alsohas 20 to 50 times the inhibitory activity of imatinib in imatinib-sensitiveCML cell lines and 3 to 7 times the activity in imatinib-resistantcell lines. Nilotinib was also active in 32 of 33 imatinib-resistantcell lines with mutant ABL kinases.8,9,10,11,12 This reportsummarizes the results of a phase 1 dose-escalation study ofnilotinib in patients with CML and Ph-positive ALL whose diseasewas resistant to imatinib.
Methods
Patients
Patients with Ph-positive imatinib-resistant CML or ALL wereeligible. Accelerated and blastic phases of CML were definedas previously described.13,14,15,16 Patients with a plateletcount of 800,000 per cubic millimeter or more or with clonalevolution were also considered to have the accelerated phaseof disease. Clonal evolution was defined by the presence ofadditional chromosomal abnormalities in the Ph-positive cells,excluding variant Ph translocations, a loss of chromosome Y,or constitutional abnormalities.13,14 Patients with only clonalevolution have a better prognosis and were analyzed separately.17Patients with imatinib-resistant chronic-phase CML were enrolledin the study after the first four dose cohorts. Imatinib resistancewas defined as a lack of complete hematologic response after3 months of imatinib treatment, a lack of any cytogenetic response(Ph-positive cells, >95 percent) after 6 months of treatment,a lack of a substantial cytogenetic response (Ph-positive cells,>35 percent) after 12 months of treatment, or a relapse aftera hematologic response or a substantial cytogenetic response.
Patients had to be at least 18 years of age and have an adequateperformance status and normal hepatic, renal, and cardiac function.Patients who had received imatinib therapy seven days beforeor hydroxyurea two days before the study began were not eligibleto participate. The study was conducted in accordance with theDeclaration of Helsinki. Patients gave written informed consent,according to institutional guidelines. The study was approvedby the institutional review board at each study center.
Study Design and Therapy
The study was designed to evaluate the safety and tolerabilityof nilotinib. Patients were successively assigned to one ofnine dose cohorts, ranging from 50 to 1200 mg once daily andfrom 400 to 600 mg twice daily. Patients received nilotinibdaily unless unacceptable adverse events or disease progressionoccurred. Dose escalation (not exceeding two dose levels beyondthe level administered to newly enrolled patients) was permittedfor patients with an inadequate response and no prohibitivetoxic effects. Patients who had been treated at lower doseshad the option to receive higher doses, with escalation to alevel that was declared safe. During the first cycle of therapyor at times of worsening disease before intrapatient dose escalation,patients were allowed to receive cytoreductive therapy (leukapheresesand hydroxyurea) to control elevated counts of blasts, platelets,or both. Responses in patients requiring leukapheresis or hydroxyureaconcurrently with nilotinib could not be evaluated. The selectionof the dose and the determination of the maximum dose that wastolerated followed a continuous modified reassessment method,18described in the Supplementary Appendix (available with thefull text of this article at www.nejm.org).
The academic investigators and representatives of the sponsor,Novartis, designed the study and collected and analyzed thedata. Drs. Kantarjian and Alland, who wrote the article withhelp from all the authors, vouch for the accuracy and completenessof the data and the analysis. All data were available to allinvestigators.
Assessment of Toxic Effects and Response
Complete blood counts and biochemical analysis were obtainedweekly for the first eight weeks and then every other week.Bone marrow assessments were done on days 15 and 28 of the firstcycle and on day 28 of every even-numbered cycle. Patients wereevaluated for cytogenetic response at baseline and in repeatedanalyses if they had a response. Safety assessments includedan evaluation of adverse events, hematologic and cardiac-enzymeassessment, biochemical testing, urinalysis, electrocardiography,and physical examination.
Toxic effects were graded according to the National Cancer Institute'sCommon Terminology Criteria for Adverse Events (version 3.0).Criteria with respect to hematologic and cytogenetic responseshave been described previously.1,16,17,19,20,21 Cytogeneticresponses were as follows (percentages refer to the percentageof Ph-positive metaphases): complete response, 0 percent; partialresponse, 1 to 35 percent; minor response, 36 to 65 percent;and minimal response, 66 to 95 percent.16 Response criteriaamong patients with Ph-positive ALL were described previously.5,20
Other Analyses
Patients were evaluated for the inhibition of biomarker phosphorylation,the mutational status of BCR-ABL, and Gilbert's syndrome. Themethods used in these analyses are detailed in the Supplementary Appendix.
Results
Patients
At three centers, from May 25, 2004, to May 4, 2005, we enrolled119 patients whose disease was resistant to imatinib. The patientswere assigned to receive daily doses of nilotinib accordingto the following dosing schedule: 50 mg (7 patients), 100 mg(7), 200 mg (10), 400 mg (10), 600 mg (6), 800 mg (19), and1200 mg (10) or to receive 400 mg twice daily (32) or 600 mgtwice daily (18). The characteristics of patients are shownin Table 1. As of June 15, 2005, 66 patients remained in thestudy, including all 17 patients with chronic-phase CML. Reasonsfor discontinuation included adverse events (8 patients), deathduring the study period (5), disease progression (35), and withdrawalof consent (5). Four patients who withdrew their consent underwenthematopoietic stem-cell transplantation.
The median time to peak concentrations of nilotinib was threehours after administration, and the mean peak concentrationwas 3.6 µM at steady state among patients receiving 400mg twice daily. The apparent half-life of the drug was 15 hours.The steady-state level was achieved by day 8. The steady-stateserum level of the drug was two to three times the level measuredafter the first dose. With the administration of daily dosesat the steady-state level, the peak concentration and the areaunder the concentration–time curve increased among patientsreceiving 50 to 400 mg of the drug and reached a plateau amongpatients receiving more than 400 mg. Considering that saturationmay have been caused by gastrointestinal absorption, the dosewas reduced to 400 mg twice daily and then was further escalatedto 600 mg twice daily. Exposure at the steady-state level wasgreater with 400 mg twice daily than with a daily dose of 800mg, and there was a dose-proportional increase in exposure between400 mg twice daily and 600 mg twice daily (Figure 1).
Figure 1. Total Steady-State Serum Levels of Nilotinib, According to the Daily Dose.
The graph shows the area under the concentration–time curve (AUC) during the first 24 hours after the first dose of nilotinib was administered, according to the total amount of drug patients received either once or twice daily. The points represent the mean levels of the drug, and the I bars represent the standard deviations. The total number of patients in whom levels were tested were as follows: 50 mg daily (3 patients), 100 mg daily (4 patients), 200 mg daily (3 patients), 400 mg daily (8 patients), 600 mg daily (4 patients), 800 mg daily (18 patients), and 1200 mg daily (8 patients), as well as 400 mg twice daily (30 patients) and 600 mg twice daily (18 patients).
The mean serum trough level at the steady-state level was 1.0µM at 400 mg daily, 1.7 µM at 400 mg twice daily,and 2.3 µM at 600 mg twice daily. All trough levels exceededthe 50 percent inhibitory concentration of cellular phosphorylationof BCR-ABL (20 to 57 nM, depending on cell type) and 32 of 33BCR-ABL kinase mutants (19 to 709 nM).12
Safety Profile
No dose-limiting toxic effects were seen at doses of up to 600mg daily. Dose-limiting toxic effects occurred among 18 patientsat doses higher than 600 mg. Such effects included an elevationin bilirubin level (predominantly grade 3), mostly indirectbilirubin (nine patients); a grade 3 elevation in the aminotransferaselevel (three patients); a grade 4 elevation in the lipase level(one patient); a grade 3 or 4 elevation in amylase and lipaselevels (two patients, one of whom had grade 2 pancreatitis);grade 4 hematologic toxic effects (two patients); and a grade3 subdural hematoma (one patient). The method of continuousmodified reassessment indicated that 600 mg administered twicedaily is the maximum tolerated dose. (The posterior probabilityof dose-limiting toxicity was 0.30, which is discussed in theSupplementary Appendix.)
Table 2 presents a list of adverse events with an incidenceof at least 4 percent that were potentially associated withnilotinib. Thrombocytopenia (21 percent) and neutropenia (14percent) were mainly grade 3 or 4 and appeared to increase withincreasing doses of the drug. Pruritus, rash, and dry skin werealmost exclusively grade 1 or 2. When all categories of rashwere combined, there appeared to be a dose-related increasein incidence.
Table 2. Adverse Events Reported by at Least 4 Percent of Patients.
Grade 3 elevations in levels of alanine aminotransferase andaspartate aminotransferase were infrequent and observed at dailydoses of 600 mg or more. Elevations in total, conjugated, andunconjugated bilirubin levels accounted for 14 percent of adverseevents. These increases were primarily in unconjugated bilirubinand were not accompanied by an increase in levels of aminotransferaseor evidence of increased hemolysis; the increased levels oftenoccurred during the first week of therapy. The frequency andgrade of elevation in bilirubin levels increased with increasingamounts of nilotinib. Elevations frequently resolved spontaneouslywith continued administration of nilotinib. There was a positivecorrelation (P=0.009) between the presence of the (TA)7/(TA)7sequence in the promoter regions of the gene encoding bilirubinuridine diphosphoglucuronate (UDP) glucuronosyltransferase 1A1,a genotype associated with Gilbert's syndrome,22 and the incidenceof grade 3 or 4 elevations of total bilirubin levels, as wellas a higher mean level of bilirubin. Among 14 patients withGilbert's syndrome, 7 had elevations in bilirubin levels, ascompared with 10 of 97 patients who did not have the syndrome.
A grade 3 elevation in the amylase level was reported in onepatient, and six patients had grade 3 or 4 elevations in lipaselevels; of those six patients, three reported having abdominalpain. One of these patients (with a history of pancreatitis)had grade 2 pancreatitis. Among patients with available laboratorydata, grade 3 or 4 elevations in lipase levels were seen in9 of 55 patients (16 percent), and grade 3 elevations in amylaselevels were seen in 3 of 57 patients (5 percent). All the increasedlevels were observed at daily doses of 600 mg or more.
In an exploratory analysis of more than 2200 electrocardiogramsfrom 119 patients, the only abnormality associated with nilotinibwas in the corrected QT interval by Fridericia's formula (QTcF),which appeared to increase by 5 to 15 msec in the study group.One patient had two adverse cardiac events associated with nilotinib,which included pericardial effusion (grade 1) and atrial fibrillation(grade 2), with no elevation in cardiac enzymes.
After the data cutoff for our study, two study patients diedunexpectedly. One patient was a 30-year-old man with CML incomplete remission; an autopsy confirmed an overdose of methadone.The other patient was a 56-year-old man with CML in an acceleratedphase; there was no autopsy, and the cause of death was unknown.
Response
All patients in our study had disease that was resistant toimatinib. Overall, of 33 patients with the blastic phase, 13had a hematologic response to nilotinib (39 percent) (Table 3)and 9 patients (27 percent) had a cytogenetic response, 6 ofwhom had a major cytogenetic response (Ph-positive cells inmetaphase, 35 percent). Of 46 patients with accelerated-phaseCML (excluding those with clonal evolution only), 33 had a hematologicresponse; 22 had a cytogenetic response, and 9 of those responseswere major. Among the 10 patients who had clonal evolution asthe only feature of the accelerated phase of CML, 5 had activedisease and 5 were in complete hematologic remission. All 5patients with clonal evolution and hematologic disease had acomplete hematologic response; 6 of 10 had a major cytogeneticresponse (Table 3).
Table 4 shows the results in patients who had accelerated orblastic phases of disease who had a dose escalation owing toinadequate response at the initial dose level. Overall, 13 of23 patients who were initially treated at daily doses of 50to 400 mg had hematologic responses when they received 600 mgdaily or 400 mg twice daily. At once-daily doses of 600 mg ormore, less than 10 percent of patients required a dose escalation.Response rates at the twice-daily doses of 400 and 600 mg weresimilar.
Table 4. Dose Escalation and Hematologic Response in Patients with Accelerated and Blastic Phases of Disease.
Among 17 patients with the chronic phase of disease, the medianduration of therapy was 4.9 months (range, 1.4 to 9.3), andall of the patients have continued therapy. At the present time,11 of 12 patients with active disease have had a complete hematologicremission. There were cytogenetic responses in 9 of 17 patientswho could be evaluated, including 6 responses that were complete(Table 3). Complete cytogenetic responses were noted in 3 of12 patients who had hematologic disease at baseline and in 3of 5 patients who were in complete hematologic remission atthe start of therapy (Table 5).
Table 5. Response to Nilotinib among Patients with Chronic-Phase CML, According to the Starting-Dose Cohort.
One of 10 patients with Ph-positive ALL (hematologic relapse)had a partial hematologic response, and 1 of 3 patients withPh-positive ALL and persistent molecular signs of ALL had acomplete molecular remission.
Signaling Molecules
Phosphorylation of AKT, CRKL, STAT1, and STAT5 in all cellswas compared at baseline and on day 15 in patients in blasticand accelerated phases of disease whose leukemic cells had phosphorylationof these proteins at baseline and who received 400 or 600 mgof nilotinib twice daily. In all four signaling molecules, therewas significantly decreased phosphorylation on day 15 of nilotinibtreatment, as compared with that at baseline after adjustmentfor multiple testing (overall significance level for all comparisons,0.05). (See the section entitled "Assessment of Biomarker Inhibition"in the Supplementary Appendix.)
ABL Mutations and Response to Nilotinib
In about 50 percent of samples, a duplicate baseline samplewas available for confirmatory analysis of ABL mutations byan academic laboratory; the concordance was 100 percent betweenthe central and academic laboratories. A total of 51 ABL mutationswere observed in 37 of 91 patients who had a baseline assessmentfor mutational status. Nilotinib was active in patients withand in those without mutations, but there were no significantdifferences in the response rates between the two groups. (Seethe section entitled "Assessment of BCR-ABL Mutational Status"in the Supplementary Appendix.) Two patients with a T315I mutation(one with chronic-phase CML and one with blastic-phase CML)had no response to nilotinib.
Discussion
This phase 1 study of nilotinib defined the dose-limiting toxiceffects and the maximum tolerated dose of the drug. We alsoreport adverse events associated with treatment and an assessmentof the activity of nilotinib in imatinib-resistant CML. We foundthat nilotinib has activity in imatinib-resistant CML, includingin cases with mutations in the gene that encodes the ABL kinasethat cause imatinib resistance.8,9,10,11,12
Imatinib therapy has side effects that can be dose-limitingin 10 percent of patients.23 In this study, nilotinib was notassociated with the common toxic effects seen with imatinib(e.g., fluid retention, edema, and weight gain) or with pleuraleffusions. Frequently noted side effects of nilotinib were mild-to-moderaterashes; transient, clinically insignificant elevations of indirectbilirubin levels; and myelosuppression, which was dose-relatedand dose-limiting. The method of continuous modified reassessmentselected the twice-daily dose of nilotinib of 600 mg as themaximum tolerated dose, but the value of lower doses shouldbe explored, since the 400-mg twice-daily dose appeared to havea response rate similar to that of the 600-mg twice-daily doseand had a better safety profile. The incidence of grade 3 or4 neutropenia was 22 percent with 600 mg twice daily and 9 percentwith 400 mg twice daily; the incidence of increased indirectbilirubinemia was 11 percent with 600 mg twice daily and 3 percentwith 400 mg twice daily. The recommended dose of nilotinib forphase 2 studies is 400 mg twice daily, with possible dose escalationto 600 mg twice daily in patients with an inadequate response.
Nilotinib has a serum half-life of 15 hours and thus was initiallygiven as a single daily dose. However, saturation of serum levelswas observed with this schedule at doses ranging from 400 to1200 mg daily. When the schedule was modified to a twice-dailyregimen, there were increases of 50 to 80 percent in peak serumlevels and in levels in the area under the concentration–timecurve at the same total daily dose of nilotinib (Figure 1).At a steady-state level of twice-daily doses of 400 mg and 600mg, there was a significant reduction in phosphorylation ofAKT, CRKL, STAT1, and STAT5, as compared with levels at baseline.
The rates of hematologic response in patients with resistanceto imatinib were 75 percent for patients with the acceleratedphase and 39 percent for those with the blastic phase. Cytogeneticresponse rates in these two phases were 55 percent and 27 percent,respectively. The rate of complete hematologic response in patientswith chronic-phase CML was 92 percent, and the rate of completecytogenetic response was 35 percent. The disease of all thesepatients was resistant to imatinib (median dose, 800 mg).
Mutations in the gene that encodes the ABL kinase, a mechanismof resistance to imatinib, were noted in 45 percent of patients.In this study, response rates were similar in patients withand those without such mutations. Two patients with a mutationof T315I did not have a response to nilotinib, as predictedfrom preclinical studies.11,12 These findings suggest that nilotinibmay overcome mutation-associated resistance to imatinib.
Our results in patients with Ph-positive ALL who did not havea response to imatinib suggest that nilotinib has limited efficacyin this subgroup, since only 2 of 13 such patients had a responseto the drug. Therefore, nilotinib may have a limited role inpatients with Ph-positive ALL.
We found that nilotinib prolongs the QTcF interval in some patients.One unexplained sudden death was reported beyond the follow-uptime analysis. This finding indicates the need for careful monitoringfor cardiac events and arrhythmias in all patients who are receivingnilotinib and a strict avoidance of medications that may prolongthe QTcF interval.
In summary, nilotinib has a relatively favorable safety profile,and preliminary results obtained with a relatively short follow-upperiod indicate that the drug is active in CML. Phase 2 studiesof nilotinib and other BCR-ABL inhibitors, such as dasatinib,24are ongoing in patients with CML.
Supported by a grant from Novartis Pharmaceuticals.
Dr. Kantarjian reports having received lecture fees from Bristol-MyersSquibb and Novartis Pharmaceuticals and research grants fromBristol-Myers Squibb, Novartis Pharmaceuticals, and MGI Pharma;Dr. Giles, research grants from Bristol-Myers Squibb and NovartisPharmaceuticals; Dr. Bhalla, consulting fees and research grantsfrom Novartis Pharmaceuticals; Dr. Hochhaus, consulting feesand research grants from Novartis Pharmaceuticals, Bristol-MyersSquibb, and Roche and lecture fees from Novartis Pharmaceuticalsand Bristol-Myers Squibb; Dr. Griffin, consulting fees and researchgrants from Novartis Pharmaceuticals and research grants fromthe National Institutes of Health; Dr. Cortes, research grantsfrom Bristol-Myers Squibb and Novartis Pharmaceuticals; andDr. Ottmann, consulting fees from Novartis Pharmaceuticals.Drs. Tanaka, Manley, Mietlowski, Dugan, and Alland and Ms. Raeand Ms. Bochiniski report having an equity interest in NovartisPharmaceuticals and being employees of the company. No otherpotential conflict of interest relevant to this article wasreported.
Source Information
From the Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston (H.K., F.G., S.O., J.C.); J.W. Goethe Universität, Frankfurt, Germany (L.W., B.W., D.H., O.G.O.); Moffitt Cancer Center, Tampa, Fla. (K.B.); Novartis Pharmaceuticals, East Hanover, N.J. (C.T., P.M., P.R., W.M., K.B., M.D., L.A.); Quest Diagnostics, San Juan Capistrano, Calif. (M.A.); Fakultät fur Klinische Medizin Mannheim, Universität Heidelberg, Mannheim, Germany (A.H.); and the Department of Medical Oncology, Dana–Farber Cancer Institute, Boston (J.D.G.). Drs. Kantarjian and Giles contributed equally to this article.
Address reprint requests to Dr. Kantarjian at the Department of Leukemia, Unit 428, University of Texas M.D. Anderson Cancer Center, P.O. Box 301402, Houston, TX 77230-1402, or at hkantarj{at}mdanderson.org.
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Weisberg, E., Banerji, L., Wright, R. D., Barrett, R., Ray, A., Moreno, D., Catley, L., Jiang, J., Hall-Meyers, E., Sauveur-Michel, M., Stone, R., Galinsky, I., Fox, E., Kung, A. L., Griffin, J. D.
(2008). Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL- and mutant FLT3-expressing cells. Blood
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Carayol, N., Katsoulidis, E., Sassano, A., Altman, J. K., Druker, B. J., Platanias, L. C.
(2008). Suppression of Programmed Cell Death 4 (PDCD4) Protein Expression by BCR-ABL-regulated Engagement of the mTOR/p70 S6 Kinase Pathway. J. Biol. Chem.
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Kaune, K. M., Baumgart, M., Gesk, S., Mitteldorf, C., Baesecke, J., Glass, B., Haase, D., Siebert, R., Ghadimi, B. M., Neumann, C., Emmert, S.
(2008). Bullous Sweet Syndrome in a Patient With t(9;22)(q34;q11)-Positive Chronic Myeloid Leukemia Treated With the Tyrosine Kinase Inhibitor Nilotinib: Interphase Cytogenetic Detection of BCR-ABL- Positive Lesional Cells. Arch Dermatol
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(2008). An Intron-Derived Insertion/Truncation Mutation in the BCR-ABL Kinase Domain in Chronic Myeloid Leukemia Patients Undergoing Kinase Inhibitor Therapy. J. Mol. Diagn.
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(2008). Commentary: Novel Therapies for Cancer: Why Dirty Might Be Better. The Oncologist
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(2008). BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors. Blood
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Mayerhofer, M., Gleixner, K. V., Mayerhofer, J., Hoermann, G., Jaeger, E., Aichberger, K. J., Ott, R. G., Greish, K., Nakamura, H., Derdak, S., Samorapoompichit, P., Pickl, W. F., Sexl, V., Esterbauer, H., Schwarzinger, I., Sillaber, C., Maeda, H., Valent, P.
(2008). Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib. Blood
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le Coutre, P., Ottmann, O. G., Giles, F., Kim, D.-W., Cortes, J., Gattermann, N., Apperley, J. F., Larson, R. A., Abruzzese, E., O'Brien, S. G., Kuliczkowski, K., Hochhaus, A., Mahon, F.-X., Saglio, G., Gobbi, M., Kwong, Y.-L., Baccarani, M., Hughes, T., Martinelli, G., Radich, J. P., Zheng, M., Shou, Y., Kantarjian, H.
(2008). Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood
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(2008). Small Molecules: Big Changes in the Cancer Treatment Paradigm. Journal of Pharmacy Practice
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(2008). Karyotype at diagnosis is the major prognostic factor predicting relapse-free survival for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with imatinib-combined chemotherapy. haematol
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Marshall, H. M, Hammond, J. M
(2008). Treatment Options in Imatinib-Resistant Chronic Myelogenous Leukemia. The Annals of Pharmacotherapy
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(2008). Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia: On Target to Improve Outcome. Am Soc Clin Oncol Ed Book
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Rix, U., Hantschel, O., Durnberger, G., Remsing Rix, L. L., Planyavsky, M., Fernbach, N. V., Kaupe, I., Bennett, K. L., Valent, P., Colinge, J., Kocher, T., Superti-Furga, G.
(2007). Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood
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Cortes, J., Jabbour, E., Kantarjian, H., Yin, C. C., Shan, J., O'Brien, S., Garcia-Manero, G., Giles, F., Breeden, M., Reeves, N., Wierda, W. G., Jones, D.
(2007). Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood
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Kantarjian, H. M., Giles, F., Gattermann, N., Bhalla, K., Alimena, G., Palandri, F., Ossenkoppele, G. J., Nicolini, F.-E., O'Brien, S. G., Litzow, M., Bhatia, R., Cervantes, F., Haque, A., Shou, Y., Resta, D. J., Weitzman, A., Hochhaus, A., le Coutre, P.
(2007). 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. Blood
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Press, R. D., Galderisi, C., Yang, R., Rempfer, C., Willis, S. G., Mauro, M. J., Druker, B. J., Deininger, M. W.N.
(2007). A Half-Log Increase in BCR-ABL RNA Predicts a Higher Risk of Relapse in Patients with Chronic Myeloid Leukemia with an Imatinib-Induced Complete Cytogenetic Response. Clin. Cancer Res.
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(2007). How I treat chronic myeloid leukemia in the imatinib era. Blood
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(2007). Crystal Structure of the T315I Abl Mutant in Complex with the Aurora Kinases Inhibitor PHA-739358. Cancer Res.
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Nicolini, F. E., Hayette, S., Corm, S., Bachy, E., Bories, D., Tulliez, M., Guilhot, F., Legros, L., Maloisel, F., Kiladjian, J.-J., Mahon, F.-X., Le, Q.-H., Michallet, M., Roche-Lestienne, C., Preudhomme, C.
(2007). Clinical outcome of 27 imatinib mesylate-resistant chronic myelogenous leukemia patients harboring a T315I BCR-ABL mutation. haematol
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(2007). BCR-ABL Tyrosine Kinase Inhibitors for Chronic Myelogenous Leukemia. NEJM
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Pfeifer, H., Wassmann, B., Pavlova, A., Wunderle, L., Oldenburg, J., Binckebanck, A., Lange, T., Hochhaus, A., Wystub, S., Bruck, P., Hoelzer, D., Ottmann, O. G.
(2007). Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood
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Carew, J. S., Nawrocki, S. T., Kahue, C. N., Zhang, H., Yang, C., Chung, L., Houghton, J. A., Huang, P., Giles, F. J., Cleveland, J. L.
(2007). Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood
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(2007). No more transplantation in CML?. Blood
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Hehlmann, R., Berger, U., Pfirrmann, M., Heimpel, H., Hochhaus, A., Hasford, J., Kolb, H.-J., Lahaye, T., Maywald, O., Reiter, A., Hossfeld, D. K., Huber, C., Loffler, H., Pralle, H., Queisser, W., Tobler, A., Nerl, C., Solenthaler, M., Goebeler, M. E., Griesshammer, M., Fischer, T., Kremers, S., Eimermacher, H., Pfreundschuh, M., Hirschmann, W.-D., Lechner, K., Wassmann, B., Falge, C., Kirchner, H. H., Gratwohl, A., for the Schweizerische Arbeitsgemeinschaft fur Kli,
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(2007). Clearance of minimal residual disease after allogeneic stem cell transplantation and the prediction of the clinical outcome of adult patients with high-risk acute lymphoblastic leukemia. haematol
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(2007). MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825. Blood
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Martinelli, G., Soverini, S., Iacobucci, I., Baccarani, M.
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Radich, J. P.
(2007). The Biology of CML Blast Crisis. ASH Education Book
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(2007). Philadelphia Chromosome Positive Acute Lymphocytic Leukemia: A New Era of Challenges. ASH Education Book
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Kantarjian, H. M., Talpaz, M., Giles, F., O'Brien, S., Cortes, J.
(2006). New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance. ANN INTERN MED
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(2006). Contribution of ABL Kinase Domain Mutations to Imatinib Resistance in Different Subsets of Philadelphia-Positive Patients: By the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin. Cancer Res.
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Druker, B. J., Guilhot, F., O'Brien, S. G., Gathmann, I., Kantarjian, H., Gattermann, N., Deininger, M. W.N., Silver, R. T., Goldman, J. M., Stone, R. M., Cervantes, F., Hochhaus, A., Powell, B. L., Gabrilove, J. L., Rousselot, P., Reiffers, J., Cornelissen, J. J., Hughes, T., Agis, H., Fischer, T., Verhoef, G., Shepherd, J., Saglio, G., Gratwohl, A., Nielsen, J. L., Radich, J. P., Simonsson, B., Taylor, K., Baccarani, M., So, C., Letvak, L., Larson, R. A., the IRIS Investigators,
(2006). Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia. NEJM
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Fausel, C. A.
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(2006). Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.. NEJM
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(2006). Circumventing resistance to kinase-inhibitor therapy.. NEJM
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Mauro, M. J.
(2006). Defining and Managing Imatinib Resistance. ASH Education Book
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35 percent). Of 46 patients with accelerated-phase CML (excluding those with clonal evolution only), 33 had a hematologic response; 22 had a cytogenetic response, and 9 of those responses were major. Among the 10 patients who had clonal evolution as the only feature of the accelerated phase of CML, 5 had active disease and 5 were in complete hematologic remission. All 5 patients with clonal evolution and hematologic disease had a complete hematologic response; 6 of 10 had a major cytogenetic response (Table 3). 
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