Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia
Brian J. Druker, M.D., Moshe Talpaz, M.D., Debra J. Resta, R.N., Bin Peng, Ph.D., Elisabeth Buchdunger, Ph.D., John M. Ford, M.D., Nicholas B. Lydon, Ph.D., Hagop Kantarjian, M.D., Renaud Capdeville, M.D., Sayuri Ohno-Jones, B.S., and Charles L. Sawyers, M.D.
Background BCR-ABL is a constitutively activated tyrosine kinasethat causes chronic myeloid leukemia (CML). Since tyrosine kinaseactivity is essential to the transforming function of BCR-ABL,an inhibitor of the kinase could be an effective treatment forCML.
Methods We conducted a phase 1, dose-escalating trial of STI571(formerly known as CGP 57148B), a specific inhibitor of theBCR-ABL tyrosine kinase. STI571 was administered orally to 83patients with CML in the chronic phase in whom treatment withinterferon alfa had failed. Patients were successively assignedto 1 of 14 doses ranging from 25 to 1000 mg per day.
Results Adverse effects of STI571 were minimal; the most commonwere nausea, myalgias, edema, and diarrhea. A maximal tolerateddose was not identified. Complete hematologic responses wereobserved in 53 of 54 patients treated with daily doses of 300mg or more and typically occurred in the first four weeks oftherapy. Of the 54 patients treated with doses of 300 mg ormore, cytogenetic responses occurred in 29, including 17 (31percent of the 54 patients who received this dose) with majorresponses (0 to 35 percent of cells in metaphase positive forthe Philadelphia chromosome); 7 of these patients had completecytogenetic remissions.
Conclusions STI571 is well tolerated and has significant antileukemicactivity in patients with CML in whom treatment with interferonalfa had failed. Our results provide evidence of the essentialrole of BCR-ABL tyrosine kinase activity in CML and demonstratethe potential for the development of anticancer drugs basedon the specific molecular abnormality present in a human cancer.
Chronic myeloid leukemia (CML) is a clonal disorder in whichcells of the myeloid lineage undergo massive clonal expansion.The disease progresses through three distinct phases —chronic phase, accelerated phase, and blast crisis — duringwhich the leukemic clone progressively loses its ability todifferentiate.1,2 Current therapies include allogeneic bonemarrow transplantation and drug regimens including interferonalfa.3,4 Interferon alfa prolongs overall survival but has considerableadverse effects. Allogeneic bone marrow transplantation, theonly curative treatment for CML, is associated with substantialmorbidity and mortality and is limited to patients for whoma suitable donor is available.
The characteristic genetic abnormality of CML, the Philadelphia(Ph) chromosome,5 results from a reciprocal translocation betweenthe long arms of chromosomes 9 and 22.6 The molecular consequenceof this translocation is the generation of the fusion proteinBCR-ABL, a constitutively activated tyrosine kinase, which ispresent in virtually all patients with CML. In vitro studiesand studies in animal models have established that BCR-ABL aloneis sufficient to cause CML, and mutational analysis has establishedthat the tyrosine kinase activity of the protein is requiredfor its oncogenic activity.7,8,9,10 For these reasons, an inhibitorof the BCR-ABL tyrosine kinase should be an effective and selectivetreatment for CML.
STI571 (4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamidemethanesulfonate; Glivec, Novartis, Basel, Switzerland) wassynthesized after a compound was identified by in vitro screeningfor tyrosine kinase inhibitors and its activity was optimizedfor specific kinases. STI571 functions through competitive inhibitionat the ATP-binding site of the enzyme, which leads to the inhibitionof tyrosine phosphorylation of proteins involved in BCR-ABLsignal transduction. It shows a high degree of specificity forBCR-ABL, the receptor for platelet-derived growth factor, andc-kit tyrosine kinases.11 STI571 causes arrest of growth orapoptosis in hematopoietic cells that express BCR-ABL but doesnot affect normal cells.12,13,14 On the basis of its antileukemicactivity in preclinical models, we conducted a phase 1 trialof STI571 in patients with CML in whom treatment with interferonalfa had failed.
Methods
Characteristics of the Patients
Patients with CML in the chronic phase (defined by the presenceof less than 15 percent blasts or basophils in the peripheralblood or bone marrow) were eligible if they were 18 years ofage or older, if they tested positive for the Ph chromosome,and if treatment with interferon alfa had failed. A failureof treatment with interferon alfa was defined as the lack ofa complete hematologic response despite three months of treatmentwith a regimen containing interferon alfa (hematologic resistance),the lack of a cytogenetic response despite one year of treatmentwith a regimen containing interferon alfa (cytogenetic resistance),or a hematologic or cytogenetic relapse. Patients with severeintolerance to interferon alfa were included after safety datahad been obtained for the first seven cohorts of patients treatedwith STI571. The minimal interval between the discontinuationof prior therapies and the initiation of treatment with STI571was one week for hydroxyurea, two weeks for interferon alfaand cytarabine, and six weeks for busulfan. Patients with aplatelet count of less than 100,000 per cubic millimeter wereexcluded; adequate renal, hepatic, and cardiac function andperformance status were required. Written informed consent wasobtained from all patients before they enrolled in the study.
Study Design
The primary end point of this phase 1, dose-escalation trialwas the safety and tolerability of STI571; antileukemic activitywas a secondary end point. Patients were successively assignedto 1 of 14 dose cohorts, which ranged from 25 to 1000 mg perday. Doses of STI571 were administered orally once daily, exceptfor 800 and 1000 mg, which were administered twice daily asdoses of 400 and 500 mg, respectively. Patients received continuousdaily therapy with STI571 unless unacceptable adverse effectsor disease progression occurred. There was no intrapatient doseescalation. Dose escalation among cohorts was allowed if after28 days of therapy, none of three or one of six patients hadgrade 3 (severe) or grade 4 (life-threatening) adverse nonhematologiceffects. No other cytoreductive agents were allowed during thestudy. Complete blood counts were obtained twice a week forthe first four weeks, once a week for the next four weeks, andthen once every two weeks. Assessments of bone marrow, includingcytogenetic analyses, were performed after 8 weeks of therapyand then once every 12 weeks.
Assessment of Toxicity and Response
Safety assessments included the evaluation of adverse events,hematologic assessment, biochemical testing, urinalysis, andphysical examination. Toxicity was graded in accordance withthe Common Toxicity Criteria of the National Cancer Institute.15
A hematologic response was defined as a 50 percent reductionin the white-cell count from base line, maintained for at leasttwo weeks. A complete hematologic response was defined as areduction in the white-cell count to less than 10,000 per cubicmillimeter and in the platelet count to less than 450,000 percubic millimeter, maintained for at least four weeks.
Cytogenetic responses were determined by the percentage of cellsin metaphase that were positive for the Ph chromosome in thebone marrow. Cytogenetic responses, based on analysis of 20cells in metaphase, were categorized as complete (no cells positivefor the Ph chromosome), partial (1 to 35 percent of cells positivefor the Ph chromosome), minor (36 to 65 percent of cells positivefor the Ph chromosome), and absent (over 65 percent of cellspositive for the Ph chromosome). Major responses were definedas complete or partial responses.
Pharmacokinetics
Samples for pharmacokinetic analysis were collected on day 1and day 28 of treatment, and plasma STI571 concentrations weredetermined with a liquid chromatographic and mass spectrophotometricassay. The concentration–time curves of STI571 in plasmawere evaluated by a noncompartmental analysis (with the useof WinNonlin Pro, version 2.0, Pharsight, Mountain View, Calif.).The variables analyzed were the time to the maximal concentration,the maximal concentration, the terminal half-life, and the areaunder the concentration–time curve (AUC) from time zeroto infinity.
Assessment of BCR-ABL Tyrosine Kinase Inhibition
BCR-ABL kinase activity was determined from samples of peripheralblood obtained before the first dose of STI571 and two hoursafter the second dose of STI571. Samples were collected in tubestreated with heparin, and white cells were prepared and lysedas described.16 Cell lysates were separated by electrophoresison 12.5 percent sodium dodecyl sulfate–polyacrylamidegels, followed by electrophoretic transfer to nylon membranes.16The extent of tyrosine phosphorylation of CRK-oncogene–likeprotein (CRKL) in BCR-ABL–positive neutrophils17,18,19was assessed by gel electrophoresis and immunoblotting withanti-CRKL antiserum.20
Results
Enrollment of Patients
From June 1998 to May 2000, 83 patients in whom treatment withinterferon alfa had failed, or who could not tolerate the drug,were enrolled at three participating study centers. The characteristicsof the patients are summarized in Table 1. Of the 83 patients,37 had hematologic resistance or relapse, 33 had cytogeneticresistance or relapse, and 13 could not tolerate interferonalfa. The median duration of disease was 3.8 years (range, 0.8to 14), and the median duration of therapy with interferon alfawas 8.5 months (range, 1 week to 8.5 years). Nineteen patientshad had findings suggestive of accelerated disease (5 to 15percent blasts or basophils in the bone marrow).
The median duration of treatment with STI571 was 310 days (range,17 to 607). Half of the patients assigned to receive daily dosesof 25, 50, or 85 mg of STI571 were removed from the study withintwo months because of elevated white-cell or platelet countsrequiring therapy prohibited by the protocol. The study is ongoingand the results presented here represent an interim analysisof the data.
Pharmacokinetics
STI571 was rapidly absorbed after oral administration, and amean maximal concentration of 2.3 µg per milliliter (4.6µM) was reached at steady state by once-daily administrationof 400 mg of STI571. The half-life of the drug in the circulationranged from 13 to 16 hours, and the levels of the drug increasedby a factor of 2 or 3 at steady state with once-daily dosing.The mean plasma trough concentration was 0.72 µg per milliliter(1.46 µM) 24 hours after the administration of 400 mgof STI571 at steady state. This amount exceeded the concentrationrequired for the inhibition of cellular phosphorylation by BCR-ABL(concentration required for 50 percent inhibition, 0.25 µM),12and this concentration caused the death of cell lines positivefor BCR-ABL in vitro.12,13,14 The increase in the mean plasmaSTI571 AUC values was proportional to the administered dose.
Safety Profile
STI571 was generally well tolerated, and a maximal tolerateddose was not identified. The frequency of adverse effects attributableto STI571 is summarized in Table 2. The most common adverseeffects included nausea (in 43 percent of patients), myalgias(41 percent), edema (39 percent), and diarrhea (25 percent).Most adverse effects, even at the highest doses, were grade1 (mild) or grade 2 (moderate). Most patients had a reductionin the hemoglobin level of 1 to 2 g per deciliter; the hemoglobinlevel typically increased to base-line values or higher withcontinued therapy. Two patients taking the 600-mg dose, onepatient taking the 800-mg dose, and one patient taking the 1000-mgdose had grade 3 anemia. Grade 3 thrombocytopenia and neutropeniaoccurred in 16 percent and 14 percent of the patients, respectively,receiving doses of 200 mg or more. Elevations of liver-enzymelevels of grade 2 or higher were reported in seven patients;in some of these patients, the abnormalities were reversed duringtreatment with STI571, whereas in others, persistent elevationsrequired the temporary interruption of therapy or a reductionin the dose.
Table 2. Drug-Related Adverse Events According to the Daily Dose of STI571.
Only two patients receiving doses of STI571 of 300 mg or morediscontinued therapy prematurely. One patient with a historyof coronary artery disease discontinued therapy because of therecurrence of angina, and a second patient discontinued therapybecause of a persistent and progressive rash. There were nodeaths during the study.
Hematologic Responses
Hematologic responses occurred in all patients who were treatedwith 140 mg or more of STI571 per day (Table 3). Of the patientstreated with daily doses of 300 mg or more, 53 of 54 had completehematologic responses and 1 discontinued therapy prematurely(on day 17) because of the recurrence of angina. Hematologicresponses typically occurred within two weeks after the initiationof therapy with STI571, as illustrated in Figure 1. In all butone patient treated with 300 mg or more per day, a completehematologic response was evident within four weeks after theinitiation of treatment. Complete hematologic responses havebeen maintained in 51 of 53 patients with a median follow-upof 265 days (range, 17 to 468). One patient relapsed with chronic-phasedisease, whereas CML progressed to the blast phase in a secondpatient.
Figure 1. Hematologic Responses in Six Patients Receiving 500 mg of STI571 per day.
Each line represents the white-cell counts for an individual patient. The dotted line indicates the upper limit of a normal white-cell count.
Cytogenetic Responses
One patient each in the groups receiving daily doses of 200mg and 250 mg had a cytogenetic response. As shown in Table 4,29 of the 54 patients treated with doses of 300 mg or moreper day (54 percent) had major or minor cytogenetic responses.Of the 54 patients, 17 (31 percent of the group receiving 300mg or more per day) had major responses (35 percent or lessof cells in metaphase positive for the Ph chromosome); 7 ofthese were complete cytogenetic remissions (13 percent).
Figure 2 shows data on the 17 patients who had a major cytogeneticresponse. Cytogenetic responses occurred as early as 2 monthsand as late as 10 months after the initiation of treatment withSTI571. The median time to the best cytogenetic response (thelowest percentage of cells in metaphase that were positive forthe Ph chromosome) was 148 days (range, 48 to 331). Two of theseven patients who had a complete cytogenetic response testednegative for BCR-ABL by fluorescence in situ hybridization,and one patient tested negative for BCR-ABL messenger RNA (mRNA)by the polymerase chain reaction.
Figure 2. Patients with a Major Cytogenetic Response.
The percentage of cells in metaphase positive for the Ph chromosome (in bone marrow) and the number of days that the patients received STI571 are shown. Each line represents the cytogenetic response for an individual patient.
Inhibition of BCR-ABL–Induced Tyrosine Phosphorylation
Blood samples from treated patients were tested to determinewhether BCR-ABL tyrosine kinase activity was inhibited. A majorsubstrate of the enzyme is CRKL, which is the most heavily tyrosine-phosphorylatedprotein in neutrophils from patients with CML.17,18,19,20 CRKLthat is phosphorylated by BCR-ABL migrates more slowly on electrophoresisthan the unphosphorylated form.21 Low doses (25 to 50 mg) ofSTI571 caused no alteration in the mobility of CRKL. An increasein the levels of the rapidly migrating unphosphorylated formand a concomitant decrease in the levels of the slowly migratingphosphorylated form were seen in patients receiving the 85-mgdose of STI571; these changes were more prominent in patientsreceiving a daily dose of 140 mg and appeared to reach a plateauin patients receiving a daily dose of 250 to 750 mg (Figure 3).
Figure 3. Immunoblot Assays Demonstrating the Degree of Phosphorylation of the BCR-ABL Substrate CRKL in Individual Patients in the Groups Receiving Daily Doses of 25, 85, 140, 250, and 750 mg of STI571.
Discussion
The presence of the BCR-ABL fusion protein in virtually allpatients with CML and its required tyrosine kinase activitymake CML ideal for testing a specific inhibitor of this enzyme.In our phase 1 study, STI571, an oral, specific inhibitor ofthe BCR-ABL tyrosine kinase, was well tolerated and had substantialactivity against CML. These results were obtained in patientswith late-stage disease, in all of whom standard therapy withinterferon alfa had failed.
The rate of complete hematologic responses increased as thedaily dose increased from 85 mg to 250 mg and reached 98 percentin patients treated with 300 mg or more of STI571. Completehematologic responses typically occurred within four weeks afterthe initiation of therapy. The exception was a patient in the350-mg group in whom the plasma half-life of STI571 was short(seven hours) and the AUC was similar to that for patients inthe 85-mg group. STI571 is metabolized primarily by the CYP3A4enzyme, and the patient in the 350-mg group was being treatedwith phenytoin, a known inducer of CYP3A4. When treatment withphenytoin was discontinued and the dose of STI571 was increasedto 500 mg, the patient had a complete hematologic response associatedwith trough levels of STI571 similar to those observed in otherpatients in the 500-mg group. This observation suggests thatdrugs that induce CYP3A4 could lead to low and ineffective levelsof STI571, whereas drugs that interfere with the activity ofthe CYP3A4 enzyme could decrease the metabolism of STI571, leadingto increased levels of STI571 and thereby causing toxic effects.
During treatment with STI571, blood counts gradually returnedto normal during the first month, suggesting that the drug doesnot rapidly induce apoptosis, as would be expected with standardchemotherapy. Blood counts were maintained within normal limitsregardless of whether a cytogenetic response was observed. Thissuggests that inhibition of the BCR-ABL tyrosine kinase restoresnormal regulatory behavior to the leukemic clone. Cytogeneticresponses might follow if, over time, the leukemic clone wasdisplaced either by normal hematopoietic progenitors that hadregained a proliferative advantage or by differentiation ofthe leukemic stem cell, which leads to its elimination.
Of the 54 patients treated with at least 300 mg of STI571 perday, 29 (54 percent) had cytogenetic responses, including 7with complete cytogenetic remissions. As compared with the cytogeneticresponses during therapy with interferon alfa, those duringtreatment with STI571 occurred relatively rapidly. In one patient,BCR-ABL mRNA could not be detected by polymerase chain reaction.
The most frequent adverse effects that seemed to be relatedto treatment with STI571 were nausea, edema, myalgias, and diarrhea;overall, most were mild. In seven patients, there were elevationsof liver-enzyme levels of grade 2 or higher, as was also seenin our study of patients with acute leukemia, reported elsewherein this issue of the Journal.22 Myelosuppression, which occurredin up to a quarter of the patients, was not dose limiting andwas managed by temporary interruption of treatment or dose reduction.Myelosuppression may be either a consequence of a pharmacologiceffect of STI571 through inhibition of c-kit or a reflectionof compromised underlying normal hematopoiesis in patients withleukemia.
We did not identify a maximal tolerated dose for STI571, butother end points could be used to choose a dose for future trials.One is the pharmacokinetic profile of STI571. Levels of thedrug that killed CML cells in vitro correlated well with clinicalresponse and serum drug levels in the 400-mg group. The dose–responsecurve clearly demonstrates a relation between dose and hematologicresponse. Also, there is substantial in vivo inhibition of theenzymatic activity of BCR-ABL at the 400-mg dose, as demonstratedby decreased phosphorylation of CRKL, a substrate of BCR-ABL.For these reasons, we recommend a daily dose of at least 400mg for future studies.
These results show that the BCR-ABL tyrosine kinase is criticalto the development of CML and demonstrate the potential forthe development of anticancer drugs based on the specific molecularabnormality in a human cancer.
Supported by grants from the National Cancer Institute (CA65823,to Dr. Druker, and CA32737, to Dr. Sawyers) and by NovartisPharmaceuticals. Dr. Druker is the recipient of a TranslationalResearch Award from the Leukemia and Lymphoma Society, and Dr.Sawyers is a Scholar of the Leukemia and Lymphoma Society.
Drs. Druker, Talpaz, and Sawyers served as consultants to NovartisPharmaceuticals during the design of this study.
We are indebted to the following people for their assistancewith various aspects of this study: Alex Matter, Juerg Zimmerman,John Goldman, Gregory Burke, David Parkinson, Michael Hayes,Ulrike Zoellner, William Palo, Marianne Rosamilia, Carolyn Blasdel,Virginia Naessig, Sheila Broussard, Mary Beth Rios, Ronald Paquette,Kathryn Kolibaba, Richard Maziarz, Peter Graf, and Hans MichaelBuerger.
Source Information
From the Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland (B.J.D., S.O.-J.); the Departments of Bioimmunotherapy (M.T.) and Leukemia (H.K.), University of Texas M.D. Anderson Cancer Center, Houston; the Department of Oncology Clinical Research, Novartis Pharmaceuticals, East Hanover, N.J. (D.J.R.), and Basel, Switzerland (B.P., E.B., J.M.F., N.B.L., R.C.); and the Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles (C.L.S.).
Address reprint requests to Dr. Druker at Oregon Health Sciences University, L592, 3181 SW Sam Jackson Park Rd., Portland, OR 97201, or at drukerb{at}ohsu.edu.
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Bixby, D., Talpaz, M.
(2009). Imatinib As Frontline Therapy for Patients with Newly Diagnosed Chronic-phase Chronic Myeloid Leukemia. Am Soc Clin Oncol Ed Book
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Yogalingam, G., Pendergast, A. M.
(2008). Abl Kinases Regulate Autophagy by Promoting the Trafficking and Function of Lysosomal Components. J. Biol. Chem.
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Druker, B. J.
(2008). Translation of the Philadelphia chromosome into therapy for CML. Blood
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Miller, F. G, Joffe, S.
(2008). Benefit in phase 1 oncology trials: therapeutic misconception or reasonable treatment option?. Clin Trials
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Morse, M.
(2008). Comment regarding benefit in phase 1 oncology trials. Clin Trials
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Jiang, X., Zhou, J., Yuen, N. K., Corless, C. L., Heinrich, M. C., Fletcher, J. A., Demetri, G. D., Widlund, H. R., Fisher, D. E., Hodi, F. S.
(2008). Imatinib Targeting of KIT-Mutant Oncoprotein in Melanoma. Clin. Cancer Res.
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Larmonier, N., Janikashvili, N., LaCasse, C. J., Larmonier, C. B., Cantrell, J., Situ, E., Lundeen, T., Bonnotte, B., Katsanis, E.
(2008). Imatinib Mesylate Inhibits CD4+CD25+ Regulatory T Cell Activity and Enhances Active Immunotherapy against BCR-ABL- Tumors. J. Immunol.
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Hughes, T. P., Branford, S., White, D. L., Reynolds, J., Koelmeyer, R., Seymour, J. F., Taylor, K., Arthur, C., Schwarer, A., Morton, J., Cooney, J., Leahy, M. F., Rowlings, P., Catalano, J., Hertzberg, M., Filshie, R., Mills, A. K., Fay, K., Durrant, S., Januszewicz, H., Joske, D., Underhill, C., Dunkley, S., Lynch, K., Grigg, A., on behalf of the Australasian Leukaemia and Lympho,
(2008). Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood
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Petain, A., Kattygnarath, D., Azard, J., Chatelut, E., Delbaldo, C., Geoerger, B., Barrois, M., Seronie-Vivien, S., LeCesne, A., Vassal, G., On behalf of the Innovative Therapies with Childre,
(2008). Population Pharmacokinetics and Pharmacogenetics of Imatinib in Children and Adults. Clin. Cancer Res.
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Zhou, L. L., Zhao, Y., Ringrose, A., DeGeer, D., Kennah, E., Lin, A. E.-J., Sheng, G., Li, X.-J., Turhan, A., Jiang, X.
(2008). AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells. JEM
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Raymond, E., Brandes, A. A., Dittrich, C., Fumoleau, P., Coudert, B., Clement, P. M.J., Frenay, M., Rampling, R., Stupp, R., Kros, J. M., Heinrich, M. C., Gorlia, T., Lacombe, D., van den Bent, M. J.
(2008). Phase II Study of Imatinib in Patients With Recurrent Gliomas of Various Histologies: A European Organisation for Research and Treatment of Cancer Brain Tumor Group Study. JCO
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Toschi, L., Janne, P. A.
(2008). Single-Agent and Combination Therapeutic Strategies to Inhibit Hepatocyte Growth Factor/MET Signaling in Cancer. Clin. Cancer Res.
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(2008). Characteristics of Dasatinib- and Imatinib-Resistant Chronic Myelogenous Leukemia Cells. Clin. Cancer Res.
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Brenner, H., Gondos, A., Pulte, D.
(2008). Recent trends in long-term survival of patients with chronic myelocytic leukemia: disclosing the impact of advances in therapy on the population level. haematol
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Schilsky, R. L., Gordon, G., Gilmer, T. M., Courtneidge, S. A., Matrisian, L. M., Grad, O., Nelson, W. G., on behalf of the Translational Research Working Gr,
(2008). The Translational Research Working Group Developmental Pathway for Anticancer Agents (Drugs or Biologics). Clin. Cancer Res.
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Levine, R. L., Gilliland, D. G.
(2008). Myeloproliferative disorders. Blood
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Chu, T. S., Chen, J. S., Lopez, J. P., Pardo, F. S., Aguilera, J., Ongkeko, W. M.
(2008). Imatinib-Mediated Inactivation of Akt Regulates ABCG2 Function in Head and Neck Squamous Cell Carcinoma. Arch Otolaryngol Head Neck Surg
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Lioni, M., Noma, K., Snyder, A., Klein-Szanto, A., Diehl, J. A., Rustgi, A. K., Herlyn, M., Smalley, K. S.M.
(2008). Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway. Molecular Cancer Therapeutics
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Rothenberg, S. M., Engelman, J. A., Le, S., Riese, D. J. II, Haber, D. A., Settleman, J.
(2008). Modeling oncogene addiction using RNA interference. Proc. Natl. Acad. Sci. USA
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Azad, N. S., Posadas, E. M., Kwitkowski, V. E., Steinberg, S. M., Jain, L., Annunziata, C. M., Minasian, L., Sarosy, G., Kotz, H. L., Premkumar, A., Cao, L., McNally, D., Chow, C., Chen, H. X., Wright, J. J., Figg, W. D., Kohn, E. C.
(2008). Combination Targeted Therapy With Sorafenib and Bevacizumab Results in Enhanced Toxicity and Antitumor Activity. JCO
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Smalley, K. S.M., Contractor, R., Nguyen, T. K., Xiao, M., Edwards, R., Muthusamy, V., King, A. J., Flaherty, K. T., Bosenberg, M., Herlyn, M., Nathanson, K. L.
(2008). Identification of a Novel Subgroup of Melanomas with KIT/Cyclin-Dependent Kinase-4 Overexpression. Cancer Res.
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Schilder, R. J., Sill, M. W., Lee, R. B., Shaw, T. J., Senterman, M. K., Klein-Szanto, A. J., Miner, Z., Vanderhyden, B. C.
(2008). Phase II Evaluation of Imatinib Mesylate in the Treatment of Recurrent or Persistent Epithelial Ovarian or Primary Peritoneal Carcinoma: A Gynecologic Oncology Group Study. JCO
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de Lavallade, H., Apperley, J. F., Khorashad, J. S., Milojkovic, D., Reid, A. G., Bua, M., Szydlo, R., Olavarria, E., Kaeda, J., Goldman, J. M., Marin, D.
(2008). Imatinib for Newly Diagnosed Patients With Chronic Myeloid Leukemia: Incidence of Sustained Responses in an Intention-to-Treat Analysis. JCO
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Shah, N. P., Kantarjian, H. M., Kim, D.-W., Rea, D., Dorlhiac-Llacer, P. E., Milone, J. H., Vela-Ojeda, J., Silver, R. T., Khoury, H. J., Charbonnier, A., Khoroshko, N., Paquette, R. L., Deininger, M., Collins, R. H., Otero, I., Hughes, T., Bleickardt, E., Strauss, L., Francis, S., Hochhaus, A.
(2008). Intermittent Target Inhibition With Dasatinib 100 mg Once Daily Preserves Efficacy and Improves Tolerability in Imatinib-Resistant and -Intolerant Chronic-Phase Chronic Myeloid Leukemia. JCO
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Perros, F., Montani, D., Dorfmuller, P., Durand-Gasselin, I., Tcherakian, C., Le Pavec, J., Mazmanian, M., Fadel, E., Mussot, S., Mercier, O., Herve, P., Emilie, D., Eddahibi, S., Simonneau, G., Souza, R., Humbert, M.
(2008). Platelet-derived Growth Factor Expression and Function in Idiopathic Pulmonary Arterial Hypertension. Am. J. Respir. Crit. Care Med.
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Akhmetshina, A., Dees, C., Pileckyte, M., Maurer, B., Axmann, R., Jungel, A., Zwerina, J., Gay, S., Schett, G., Distler, O., Distler, J. H. W.
(2008). Dual inhibition of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis. FASEB J.
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(2008). Report of an international expanded access program of imatinib in adults with Philadelphia chromosome positive leukemias. Ann Oncol
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(2008). Modeling Chromosomal Translocations Using Conditional Alleles to Recapitulate Initiating Events in Human Leukemias. J Natl Cancer Inst Monogr
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(2008). Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc. Natl. Acad. Sci. USA
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Montagut, C., Sharma, S. V., Shioda, T., McDermott, U., Ulman, M., Ulkus, L. E., Dias-Santagata, D., Stubbs, H., Lee, D. Y., Singh, A., Drew, L., Haber, D. A., Settleman, J.
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(2008). Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood
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Kavalerchik, E., Goff, D., Jamieson, C. H.M.
(2008). Chronic Myeloid Leukemia Stem Cells. JCO
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Katsoulas, A., Rachid, Z., McNamee, J. P., Williams, C., Jean-Claude, B. J.
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Loriaux, M. M., Levine, R. L., Tyner, J. W., Frohling, S., Scholl, C., Stoffregen, E. P., Wernig, G., Erickson, H., Eide, C. A., Berger, R., Bernard, O. A., Griffin, J. D., Stone, R. M., Lee, B., Meyerson, M., Heinrich, M. C., Deininger, M. W., Gilliland, D. G., Druker, B. J.
(2008). High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia. Blood
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Tomasson, M. H., Xiang, Z., Walgren, R., Zhao, Y., Kasai, Y., Miner, T., Ries, R. E., Lubman, O., Fremont, D. H., McLellan, M. D., Payton, J. E., Westervelt, P., DiPersio, J. F., Link, D. C., Walter, M. J., Graubert, T. A., Watson, M., Baty, J., Heath, S., Shannon, W. D., Nagarajan, R., Bloomfield, C. D., Mardis, E. R., Wilson, R. K., Ley, T. J.
(2008). Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood
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Hodi, F. S., Friedlander, P., Corless, C. L., Heinrich, M. C., Mac Rae, S., Kruse, A., Jagannathan, J., Van den Abbeele, A. D., Velazquez, E. F., Demetri, G. D., Fisher, D. E.
(2008). Major Response to Imatinib Mesylate in KIT-Mutated Melanoma. JCO
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Weichsel, R., Dix, C., Wooldridge, L., Clement, M., Fenton-May, A., Sewell, A. K., Zezula, J., Greiner, E., Gostick, E., Price, D. A., Einsele, H., Seggewiss, R.
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(2008). Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia. Molecular Cancer Therapeutics
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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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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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Judson, I. R.
(2008). Imatinib for Patients With Liver or Kidney Dysfunction: No Need to Modify the Dose. JCO
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Ramanathan, R. K., Egorin, M. J., Takimoto, C. H.M., Remick, S. C., Doroshow, J. H., LoRusso, P. A., Mulkerin, D. L., Grem, J. L., Hamilton, A., Murgo, A. J., Potter, D. M., Belani, C. P., Hayes, M. J., Peng, B., Ivy, S. P.
(2008). Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Liver Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group. JCO
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Gibbons, J., Egorin, M. J., Ramanathan, R. K., Fu, P., Mulkerin, D. L., Shibata, S., Takimoto, C. H.M., Mani, S., LoRusso, P. A., Grem, J. L., Pavlick, A., Lenz, H.-J., Flick, S. M., Reynolds, S., Lagattuta, T. F., Parise, R. A., Wang, Y., Murgo, A. J., Ivy, S. P., Remick, S. C.
(2008). Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Renal Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group. JCO
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(2008). Revoking the Privilege: Targeting HER2 in the Central Nervous System. Mol. Pharmacol.
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(2008). Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-{alpha} treatment. Blood
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(2008). Oncogenes and Cancer. NEJM
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Hedley, D. W., Chow, S., Goolsby, C., Shankey, T. V.
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(2008). New Advances in the Pathogenesis and Therapy of Essential Thrombocythemia. ASH Education Book
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(2007). Sustained suppression of Bcr-Abl-driven lymphoid leukemia by microRNA mimics. Proc. Natl. Acad. Sci. USA
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(2007). Role of {alpha}1-Acid Glycoprotein in Therapeutic Antifibrotic Effects of Imatinib with Macrolides in Mice. Am. J. Respir. Crit. Care Med.
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(2007). Clinical and prognostic significance of histamine monitoring in patients with CML during treatment with imatinib (STI571). Ann Oncol
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(2007). Inhibition of HMGcoA reductase by atorvastatin prevents and reverses MYC-induced lymphomagenesis. Blood
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(2007). Recent Developments in Acute Myelogenous Leukemia Therapy. The Oncologist
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