Originally published as JCO Early Release 10.1200/JCO.2007.14.9260 on June 9 2008

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Intermittent Target Inhibition With Dasatinib 100 mg Once Daily Preserves Efficacy and Improves Tolerability in Imatinib-Resistant and -Intolerant Chronic-Phase Chronic Myeloid Leukemia

Neil P. Shah, Hagop M. Kantarjian, Dong-Wook Kim, Delphine Réa, Pedro E. Dorlhiac-Llacer, Jorge H. Milone, Jorge Vela-Ojeda, Richard T. Silver, H. Jean Khoury, Aude Charbonnier, Nina Khoroshko, Ronald L. Paquette, Michael Deininger, Robert H. Collins, Irma Otero, Timothy Hughes, Eric Bleickardt, Lewis Strauss, Stephen Francis, Andreas Hochhaus

From the Division of Hematology/Oncology, University of California at San Francisco School of Medicine, San Francisco; University of California at Los Angeles, Los Angeles, CA; Department of Leukemia, M.D. Anderson Cancer Center, Houston; University of Texas Southwestern Medical Center, Dallas, TX; Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY; Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA; Oregon Health Science University, Portland, OR; Bristol-Myers Squibb Co, Wallingford, CT; Department of Internal Medicine, St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea; Hôpital Saint-Louis, Paris; Département d'Onco-hématologie, Institut Paoli Calmettes, Marseille, France; Department of Hematology and Hemotherapy, Hospital das Clínicas, University of São Paulo, São Paulo, Brazil; Instituto de Trasplante de Medula Osea; Division of Hematology and Medical Oncology, Hospital Ramos Mejía, Buenos Aires, Argentina; National Medical Center, La Raza, IMSS, Mexico; National Research Hematology Center, Moscow, Russian Federation; Division of Hematology, Institute of Medical and Veterinary Science, Adelaide, Australia; and III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany

Corresponding author: Neil P. Shah, Division of Hematology/Oncology, University of California, San Francisco School of Medicine, Box 1270, 505 Parnassus Ave, San Francisco, CA 94143; e-mail: nshah{at}medicine.ucsf.edu

	ABSTRACT

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Purpose Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose- and schedule-optimization study is reported.

Patients and Methods In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1:1:1:1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily.

Results With minimum follow-up of 6 months (median treatment duration, 8 months; range, < 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11% of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P = .024) and grade 3 to 4 thrombocytopenia (22% v 37%; P = .004), and fewer patients required dose interruption (51% v 68%), reduction (30% v 55%), or discontinuation (16% v 23%).

Conclusion Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.

	INTRODUCTION

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Leukemic cells from patients with chronic myeloid leukemia (CML) are characterized by the presence of the Philadelphia chromosome (Ph), which contains the oncogenic BCR-ABL fusion gene. The majority of patients with CML are diagnosed during the initial chronic phase (CP) and receive first-line treatment with imatinib mesylate (Gleevec; Novartis Pharma, East Hanover, NJ), an inhibitor of BCR-ABL tyrosine kinase activity.^1,2 Dasatinib (Sprycel; Bristol-Myers Squibb, New York, NY) is structurally unrelated to imatinib, 325-times more potent than imatinib in inhibiting the growth of BCR-ABL–expressing cells in vitro, and, unlike imatinib, able to bind to the BCR-ABL kinase in the functionally relevant, catalytically active conformation.^3-5 Dasatinib has been approved for the treatment of imatinib-resistant and -intolerant CML in all phases of the disease.^6-11

Nearly all approved tyrosine kinase inhibitors are administered orally and have pharmacokinetic properties that result in continuous target inhibition when administered once daily. For example, the half-life of imatinib is 18 hours, and that of its primary active metabolite, N-desmethyl imatinib, is 40 hours.^12,13 Epidermal growth factor receptor tyrosine kinase inhibitors gefitinib, erlotinib, and lapatinib show in vivo half-lives of 48 hours, 36 hours, and 24 hours, respectively, and vascular endothelial growth factor receptor tyrosine kinase inhibitors sunitinib and sorafenib exhibit half-lives of 40 to 60 hours and 20 to 27 hours, respectively.^14-18 In contrast, the half-life of dasatinib is only 3 to 5 hours. The dasatinib 70-mg twice-daily regimen used for phase II studies and subsequently approved was selected on the basis of pharmacokinetic and pharmacodynamic studies on the phosphorylation of CRK-like protein (CRKL),^19-21 a substrate specific to BCR-ABL, which was previously used to guide imatinib dose selection.²² In the dasatinib phase I program, BCR-ABL kinase inhibition was more sustained across a 24-hour period with the twice-daily schedule, consistent with pharmacokinetic analyses.

Notably, cytogenetic responses were observed in phase I with both once-daily and twice-daily dosing (major cytogenetic response [MCyR]: once daily, 48%; twice daily, 42%), including cases treated with dasatinib once-daily 5 days per week.²³ Longer-term follow-up has indicated that pleural effusions were less frequent with once-daily than with twice-daily dosing. Because of dose reductions (initial dose, 70 mg twice daily), the median total daily dose across the phase II program in CP-CML was close to 100 mg/d.^6,8

To confirm preliminary findings that intermittent BCR-ABL inhibition is efficacious and to test whether toxicity could be minimized with less frequent dosing, a randomized phase III study was performed investigating dasatinib administered as once-daily and twice-daily schedules at two total daily doses (100 mg and 140 mg) in patients with CP-CML after imatinib resistance or intolerance.

	PATIENTS AND METHODS

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Study Design and Patient Eligibility
This was a randomized, international, multicenter, open-label, phase III trial with a 2 x 2 factorial design. A permuted block design was used to randomly assign patients with a 1:1:1:1 ratio. The study was conducted in accordance with the Declaration of Helsinki and was approved by local ethical committees. Written, informed consent was obtained from every patient before participation.

Patients at least 18 years of age with Ph-positive CP-CML and primary or acquired hematologic resistance or intolerance to imatinib were enrolled. To meet inclusion criteria for Ph-positive CP-CML, patients were required to have less than 15% blasts in peripheral blood or bone marrow, less than 30% blasts and promyelocytes in peripheral blood or bone marrow, less than 20% basophils in peripheral blood, 100,000/µL platelets (or less if related to prior drug therapy), and no extramedullary involvement (except liver or spleen). Patients were stratified by imatinib resistance or intolerance. Primary resistance to imatinib (400 to 800 mg/d) was defined as no decrease in WBC count after 4 weeks of treatment, no complete hematologic response (CHR) after 3 months, no MCyR after 6 months, and no complete cytogenetic response (CCyR) after 12 months. Acquired resistance was defined as loss of MCyR ( 30% absolute increase in the percentage of Ph-positive metaphases), loss of molecular response (concomitant with a 10% Ph-positive metaphases at cytogenetic analysis), evidence of a new mutation in the BCR-ABL kinase domain, or loss of a confirmed CHR (WBC count > 10,000/µL on all assessments over at least a consecutive 2-week period). Intolerance to imatinib was defined as grade 3 or worse toxicity (considered at least possibly related to imatinib at a dose of 400 mg/d) which led to discontinuation of therapy. Patients who tolerated 400 mg/d imatinib but who did not achieve a CCyR and subsequently did not tolerate doses of 600 mg/d were considered to be resistant to imatinib.

Exclusion criteria included but were not limited to the following: treatment with imatinib, interferon alfa, cytarabine therapy, or any targeted small-molecule anticancer agent within 7 days of initiation; uncontrolled or significant cardiovascular disease (eg, myocardial infarction within 6 months, congestive heart failure within 3 months, congenital prolonged QT syndrome, or QTcF interval of more than 450 milliseconds on pre-entry ECG); history of a significant bleeding disorder unrelated to CML; eligibility for immediate autologous or allogeneic stem-cell transplantation; or concurrent incurable malignancy other than CML.

Treatment with Dasatinib
Four dasatinib treatment groups, to which patients were randomly assigned after stratification by imatinib resistance or intolerance, were defined according to schedule and total dose: 100 mg once daily; 50 mg twice daily; 140 mg once daily; and 70 mg twice daily. All doses were administered orally.

Dose escalation to 140 mg once daily (100-mg once-daily group), 70 mg twice daily (50-mg twice-daily group), 180 mg once daily (140-mg once-daily group), or 90 mg twice daily (70-mg twice-daily group) was allowed for inadequate response, defined as no decrease in WBC after 1 month of uninterrupted dasatinib treatment, no CHR after 3 months, no MCyR after 6 months, or no CCyR after 12 months. Dose interruption or reduction to 80 mg once daily (100-mg once-daily and 140-mg once-daily groups) or 40 mg twice daily (50-mg twice-daily and 70-mg twice-daily groups) was allowed after grade 2 or worse nonhematologic toxicity deemed to be drug related or grade 3 or worse hematologic toxicity. Treatment was administered until disease progression or intolerable toxicity, as determined by the treating physician. CML therapies other than dasatinib were prohibited, with the exception of hydroxyurea (for a maximum of 2 weeks) for elevated WBC counts (> 50,000/µL). Administration of myeloid growth factors or recombinant erythropoietin was permitted at the discretion of the investigator. Patients were supported with platelet transfusions as required.

Patient Evaluation
Treatment efficacy was evaluated on the basis of hematologic assessments and bone marrow cytogenetics.^6,8 Standard definitions of cytogenetic response according to number of Ph-positive metaphases in bone marrow were used (CCyR, 0%; partial cytogenetic response [PCyR], > 0% to 35%; minor cytogenetic response, > 35% to 65%; minimal cytogenetic response, > 65% to 95%; no cytogenetic response, > 95% to 100%). Patients with a CCyR or PCyR were considered to have a MCyR. Definitions of CHR and CML disease progression have been published previously^6,8; the latter was defined as confirmed accelerated- or blast-phase disease, loss of a previous CHR or MCyR, 30% increase in Ph-positive metaphases, increasing WBC count (recorded by the investigator as a doubling from lowest value to > 20,000/µL or an increase by > 50,000/µL on two assessments performed at least 2 weeks apart), or death from any cause. Calculations of hematologic or cytogenetic response rates did not exclude patients who had had responses at baseline.

Peripheral-blood cell mRNA was collected and analyzed for BCR-ABL gene point mutations by denaturing high-performance liquid chromatography and sequencing. Different BCR-ABL mutations were classified as being associated with imatinib resistance if supported by current literature.

Safety and tolerability were assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0. In all patients, monitoring for pleural effusions included scheduled chest x-rays. Classifications of pleural effusions were as follows: grade 1, asymptomatic; grade 2, symptomatic, with intervention such as diuretics or up to two therapeutic thoracenteses indicated; grade 3, symptomatic and supplemental oxygen, more than two therapeutic thoracenteses, tube drainage, or pleurodesis indicated; grade 4, life-threatening (eg, causing hemodynamic instability or ventilatory support indicated).

The primary end point was the rate of MCyR in patients with imatinib resistance, with a minimum follow-up of 6 months. The primary analysis was the comparison between dosing schedules; the main secondary analysis was the comparison of daily doses (100 mg v 140 mg). Secondary end points included rates of MCyR in imatinib-intolerant patients, rates of CHR, time to and duration of MCyR and CHR, progression-free survival (PFS), overall survival, and safety evaluations.

Statistical Analysis
Efficacy data were analyzed for all randomly assigned patients as part of an intent-to-treat analysis. Noninferiority for the primary end point was assessed by determining whether the lower bound of the 95% CI of the difference between MCyR rates for once-daily and twice-daily schedules was –15%. Time to and duration of MCyR and CHR, PFS, and overall survival were estimated using Kaplan-Meier product-limit methodology. Fisher's exact test was used to compare the incidence of selected adverse events (AEs) using the worst Common Terminology Criteria for Adverse Events grade per patient.

	RESULTS

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Between July 2005 and March 2006, 670 patients were randomly assigned at 139 centers worldwide. A total of 662 patients were treated (Fig 1), including 491 patients (74%) with imatinib resistance and 171 patients (26%) with imatinib intolerance.

View larger version (43K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. CONSORT diagram for the CA180-034 study. (* Reasons for discontinuation are listed in Table 4.) Ph+, Philadelphia chromosome positive.

Patient Demographics and Disease Characteristics
Patient demographics and baseline disease characteristics were well balanced (Table 1) and similar to cohorts of patients with CP-CML and imatinib resistance or intolerance from previous studies. Median age was 55 years and 47% of patients were male. Median time from CML diagnosis to randomization was 54 months. All patients received prior imatinib therapy, with 34% having received doses of 800 mg/d or more. The best previous hematologic response to imatinib was CHR in 84% of patients, and best previous cytogenetic response was MCyR in 41% (CCyR in 21%). The median duration of prior imatinib treatment was approximately 3 years. Prior treatment for CML included interferon alfa in 52%, chemotherapy in 26%, and stem-cell transplantation in 5% of cases.

With the current minimum follow-up of 6 months, disease progression for patients who experienced an MCyR is minimal, with similar rates observed across the four treatment groups (100 mg once daily, 1%; 50 mg twice daily, 1%; 140 mg once daily, 3%; 70 mg twice daily, 3%; Fig 2A). Time to CHR and MCyR were similar between treatment groups.

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier analyses. (A) Duration of major cytogenetic response. (B) Progression-free survival (progression was defined as confirmed accelerated- or blast-phase disease, loss of previous complete hematologic response or major cytogenetic response, or increasing WBC count [see Patients and Methods for definition]). (C) Overall survival. QD, once daily; BID, twice daily.

Overall Survival
Rates of overall survival were also similar across the various treatment groups, with few patients having died (100 mg once daily, 2% [n = 3]; 50 mg twice daily, 4%, [n = 6]; 140 mg once daily, 2% [n = 4]; 70 mg twice daily, 5% [n = 8]; Fig 2C). Other than CML disease (n = 6), reasons for death assigned by study investigators were as follows: infection (n = 4), cardiovascular disease (n = 1), bleeding (n = 1), study drug toxicity (n = 1), other (n = 5: idiopathic pneumonia syndrome, secondary to stem-cell transplantation, suicide, relapse of tuberculosis/liver insufficiency, and left ventricular diastolic dysfunction), not reported (n = 2), and unknown (n = 1).

Adverse Events
Rates of key treatment-related AEs (ie, cytopenia and pleural effusion) were consistently lower in patients receiving dasatinib 100 mg once daily than for the other treatment groups (Table 4). Overall, significantly fewer patients treated with 100 mg once daily experienced grade 3 to 4 AEs than patients receiving the currently approved 70-mg twice-daily dose (30% v 48%; P = .001), particularly grade 3 to 4 thrombocytopenia (22% v 37%; P = .004). In general, cytopenia was reversible and could be managed effectively through dose interruption or reduction and/or with the addition of growth factors or transfusions.

Drug-related nausea (15% v 25%) and vomiting (5% v 10%) of any grade occurred in fewer patients receiving 100 mg once daily than 70 mg twice daily. Rates of other treatment-related nonhematologic AEs were similar between treatment groups. The most commonly reported grade 3 to 4 nonhematologic AEs among all four treatment groups were diarrhea (2% to 5%), dyspnea (1% to 5%), fatigue (0% to 3%), and headache (0% to 3%).

Dose Adjustments and Treatment Discontinuations
Fewer patients in the 100 mg once daily group required dose interruption or reduction as compared with 70 mg twice daily (Table 5). In particular, the 100-mg once-daily regimen was associated with lower rates of treatment interruptions (27% v 35%) and dose reductions (22% v 32%) because of hematologic toxicity than was the 70-mg twice-daily regimen. The 100-mg once-daily group was also associated with a higher rate of dose escalation as compared with the 70-mg twice-daily group (15% v 7%).

Discontinuation rates were lower for the dasatinib 100-mg once-daily group than for the 70-mg twice-daily group (16% v 23%). In particular, discontinuation owing to toxicity occurred in only 4% of patients treated with 100 mg once daily as compared with 11% of patients treated with 70 mg twice daily. Overall, 536 patients (80%) remain on the trial, with most discontinuations attributable to disease progression or toxicity.

	DISCUSSION

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Dasatinib 100 mg once daily offered the most favorable overall benefit-risk assessment in this study evaluating dose and schedule optimization in patients with CP-CML that is resistant or intolerant to imatinib. This finding is noteworthy, given that the target kinase, BCR-ABL, is inhibited only intermittently. In comparison with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily was associated with improved tolerability, with significantly reduced incidences of key treatment-related AEs (grade 3 to 4 thrombocytopenia and pleural effusions). Other treatment-related nonhematologic AEs were generally mild to moderate in nature. The 100-mg once-daily regimen also resulted in the lowest incidence of treatment interruption and discontinuation, and once-daily treatment groups (100 mg or 140 mg) received higher median total daily doses than did corresponding twice-daily groups. These findings support the concept that some toxicities associated with kinase inhibitors may be driven by persistent exposure to inhibitory drug concentrations. However, peak levels must also be relevant, as patients in the 100-mg once-daily cohort experienced fewer adverse effects as compared with patients in the 140-mg once-daily cohort. All four dasatinib treatment arms displayed marked and comparable levels of hematologic and cytogenetic efficacy. Notably, no major differences in durability of response (CHR or MCyR) or in the rates of PFS and overall survival were reported.

Laboratory studies have revealed that transient exposure of three CML cell lines to clinically relevant dasatinib concentrations (100 nmol/L) results in apoptosis of the majority of cells when assessed 48 hours later.²⁴ Similar findings were observed when a non–small-cell lung cancer cell line harboring an activating epidermal growth factor mutation was transiently exposed to high concentrations of erlotinib.²⁴

The findings described in this study have important implications for the emerging field of kinase inhibitor treatment for human malignancies. Specifically, compounds with pharmacokinetic properties requiring intravenous administration may retain significant efficacy, and tyrosine kinase inhibitor development should not be abandoned if promising compounds are found to have short half-lives. Of particular interest is the promise of intermittent high-dose kinase inhibitor therapy for malignancies that have developed resistance after an initial response, because this phenomenon is frequently mediated by kinase domain mutations within the target that result in a relative degree of resistance.

Response rates to dasatinib reported here after a median of 8 months' treatment are notable (MCyR, 54% to 59%; CCyR, 41% to 45%) and consistent with the responses observed after 8 months in START-C, a phase II, single-arm study of dasatinib in CP-CML (MCyR, 52%; CCyR, 39%).⁶

The rapid clinical development and approval of dasatinib enabled prompt access to an effective and potentially life-saving treatment for patients with CML and imatinib treatment failure. Dose optimization may now improve the safety profile of dasatinib in clinical practice. Patients in this study will continue dasatinib therapy according to their randomly assigned treatments, and longer-term follow-up results will be reported.

Treatment with dasatinib 100 mg once daily provides the most favorable overall benefit-risk profile, with improved tolerability and consistent efficacy to the recommended 70-mg twice-daily dose in patients with CP-CML. On the basis of these findings, the 100-mg once-daily regimen should be used for patients with CP-CML who are initiating dasatinib treatment.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Eric Bleickardt, Bristol-Myers Squibb (C); Lewis Strauss, Bristol-Myers Squibb (C); Stephen Francis, Bristol-Myers Squibb (C) Consultant or Advisory Role: Neil P. Shah, Bristol-Myers Squibb (C), Novartis Oncology (C); Michael Deininger, Novartis (C), Bristol-Myers Squibb (C); Robert H. Collins, Bristol-Myers Squibb (C); Timothy Hughes, Bristol-Myers Squibb (C); Andreas Hochhaus, Bristol-Myers Squibb (C), Novartis (C) Stock Ownership: Eric Bleickardt, Bristol-Myers Squibb; Lewis Strauss, Bristol-Myers Squibb Honoraria: Dong-Wook Kim, Bristol-Myers Squibb, Novartis; Ronald L. Paquette, Bristol-Myers Squibb; Timothy Hughes, Bristol-Myers Squibb; Andreas Hochhaus, Bristol-Myers Squibb, Novartis Research Funding: Hagop M. Kantarjian, Novartis, Bristol-Myers Squibb, MGJ; Pedro E. Dorlhiac-Llacer, Bristol-Myers Squibb; Richard T. Silver, Weill Cornell Medical Center; Michael Deininger, Calistoga, SGX; Robert H. Collins, Bristol-Myers Squibb; Timothy Hughes, Bristol-Myers Squibb; Andreas Hochhaus, Bristol-Myers Squibb, Novartis Expert Testimony: None Other Remuneration: Richard T. Silver, Bristol-Myers Squibb; Lewis Strauss, Bristol-Myers Squibb

	AUTHOR CONTRIBUTIONS

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Conception and design: Neil P. Shah, Richard Silver, Timothy Hughes, Eric Bleickardt, Lewis Strauss, Andreas Hochhaus

Administrative support: Eric Bleickardt

Provision of study materials or patients: Neil P. Shah, Hagop M. Kantarjian, Dong-Wook Kim, Delphine Réa, Pedro E. Dorlhiac-Llacer, Jorge H. Milone, Jorge Vela-Ojeda, Richard T. Silver, H. Jean Khoury, Aude Charbonnier, Nina Khoroshko, Ronald L. Paquette, Michael Deininger, Robert H. Collins, Irma Otero, Timothy Hughes, Andreas Hochhaus

Collection and assembly of data: Neil P. Shah, Dong-Wook Kim, Jorge Vela-Ojeda, Robert H. Collins, Irma Otero, Eric Bleickardt, Lewis Strauss, Andreas Hochhaus

Data analysis and interpretation: Neil P. Shah, Hagop M. Kantarjian, Dong-Wook Kim, Richard T. Silver, H. Jean Khoury, Timothy Hughes, Eric Bleickardt, Lewis Strauss, Stephen Francis, Andreas Hochhaus

Manuscript writing: Neil P. Shah, Hagop M. Kantarjian, Jorge Vela-Ojeda, Richard T. Silver, H. Jean Khoury, Ronald L. Paquette, Eric Bleickardt, Stephen Francis, Andreas Hochhaus

Final approval of manuscript: Neil P. Shah, Hagop M. Kantarjian, Dong-Wook Kim, Delphine Réa, Pedro E. Dorlhiac-Llacer, Jorge H. Milone, Jorge Vela-Ojeda, Richard T. Silver, H. Jean Khoury, Aude Charbonnier, Nina Khoroshko, Ronald L. Paquette, Michael Deininger, Robert H. Collins, Irma Otero, Timothy Hughes, Eric Bleickardt, Lewis Strauss, Andreas Hochhaus

	Appendix

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The following investigators also participated in the CA180-034 trial:

Argentina, E. Bullorsky, J.J. Garcia; Australia, C. Arthur, J. Gibson, J. Seymour, K. Taylor, R. Herrmann; Austria, P. Valent; Belgium, A. Bosly, D. Bron, G.E.G. Verhoef, J. Van Droogenbroeck, M. Andre, W. Schroyens; Brazil, A. Moellmann, C. Carmino, A. Souza, N. Hamerschlak, P. Enrique, R. Pasquini; Canada, A.R. Turner, B.F. Leber, C. Gambacorti-Passerini; Czech Republic, H. Klamova, J. Mayer; Denmark, H. Hasselbalch, I. Dufva, J. Nielsen; Finland, K. Porkka; France, F. Guilhot-Gaudeffroy, F. Huguet, F. Maloisel, J. Harrousseau, J. Cahn, M. Michalet, M. Leporrier, M. Tulliez, T. Facon; Germany, C. Bokemeyer, D. Niederwieser, G. Ehninger, O.G. Ottmann, T. Fischer; Hungary, T. Masszi; Ireland, E. Conneally, M. O'Dwyer; Israel, A. Nagler; Italy, B. Rotoli, E. Abruzzese, E. Pogliani, F. Ferrara, G. Alimena, G. Saglio, V. Liso; Netherlands, A. Schattenberg, J. Cornelissen; Norway, H. Hjorth-Hansen; Peru, J. Navarro, L. Casanova; Philippines, P. Caguioa; Poland, A. Skotnicki, A. Hellmann, A. Dmoszynska, J. Holowiecki, T. Robak, W. Jedrzejczak; Republic of Korea, H.J. Kim, K.-H. Lee, S.-S. Yoon; Russian Federation, A. Zaritsky; Singapore, C. Chuah; South Africa, G. Cohen, M. Patel, N. Novitzky, P. Ruff, V. Louw; Spain, F. Prosper, J. Odriozola, J. Steegmann; Sweden, B. Simonsson, M. Ekblom; Switzerland, A. Gratwohl; Taiwan, J. Tang, L. Shih; UK, A. Green, C. Craddock, J. Apperley, R. Clark, S. O'Brien, T. Holyoake; United States, A. Rapoport, A. Maniam, A. Liem, B. Wong, C. Schiffer, C. Hagenstad, D. Bodensteiner, E. Hu, E. Asatiani, F.A. Greco, J. Schwartz, J.G. Berdeja, J.F. Dipersio, J. Lister, J. Catlett, J. Hajdenberg, K. Jamieson, K. Mcdonagh, L. Fehrenbacher, M. Saleh, M. Devetten, M. Goodman, M. Tallman, M. Kalaycio, P. Emanuel, R. Larson, R.M. Stone, R. Strair, R. Mcintyre, S. Thomas, S. Tarantolo, S. Petersdorf, S. Goldberg, T. Shea.

	ACKNOWLEDGMENTS

 
We thank Jeremy Gardner for professional writing and editorial assistance (funded by Bristol-Myers Squibb).

	NOTES

 
published online ahead of print at www.jco.org on June 9, 2008.

Supported by research funding from Bristol-Myers Squibb (Grant No. CA180-034). This trial is registered at www.clinicaltrials.gov as NCT00123474 [ClinicalTrials.gov] . N.P.S. is supported by the Doris Duke Charitable Foundation, the Leukemia & Lymphoma Society, and the Sandler Foundation.

Presented in part at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL; the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL; and the 12th Annual Congress of the European Hematology Association, June 7-10, 2007, Vienna, Austria.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on www.JCO.org.

	REFERENCES

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1. Hehlmann R, Berger U, Hochhaus A: Chronic myeloid leukemia: A model for oncology. Ann Hematol 84:487-497, 2005[CrossRef][Medline]

2. Quintás-Cardama A, Cortes JE: Chronic myeloid leukemia: Diagnosis and treatment. Mayo Clin Proc 81:973-988, 2006[Abstract/Free Full Text]

3. O'Hare T, Walters DK, Stoffregen EP, et al: In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 65:4500-4505, 2005[Abstract/Free Full Text]

4. Tokarski JS, Newitt JA, Chang CY, et al: The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res 66:5790-5797, 2006[Abstract/Free Full Text]

5. Shah NP: Dasatinib. Drugs Today (Barc) 43:5-12, 2007[CrossRef][Medline]

6. Hochhaus A, Kantarjian HM, Baccarani M, et al: Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109:2303-2309, 2007[Abstract/Free Full Text]

7. Guilhot F, Apperley J, Kim DW, et al: Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 109:4143-4150, 2007[Abstract/Free Full Text]

8. Kantarjian H, Pasquini R, Hamerschlak N, et al: Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: A randomized phase 2 trial. Blood 109:5143-5150, 2007[Abstract/Free Full Text]

9. Cortes J, Rousselot P, Kim DW, et al: Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 109:3207-3213, 2007[Abstract/Free Full Text]

10. Ottmann O, Dombret H, Baccarani M, et al: Dasatinib (BMS-354825) induces rapid hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant Philadelphia chromosome-positive acute lymphoblastic leukemia: Interim results of a phase II study. Blood 110:2309-2315, 2007[Abstract/Free Full Text]

11. National Comprehensive Cancer Network (NCCN): Clinical Practice Guidelines in Oncology(TM): Chronic myelogenous leukemia, V. 2.2007. http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf. Accessed November 2007

12. le Coutre P, Kreuzer KA, Pursche S, et al: Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588. Cancer Chemother Pharmacol 53:313-323, 2004[CrossRef][Medline]

13. Bornhäuser M, Pursche S, Bonin M, et al: Elimination of imatinib mesylate and its metabolite N-desmethyl-imatinib. J Clin Oncol 23:3855-3856, 2005[Free Full Text]

14. Ranson M, Hammond LA, Ferry D, et al: ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial. J Clin Oncol 20:2240-2250, 2002[Abstract/Free Full Text]

15. Lu JF, Eppler SM, Wolf J, et al: Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer. Clin Pharmacol Ther 80:136-145, 2006[CrossRef][Medline]

16. Burris HA III, Hurwitz HI, Dees EC, et al: Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23:5305-5313, 2005[Abstract/Free Full Text]

17. Motzer RJ, Hoosen S, Bello CL, et al: Sunitinib malate for the treatment of solid tumours: A review of current clinical data. Expert Opin Investig Drugs 15:553-561, 2006[CrossRef][Medline]

18. Strumberg D, Clark JW, Awada A, et al: Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: A review of four phase I trials in patients with advanced refractory solid tumors. Oncologist 12:426-437, 2007[Abstract/Free Full Text]

19. ten Hoeve J, Arlinghaus RB, Guo JQ, et al: Tyrosine phosphorylation of CRKL in Philadelphia+ leukemia. Blood 84:1731-1736, 1994[Abstract/Free Full Text]

20. Oda T, Heaney C, Hagopian JR, et al: Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. J Biol Chem 269:22925-22928, 1994[Abstract/Free Full Text]

21. Nichols GL, Raines MA, Vera JC, et al: Identification of CRKL as the constitutively phosphorylated 39-kD tyrosine phosphoprotein in chronic myelogenous leukemia cells. Blood 84:2912-2918, 1994[Abstract/Free Full Text]

22. Druker BJ, Talpaz M, Resta DJ, et al: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031-1037, 2001[Abstract/Free Full Text]

23. Talpaz M, Shah NP, Kantarjian H, et al: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354:2531-2541, 2006[Abstract/Free Full Text]

24. Shah NP, Nicoll JM, Bleickardt E, et al: Potent transient inhibition of BCR-ABL by dasatinib leads to complete cytogenetic remissions in patients with chronic myeloid leukemia: Implications for patient management and drug development. Blood 108:614a, 2006 (suppl; abstr 2166)

Submitted November 14, 2007; accepted March 31, 2008.

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