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

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.

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.

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