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Blood, 15 May 2002, Vol. 99, No. 10, pp. 3530-3539
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Imatinib induces hematologic and cytogenetic responses in
patients with chronic myelogenous leukemia in myeloid blast
crisis: results of a phase II study
Charles L. Sawyers,
Andreas Hochhaus,
Eric Feldman,
John M. Goldman,
Carole B. Miller,
Oliver G. Ottmann,
Charles A. Schiffer,
Moshe Talpaz,
Francois Guilhot,
Michael W. N. Deininger,
Thomas Fischer,
Steve G. O'Brien,
Richard M. Stone,
Carlo B. Gambacorti-Passerini,
Nigel H. Russell,
Jose J. Reiffers,
Thomas C. Shea,
Bernard Chapuis,
Steven Coutre,
Sante Tura,
Enrica Morra,
Richard A. Larson,
Alan Saven,
Christian Peschel,
Alois Gratwohl,
Franco Mandelli,
Monique Ben-Am,
Insa Gathmann,
Renaud Capdeville,
Ronald L. Paquette, and
Brian J. Druker
From the Department of Medicine and Molecular Biology
Institute, University of California, Los Angeles, CA; III. Medizinische
Universitätsklinik Mannheim der Universität Heidelberg,
Mannheim, Germany; New York Presbyterian Hospital-Weill Medical College
of Cornell University, New York, NY; Department of Haematology,
Hammersmith Hospital/ICSM, London, United Kingdom ; Johns Hopkins
Oncology Center, Baltimore, MD; Medizinische Klinik III, Johann
Wolfgang Goethe-Universität, Frankfurt, Germany; Barbara Ann
Karmanos Cancer Institute, Wayne State University, Detroit, MI; MD
Anderson Cancer Center, Houston, TX; Department of Oncology, Hematology
and Cell Therapy, CHU de Poitiers, Poitiers, France; Abteilung
Haematologie/Onkologie, Universität Leipzig, Germany;
Universitätsklinikum, 3. Medizinische Klinik und Poliklinik,
Mainz, Germany; Department of Haematology, Royal Victoria Infirmary,
University of Newcastle upon Tyne, United Kingdom; Dana Farber Cancer
Institute, Boston, MA; Hematology Section, San Gerardo Hospital, Monza,
and Department of Experimental Oncology, National Cancer Institute,
Milano, Italy; Department of Haematology, City Hospital, Nottingham,
United Kingdom; Laboratoire de Greffe de Moelle, Universite Victor
Segalen, Bordeaux, France; Division of Hematology/Oncology, University
of North Carolina, Chapel Hill; Division d'hématologie,
Hopitâl cantonal universitaire, Geneva, Switzerland; Division of
Hematology, Stanford University School of Medicine, Stanford, CA;
Instituto di Ematologia, Ospedale Policlinicl Sant'Orsola-Malpighi,
Bologna, Italy; Divisione di Ematologia, Azienda Ospedaliera Niguarda
Ca'Granda, Milan, Italy; University of Chicago Medical Center, IL; Ida
and Cecil Green Cancer Center, Scripps Clinic, La Jolla, CA; III.
Medizinische Klinik und Poliklinik der TU, Haematologie/Onkologie,
Munich, Germany; Division of Hematology, Universitätsklinik,
Kantonspital, Basel, Switzerland; Dipartimento di Biotechologie
Cedulari ed Ematologia, Azienda Policlinico Umberto 1, Universita La
Sapienza, Rome, Italy; Novartis Pharmaceuticals, Basel, Switzerland;
School of Medicine, University of California, Los Angeles, CA; and
Division of Hematology, Oregon Health Sciences University, Portland,
OR.
Blast crisis is the most advanced stage of chronic myelogenous
leukemia (CML) and is highly refractory to therapy. CML is caused by
expression of the chimeric BCR-ABL tyrosine kinase
oncogene, the product of the t(9;22) Philadelphia translocation.
Imatinib (Glivec, formerly STI571) is a rationally developed, orally
administered inhibitor of the Bcr-Abl tyrosine kinase. A total of 260 patients with CML were enrolled in a phase II trial, of whom 229 had a confirmed diagnosis of CML in blast crisis. Patients were treated with
imatinib in daily oral doses of 400 mg or 600 mg. Imatinib induced
hematologic responses in 52% of patients and sustained hematologic
responses lasting at least 4 weeks in 31% of patients, including
complete hematologic responses in 8%. For patients with a sustained
response, the estimated median response duration was 10 months.
Imatinib induced major cytogenetic responses in 16% of patients, with
7% of the responses being complete. Median survival time was 6.9 months. Nonhematologic adverse reactions were frequent but generally
mild or moderate. Episodes of severe cytopenia were also frequent and
were attributable to the underlying condition and treatment with
imatinib. Drug-related adverse events led to discontinuation of therapy
in 5% of patients, most often because of cytopenia, skin disorders, or
gastrointestinal reactions. These results demonstrate that imatinib has
substantial activity and a favorable safety profile when used as a
single agent in patients with CML in blast crisis. Additional clinical
studies are warranted to explore the efficacy and feasibility of
imatinib used in combination with other antileukemic drugs.

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