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 Prepublished online as a Blood First Edition Paper on May 24, 2002; DOI 10.1182/blood-2001-12-0181.

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Blood, 15 September 2002, Vol. 100, No. 6, pp. 1965-1971

CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS

A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias

Oliver G. Ottmann, Brian J. Druker, Charles L. Sawyers, John M. Goldman, Jose Reiffers, Richard T. Silver, Sante Tura, Thomas Fischer, Michael W. Deininger, Charles A. Schiffer, Michele Baccarani, Alois Gratwohl, Andreas Hochhaus, Dieter Hoelzer, Sofia Fernandes-Reese, Insa Gathmann, Renaud Capdeville, and Stephen G. O'Brien

From the Medizinische Klinik III, Johann Wolfgang Goethe Universität, Frankfurt, Germany; Division of Hematology, Oregon Health Sciences University, Portland; Department of Medicine and Molecular Biology Institute, University of California at Los Angeles; Department of Haematology, Hammersmith Hospital/Imperial College School of Medicine, London, United Kingdom; Laboratoire de Greffe de Moelle, Université Victor Segalen, Bordeaux, France; New York-Presbyterian Hospital Weill Medical College of Cornell University, New York, NY; Instituto di Ematologia, Ospedale Policlinico Sant'Orsola-Malpighi, Bologna, Italy; Universitätsklinikum, 3 Medizinische Klinik und Poliklinik, Mainz, Germany; Abteilung Hämatologie/Onkologie, Universität Leipzig, Leipzig, Germany; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI; Division of Hematology, Udine University Hospital, Udine, Italy; Division of Hematology, Universitätsklinik, Kantonspital, and Novartis Pharma, Basel, Switzerland; III Medizinische Universitätsklinik Mannheim der Universität Heidelberg, Mannheim, Germany; Department of Haematology, Royal Victoria Infirmary, University of Newcastle, United Kingdom.

The translocation (9;22) gives rise to the p190Bcr-Abl and p210Bcr-Abl tyrosine kinase proteins, considered sufficient for leukemic transformation. Philadelphia-positive (Ph+) acute leukemia patients failing to respond to initial induction therapy have a poor prognosis with few effective treatment options. Imatinib is an orally administered, potent inhibitor of the Bcr-Abl tyrosine kinase. We conducted a clinical trial in 56 patients with relapsed or refractory Ph+ acute lymphoblastic leukemia (ALL; 48 patients) or chronic myelogenous leukemia in lymphoid blast crisis (LyBC; 8 patients). Imatinib was given once daily at 400 mg or 600 mg. Imatinib induced complete hematologic responses (CHRs) and complete marrow responses (marrow-CRs) in 29% of ALL patients (CHR, 19%; marrow-CR, 10%), which were sustained for at least 4 weeks in 6% of patients. Median estimated time to progression and overall survival for ALL patients were 2.2 and 4.9 months, respectively. CHRs were reported for 3 (38%) of the patients with LyBC (one sustained CHR). Grade 3 or 4 treatment-related nonhematologic toxicity was reported for 9% of patients; none of the patients discontinued therapy because of nonhematologic adverse reactions. Grade 4 neutropenia and thrombocytopenia occurred in 54% and 27% of patients, respectively. Imatinib therapy resulted in a clinically relevant hematologic response rate in relapsed or refractory Ph+ acute lymphoid leukemia patients, but development of resistance and subsequent disease progression were rapid. Further studies are warranted to test the effects of imatinib in combination with other agents and to define the mechanisms of resistance to imatinib.

© 2002 by The American Society of Hematology.
 

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