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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.
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