Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia

The HOVON cooperative study group performed a feasibility study of escalated imatinib and intravenous cytarabine in 165 patients with early chronic-phase chronic myeloid leukemia (CML). Patients received 2 cycles of intravenous cytarabine (200 mg/m2 or 1000 mg/m2 days 1-7) in conjunction with imatin...

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Published in:	Blood Vol. 111; no. 5; pp. 2581 - 2588
Main Authors:	Deenik, Wendy, van der Holt, Bronno, Verhoef, Gregor E.G., Smit, Willem M., Kersten, Marie J., Kluin-Nelemans, Hanneke C., Verdonck, Leo F., Ferrant, Augustin, Schattenberg, Anton V. M.B., Janssen, Jeroen J. W.M., Sonneveld, Pieter, van Marwijk Kooy, Marinus, Wittebol, Shulamit, Willemze, Roelof, Wijermans, Pierre W., Westveer, Petra H.M., Beverloo, H. Berna, Valk, Peter, Löwenberg, Bob, Ossenkoppele, Gert J., Cornelissen, Jan J.
Format:	Journal Article
Language:	English
Published:	Washington, DC Elsevier Inc 01-03-2008 The Americain Society of Hematology
Subjects:	Adult Aged Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Antineoplastic Agents - therapeutic use Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use Benzamides Biological and medical sciences Communicable Diseases - complications Cytarabine - administration & dosage Cytarabine - adverse effects Cytarabine - therapeutic use Cytogenetic Analysis Dose-Response Relationship, Drug Feasibility Studies Female Hematologic and hematopoietic diseases Hematologic Tests Humans Imatinib Mesylate Injections, Intravenous Leukemia, Myelogenous, Chronic, BCR-ABL Positive - diagnosis Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy Leukemia, Myelogenous, Chronic, BCR-ABL Positive - mortality Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Male Medical sciences Middle Aged Mortality Piperazines - administration & dosage Piperazines - adverse effects Piperazines - therapeutic use Pyrimidines - administration & dosage Pyrimidines - adverse effects Pyrimidines - therapeutic use Antineoplastic agent Human Drug combination Imatinib Intravenous administration Hematology Enzyme Tyrosine kinase inhibitor Transferases Enzyme inhibitor Chronic myelogenous leukemia Early stage Malignant hemopathy Myeloproliferative syndrome Cytarabine Antimetabolic Feasibility Pyrimidine nucleoside Dose Protein-tyrosine kinase Cancer
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Summary:	The HOVON cooperative study group performed a feasibility study of escalated imatinib and intravenous cytarabine in 165 patients with early chronic-phase chronic myeloid leukemia (CML). Patients received 2 cycles of intravenous cytarabine (200 mg/m2 or 1000 mg/m2 days 1-7) in conjunction with imatinib (200 mg, 400 mg, 600 mg, or 800 mg), according to predefined, successive dose levels. All dose levels proved feasible. Seven dose-limiting toxicities (DLTs) were observed in 302 cycles of chemotherapy, which were caused by streptococcal bacteremia in 5 cases. Intermediate-dose cytarabine (1000 mg/m2) prolonged time to neutrophil recovery and platelet recovery compared with a standard dose (200 mg/m2). High-dose imatinib (600 mg or 800 mg) extended the time to platelet recovery compared with a standard dose (400 mg). More infectious complications common toxicity criteria (CTC) grade 3 or 4 were observed after intermediate-dose cytarabine compared with a standard-dose of cytarabine. Early response data after combination therapy included a complete cytogenetic response in 48% and a major molecular response in 30% of patients, which increased to 46% major molecular responses at 1 year, including 13% complete molecular responses. We conclude that combination therapy of escalating dosages of imatinib and cytarabine is feasible. This study was registered at www.kankerbestrijding.nl as no. CKTO-2001-03.
ISSN:	0006-4971 1528-0020
DOI:	10.1182/blood-2007-08-107482