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

• 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
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-08-107482

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.