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/m(2) or 1000 mg/m(2) 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/m(2)) prolonged time to neutrophil recovery and platelet recovery compared with a standard dose (200 mg/m(2)). 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.
Deenik
Wendy
W
Department of Hematology, Erasmus University Medical Center, Groene Hilledijk 301, Rotterdam, The Netherlands.
van der Holt
Bronno
B
Verhoef
Gregor E G
GE
Smit
Willem M
WM
Kersten
Marie J
MJ
Kluin-Nelemans
Hanneke C
HC
Verdonck
Leo F
LF
Ferrant
Augustin
A
Schattenberg
Anton V M B
AV
Janssen
Jeroen J W M
JJ
Sonneveld
Pieter
P
van Marwijk Kooy
Marinus
M
Wittebol
Shulamit
S
Willemze
Roelof
R
Wijermans
Pierre W
PW
Westveer
Petra H M
PH
Beverloo
H Berna
HB
Valk
Peter
P
Löwenberg
Bob
B
Ossenkoppele
Gert J
GJ
Cornelissen
Jan J
JJ
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001549:Benzamides; D003141:Communicable Diseases / Q000150:complications; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D020732:Cytogenetic Analysis; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005260:Female; D006403:Hematologic Tests; D006801:Humans; D000068877:Imatinib Mesylate; D007275:Injections, Intravenous; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009026:Mortality; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D003561:Cytarabine; D000068877:Imatinib Mesylate