Sequential oral hydroxyurea and intravenous cytosine arabinoside in refractory childhood acute leukemia: a pediatric oncology group phase 1 study.
At concentrations >0.1 mM, hydroxyurea (HU) enhances the accumulation of cytosine arabinoside (ara-C) in leukemia cells in vitro. This study of children with refractory acute leukemia was designed to take advantage of this biochemical modulation. A fixed dose of HU and an escalating dose of ara-C were used. Oral HU (1200 mg/m2) was followed 2 hours later by ara-C (250-3100 mg/m2) intravenously in 15 minutes. The combination was given on days 1, 2, 3 and 8, 9, 10. Thirty-three children [26 acute lymphocytic leukemia (ALL), 7 acute nonlymphocytic leukemia] were treated; 29 received at least 1 full course. All patients developed grade 4 cytopenias. Other grade 3 to 4 toxicities included hyperbilirubinemia (2), elevated transaminases (3), transient gait disturbance (1), stomatitis (3), typhlitis (1), nausea/vomiting (9), and marrow aplasia >4 weeks (1). Three patients had intracranial bleeds while thrombocytopenic. Only liver toxicities and nausea/vomiting exhibited any dosage effect. The maximum tolerated dose of ara-C was 2400 mg/m2. There were 6 complete responses (5 ALL), 5 partial responses (3 ALL), and 19 patients with no response or progressive disease. There was no dosage effect for response with 2 complete responses occurring at the lowest ara-C level. Responses were transient (1 to 3 mo). Twenty of twenty-six patients achieved a peak serum HU level >0.5 mM by 2 hours after the HU dose. The mean level at 2 hours was 0.57 mM (range: 0.21 to 0.99 mM). This combination of HU and ara-C is tolerable and has efficacy in refractory leukemias. Responses at the lowest ara-C dose level suggests synergism.
Dubowy
Ronald
R
Department of Pediatrics of the State University of New York, Health Science Center, Syracuse, NY, USA.
Graham
Michael
M
Hakami
Nasrollah
N
Kletzel
Morris
M
Mahoney
Donald
D
Newman
Edward
E
Ravindranath
Yaddanapudi
Y
Camitta
Bruce
B
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage / Q000633:toxicity*; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000633:toxicity*; D007239:Infections / Q000453:epidemiology; D007938:Leukemia / Q000188:drug therapy* / Q000401:mortality; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000401:mortality; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000401:mortality; D008099:Liver / Q000187:drug effects / Q000473:pathology; D012867:Skin / Q000187:drug effects / Q000473:pathology; D016019:Survival Analysis
D003561:Cytarabine; D006918:Hydroxyurea