A pilot study of high-dose 1-beta-D-arabinofuranosylcytosine for acute leukemia and refractory lymphoma: clinical response and pharmacology.
1-beta-D-Arabinofuranosylcytosine (ara-C), 2 or 3 g/sq m, was administered as a 1-hr i.v. infusion every 12 hr for 10 or 12 doses to patients with acute leukemia and refractory lymphoma. Four of seven patients with relapsed or refractory acute myelocytic leukemia and two of four patients with previously untreated acute myelocytic leukemia achieved complete remission. Of five treatment failures, two patients had leukemia which was clearly resistant to high-dose ara-C, and three patients died of infections or hemorrhagic complications during periods of pancytopenia. Three patients with acute myelocytic leukemia in remission received high-dose ara-C as consolidation therapy following previous courses of intensive, multiagent consolidation chemotherapy. Two of these three patients had prolonged thrombocytopenia following high-dose ara-C. Five patients with refractory acute lymphocytic leukemia were treated. Three patients achieved partial remission, and two patients had drug-resistant disease. Complete or partial disappearance of measurable disease parameters was seen in three of three patients with refractory lymphoma. Response was seen in five of five patients with meningeal leukemia, including complete response in one patient with extensive meningeal infiltration. Toxicity of this regimen was generally moderate and limited to pancytopenia and mild nausea. Patients who had received prior multiagent consolidation chemotherapy appeared to be at greater risk for hematopoietic toxicity. Patients who had received prior cranial irradiation or intrathecal chemotherapy appeared to be at greater risk for neurological toxicity. Plasma levels of ara-C immediately after completion of the infusion were 17.96 +/- 8.02 (S.D.) and 35.0 +/- 2.8 micrograms/ml for doses of 2 and 3 g/sq m, respectively. From 160 to 720 min following completion of the infusion, the plasma levels of drug were comparable to steady-state levels achieved with a continuous infusion of ara-C at 100 mg/sq m over 24 hr. A high degree of penetration into the central nervous system was demonstrated. High-dose ara-C has substantial activity against leukemic and lymphomatous cell populations, including cell populations resistant to conventional doses of the drug, and is an effective treatment modality for patients with these diseases. The high degree of penetration into the central nervous system suggests that this drug regimen may be useful as consolidation therapy for patients at high risk for central nervous system disease.
D000293:Adolescent; D000328:Adult; D000368:Aged; D001769:Blood / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy; D002648:Child; D003561:Cytarabine / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D004341:Drug Evaluation; D005123:Eye / Q000187:drug effects; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D007945:Leukemia, Lymphoid / Q000188:drug therapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008223:Lymphoma / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects
D003561:Cytarabine