Oral etoposide in patients with hematological malignancies: a clinical and pharmacokinetic study

Tumor responses after daily oral administration of low-dose etoposide have been demonstrated in both hematological and solid tumors. The aim of the present phase II trial was to determine tumor response, and toxicity and to delineate the pharmacokinetics of oral low-dose etoposide in patients with hematological malignancies in a palliative treatment setting. Thirty-two patients with non-Hodgkin's lymphoma (NHL), acute myeloblastic (AML) and lymphoblastic leukemia, multiple myeloma, and myelodysplastic syndrome (MDS) were included. Patients were given oral etoposide, 100 mg once daily for 14 d in a 21-d cycle. Serum etoposide concentrations were determined on d 1, 7, and 14 of every cycle before etoposide administration and, in addition, 1, 2, 3, 4, and 24 h after drug intake on d 1. The median age of patients was 68 yr (range: 50-89 yr). The median time from diagnosis to inclusion in the study was 21 mo (range: 0.5-144 mo) and most patients had advanced disease and were heavily pretreated. Eleven patients completed three or more cycles. Eight of 11 patients with acute leukemia and 1 of 2 with MDS received only 1 course because of toxicity (n = 5) or progression (n = 4). One patient with AML, a Jehovah's Witness, was treated up-front and achieved a complete remission and two patients with low-grade NHL gained a complete and a partial remission, respectively. Twenty-one of 32 patients were evaluable for toxicity during the first cycle. In 67%, the white blood cell count nadir was < 2.0 x 109/L and in 38% < 1.0 x 10(9)/L. Platelet count nadir was less than 25 x 10(9)/L in 24% of evaluable patients. During all cycles (n = 79), eight patients developed febrile neutropenia, four of whom with a fatal outcome. The correlation between the area under the curve (AUC) of the free fraction of etoposide and leukopenia was statistically significant at a log analysis (n = 12; p < 0.05). There was also a statistically significant correlation between the AUC and the 24-h concentration (n = 15; p < 0.005) and between the concentrations at 24 h and d 7 (n = 11; p < 0.005) of the free fractions of etoposide. In conclusion, etoposide had a moderate clinical effect in this group of heavily pretreated patients. Moreover, toxicity was substantial, in particular leukopenia, which correlated to the free-etoposide AUC.