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We reported marked biologic activity with the epipodophyllotoxins in phase I/II studies of childhood cancer conducted in the 1970s. We have since extensively used the combination of teniposide and ara-C in the treatment of acute lymphoblastic leukemia (ALL). Initially we treated patients with refractory disease and found that the combination lacked clinical cross-resistance with standard antileukemic drugs. This formed a rationale to move teniposide and/or etoposide to front-line therapy of childhood ALL. The superior results projected for our last trial, an overall cure rate of about 75%, are attributable in part to early use of epipodophyllotoxins. This class of agents is also used extensively in the treatment of newly diagnosed childhood solid tumors, including neuroblastoma, medulloblastoma, rhabdomyosarcoma, and germ-cell tumors. Secondary leukemias following treatment with epipodophyllotoxins have been reported in a small subset of patients. Current data show that the most important risk factor is the schedule of drug delivery, which has led to appropriate protocol modifications.

We describe the development of VM-26 (teniposide) as an effective agent in combination chemotherapy for childhood acute lymphocytic leukemia (ALL). Beginning with its paired use with cytarabine for patients relapsing on conventional therapy, teniposide has shown consistent ability to reduce leukemic cell populations not responsive to other agents. Encouraging results in the treatment of refractory ALL led to the decision to incorporate teniposide into combination chemotherapy for patients with newly diagnosed leukemia. This strategy has yielded higher cure rates for subsets of patients at high risk of treatment failure, including those with initial leukocyte counts of more than 100 x 10(9)/L, and may extend remission lengths for all patients, regardless of risk status. In view of the prolonged marrow aplasia seen with use of teniposide and cytarabine as inducing agents, the optimal role of this combination may be that of "remission reinforcement" therapy. Because of its novel mechanism of action, teniposide affords opportunities to develop new drug combinations that may increase the proportion of long-term ALL survivors still further.

Teniposide, a widely used investigational anticancer drug, is extensively bound to plasma proteins (greater than 95%). The present study evaluated the clearance and pharmacodynamics of total and unbound teniposide in patients with acute lymphocytic leukemia who were either in first complete remission or who had relapsed and achieved a subsequent complete remission. When compared to values of patients in first remission, the mean total systemic clearance of teniposide in relapsed patients was significantly lower at the time remission reinduction therapy was initiated, but increased to values greater than first remission patients after a subsequent remission was achieved. However, the mean clearance of unbound teniposide (ml/min/m2) was 3-fold lower in relapsed patients during reinduction therapy (1224 vs. 4261, P less than .0001), and improved but remained low after these patients achieved a subsequent remission (1965, P = .025). Changes in plasma protein binding accounted for the increase in total clearance when unbound clearance decreased. Continuous therapy with L-asparaginase was the major treatment difference in those patients with hypoalbuminemia and lower clearance of unbound teniposide. In 15 evaluable patients in complete remission, there was a statistically significant (P = .039) linear correlation between the percentage decrease in white blood cell count and the systemic exposure (AUC) to unbound teniposide, with higher exposure associated with a greater decrease in white blood cell count. There was not a significant correlation between the percent decrease in white blood cell count and the dosage given or the systemic exposure to total teniposide.(ABSTRACT TRUNCATED AT 250 WORDS)

Teniposide is a widely used anticancer drug that is extensively bound to plasma proteins (greater than 95%). We evaluated the drug's plasma protein binding in nine patients with acute lymphocytic leukemia who were in their first complete remission, and in a second group of nine patients at the time of relapse and subsequently after achieving another complete remission. Plasma protein binding was assessed by equilibrium dialysis, with direct high-performance liquid chromatographic measurement of total and free teniposide. The mean unbound fraction was 0.44% (0.21-0.88%) in the plasma of patients in first remission. It was significantly higher in patients at the time of relapse (mean = 0.86%; range 0.68-1.08%) and after achieving another complete remission (mean = 1.25%; range 0.51-2.11%). Serum albumin values were significantly lower at the time of relapse (mean = 4.6 vs 4.0 mg/dl; p less than 0.014), and decreased further during intensive postremission therapy containing L-asparaginase (mean = 3.2; p less than 0.05). For all 18 patients, a significant negative correlation (r2 = 0.667; p less than 0.001) was found between serum albumin and unbound teniposide, with low albumin being associated with higher unbound fraction. Such patients have higher systemic exposure to unbound (presumably active) teniposide at any given total plasma concentration of the agent.

The incidence, clinical characteristics, and outcome of hypersensitivity reactions to teniposide (VM-26), etoposide (VP-16), or both were determined in 108 children with acute lymphoblastic leukemia (ALL) treated with a contemporary regimen of intensive multiagent chemotherapy. Fifty (46%) of the 108 patients had one or more hypersensitivity reactions. The risk of any child having an initial reaction over the cumulative dose range studied was 52% (95% confidence limits, 41% and 63%) for VM-26, compared with 34% (95% confidence limits, 24% and 44%) for VP-16. The risk of having an initial reaction to VM-26 or VP-16 was clearly related to the cumulative dose. This risk peaked at 1500 to 2000 mg/m2 for VM-26 and at 2000-3000 mg/m2 for VP-16. All reactions were Type 1 reactions according to the Gell and Coombs classification, characterized by urticaria, angioedema, flushing, rashes, or hypotension, and 86% of reactions were of Grade 1 or 2 severity according to standard criteria. There was no evidence of increasing clinical severity on repeated rechallenge with premedication, and no deaths occurred. The findings suggested that hypersensitivity reactions to epipodophyllotoxins in children with ALL are more common than previously reported, but only rarely constitute dose-limiting toxicity.

Laboratory studies have demonstrated the ability of teniposide to markedly enhance the intracellular accumulation of methotrexate suggesting that combination therapy with these agents may produce clinical benefit. Studies of methotrexate and teniposide were conducted in 19 children with relapsed acute lymphocytic leukemia to evaluate the pharmacokinetics of this previously untested combination of agents given alone or in combination and to demonstrate the feasibility of a Bayesian dose optimization strategy. Patients were randomly assigned to receive intermediate dose methotrexate as a 24-h continuous infusion, administered either simultaneously with continuous infusion teniposide or sequentially with the teniposide infusion beginning 12 h after the end of the methotrexate infusion. Plasma samples were obtained during and after infusions at appropriate times for a comprehensive pharmacokinetic study of each drug. Two measured drug concentrations obtained during the infusion were used to adjust each patient's dose rate to achieve target values of 10 microM for methotrexate and 15 microM for teniposide. Pharmacokinetic parameters for teniposide were not different for patients given simultaneous methotrexate from parameters estimated for patients receiving teniposide 12 h after the end of the methotrexate infusion. Despite similar end of infusion methotrexate concentrations, 24-h postinfusion methotrexate concentrations were lower (0.137 versus 0.235 microM; P less than 0.05) in the patients receiving simultaneous infusions. The patient specific dose regimens yielded acceptably precise, minimally biased steady state drug concentrations. These pharmacokinetic results provide the basis for further clinical studies with this combination of antileukemic agents.

Teniposide (VM-26) is an effective anticancer drug usually administered as a short infusion in doses of 150 to 165 mg/m2. The objectives of the trial reported here were to evaluate clinical responses and assess pharmacokinetic parameters as a determinant of outcome when VM-26 was administered as a 72-hour continuous infusion (CI) with doses escalated from 300 to 750 mg/m2 per course. Twenty-eight patients with recurrent leukemia, lymphoma, or neuroblastoma received 53 courses of CI VM-26 and 16 had measurable responses. There were two partial remissions and one stable disease among seven neuroblastoma patients and 13 of 21 leukemia/lymphoma patients had oncolytic responses (greater than or equal to 75% decrease in circulating blasts). Toxicity included moderate to severe mucositis and myelosuppression. Pharmacokinetic parameters determined during 35 courses administered to 23 patients were highly variable. Clearance (CI) ranged between 3.7 and 43.8 ml/min/m2, resulting in VM-26 plasma concentrations from 2.8 to 30.6 mg/L across all dose levels. The interpatient pharmacokinetic variability reflected in CI and VM-26 steady state concentrations (Css), obscured any dose-response relationship. However, when pharmacokinetic parameters for responding and nonresponding patients were compared, statistically significant relationships were observed. For responders, the mean Css was 15.2 mg/L and mean CI was 12.1 mL/min/m2; for nonresponders, mean Css was 6.2 mg/L (P less than .01) and mean CI was 21.3 mL/min/m2 (P less than .05). Thus, patients with higher CI and lower Css were less likely to respond. Clinical responses occurred in ten of ten patients with Css greater than 12 mg/L, and only five of 13 patients with Css less than 12 mg/L (P less than .01). In this study, interpatient pharmacokinetic variability yielded a four- to sixfold difference in intensity of systemic exposure (Css) within the same dose level, which was an important determinant of clinical response. These data indicate that achieving a VM-26 target concentration for individual patients could ensure an increased intensity of systemic exposure in patients with a high CI and improve the likelihood of effective therapy.