Phase I trial of sequential topotecan followed by etoposide in adults with myeloid leukemia: a National Cancer Institute of Canada Clinical Trials Group Study

Abstract

Prolonged exposure to a topoisomerase I inhibitor may increase expression of topoisomerase II, making cells more susceptible inhibitors of that enzyme. This study was undertaken to establish the maximum tolerated dose (MTD) of a topotecan/topoisomerase II inhibitor sequential combination that may be active in acute leukemia, and to evaluate the effects of in vivo exposure to topotecan on topoisomerase II levels in leukemic blast cells as measured by image cytometry. Patients who were eligible for this phase I study had relapsed or refractory acute myeloid leukemia (⩽2 prior regimens) or CML blast crisis (0 or 1 prior regimen). Topotecan was given as a 5 day continuous i.v. infusion and was to be escalated through three levels (1.5, 1.75 and 2.0 mg/m² day), followed by etoposide at two dose levels (100 and 150 mg/m²) i.v. bolus days 6, 7 and 8. Topoisomerase IIαlevels in leukemic blasts from bone marrow were measured by image cytometry prior to starting treatment, on day 5 of topotecan infusion and on day 28; and daily during topotecan in peripheral blood blasts. Dose-limiting toxicity was seen in two of six patients at the first dose level (topotecan 1.5 mg/m²/day, etoposide 100 mg/m²/day; ⩾grade 3 mucositis in both cases). This cohort was expanded to 10 patients; no further non-hematologic dose-limiting toxicity was observed, but given the extent of toxicity seen, further dose escalation was judged not to be feasible. Topo IIαox levels increased in peripheral blood blasts during the first 72 h of topotecan infusion and returned to near baseline by day 5, whereas levels appeared to decrease in bone marrow blasts by day 5 compared to pretreatment. One complete hematologic and cytogenetic remission in a patient with CML blast crisis was observed in the 10 patients evaluable for response. The sequential administration of topotecan 1.5 mg/m²/day con- tinuous infusion for 5 days followed by etoposide 100 mg/m²/day × 3 is the recommended phase II dose for this schedule. Topotecan increases topo IIα expression in vivo in leukemia cells, but levels of the enzyme are cell cycle dependent. Pharmacodynamic evaluation of the sequential or combination administration of novel antileukemic agents may help improve treatment strategies in acute leukemia.