Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia.

• DOI: 10.1200/jco.1994.12.10.2193
• Publication Date: 2017-02-23T13:09:15Z
• Authors: E K Rowinsky; A Adjei; R C Donehower; S D Gore; R J Jones; P J Burke; Y C Cheng; L B Grochow; S H Kaufmann
• Keywords: Topotecan; Mucositis; Pharmacodynamics; Refractory (planetary science); Chronic myelogenous leukemia; Ex vivo; Clonogenic assay

PURPOSE To determine the feasibility of escalating hydrophilic topoisomerase I (topo I)-inhibitor topotecan (TPT) above myelosuppressive doses in adults with refractory or relapsed acute leukemias and to assess pharmacodynamic determinants TPT action. PATIENTS AND METHODS Seventeen patients received 33 courses as a 5-day infusion at ranging from 0.70 2.7 mg/m2/d. Pharmacologic studies were performed concentrations steady-state (Css) examine parameters patients' leukemic blasts ex vivo that may be related sensitivity, eg, topo content, p-glycoprotein (Pgp) expression, inhibitory effects relevant on growth blast colonies clonogenic assays relative range Css values achieved. RESULTS Severe mucositis oropharynx perianal tissues was intolerable greater than 2.1 mg/m2/d, recommended dose for phase II leukemia. One complete response (CR) patient chronic myelogenous leukemia crisis (CML-B) one partial (PR) (AML) noted. Significant reductions circulating blast-cell numbers occurred all courses, clearance peripheral blood, albeit transient, noted 11 courses. ranged 4.8 72.5 nmol/L. Colony-forming showed LD90 (dose inhibits by 90%) varied 6 22 nmol/L, overlapped values. In view these variations several aspects I-mediated drug action also studied. 10 samples, multi-drug resistance (Mdr) modulator quinidine altered nuclear daunorubicin (DNR) accumulation whole-cell less 15%, which suggests Pgp-mediated efflux are insufficient explain fourfold sensitivities colony-forming assays. Immunohistochemistry expressed individual without detectable cell-to-cell heterogeneity each marrow. Western blots indicated content over 10-fold range. Although sample size small, appeared higher lymphoblastic (ALL), intermediate AML, lower CML-B. Topo did not appear proliferative status blasts. CONCLUSION These results indicate substantial escalation reached solid-tumor is feasible leukemia, biologically achievable, further developmental trials warranted.