Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia.
OBJECTIVE
To determine the feasibility of escalating the hydrophilic topoisomerase I (topo I)-inhibitor topotecan (TPT) above myelosuppressive doses in adults with refractory or relapsed acute leukemias and to assess pharmacodynamic determinants of TPT action.


METHODS
Seventeen patients received 33 courses of TPT as a 5-day infusion at doses ranging from 0.70 to 2.7 mg/m2/d. Pharmacologic studies were performed to determine the TPT concentrations at steady-state (Css) and to examine parameters in the patients' leukemic blasts ex vivo that may be related to TPT sensitivity, eg, topo I content, p-glycoprotein (Pgp) expression, and the inhibitory effects of relevant TPT concentrations on the growth of blast colonies in clonogenic assays relative to the range of TPT Css values achieved.


RESULTS
Severe mucositis of the oropharynx and perianal tissues was intolerable at TPT doses greater than 2.1 mg/m2/d, the recommended dose for phase II studies in leukemia. One complete response (CR) in a patient with chronic myelogenous leukemia in blast crisis (CML-B) and one partial response (PR) in a patient with acute myelogenous leukemia (AML) were noted. Significant reductions in circulating blast-cell numbers occurred in all courses, and complete leukemia clearance from the peripheral blood, albeit transient, was noted in 11 courses. TPT Css values ranged from 4.8 to 72.5 nmol/L. Colony-forming assays showed that the TPT LD90 (dose that inhibits the growth of leukemia blast colonies by 90%) values for blasts varied from 6 to 22 nmol/L, a range that overlapped with TPT Css values. In view of these variations in TPT sensitivity, several aspects of topo I-mediated drug action were also studied. In 10 of 11 samples, the multi-drug resistance (Mdr) modulator quinidine altered nuclear daunorubicin (DNR) accumulation and whole-cell TPT accumulation by less than 15%, which suggests that Pgp-mediated effects on drug efflux are insufficient to explain the fourfold range of TPT sensitivities in the colony-forming assays. Immunohistochemistry showed that topo I was expressed in all of the blasts from individual patients without detectable cell-to-cell heterogeneity in each marrow. Western blots indicated that topo I content varied over a 10-fold range. Although the sample size was small, topo I content appeared to be higher in acute lymphoblastic leukemia (ALL), intermediate in AML, and lower in CML-B. Topo I content did not appear to be related to the proliferative status of the blasts.


CONCLUSIONS
These results indicate that substantial dose escalation of TPT above myelosuppressive doses reached in solid-tumor patients is feasible in patients with refractory leukemia, that biologically relevant TPT Css values are achievable, and that further developmental trials are warranted.
Rowinsky
E K
EK
Division of Pharmacology, Johns Hopkins Oncology Center, Baltimore, MD 21287-8934.
Adjei
A
A
Donehower
R C
RC
Gore
S D
SD
Jones
R J
RJ
Burke
P J
PJ
Cheng
Y C
YC
Grochow
L B
LB
Kaufmann
S H
SH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000208:Acute Disease; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D015153:Blotting, Western; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D003630:Daunorubicin / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D018432:Drug Resistance, Multiple; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa; D011802:Quinidine / Q000494:pharmacology; D012074:Remission Induction; D013280:Stomatitis / Q000139:chemically induced; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D014410:Tumor Stem Cell Assay
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D011802:Quinidine; D002166:Camptothecin; D003630:Daunorubicin