Phase I and pharmacologic study of infusional topotecan and Carboplatin in relapsed and refractory acute leukemia.
OBJECTIVE
To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias.


METHODS
Patients received topotecan and carboplatin by 5-day continuous infusion at nine dose levels. Patients achieving a complete remission received up to two additional courses for consolidation. Plasma topotecan and ultrafilterable platinum were assayed on days 1 to 5. In addition, pretreatment levels of various polypeptides in leukemic cells were examined by immunoblotting to assess possible correlations with response.


RESULTS
Fifty-one patients received a total of 69 courses of therapy. Dose-limiting toxicity consisted of grade 4/5 typhlitis and grade 3/4 mucositis after one course of therapy or grade 4 neutropenia and thrombocytopenia lasting >50 days when a second course was administered on day 21. Among 45 evaluable patients, there were 7 complete remissions, 2 partial remissions, 1 incomplete complete remission, and 1 reversion to chronic-phase chronic myelogenous leukemia. Topotecan steady-state plasma concentrations increased with dose. No accumulation of topotecan or ultrafilterable platinum occurred between days 1 and 5 of therapy. Leukemic cell levels of topoisomerase I, checkpoint kinase 1, checkpoint kinase 2, and Mcl-1 correlated with proliferating cell nuclear antigen but not with response. In contrast, low Bcl-2 expression correlated with response (P = 0.014, Mann-Whitney U test).


CONCLUSIONS
The maximum tolerated dose was 1.6 mg/m(2)/d topotecan plus 150 mg/m(2)/d carboplatin. The complete remission rate in a heavily pretreated population was 16% (33% at the highest three dose levels). Responses seem to correlate with low pretreatment blast cell Bcl-2 expression.
Kaufmann
Scott H
SH
Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55901, USA. kaufmann.scott@mayo.edu
Karp
Judith E
JE
Letendre
Louis
L
Kottke
Timothy J
TJ
Safgren
Stephanie
S
Greer
Jackie
J
Gojo
Ivana
I
Atherton
Pamela
P
Svingen
Phyllis A
PA
Loegering
David A
DA
Litzow
Mark R
MR
Sloan
Jeff A
JA
Reid
Joel M
JM
Ames
Matthew M
MM
Adjei
Alex A
AA
Erlichman
Charles
C
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018797:Cell Cycle Proteins / Q000378:metabolism; D003131:Combined Modality Therapy; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D018922:HL-60 Cells; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015151:Immunoblotting; D007262:Infusions, Intravenous; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
D018797:Cell Cycle Proteins; D018809:Proliferating Cell Nuclear Antigen; D019772:Topotecan; D016190:Carboplatin; D004264:DNA Topoisomerases, Type I