Phase I and pharmacologic study of infusional topotecan and carboplatin in relapsed and refractory acute leukemia

Scott H. Kaufmann, Judith Karp, Louis Letendre, Timothy J. Kottke, Stephanie Safgren, Jackie Greer, Ivana Gojo, Pamela Atherton, Phyllis A. Svingen, David A. Loegering, Mark R. Litzow, Jeff A. Sloan, Joel M. Reid, Matthew M. Ames, Alex A. Adjei, Charles Erlichman

Research output: Contribution to journalArticle

Abstract

Purpose: To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias. Experimental Design: 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.

Original languageEnglish (US)
Pages (from-to)6641-6649
Number of pages9
JournalClinical Cancer Research
Volume11
Issue number18
DOIs
StatePublished - Sep 15 2005
Externally publishedYes

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Topotecan
Carboplatin
Leukemia
Maximum Tolerated Dose
Platinum
Checkpoint Kinase 2
Typhlitis
Leukemia, Myeloid, Chronic Phase
Type I DNA Topoisomerase
Mucositis
Proliferating Cell Nuclear Antigen
Nonparametric Statistics
Neutropenia
Immunoblotting
Research Design
Therapeutics
Pharmacokinetics
Peptides
Population

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I and pharmacologic study of infusional topotecan and carboplatin in relapsed and refractory acute leukemia. / Kaufmann, Scott H.; Karp, Judith; Letendre, Louis; Kottke, Timothy J.; Safgren, Stephanie; Greer, Jackie; Gojo, Ivana; Atherton, Pamela; Svingen, Phyllis A.; Loegering, David A.; Litzow, Mark R.; Sloan, Jeff A.; Reid, Joel M.; Ames, Matthew M.; Adjei, Alex A.; Erlichman, Charles.

In: Clinical Cancer Research, Vol. 11, No. 18, 15.09.2005, p. 6641-6649.

Research output: Contribution to journalArticle

Kaufmann, SH, Karp, J, Letendre, L, Kottke, TJ, Safgren, S, Greer, J, Gojo, I, Atherton, P, Svingen, PA, Loegering, DA, Litzow, MR, Sloan, JA, Reid, JM, Ames, MM, Adjei, AA & Erlichman, C 2005, 'Phase I and pharmacologic study of infusional topotecan and carboplatin in relapsed and refractory acute leukemia', Clinical Cancer Research, vol. 11, no. 18, pp. 6641-6649. https://doi.org/10.1158/1078-0432.CCR-05-0817
Kaufmann, Scott H. ; Karp, Judith ; Letendre, Louis ; Kottke, Timothy J. ; Safgren, Stephanie ; Greer, Jackie ; Gojo, Ivana ; Atherton, Pamela ; Svingen, Phyllis A. ; Loegering, David A. ; Litzow, Mark R. ; Sloan, Jeff A. ; Reid, Joel M. ; Ames, Matthew M. ; Adjei, Alex A. ; Erlichman, Charles. / Phase I and pharmacologic study of infusional topotecan and carboplatin in relapsed and refractory acute leukemia. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 18. pp. 6641-6649.
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T1 - Phase I and pharmacologic study of infusional topotecan and carboplatin in relapsed and refractory acute leukemia

AU - Kaufmann, Scott H.

AU - Karp, Judith

AU - Letendre, Louis

AU - Kottke, Timothy J.

AU - Safgren, Stephanie

AU - Greer, Jackie

AU - Gojo, Ivana

AU - Atherton, Pamela

AU - Svingen, Phyllis A.

AU - Loegering, David A.

AU - Litzow, Mark R.

AU - Sloan, Jeff A.

AU - Reid, Joel M.

AU - Ames, Matthew M.

AU - Adjei, Alex A.

AU - Erlichman, Charles

PY - 2005/9/15

Y1 - 2005/9/15

N2 - Purpose: To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias. Experimental Design: 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.

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