Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia

Scott H Kaufmann, Judith E. Karp, Mark R Litzow, Ruben A. Mesa, William Hogan, David P. Steensma, Karen S. Flatten, David A. Loegering, Paula A. Schneider, Kevin L. Peterson, Matthew J. Maurer, B. Douglas Smith, Jacqueline Greer, Yuhong Chen, Joel M Reid, S. Percy Ivy, Matthew M. Ames, Alex Adjei, Charles Erlichman, Larry M Karnitz

Research output: Contribution to journalArticle

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Abstract

Background In preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced downregulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia. Design and Methods Patients received cytarabine 400 mg/m 2/day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients. Results Twenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m 2/day for 5 days along with tanespimycin 300 mg/m 2 on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17-aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80% of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest. Conclusions Because exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine.

Original languageEnglish (US)
Pages (from-to)1619-1626
Number of pages8
JournalHaematologica
Volume96
Issue number11
DOIs
StatePublished - Nov 1 2011

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tanespimycin
Cytarabine
Leukemia
Pharmacology
HSP90 Heat-Shock Proteins
Down-Regulation
Proteins
Maximum Tolerated Dose
Disseminated Intravascular Coagulation
Adult Respiratory Distress Syndrome
Immunoblotting

Keywords

  • Acute leukemia
  • Cytarabine
  • Pharmacological study
  • Phase I study
  • Tanespimycin

ASJC Scopus subject areas

  • Hematology

Cite this

Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia. / Kaufmann, Scott H; Karp, Judith E.; Litzow, Mark R; Mesa, Ruben A.; Hogan, William; Steensma, David P.; Flatten, Karen S.; Loegering, David A.; Schneider, Paula A.; Peterson, Kevin L.; Maurer, Matthew J.; Smith, B. Douglas; Greer, Jacqueline; Chen, Yuhong; Reid, Joel M; Ivy, S. Percy; Ames, Matthew M.; Adjei, Alex; Erlichman, Charles; Karnitz, Larry M.

In: Haematologica, Vol. 96, No. 11, 01.11.2011, p. 1619-1626.

Research output: Contribution to journalArticle

Kaufmann, SH, Karp, JE, Litzow, MR, Mesa, RA, Hogan, W, Steensma, DP, Flatten, KS, Loegering, DA, Schneider, PA, Peterson, KL, Maurer, MJ, Smith, BD, Greer, J, Chen, Y, Reid, JM, Ivy, SP, Ames, MM, Adjei, A, Erlichman, C & Karnitz, LM 2011, 'Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia', Haematologica, vol. 96, no. 11, pp. 1619-1626. https://doi.org/10.3324/haematol.2011.049551
Kaufmann, Scott H ; Karp, Judith E. ; Litzow, Mark R ; Mesa, Ruben A. ; Hogan, William ; Steensma, David P. ; Flatten, Karen S. ; Loegering, David A. ; Schneider, Paula A. ; Peterson, Kevin L. ; Maurer, Matthew J. ; Smith, B. Douglas ; Greer, Jacqueline ; Chen, Yuhong ; Reid, Joel M ; Ivy, S. Percy ; Ames, Matthew M. ; Adjei, Alex ; Erlichman, Charles ; Karnitz, Larry M. / Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia. In: Haematologica. 2011 ; Vol. 96, No. 11. pp. 1619-1626.
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abstract = "Background In preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced downregulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia. Design and Methods Patients received cytarabine 400 mg/m 2/day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients. Results Twenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m 2/day for 5 days along with tanespimycin 300 mg/m 2 on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17-aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80{\%} of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest. Conclusions Because exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine.",
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T1 - Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia

AU - Kaufmann, Scott H

AU - Karp, Judith E.

AU - Litzow, Mark R

AU - Mesa, Ruben A.

AU - Hogan, William

AU - Steensma, David P.

AU - Flatten, Karen S.

AU - Loegering, David A.

AU - Schneider, Paula A.

AU - Peterson, Kevin L.

AU - Maurer, Matthew J.

AU - Smith, B. Douglas

AU - Greer, Jacqueline

AU - Chen, Yuhong

AU - Reid, Joel M

AU - Ivy, S. Percy

AU - Ames, Matthew M.

AU - Adjei, Alex

AU - Erlichman, Charles

AU - Karnitz, Larry M

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N2 - Background In preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced downregulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia. Design and Methods Patients received cytarabine 400 mg/m 2/day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients. Results Twenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m 2/day for 5 days along with tanespimycin 300 mg/m 2 on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17-aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80% of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest. Conclusions Because exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine.

AB - Background In preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced downregulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia. Design and Methods Patients received cytarabine 400 mg/m 2/day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients. Results Twenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m 2/day for 5 days along with tanespimycin 300 mg/m 2 on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17-aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80% of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest. Conclusions Because exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine.

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KW - Cytarabine

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