Phase I and pharmacokinetic study of bortezomib in combination with idarubicinand cytarabine in patients with acute myelogenous leukemia

Eyal C. Attar, Daniel J. DeAngelo, Jeffrey G. Supko, Ferdinando D'Amato, David Zahrieh, Andres Sirulnik, Martha Wadleigh, Karen K. Ballen, Steve McAfee, Kenneth B. Miller, James Levine, Ilene Galinsky, Elizabeth G. Trehu, David Schenkein, Donna Neuberg, Richard M. Stone, Philip C. Amrein

Research output: Contribution to journalArticle

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Abstract

Purpose: Proteasome inhibition results in cytotoxicity to the leukemia stem cell in vitro. We conducted this phase I study to determine if the proteasome inhibitor bortezomib could be safely added to induction chemotherapy in patients with acute myelogenous leukemia (AML). Experimental Design: Bortezomib was given on days 1, 4, 8, and 11 at doses of 0.7, 1.0, 1.3, or 1.5 mg/m2 with idarubicin 12 mg/m2 on days 1 to 3 and cytarabine 100 mg/m 2/day on days 1 to 7. Results: A total of 31 patients were enrolled. The median age was 62 years, and 16 patients were male. Nine patients had relapsed AML (ages, 18-59 years, n = 4 and ≥60 years, n = 5). There were 22 patients of ≥60 years with previously untreated AML (eight with prior myelodysplasia/myeloproliferative disorder or cytotoxic therapy). All doses of bortezomib, up to and including 1.5 mg/m2, were tolerable. Nonhematologic grade 3 or greater toxicities included 12 hypoxia (38%; 11 were grade 3), 4 hyperbilirubinemia (13%), and 6 elevated aspartate aminotransferase (19%). Overall, 19 patients (61%) achieved complete remission (CR) and three had CR with incomplete platelet recovery. Pharmacokinetic studies revealed that the total body clearance of bortezomib decreased significantly (P < 0.01, N = 26) between the first (mean ± SD, 41.9 ± 17.1 L/h/m2) and th ird (18.4 ± 7.0 L/h/m2) doses. Increased bone marrow expression of CD74 was associated with CR. Conclusions: The combination of bortezomib, idarubicin, and cytarabine showed a good safety profile. The recommended dose of bortezomib for phase II studies with idarubicin and cytarabine is 1.5 mg/m2.

Original languageEnglish (US)
Pages (from-to)1446-1454
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number5
DOIs
StatePublished - Mar 1 2008
Externally publishedYes

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Cytarabine
Acute Myeloid Leukemia
Pharmacokinetics
Idarubicin
Myeloproliferative Disorders
Induction Chemotherapy
Proteasome Inhibitors
Hyperbilirubinemia
Proteasome Endopeptidase Complex
Aspartate Aminotransferases
Bortezomib
Leukemia
Research Design
Stem Cells
Blood Platelets
Bone Marrow
Safety

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase I and pharmacokinetic study of bortezomib in combination with idarubicinand cytarabine in patients with acute myelogenous leukemia. / Attar, Eyal C.; DeAngelo, Daniel J.; Supko, Jeffrey G.; D'Amato, Ferdinando; Zahrieh, David; Sirulnik, Andres; Wadleigh, Martha; Ballen, Karen K.; McAfee, Steve; Miller, Kenneth B.; Levine, James; Galinsky, Ilene; Trehu, Elizabeth G.; Schenkein, David; Neuberg, Donna; Stone, Richard M.; Amrein, Philip C.

In: Clinical Cancer Research, Vol. 14, No. 5, 01.03.2008, p. 1446-1454.

Research output: Contribution to journalArticle

Attar, EC, DeAngelo, DJ, Supko, JG, D'Amato, F, Zahrieh, D, Sirulnik, A, Wadleigh, M, Ballen, KK, McAfee, S, Miller, KB, Levine, J, Galinsky, I, Trehu, EG, Schenkein, D, Neuberg, D, Stone, RM & Amrein, PC 2008, 'Phase I and pharmacokinetic study of bortezomib in combination with idarubicinand cytarabine in patients with acute myelogenous leukemia', Clinical Cancer Research, vol. 14, no. 5, pp. 1446-1454. https://doi.org/10.1158/1078-0432.CCR-07-4626
Attar, Eyal C. ; DeAngelo, Daniel J. ; Supko, Jeffrey G. ; D'Amato, Ferdinando ; Zahrieh, David ; Sirulnik, Andres ; Wadleigh, Martha ; Ballen, Karen K. ; McAfee, Steve ; Miller, Kenneth B. ; Levine, James ; Galinsky, Ilene ; Trehu, Elizabeth G. ; Schenkein, David ; Neuberg, Donna ; Stone, Richard M. ; Amrein, Philip C. / Phase I and pharmacokinetic study of bortezomib in combination with idarubicinand cytarabine in patients with acute myelogenous leukemia. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 5. pp. 1446-1454.
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T1 - Phase I and pharmacokinetic study of bortezomib in combination with idarubicinand cytarabine in patients with acute myelogenous leukemia

AU - Attar, Eyal C.

AU - DeAngelo, Daniel J.

AU - Supko, Jeffrey G.

AU - D'Amato, Ferdinando

AU - Zahrieh, David

AU - Sirulnik, Andres

AU - Wadleigh, Martha

AU - Ballen, Karen K.

AU - McAfee, Steve

AU - Miller, Kenneth B.

AU - Levine, James

AU - Galinsky, Ilene

AU - Trehu, Elizabeth G.

AU - Schenkein, David

AU - Neuberg, Donna

AU - Stone, Richard M.

AU - Amrein, Philip C.

PY - 2008/3/1

Y1 - 2008/3/1

N2 - Purpose: Proteasome inhibition results in cytotoxicity to the leukemia stem cell in vitro. We conducted this phase I study to determine if the proteasome inhibitor bortezomib could be safely added to induction chemotherapy in patients with acute myelogenous leukemia (AML). Experimental Design: Bortezomib was given on days 1, 4, 8, and 11 at doses of 0.7, 1.0, 1.3, or 1.5 mg/m2 with idarubicin 12 mg/m2 on days 1 to 3 and cytarabine 100 mg/m 2/day on days 1 to 7. Results: A total of 31 patients were enrolled. The median age was 62 years, and 16 patients were male. Nine patients had relapsed AML (ages, 18-59 years, n = 4 and ≥60 years, n = 5). There were 22 patients of ≥60 years with previously untreated AML (eight with prior myelodysplasia/myeloproliferative disorder or cytotoxic therapy). All doses of bortezomib, up to and including 1.5 mg/m2, were tolerable. Nonhematologic grade 3 or greater toxicities included 12 hypoxia (38%; 11 were grade 3), 4 hyperbilirubinemia (13%), and 6 elevated aspartate aminotransferase (19%). Overall, 19 patients (61%) achieved complete remission (CR) and three had CR with incomplete platelet recovery. Pharmacokinetic studies revealed that the total body clearance of bortezomib decreased significantly (P < 0.01, N = 26) between the first (mean ± SD, 41.9 ± 17.1 L/h/m2) and th ird (18.4 ± 7.0 L/h/m2) doses. Increased bone marrow expression of CD74 was associated with CR. Conclusions: The combination of bortezomib, idarubicin, and cytarabine showed a good safety profile. The recommended dose of bortezomib for phase II studies with idarubicin and cytarabine is 1.5 mg/m2.

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