Phase I study of bortezomib in refractory of relapsed acute leukemias

Jorge Cortes, Deborah Thomas, Charles Koller, Francis Giles, Elihu Estey, Stefan Faderl, Guillermo Garcia-Manero, David McConkey, Gira Patel, Roberto Guerciolini, John Wright, Hagop Kantarjian

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178 Scopus citations


Bortezomib (Velcade, formerly PS-341) is proteasome inhibitor with documented antitumor activity in multiple myeloma and other lymphoid malignancies. We performed a Phase I study to investigate the maximum tolerated dose and dose-limiting toxicity of bortezomib in patients with acute leukemias refractory to or relapsing after prior therapy. Fifteen patients were treated with 0.75 (n = 3), 1.25 (n = 7), or 1.5 (n = 5) mg/m2 bortezomib administered twice weekly for 4 weeks every 6 weeks. Dose-limiting toxicity included orthostatic hypotension (n = 2), nausea (n = 2), diarrhea (n = 1), and fluid retention (n = 1), all at 1.5 mg/m2 bortezomib. Proteasome inhibition was dose dependent and reached 68% at 1.5 mg/m2 bortezomib. Peak inhibition was observed 1 h after treatment and returned to near baseline levels by 72 h after treatment. Incubation of blast cells with bortezomib in vitro showed induction of apoptosis in three of five patients investigated. We conclude that the maximum tolerated dose of bortezomib in patients with acute leukemia is 1.25 mg/m2, using a twice-weekly for 4 weeks every 6 weeks schedule. The in vitro evidence of antileukemia and transient hematological improvements observed in some patients warrants further investigation of bortezomib in acute leukemias, probably in combination with other agents.

Original languageEnglish (US)
Pages (from-to)3371-3376
Number of pages6
JournalClinical Cancer Research
Issue number10
StatePublished - May 15 2004
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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