Phase I Study of Bortezomib in Refractory or Relapsed Acute Leukemias

Abstract

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/m 2 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/m 2 bortezomib. Proteasome inhibition was dose dependent and reached 68% at 1.5 mg/m 2 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/m 2 , 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.

Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients

“…In comparison, maximal whole blood CT‐L inhibition in several clinical studies with BTZ was reported to be 65–69% by either the intravenous or subcutaneous routes of administration on a twice‐weekly schedule (Cortes et al , 2004; Dy et al , 2005; Moreau et al , 2008), although sporadic individuals with up to 84% CT‐L reduction have been described (Reece et al , 2011). CFZ is a highly potent, irreversible and specific inhibitor of the CT‐L subunit (Kuhn et al , 2007) and, accordingly, was able to block 75% of CT‐L activity after one dose (O'Connor et al , 2009) in whole blood or PBMCs and up to 80–90% after repeat dosing (Alsina et al , 2012), although the most impressive activity was seen on an unapproved schedule of five daily doses (O'Connor et al , 2009).…”

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

“…Given the clinical success of proteasome inhibitors in two hematologic malignancies (myeloma and mantle cell lymphoma), considerable interest exists in expanding the use of proteasome inhibitors to leukemias and other lymphomas. Unfortunately, bortezomib did not exert substantial clinical activity in these other hematologic malignancies (15), prompting studies to examine other proteasome inhibitors and to understand better the role of the proteasome in leukemia biology.…”

Proteasome inhibitor‐induced apoptosis in human monocyte‐derived dendritic cells

“…In this setting, bortezomib (Velcade) was demonstrated to be effective in the treatment of multiple myeloma and non-Hodgkin's lymphoma, when taken alone or in combination with traditional anticancer drugs [3][4][5][6][7]. Similarly, preliminary studies indicated that proteasome inhibitors induce clinical responses in patients with acute leukemia, prostate cancer, renal cell carcinoma, neuroendocrine tumors, and in children solid tumors [8][9][10][11][12]. How proteasome inhibition translates into a potent cytotoxic effect in tumor cells is not fully understood, even though inhibition of NF-jB and deregulated expression of p53, caspases, Bcl-2 family members, CDC25 family proteins and cyclins were all proposed to be relevant in this context [1,2].…”