Bortezomib for the Treatment of Mantle Cell Lymphoma

Abstract

Purpose: To describe the Food and Drug Administration review and marketing approval considerations for bortezomib (Velcade) for the treatment of patients with mantle cell lymphoma. Experimental Design: Food and Drug Administration reviewed a multicenter study of bortezomib in 155 patients with progressive mantle cell lymphoma after at least one prior therapy. Results: Seventy-seven percent were stage IV, and 75% had one or more extranodal sites of disease. Prior therapy included an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. Median age was 65 years. All received bortezomib 1.3 mg/m 2 i.v. on days 1, 4, 8, and 11 of each 3-week cycle. The primary end point was response. Response and progression were determined by independent review of serial computed tomography scans using International Lymphoma Workshop Response Criteria. The overall response rate was 31%, including complete response (CR) plus CR unconfirmed (CRu) plus partial response; median response duration was 9.3 months. The CR plus CRu response rate was 8% with a median duration of 15.4 months. Adverse events were similar to those observed previously for bortezomib. The most commonly reported treatment-emergent adverse events were asthenia (72%), peripheral neuropathies (55%), constipation (50%), diarrhea (47%), nausea (44%), and anorexia (39%). The most common adverse event leading to discontinuation was neuropathy. Conclusions: Bortezomib received regular approval for the treatment of patients with mantle cell lymphoma in relapse after prior therapy.On December 8, 2006, bortezomib (Velcade for injection) received marketing approval by the U.S. Food and Drug Administration (FDA) for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy for their disease. This drug approval is the first for the specific indication of mantle cell lymphoma, a subtype of nonHodgkin's lymphoma characterized by unique pathologic, cytogenetic, and clinical features (1).Bortezomib, a modified dipeptidyl boronic acid derived from leucine and phenylalanine, is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome, a large protein complex that degrades most intracellular proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins. Inhibition of the 26S proteasome prevents this targeted proteolysis, which then may alter multiple signaling cascades within the cell.Bortezomib had received accelerated approval in 2003 for multiple myeloma after two prior therapies and in 2005 received regular approval for the treatment of multiple myeloma after one prior therapy (2). The sponsor, Millennium Pharmaceuticals, Inc., in conjunction with Johnson and Johnson Research and Pharmaceutical Development, met with FDA during the design of this registration study and during the conduct and analysis phases to assure agreement on the study design, end points, adjudication plan for assessing the end points, and the analysis plan in...

Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia

“…[69][70][71] BZ is a small dipeptidyl boronic acid that selectively and reversibly inhibits the chymotryptic activity of the proteasome. BZ is currently approved for the treatment of multiple myeloma and mantle cell lymphoma, [72][73][74] however BZ treatment did not show encouraging results in the management of solid tumors. 71,75 The toxic effects of BZ on cancer cells has been associated, in part, with its ability to stabilize IkB, inhibiting its degradation and consequently the prosurvival transcription factor Nuclear Factor-kB (NFkB) which induces expression of antiapoptotic genes, such as bcl-2 DNA replication, including aphidicolin, hydroxyurea, cytarabine, etoposide, doxorubicin and mafosfamide.…”

Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib

“…5 Bortezomib, a specific inhibitor of the 20S proteasome, has displayed clinical efficacy in a number of hematologic malignancies. [8][9][10][11][12] In addition to its direct inhibitory effects on the proteasome, 9 bortezomib has been noted to increase the level of intracellular reactive oxygen species (ROS) as an important component of its ability to induce apoptosis, [13][14][15][16][17][18] autophagy [19][20][21] and differentiation. 22 A sustained increase in ROS generation appears, in turn, to enhance the inhibitory effects of bortezomib on proteasomal activity.…”

Mechanistic Studies of Substrate-assisted Inhibition of Ubiquitin-activating Enzyme by Adenosine Sulfamate Analogues

“…The ubiquitin-proteasome system is a key system responsible for maintaining cellular protein homeostasis, an emerging research area that could potentially transform our understanding of human diseases (1)(2)(3). Bortezomib (VELCADE), a proteasome inhibitor, is currently approved in the treatment of patients with multiple myeloma and relapsed mantle cell lymphoma (4,5). The clinical success of bortezomib suggests that targeting other components in the ubiquitin-proteasome system pathway might represent an opportunity to develop novel anti-cancer therapeutics (6 -9).…”