Categories
Uncategorized

Bortezomib (Velcade)

A boronic acid that inhibit 26S proteasome, an enzymatic mediator in protein degradation.

A reversible inhibitor of the chymotrypsin-like tell lytic activity of the beta5 subunit of the 20S by mammalian proteasome.

Inhibits proteasome activity and inhibits proliferation and induce apoptosis in a variety of cell types.

Selectively but reversibly inhibits the proteasome.

Binds to beta-subunits of the core of the proteasome disrupting intracellular protein degradation and recycling and inducing apoptosis.

Proteosomal inhibition triggers factor ĸB inhibition, accumulates p53 and p21 and Bax upregulation, changes which may last longer than proteosomal inhibition and can trigger apoptosis by themselves.

72 hour break is required for recovery of the 26S proteasome subunit in peripheral blood mononuclear cells after a single dose of drug.

Targets intrinsic and extrinsic apoptotic pathways and the NF-kappaB pathway and other pathways in myeloma cells, without significantly affecting normal hematopoietic cells.

Drug resistance is mediated by overexpression of the beta5 subunit, mutation of active drug binding sites or the downstream up regulation of survival pathways.

Available for intravenous use only.

Toxicities include thrombocytopenia, hyponatremia, hypokalemia, fatigue, malaise and neuropathy.

Associated thrombocytopenia and neutropenia follow a cyclical pattern with nadir’s occurring at the last dose of each treatment cycle, and cans typically recover prior to next treatment cycle.

No evidence of cumulative thrombocytopenia and neutropenia occur.

Associated with rash in 8-40% of patients with findings ranging from systemic hypersensitivity, leukocytoclastic vasculitis, and drug eruptions.

Thrombocytopenia and neuropathy occur in approximately a third of patients.

Bortezomib can induce a peripheral neuropathy involving small fiber sensory neuropathy, with symmetric loss of all modalities, particularly in the lower extremities.

Neuropathy grade 1 and 2 occurs in approximately 24-34% of patients, and grade 3-4 peripheral neuropathy develops in up to 18% of patients treated with bortezomib.

Bortezomib induced peripheral neuropathy, risk increases about 6% per year of advancing age (Corso A et al).

It accelerates the production of sphingolipids, which have been linked to neuropathic pain.

Peripheral neuropathy risk factors include therapy duration, dose, cumulative dose, presence of diabetes, alcoholism, and pre-existing neuropathy.

Neurotoxicity is due to axonal degeneration, which often occurs within the first cycle of treatment and does not seem to increase after the fifth cycle (Richardson PG et al).

VISTA trial 44% of patients had neuropathy, but was reversible in 74% of patients, resolved in 56% of patients within median of 2 months.

Bortezomib peripheral neuropathy associated with burning dysesthesia, numbness, hyperesthesia, and pain.

Motor involvement with this agent is less likely than with thalidomide, but it may result in mild distal lower limb or weakness.

Associated with one dominant dysfunction includes: Diarrhea, nausea, constipation, vomiting, anorexia and hypotension.

The neurotoxic effects of the drug are generally reversible when doses are reduced with the drug is discontinued.

The neuropathy secondary to this drug may be related to proteasome inhibition with the dorsal root ganglion being the primary target and with secondary peripheral nerve degeneration (Silverman L).

Treatment-related peripheral neuropathy with this drug ranges from 31-64% with grade 3 or 4 symptoms in 3-22% of patients.

Overall response rate in multiple myeloma is 27%.

Herpes prophylaxis is recommended in patients receiving bortezomib with therapy and other ptoteasome inhibitors.

SUMMIT (Study of Uncontrolled Multiple Myeloma managed with proteasome Inhibition Therapy) trial 27% response rate, common remission and partial response, was 27% among 202 relapsed or refractory myeloma patients with a median of 6 prior therapies.

CREST trial out of 27 patients refractory myeloma patients treated with 1.0 mg/m2 30% achieved a complete or partial remission and 38% of patients receiving 1.3 mg/m2 obtained a complete or partial remission.

In the CREST trial the addition of dexamethasone to bortezomib increased response rates to 37% in the 1.0 mg/m2 group and to 50% in the 1.3 mg/m2 patients.

EVOLUTION trial of bortezomib, dexamethasone, cyclophosphamide and lenalidomide (VDCR) in multiple myeloma patients who were previously untreated and with a Karnofsky score of 50% or higher-bortezomib 1.3 mg/m2 I.V. days 1,4,8, and 11, dexamethasone orally 40 mg on days 1,8, and 15, lenalidomide 15 mg days 1-14 and cyclophosphamide 100-5000 mg/m2 orally days 1 an 8: overall response rate 100%, 20% with a stringent complete remission, 36% complete remission or better, and 69% a very good partial response.

Phase III study of 460 patients with newly diagnosed multiple myeloma disease who were to undergo autologous stem cell transplant were randomized to receive induction therapy with 3 cycles bortezomib, with dexamethasone plus thalidomide or dexamethasone plus thalidomide alone-following double stem cell transplantation the randomization was continued with two consolidation cycles and then dexamethasone maintenance: bortezomib containing regimens associated with superior results-complete remission rates with induction of 32% vs. 12%, higher very good response rates, 4.7% of patients without bortezomib had progressive disease and not patient with bortezomib had progressive disease.

Use as a retreatment in multiple myeloma may prolong disease control with response are as high as 60% among patients who initially responded to treatment and 29% among patients who did not (Connor).

Used with or without dexamethasone in amyloidosis associated with rapid hematologic response and organ responses (Kastritis E).

Can be associated with a small blood vessel vasculitis rash.

Subcutaneous administration is associated fewer adverse effects and approximately a 50% reduction in the risk of peripheral neuropathy.

Given subcutaneously, instead of intravenously in pretreated, myeloma patients has an identical overall response rate of 52%, with significant reductions in peripheral neuropathy of any grade.

Subcutaneous treatment major side effect has been injection site reactions, which is rarely serious enough to require changing to intravenous therapy.

Subcutaneous injections should be rotated and a small amount of air should be injected to avoid the needle leaving an injection track.

Subcutaneous administration is the pref2242ed group, based on findings showing that subcutaneous single agent drug had noninferior efficacy to IV drug with regard to overall response great after 4 cycles.

Weekly doses may be as effective as traditional twice-weekly approach, and the risk of peripheral neuropathy is substantially lower when used once weekly.

Combinations with other agents indicate that proteasome inhibition provides higher overall response rates than either agent alone.

Suppresses osteoclast function in the absence of bisphosphonate therapy.

Recommended standard dose and schedule 1.3 mg/m2 days 1, 4, 8, 11 of a 21 day cycle, and for extended maintenance treatment 1.3 mg/m2 days 1, 8, 15 and 22 on a 35 day cycle.

Bortezomib plus rituximab vs rituximab alone in follicular lymphoma: response rate 63% vs 49% and progression free survival 12.8 months vs. 11months (Coiffier B et sl).

Leave a Reply

Your email address will not be published. Required fields are marked *