Journal
QJM-AN INTERNATIONAL JOURNAL OF MEDICINE
Volume 104, Issue 11, Pages 957-970Publisher
OXFORD UNIV PRESS
DOI: 10.1093/qjmed/hcr105
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Funding
- Millennium Pharmaceuticals, Inc.
- Johnson & Johnson Pharmaceutical Research & Development, Limited Liability Corporation (L.L.C.)
- European Community
- EURAMY
- Ricerca Finalizzata Malattie Rare, Ministero della Salute, Istituto Superiore di Sanita' [526D/63]
- Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ, USA
- Ortho Biotech
- Johnson Johnson
- Janssen-Cilag
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Background: Bortezomib is approved for the treatment of multiple myeloma and a role has been suggested in the treatment of systemic AL amyloidosis (AL). Methods: In this phase 1 dose-escalation portion of the first prospective study of single-agent bortezomib in AL, 31 patients with relapsed disease, including 14 (45%) with cardiac involvement, received bortezomib in seven dose cohorts on once-weekly (0.7, 1.0, 1.3, 1.6 mg/m(2)) and twice-weekly (0.7, 1.0, 1.3 mg/m(2)) schedules. Electrocardiographic, Holter and echocardiographic studies were evaluated in all patients to determine safety and response. Results: During therapy (median treatment period 210 days), no patient developed significant ventricular or supraventricular rhythm disturbance on 24-h Holter monitoring; however, no patient satisfied study criteria for cardiac response using echocardiographic assessment or New York Heart Association classification. Seven patients (23%) had a epsilon 10% fall in left ventricular ejection fraction, but only one met criteria for cardiac deterioration. The predominant cardiac adverse events were peripheral edema (23%), orthostatic hypotension (13%) and hypotension (10%). Two patients developed grade 3 congestive heart failure, which resolved following treatment interruption. In this Phase 1 portion, the maximum tolerated dose of bortezomib on either schedule was not reached. Hematologic responses occurred in 14 patients (45%), including seven (23%) complete responses. In non-responders mean left ventricular wall thickness increased during the course of treatment. Conclusions: AL is frequently rapidly progressive; in these patients who had relapsed or progressed following previous conventional therapies, these results suggest that bortezomib may slow the progression of cardiac amyloid with limited toxicity.
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