Bortezomib in a phase 1 trial for patients with relapsed AL amyloidosis: cardiac responses and overall effects

• Published in: QJM : An International Journal of Medicine 2011-11, Vol.104 (11), p.957-970
• Main Authors: Dubrey, S.W., Reece, D.E., Sanchorawala, V., Hegenbart, U., Merlini, G., Palladini, G., Fermand, J.-P., Vescio, R.A., Bladé, J., Heffner, L.T., Hassoun, H., Liu, X., Enny, C., Ramaswami, P., Elsayed, Y., Van De Velde, H., Mortimer, S., Cakana, A., Comenzo, R.L.
• Format: Article
• Language: English
• Subjects: Aged; Amyloidosis - complications; Amyloidosis - drug therapy; Antineoplastic Agents - administration & dosage; Biological and medical sciences; Boronic Acids - administration & dosage; Bortezomib; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Female; General aspects; Heart Diseases - drug therapy; Heart Diseases - etiology; Humans; Kidney Diseases - drug therapy; Kidney Diseases - etiology; Liver Diseases - drug therapy; Liver Diseases - etiology; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Paraproteinemias - complications; Peripheral Nervous System Diseases - drug therapy; Peripheral Nervous System Diseases - etiology; Prospective Studies; Pyrazines - administration & dosage; Treatment Outcome
• ISSN: 1460-2725; 1460-2393
• DOI: 10.1093/qjmed/hcr105

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/m2) and twice-weekly (0.7, 1.0, 1.3 mg/m2) 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 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.