title: Bortezomib in a phase 1 trial for patients with relapsed AL amyloidosis: cardiac responses and overall effects.
abstract: 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 ≥ 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.
authors.affiliation: Department of Cardiology, Hillingdon Hospital, Pield Heath Road, Uxbridge, Middlesex, UB8 3NN, UK. simon.dubrey@thh.nhs.uk
authors.forename: S W
authors.initials: SW
authors.lastname: Dubrey
authors.forename: D E
authors.initials: DE
authors.lastname: Reece
authors.forename: V
authors.initials: V
authors.lastname: Sanchorawala
authors.forename: U
authors.initials: U
authors.lastname: Hegenbart
authors.forename: G
authors.initials: G
authors.lastname: Merlini
authors.forename: G
authors.initials: G
authors.lastname: Palladini
authors.forename: J-P
authors.initials: JP
authors.lastname: Fermand
authors.forename: R A
authors.initials: RA
authors.lastname: Vescio
authors.forename: J
authors.initials: J
authors.lastname: Bladé
authors.forename: L T
authors.initials: LT
authors.lastname: Heffner
authors.forename: H
authors.initials: H
authors.lastname: Hassoun
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.forename: C
authors.initials: C
authors.lastname: Enny
authors.forename: P
authors.initials: P
authors.lastname: Ramaswami
authors.forename: Y
authors.initials: Y
authors.lastname: Elsayed
authors.forename: H
authors.initials: H
authors.lastname: Van De Velde
authors.forename: S
authors.initials: S
authors.lastname: Mortimer
authors.forename: A
authors.initials: A
authors.lastname: Cakana
authors.forename: R L
authors.initials: RL
authors.lastname: Comenzo
mesh_terms: D000368:Aged; D000686:Amyloidosis / Q000150:complications / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005260:Female; D006331:Heart Diseases / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy / Q000209:etiology; D008107:Liver Diseases / Q000188:drug therapy / Q000209:etiology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010265:Paraproteinemias / Q000150:complications; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000209:etiology; D011446:Prospective Studies; D011719:Pyrazines / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib