title: Bortezomib is active in patients with untreated or relapsed Waldenstrom's macroglobulinemia: a phase II study of the National Cancer Institute of Canada Clinical Trials Group.
abstract: OBJECTIVE
  To evaluate the efficacy and toxicity of single-agent bortezomib in Waldenström's macroglobulinemia (WM).
  
  
  METHODS
  Symptomatic WM patients, untreated or previously treated, received bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, and 11 on a 21-day cycle until two cycles past complete response (CR), stable disease (SD) attained, progression (PD), or unacceptable toxicity. Responses were based on both paraprotein levels and bidimensional disease measurements.
  
  
  RESULTS
  Twenty-seven patients were enrolled. A median of six cycles (range, two to 39) of bortezomib were administered. Twenty-one patients had a decrease in immunoglobulin M (IgM) of at least 25%, with 12 patients (44%) reaching at least 50% IgM reduction. Using both IgM and bidimensional criteria, responses included seven partial responses (PRs; 26%), 19 SDs (70%), and one PD (4%). Total response rate was 26%. IgM reductions were prompt, with nodal responses lagging. Hemoglobin levels increased by at least 10 g/L in 18 patients (66%). Most nonhematologic toxicities were grade 1 to 2, but 20 patients (74%) developed new or worsening peripheral neuropathy (five patients with grade 3, no grade 4), a common cause for dose reduction. Onset of neuropathy was within two to four cycles and reversible in the majority. Hematologic toxicities included grade 3 to 4 thrombocytopenia in eight patients (29.6%) and neutropenia in five (19%). Toxicity led to treatment discontinuation in 12 patients (44%), most commonly because of neuropathy.
  
  
  CONCLUSIONS
  Bortezomib has efficacy in WM, but neurotoxicity can be dose limiting. The slower response in nodal disease may require prolonged therapy, perhaps with a less intensive dosing schedule to avoid early discontinuation because of toxicity. Future studies of bortezomib in combination with other agents are warranted.
authors.affiliation: Princess Margaret Hospital, Toronto, Ontario, Canada. christine.chen@uhn.on.ca
authors.forename: Christine I
authors.initials: CI
authors.lastname: Chen
authors.forename: C Tom
authors.initials: CT
authors.lastname: Kouroukis
authors.forename: Darrell
authors.initials: D
authors.lastname: White
authors.forename: Michael
authors.initials: M
authors.lastname: Voralia
authors.forename: Edward
authors.initials: E
authors.lastname: Stadtmauer
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Jean
authors.initials: J
authors.lastname: Powers
authors.forename: Wendy
authors.initials: W
authors.lastname: Walsh
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Eisenhauer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000553:Ambulatory Care; D001897:Boronic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D002170:Canada; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D011336:Probability; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011719:Pyrazines / Q000009:adverse effects / Q000627:therapeutic use*; D018570:Risk Assessment; D016879:Salvage Therapy; D012720:Severity of Illness Index; D015996:Survival Rate; D016896:Treatment Outcome; D008258:Waldenstrom Macroglobulinemia / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality
chemical_list: D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib