Originally published as JCO Early Release 10.1200/JCO.2006.07.8659 on March 12 2007

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Bortezomib Is Active in Patients With Untreated or Relapsed Waldenström's Macroglobulinemia: A Phase II Study of the National Cancer Institute of Canada Clinical Trials Group

Christine I. Chen, C. Tom Kouroukis, Darrell White, Michael Voralia, Edward Stadtmauer, A. Keith Stewart, John J. Wright, Jean Powers, Wendy Walsh, Elizabeth Eisenhauer

From the Princess Margaret Hospital, Toronto; Juravinski Cancer Centre, Hamilton; National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario; Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia; Saskatoon Cancer Centre, Saskatoon, Saskatchewan, Canada; Eastern Cooperative Oncology Group, Philadelphia, PA; Cancer Therapy Evaluation Program, National Cancer Institute, National Institute of Health, Bethesda, MD

Address reprint requests to Christine I. Chen, MD, Princess Margaret Hospital, 610 University Ave, Suite 5-220, Toronto, ON, Canada M5G 2M9; e-mail: christine.chen{at}uhn.on.ca

Purpose To evaluate the efficacy and toxicity of single-agent bortezomib in Waldenström's macroglobulinemia (WM).

Patients and 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.

Conclusion 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.

published online ahead of print at www.jco.org on March 12, 2007.

Supported by grants from the National Cancer Institute of Canada and funds from the Canadian Cancer Society.

Presented in part at the Annual Meeting of the American Society of Hematology, December 4-7, 2004, San Diego, CA, and at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6 2006, Atlanta, GA.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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