Originally published as JCO Early Release 10.1200/JCO.2008.20.4677 on June 8 2009

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Primary Therapy of Waldenström Macroglobulinemia With Bortezomib, Dexamethasone, and Rituximab: WMCTG Clinical Trial 05-180

From the Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA; New York Oncology and Hematology, Latham, NY; Rocky Mountain Cancer Center, Denver, CO; Virginia Oncology Associates, Newport News, VA; Littleton Regional Hospital, Littleton, NH; Charleston Hematology Oncology Associates, Charleston, SC; and Millennium: The Takeda Oncology Company, Cambridge, MA.

Corresponding author: Steven P. Treon, MD, MA, PhD, Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, M547, 44 Binney St, Boston, MA 02115; e-mail: steven_treon{at}dfci.harvard.edu.

Purpose We examined the activity of bortezomib, dexamethasone, and rituximab (BDR) in patients with symptomatic, untreated Waldenström macroglobulinemia (WM).

Patients and Methods A cycle of therapy consisted of bortezomib 1.3 mg/m² intravenously; dexamethasone 40 mg on days 1, 4, 8, and 11; and rituximab 375 mg/m² on day 11. Patients received four consecutive cycles for induction therapy and then four more cycles, each given 3 months apart, for maintenance therapy. Twenty-three patients received a median of seven cycles of treatment.

Results Median bone marrow disease involvement declined from 55% to 10% (P = .0004), serum immunoglobulin M levels declined from 4,830 to 1,115 mg/dL (P < .0001), and hematocrit increased from 29.8% to 38.2% (P = .0002) at best response. The overall response rates and major response rates were 96% and 83% with three complete responses, two near complete responses, three very good partial responses, 11 partial responses, and three minor responses. Responses occurred at a median of 1.4 months. With a median follow-up of 22.8 months, 18 of 23 patients remained free of disease progression. Peripheral neuropathy was the most common toxicity, and it resolved to grade 1 in 13 of 16 patients at a median of 6.0 months. Four of the first seven treated patients developed herpes zoster, resulting in the institution of prophylactic antiviral therapy.

Conclusion The results demonstrate that BDR produces rapid and durable responses, along with high rates of response and complete remissions in WM. Herpes zoster prophylaxis is necessary with BDR, and reversible peripheral neuropathy was the most common toxicity leading to premature discontinuation of bortezomib in 61% of patients. Exploration of alternative schedules for bortezomib administration that includes weekly dosing should be pursued.

Supported by the Peter and Helen Bing Fund for Waldenström's Macroglobulinemia at the Dana-Farber Cancer Institute, Millennium: The Takeda Oncology Company, and National Institutes of Health Career Development Award No. K23CA087977-03 (S.P.T.).

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

Clinical trial information can be found for the following: NCT00250926 [ClinicalTrials.gov] .

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