Phase II trial of weekly bortezomib in combination with rituximab in relapsed or relapsed and refractory Waldenstrom macroglobulinemia

Abstract

Purpose: This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with relapsed/refractory Waldenström macroglobulinemia (WM).

Patients and methods: Patients who had at least one previous therapy were eligible. All patients received bortezomib intravenously weekly at 1.6 mg/m(2) on days 1, 8, and 15, every 28 days for six cycles and rituximab 375 mg/m(2) weekly on cycles 1 and 4. The primary end point was the percentage of patients with at least a minor response.

Results: Thirty-seven patients were treated. The majority of patients (78%) completed treatment per protocol. At least minimal response (MR) or better was observed in 81% (95% CI, 65% to 92%), with two patients (5%) in complete remission (CR)/near CR, 17 patients (46%) in partial response, and 11 patients (30%) in MR. The median time to progression was 16.4 months (95% CI, 11.4 to 21.1 months). Death occurred in one patient due to viral pneumonia. The most common grade 3 and 4 therapy-related adverse events included reversible neutropenia in 16%, anemia in 11%, and thrombocytopenia in 14%. Grade 3 peripheral neuropathy occurred in only two patients (5%). The median progression-free (PFS) is 15.6 months (95% CI, 11 to 21 months), with estimated 12-month and 18-month PFS of 57% (95% CI, 39% to 75%) and 45% (95% CI, 27% to 63%), respectively. The median overall survival has not been reached.

Conclusion: The combination of weekly bortezomib and rituximab showed significant activity and minimal neurologic toxicity in patients with relapsed WM.

Fig 1.

CONSORT diagram. CR, complete remission; PR, partial remission; MR, minimal response; V, bortezomib 1.6 mg/m² days 1, 8, 15 every 28 days × six cycles; R, rituximab 375 mg/m² days 1, 8, 15, 22 on cycles 1 and 4.

Fig 2.

(A) The maximum percent decrease in immunoglobulin M (IgM) over all cycles in response to therapy per patient in responding patients. (B) The median and interquartile range for IgM values in response to therapy per each cycle. (C) The median and interquartile range for hemoglobin (Hgb) values in response to therapy per each cycle.

Fig 3.

(A) Duration of response (DOR), minimal response or better. The median DOR for all 30 responders was 19.5 months (95% CI, 11.5 to 26.7 months; range, 5 to 30 months). (B) The median progression-free survival (PFS) is 15.6 months (95% CI, 11.2 to 21.1 months), with estimated 12-month and 18-month PFS of 58% (95% CI, 39% to 75%) and 45% (95% CI, 27% to 63%). (C) The median time to next therapy was 17.6 months (range, 1 to 25 months).