Phase II Trial of Combination of Bortezomib and Rituximab in Relapsed and/or Refractory Waldenstrom Macroglobulinemia

INTRODUCTION: Previous studies have demonstrated the clinical activity of bortezomib as a single agent in patients with Waldenstrom Macroglobulinemia (WM). We performed preclinical studies that demonstrated synergistic activity of bortezomib with the anti-CD20 antibody rituximab in WM cell lines and patient samples. This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory WM.

METHODS: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m2 at days 1, 8, 15, 22, on cycles 1 and 4. RESULTS: 37 pts (26 men and 11 women, median age 62 years, range 42 – 73) have been treated to date. All of them had symptomatic disease and required therapy. The median number of lines of prior treatment was 3 (range 1 – 5) including prior bortezomib and prior rituximab in some of those patients. Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chloramucil, and bortezomib. The median IgM at baseline was 3540 mg/dL (range 700– 10,800). The median follow up is 10 months (range 1 – 24 months). Thirty pts are currently evaluable for response after completing at least 2 cycles of therapy using IgM monoclonal protein. Complete remission occurred in 1 (3%), partial remission in 16 (53%), and minimal response in 10 (33%). Progressive disease occurred in 1 (3%) and stable disease occurred in 2 (7%). Most patients achieved response rapidly within 3 months of therapy (2–7 months). Rituximab flare occurred only in 6 patients (20%). The median duration of response has not been reached (3–24+ months). Patients tolerated therapy well without significant toxicities: grade 3 peripheral neuropathy occurred in only 1 patient at cycle 6, and completely resolved within one month after stopping therapy. Other grade 3 and 4 toxicities included neutropenia in 3 patients, and anemia and hyponatremia in 1 patient, and thrombocytopenia in 1 patient. Grade 5 pneumonia and viral infection occurred in 1 patient who was within the first cycle of therapy and the family changed his status to comfort care, and the patient passed away within one week. Attributable toxicities otherwise proved manageable with appropriate supportive care and the combination was generally well tolerated.

CONCLUSIONS: The combination of weekly bortezomib and rituximab has been well tolerated and demonstrates encouraging activity, with CR+ PR + MR in 90% of evaluable patients with relapsed WM. No significant peripheral neuropathy has been observed to date with this regimen. Studies using this combination in newly diagnosed patients are ongoing.