Long-term outcomes by bone marrow B-cell depletion from the R2W trial of bortezomib with cyclophosphamide and rituximab in Waldenstrom macroglobulinaemia.

ABSTRACT

There remains a lack of consensus as to the most appropriate primary therapy in Waldenstrom macroglobulinemia (WM). We evaluated a novel bortezomib-based combination and developed a sensitive WM-specific flow cytometry assay (limit of detection 0.004% of leucocytes) to assess bone marrow (BM) response. Sixty treatment-naïve WM patients were enroled into this phase II trial and randomised (21) to receive cyclophosphamide and rituximab with either bortezomib (BRC) or fludarabine (FCR). The primary objective was to assess the overall response rate (ORR) in eligible patients receiving BRC (N = 41). An ORR of 97.6% (95%CI87.1-99.9) was observed; 27 (65.9%) patients remain alive without progression after 62.6 months median follow-up, with 2-, 3- and 5-year progression-free survival (PFS) rates of 92.7% (95%CI79.0-97.6), 80.5% (95%CI64.8-89.7) and 65.5% (95%CI48.8-77.9). Persistent WM B-cells were demonstrable in 19/38 patients at the end of treatment (median 0.24%, range 0.02-11.2%). PFS was markedly longer in patients with BM B-cell depletion (<0.004%) compared to those who had persistent BM B-cells detectable at end of treatment (HR = 0.06, 95%CI0.01-0.47, p < 0.001), and remained independently associated after adjusting for baseline risk stratification or investigator-assessed response. BRC is a tolerable, highly efficacious regimen for treatment-naïve WM patients. BM B-cell depletion is independently associated with patient outcomes.