Lower Doses of Bendamustine Are Not Associated with Lower Response Rates in Previously Untreated Patients with Waldenström Macroglobulinemia
Authors: Castillo Jorge J. , Gustine Joshua , Meid Kirsten , Dubeau Toni , Ghobrial Irene M. , Treon Steven P 
Published: October 2019

Abstract
Introduction: Waldenstrom macroglobulinemia (WM) is a rare B-cell lymphoma characterized by the accumulation of malignant lymphoplasmacytic cells in the bone marrow and other organs. Bendamustine-rituximab has shown in a randomized clinical trial to be highly effective on treating patients with WM (Rummel Lancet Oncol 2013). In that study, bendamustine was administered at a dose of 90 mg/m2 IV for 6 cycles (total dose: 1080 mg/m2). Recent studies have suggested that lower doses of bendamustine might be associated with similar efficacy. However, this has not been previously evaluated in WM.
Methods: In this retrospective study, we searched our database looking for previously untreated patients with WM who have received primary therapy with bendamustine and rituximab between 2008 and 2015. All patients met clinicopathological criteria for WM (Owen Smein Oncol 2003), and had at least one indication for initiation of therapy (Kyle Semin Oncol 2003). Pertinent clinical data were gathered. With regards to treatment, we calculated the total dose of bendamustine in mg/m2 received during induction therapy. Response was assessed based on current criteria (Owen Br J Haematol 2012). Logistic regression models were used to evaluate the relation between bendamustine dose with response, respectively.
Results: A total of 48 patients who received frontline bendamustine-based therapy were included in this analysis. The median age at diagnosis of WM was 66 years (range 43-91), and the median age at initiation of therapy was 69 years (range 44-95). The median time from diagnosis to therapy was 9 months (range 0-178 months). 57% of patients were male, median hemoglobin level was 10.4 g/dl (range 4-15.3), and median serum IgM level was 3,645 mg/dl (range 356-9610). The median bone marrow involvement was 50% (range 0-90%), 43% had lymphadenopathy and 30% had splenomegaly. Based on the IPSSWM, 25% of patient were low risk, 30% intermediate risk and 45% were high risk. The reasons for initiation of therapy were anemia (57%), symptomatic extramedullary disease (22%), hyperviscosity (22%), neuropathy (11%), constitutional symptoms (9%) and thrombocytopenia (4%). At best response, the ORR was 95% (19% CR, 28% VGPR, 43% PR, 5% MR and 5% NR). The rate of major response (CR+VGPR+PR) was 90%, and the rate of deep response (CR+VGPR) was 47%.
Based on total bendamustine dose, patients were divided in 3 groups: 90 mg/m2 days 1 and 2 for 6 cycles (1080 group; n=20), 90 mg/m2 on days 1 and 2 for 4 cycles (720 group; n=18), and 70 mg/m2 on days 1 and 2 for 4 cycles (560 group; n=10). There was no difference in age, hemoglobin levels, platelet counts, serum IgM levels, beta-2-microglobulin levels or IPSSWM scores between the 3 groups (Chi-square p>0.05 for all comparisons). The rates of major response were 95% in the 1080 group, 89% in the 720 group, and 90% in the 560 group (Chi-square p=0.78); and the rates of deep response were 55% in the 1080 group, 44% in the 720 group, and 50% in the 560 group (Chi-square p=0.81). Logistic regression analysis showed no relation between total bendamustine dose and attainment of major or deep response (p>0.05 in both models). Separate stratified analyses of patients who received (n=26) or did not receive (n=22) maintenance rituximab showed no relation between total bendamustine dose and depth of response (p>0.05 in all models).
Conclusion: Our study suggests that receiving lower total bendamustine dose, administered concurrently with rituximab, does not affect negatively the attainment of major or deep response to therapy in previously untreated patients with WM.

Disclosures
Castillo: Biogen: Consultancy; Otsuka: Consultancy; Abbvie: Research Funding; Pharmacyclics: Honoraria; Millennium: Research Funding; Janssen: Honoraria. Ghobrial:Novartis: Honoraria; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Noxxon: Honoraria; Amgen: Honoraria.