Deepening of Response after Completing Rituximab-Containing Primary Therapy in Patients with Waldenstrom Macroglobulinemia
Authors: Castillo Jorge J. , Gustine Joshua , Dubeau Toni , Meid Kirsten , Keezer Andrew , Xu Lian , Yang Guang , Hunter Zachary R , Treon Steven P 
Published: October 2019

Abstract
Introduction: Rituximab-containing regimens are commonly used for primary therapy in patients with symptomatic Waldenstrom macroglobulinemia (WM), and response is defined by decrease in serum IgM levels. In previous studies, we and others observed that in certain WM patients completing rituximab-based primary therapy, serum IgM levels continued to decline following completion of therapy, deepening the response to therapy. To further clarify the frequency and clinical characteristics, we evaluated a large population of treatment naïve patients treated at our WM center with rituximab-containing regimens.
Methods: Patients with a clinicopathological diagnosis of WM requiring therapy based on criteria from the 2ndInternational Workshop for WM (IWWM) who received a rituximab-containing regimen as primary therapy in the WM center at our institution from 2005 to 2016 were included. Responses were defined per criteria from the 6thIWWM. Findings were stratified based on patients having received, or not, maintenance therapy after induction therapy. We gathered pertinent clinical data, including responses at the end of induction, at the end of maintenance, and at the lowest serum IgM level after completion of induction and/or maintenance. Response deepening was defined as 25% decrease in serum IgM at any point after completion of therapy.
Results: 179 patients met eligibility criteria for this study. Induction therapy consisted of bortezomib, dexamethasone and rituximab (BDR) (N=86; 48%); bendamustine and rituximab (Benda-R) (N=57; 32%); cyclophosphamide, dexamethasone and rituximab (CDR) (N=36; 20%). 117 (65%) patients received maintenance therapy. There were no differences in baseline characteristics for age, gender, serum IgM, hemoglobin level, bone marrow involvement, hemoglobin, platelet count, beta-2-microglobulin level, MYD88 and CXCR4 mutation status, time to therapy, regimen, and receipt of maintenance therapy vs. observation status. At baseline, median serum IgM levels for patients who received maintenance was 4,445 mg/dl (range 289-8,100 mg/dl) and for those who were observed was 4,400 mg/dl (range 155-10,020 mg/dl) (p=0.37). Following induction therapy, median serum IgM levels declined to 969 mg/dl (range 33-5,940 mg/dl) and 1,366 mg/dl (114-7,108 mg/dl) for patients who subsequently received maintenance or were observed (p<0.001 for each group versus baseline; p=0.11 for serum IgM comparisons post-induction between groups). Following maintenance, median serum IgM level declined to 528 mg/dl (range 10-5,410 mg/dl; p<0.001 compared to end of induction). Further declines in serum IgM post-maintenance occurred, with best post-maintenance serum IgM level of 384 mg/dl (range 9-4,759 mg/dl; p<0.001 compared with end of maintenance, with 72/117 (62%) patients experiencing a lower serum IgM level and 44/117 (38%) having at least a 25% decrease in serum IgM levels. Median time from end of maintenance to lowest IgM level was 1.6 years (0.1-7.9 years). For patients observed after induction therapy, the median best serum IgM level was 1,253 mg/dl (11-7,108 mg/dl; p=0.01 compared to end of induction), with 29/62 (47%) patients having a lower serum IgM level than at completion of induction, and 18/62 (29%) had at least a 25% decrease in serum IgM level. Median time from end of induction to lowest IgM level for those observed was 1.6 years (0.2-5.1 years). Categorical responses are shown in Figure. Importantly, when analyzing all patients, hemoglobin level <11.5 g/dl (OR 0.44, 95% CI 0.23-0.88; p=0.02), bone marrow involvement ≥50% (OR 0.49, 95% CI 0.26-0.93; p=0.03), presence of CXCR4 mutations (OR 0.33, 95% CI 0.13-0.87; p=0.03) and serum IgM level ≥4,000 mg/dl (OR 0.53, 95% CI 0.29-0.99; p=0.04) were associated with lower odds of response deepening after completing therapy.
Conclusion: A third of WM patients who receive primary therapy with rituximab-containing regimens experienced deepening of response following completion of therapy, with a median time to best response of 1.6 years. High serum IgM levels and bone marrow burden, low hemoglobin levels, and presence of CXCR4 mutations at primary therapy initiation were associated with lower odds of response deepening.
Figure. Figure.

Disclosures
Castillo: Genentech: Consultancy; Beigene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Millennium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Hunter:Pharmacyclics: Consultancy. Treon:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Johnson & Johnson: Consultancy; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding.