Frontline Therapy with Bendamustine-Rituximab (BR) in Patients with Treatment-Naïve Waldenstrom's Macroglobulinemia Confers Similar Long-Term Outcomes to R-CVP in a Real-World Setting: A Population-Based Analysis
Authors: Kim Jowon Laura , Gerrie Alina S. , Savage Kerry J. , Villa Diego , Scott David W. , Craig Jeffrey W , Farinha Pedro , Skinnider Brian , Slack Graham W. , Connors Joseph M. , Sehn Laurie H. , Freeman Ciara L. 
Published: November 2021

Abstract
Background:
Waldenström macroglobulinemia (WM) is a rare, indolent B-cell lymphoproliferative disorder. After the STiL-1 trial (Rummel MJ. Lancet. 2013;381(9873):1203-1210) demonstrated significant benefit in a subgroup analysis as well as reduced toxicity using bendamustine and rituximab (BR) compared to R-CHOP (N=41 enrolled WM patients), BR became the preferred immunochemotherapy (IC) regimen for all patients with symptomatic treatment naïve (TN) WM in British Columbia (BC) since 2014. Prior to the introduction of BR, the combination of rituximab, cyclophosphamide, vincristine, and prednisone (RCVP), was the standard of care in BC for this population since 2004, given its widespread use across a broad range of indolent B-cell lymphomas. We report a population-based analysis evaluating outcomes in TN-WM patients comparing BR with RCVP.

Methods:
The BC Cancer Centre for Lymphoid Cancer Database was used to identify TN-WM patients treated with BR or RCVP as their first systemic therapy between August 1, 2004 - August 1, 2020. A period of observation but no prior to systemic therapy was permitted. All patients had clinicopathologically confirmed lymphoplasmacytic lymphoma and measurable monoclonal IgM. Event-free survival (EFS) was defined as time from start of IC to progression, relapse, initiation of alternative therapy, histologic transformation, or death due to any cause. Early progression (POD24) was defined as relapse or progression, death from lymphoma, or treatment toxicity within 24 months of initiation of systemic therapy. Outcomes were compared with a historical cohort of patients treated with frontline RCVP. Responding patients were eligible to receive maintenance rituximab (MR) every 3 months for 2 years since 2006; however this was discontinued in 2020 when a subgroup analysis of the MAINTAIN trial (Rummel MJ. Blood 2019; 134 (Supplement_1): 343), showed a lack of PFS benefit after BR, coupled with safety and vaccine response concerns during the COVID-19 pandemic.

Results:
A total of 111 patients with WM were identified; 57 treated with BR, 54 treated with RCVP. Median age was 69 years (range 33-89) and baseline characteristics (Table 1), were well-balanced. A higher proportion of RCVP-treated patients received &gt;4 cycles of chemotherapy (81% vs 65%, p=0.049). After IC, 75 (68%) received MR, with 36 (63%) and 39 (72%) in the BR and RCVP groups respectively (p=0.3).
Median follow-up from diagnosis for all living patients was 5.9 years (range 0.8-19.2), with median 4.4y vs 9.8y for BR and RCVP respectively. EFS estimates at 4-years achieved with BR were 57% (95% CI 40-71%) compared to RCVP 60% (95% CI 45-72%), p=0.5 (Figure 1). Median EFS was established for RCVP due to longer duration of follow up at 6.3 years (95% CI 3.6-11.8y). Overall survival (OS) estimates at 4-years were 74% (95% CI 57-85%) and 81% (95% CI 67-89%) for BR and RCVP patients respectively, p=0.6. Worse performance status (≥2) was the only pre-treatment factor identified as significant for inferior EFS. A sub-analysis limited to patients that received &gt;4 cycles of IC also showed no clear difference in outcomes between BR and RCVP.
Median time to transformation was 6.5y (5.5-13y), with only 3 late biopsy-proven events. Early progression (POD24) has occurred in 19 (18%) patients, with inferior survival observed in patients that had an early event compared with a reference cohort (2-years event free), however this did not reach statistical significance (p=0.3) (Figure 1).

Conclusion:
This population-based analysis of TN-WM patients treated with upfront IC confirms the excellent outcomes that can be achieved with a finite course of therapy. In contrast to prior studies, similar outcomes were observed with RCVP and BR. Further, regardless of front-line therapy, POD24 may be associated with inferior outcome but larger studies are needed.
To our knowledge, this study is the first to make a direct comparison between BR and RCVP, and one of the largest restricted to IC-treated TN-WM. This data supports RCVP as a viable option, and should serve to inform clinicians, patients, and policy makers in decision-making when considering upfront therapeutic options, and when considering indefinite alternative regimens such as BTK inhibitors.
Figure 1 Figure 1.

Disclosures
Gerrie: AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Astrazeneca: Honoraria, Research Funding; Sandoz: Honoraria; Roche: Research Funding. Savage: Servier: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Seattle Genetics: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; Takeda: Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; Roche: Research Funding; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Villa: Roche: Honoraria; Janssen: Honoraria; Lundbeck: Honoraria; Celgene: Honoraria; Seattle Genetics: Honoraria; AbbVie: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria; NanoString Technologies: Honoraria. Scott: BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. ; Abbvie: Consultancy; Janssen: Consultancy, Research Funding; AstraZeneca: Consultancy; Rich/Genentech: Research Funding; Celgene: Consultancy; Incyte: Consultancy; NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.. Craig: Bayer: Consultancy. Slack: Seagen: Consultancy, Honoraria. Sehn: Debiopharm: Consultancy; Novartis: Consultancy; Genmab: Consultancy. Freeman: Amgen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria, Speakers Bureau; Incyte: Honoraria; Abbvie: Honoraria; Teva: Research Funding; Roche: Research Funding; Bristol Myers Squibb: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria.