ASH 2016 | R2W: Subcutaneous Bortezomib, Cyclophosphamide and Rituximab (BCR) Versus Fludarabine, Cyclophosphamide and Rituximab (FCR) for Initial Therapy of Waldenström’s Macroglobulinemia: A Randomized Phase II Study

The 58^th Annual Meeting & Exposition of the American Society of Hematology’s (ASH) took place in San Diego, CA, and on December 5^th, Rebecca L. Auer, MD, PhD, from Barts Health NHS Trust, presented the results of a randomized, multi-center phase-II study assessing the efficacy and safety of the addition of cyclophosphoamide to the combinations of bortezomib + rituximab or fludarabine + rituximab  in untreated Waldenström’s Macroglobulinemia (WM) patients.

Highlights:

• BCR= Six 28 day cycles of 1.6mg/m² Bortezomib (SC) and 250mg/m² Cyclophosphoamide (oral) on days 1, 8 and 15 plus 375mg/m² Rituximab (IV) on days 1, 8, 15, 22 in cycles 2 and 5
• FCR= Six 28 day cycles of 40mg/m² Fludarabine (oral) and 250mg/m² Cyclophosphoamide (oral) on days 1-3 plus 375mg/m² Rituximab (IV) on days 1, 8, 15, 22 in cycles 2 and 5
• 59 ITT patients, BCR:FCR 2:1, BCR n=42, FCR n=17
• Six cycles completed by: BCR= 92.9% with 38.1% pts having dose reductions, FCR= 76.5% with 52.9% pts having dose reductions

• ORR: FCR= 82.4%, BCR=97.6%

• At 18months follow-up 3 patients had died, 2 of which from myelodysplastic syndrome MDS who had received FCR
• FCR was seen to consistently have higher rates of ≥grade 3 toxicities than BCR

Rebecca Auer concluded by summarizing that FCR is associated with higher levels of toxicity and MDS than BCR, however both were effective treatments. Follow-up for this trial is ongoing, but BCR study in a Phase-III trial in WM was deemed to be warranted.

Abstract:

Introduction: Earlier studies have indicated that the combination of bortezomib and rituximab is highly active in Waldenstrőm’s macroglobulinemia (WM). However, there is scope to improve the complete response rate, duration of response and toxicity profile. We evaluated the efficacy and tolerability of the addition of cyclophosphamide to bortezomib and rituximab in previously untreated patients with WM.

Methods: Symptomatic treatment-naïve patients were enrolled into this prospective randomised (2:1), multicentre, non-comparative Phase II study (NCT01592981). Patients were stratified according to the International Prognostic Scoring System for WM. Patients were treated with BCR (Bortezomib 1.6 mg/m2 s.c. days 1, 8, 15; Cyclophosphamide 250 mg/m2 oral days 1, 8, 15; Rituximab 375mg/m2 i.v. days 1, 8, 15, 22 cycles 2 and 5 only) or FCR (Fludarabine 40mg/m2 oral days 1-3; Cyclophosphamide 250 mg/m2 oral days 1-3; Rituximab 375mg/m2i.v. days 1, 8, 15, 22 cycles 2 and 5 only) for 6 cycles repeated every 28 days. Rituximab and bortezomib were provided free of charge by Roche and Janssen, respectively. The primary endpoint was investigator assessed overall response rate (ORR) using consensus criteria.

Results: Sixty patients were enrolled into this study and 59 received trial treatment (BCR=42, FCR=17). Of all registered patients, 73% were male, median (range) age was 67 years (43-87), Haemoglobin 9.8 g/dL (6.5-14.0), serum IgM paraprotein 34 g/L (3.2-80.2), plasma viscosity 3.6 mPa.s (2.0-9.3) and 25/30/45% were low/intermediate/high risk respectively. Six cycles were completed by 92.9% of BCR and 76.5% of FCR patients, one patient withdrew from the study prior to starting trial treatment. Dose reductions were needed in 38.1% of BCR and 52.9% of FCR patients and treatment delays occurred in 64.3% of BCR and 64.7% of FCR patients. ORR was 97.6% in BCR patients with 78.6% achieving a major response (CR=1, VGPR=8, PR=24, MR=7, SD=1), one patient was not assessed as no evidence of WM was found upon central review; 82.4% in FCR patients with a major response rate of 76.5% (CR=0, VGPR=3, PR=10, MR=1, SD=2), one patient stopped treatment after cycle 1 due to continuing cytopenia (grade 4). Responses were also evaluated in both marrow and peripheral blood using a disease specific multiparamater flow cytometric assay. After a median follow-up of 18 months, 54 patients were progression-free; 3 patients progressed (all BCR) and 3 patients died, 2 from myelodysplastic syndrome (MDS) (both FCR) and 1 from pneumonia (BCR). Grade 3 or higher toxicities included anemia (5 [11.9%] BCR; 3 [17.6%] FCR), neutropenia (11 [26.2%] BCR; 12 [70.6%] FCR), thrombocytopenia (7 [16.7%] BCR; 6 [35.3%] FCR) and infection (2 [4.8%] BCR; 5 [29.4%] FCR). No grade 3 or higher neuropathy was reported.

Conclusions: BCR and FCR are both highly effective treatments for primary therapy of WM but FCR is associated with increased toxicity and concerning incidence of secondary MDS. BCR warrants further investigation in a randomised Phase III trial. Continued follow-up of R2W patients is also important to provide reliable estimates for duration of response, progression-free survival and overall survival.