Fludarabine Plus Cyclophosphamide and Rituximab (RFC) in Waldenström’s Macroglobulinemia (WM): Results in 21 Patients (pts).
Authors: Vargaftig Jacques , Pegourié-Bandelier Brigitte , Mahé Béatrice , Le Gouill Steven , Brottier-Mancini Elisabeth , Delarue Richard , Buzyn Agnès , Raphael Martine , Choquet Sylvain , Leblond Véronique 
Published: April 2020

Abstract
Background: Waldenström’s Macroglobulinemia (WM) is a chronic lymphoproliferative disorder characterized by the secretion of a monoclonal IgM. Treatment relies on alkylator-agents based therapy, nucleoside analogs therapy and/or monoclonal antibody therapy (rituximab). We showed that combination of fludarabine and cyclophosphamide yields a 78% response rate with low toxicity. The combination of Rituximab, Fludarabine and Cyclophosphamide (RFC regimen) is effective in chronic lymphocytic leukaemia.
We performed a retrospective study for 21 WM pts who where treated with RFC regimen in five different French centers from 2003 to 2006.
Methods: The median age of the patients was 65 years (range: 40–77 years), sex ratio (M/F) was 16/5. Prior to RFC initiation, the median IgM level measured by electrophoresis was 40,9 g/L (range: 8,7–54,5 g/L)), the median haemoglobin level was 9,7 g/dL (range: 6–13,5 g/L)), the median albumin level was 39 g/L (range: 22,4–45 g/L)) and the median beta 2 microglobulin level was 3,65 mg/L (range: 1,8–8 mg/L)).
In all, 19/21 pts had previously been treated with a median of 2 lines of therapy (range: 1–6), including 3 high-dose regimen with autologous stem cell transplantation ASCT). When RFC was initiated, 15 patients had relapsed disease, with a median time to treatment failure of 29 months (range: 3–62 months). The remaining 4 patients had refractory disease.
RFC regimen was given every 4 weeks and consisted of: Rituximab 375 mg/m2 IV Day 1, Fludarabine 40 mg/m2 per os Day 1 to Day 3, Cyclophosphamide 250 mg/m2 per os Day 1 to Day 3.
Anti-infective prophylaxis was based on cotrimoxazole 800 mg, 3 times per week and valacyclovir 500 mg per day. Response rates were evaluated by electrophoresis three months after the last RFC cycle.
Response criteria were those agreed by the second international workshop on WM, updated in 2006 (Kimby E, 2006).
Results: A total 21 pts received the first cycle of RFC, and 19 received two or more cycles (median of 4.5 cycles, range 2–6 cycles).
In all, Response Rate was 76% (16/21) including 10 Partial Responses (PR) (48%), 5 Minor Responses (MR) (24%), 1 Complete Response (CR) (5%). Treatment failed in 5 pts who had Stable Diseases (SD) (24%). No Progressive Disease (PD) was observed.
Of note, all 4 pts treated previously by fludarabine IV, responded (2 PR and 2 MR). Among 3 pts treated by ASCT, 2 PR and 1 SD were observed.
Hematologic toxicity was the main source of adverse effects, with 10 pts (48%) experiencing grade III–IV neutropenia (only associated with one grade III–IV infectious episode), 5 pts (24%) with grade III–IV thrombocytopenia and 2 pts (9%) with grade III–IV anemia.
With a median follow-up of 5 months (range: 1–23) 21 pts are alive. Two pts relapsed (10 and 13 months after initiation of RFC). Conclusion: RFC regimen in previously heavily treated patients with WM gives a high response rate of 76% with acceptable toxicity. Long term efficacy of this combination needs to be confirmed in larger prospective trials with longer follow-up.