Fludarabine Based Combinations Are Highly Effective as First-Line or Salvage Treatment in Patients with Waldenström Macroglobulinemia
Authors: Peinert Stefan , Tam Constantine , Prince H. Miles , Wolf Max M. , Januszewicz E. Henry , Westerman David , Scarlett John D. , Seymour John F. 
Published: April 2020

Abstract
Treatment with single agent rituximab (R), alkylating agents or purine analogues is safe and moderately effective as first-line treatment for patients (pts) with Waldenström Macroglobulinemia (WM). However, efficacy in relapsed/refractory WM is unsatisfactory. We analysed if combinations of fludarabine (F) with alkylators and/or R were safe and more effective. From 12/94 - 08/08, 25 courses of at least 2 cycles of intravenous F-combination therapy were administered to 22 pts with WM: FC (F 25mg/m2 d1–3, cyclophosphamide (C) 250mg/m2 d1–3; n=7); FCR (FC+R 375mg/m2 d1; n=14); FM (F+mitoxantrone (M) 10mg/m2 d1; n=3); FR, n=1). The median age of pts was 57yrs [range; 36–89], 18/22 (84%) male, 6 pts received F-combination as their primary treatment (24% of courses). The 19 pre-treated pts had a median number of 2 [1–7] prior treatments, prior F-exposure in 5 cases (20%), 9 pts (36%) were alkylator-refractory. The median time from diagnosis to F-based treatment was 23 Mo [0–153], baseline paraprotein (PP) 30g/L [7–64]. A total of 99 cycles were administered, median 4 [2–6] per pt. Treatment was generally well tolerated with 5% infusion reactions grade (G) 2, gastro-intestinal toxicity was mostly limited to G 1 or 2 (35% of cycles) with only one G3 episode, no renal toxicity or hepatic side effects &gt; G 1. G 3 thrombocytopenia occurred in 5%, G ≥ 3 neutropenia and infections complicated 20% and 3% of cycles, respectively, none of which were life-threatening. However, 3 heavily pre-treated pts subsequently developed secondary AML/MDS (1 fatal) at 52, 61 and 99 Mo post-treatment. The overall response rate (RR) was 21/25 (84%) with a median PP reduction of 90% [30–100%]. One pt achieved a complete remission, 17/25 (68%) had a partial response, resulting in an objective RR of 72%, 3 responses (12%) were minor (PP-reduction of 25–&lt;50%). The median times to response and maximum response (PP nadir) were 2.6 [0.7–7.3] Mo and 9.5 [0.9–47.5] Mo, respectively. The median event free survival (EFS) for all pts was 43.4 [0.9–113.6] Mo, the median overall survival (OS) was not reached. With a median follow-up of surviving pts of 59 Mo, the 5- and 10-yearactuarial survival rates were 85 ± 8%, and 68 ± 13%, respectively. With a median followup of 51 Mo [13–97], all 6 previously untreated pts remain alive and progression-free. The RR was independent of pre-treatment status whereas untreated pts had superior EFS but not OS compared to alkylator-refractory pts (p=0.01 and 0.29, respectively). Neither rituximab administration nor the known adverse prognostic factors age &gt;60 years or increased baseline beta2 microglobulin impacted on EFS or OS. Anemia (Hb &lt;100g/L) resulted in a trend for reduced EFS (43 Mo vs. not reached, p=0.06), but not OS (p=0.24). We conclude that F-combination therapy is highly active in WM, both, untreated and alkylator-refractory, leading to high response rates and prolonged remissions. However, possible contribution to the cumulative risk of treatment-related MDS/AML in heavily pre-treated pts is a potential concern.