Incidence of Disease Transformation and Development of MDS/AML in 165 Patients with Waldenström’s Macroglobulinemia (WM) Treated with Fludarabine (F)-Based Regimen in Three Studies (French Cooperative Group on CLL/WM)
Authors: Leblond Veronique , Tamburini Jerome , Levy Vincent , Choquet Sylvain , Taksin Anne Laure , Maloisel Frederic , Morel Pierre 
Published: October 2019

Abstract
Nucleoside analogs (NA) are used alone or in combination in low grade B-cell lymphoproliferative disorders for 20 years. The incidence of disease transformation (Richter syndrome: RS) and development of MDS/AML among patients (pts) with indolent B-cell malignancies receiving NA are still controversial. We have reviewed the crude incidence of RS and MDS/AML in 165 WM patients treated with 3 F-based regimens.
Results: Retrospective Study 1 (Leblond J Clin Oncol 1998): F (25mg/m2 iv D1–5) in 71 WM pts in relapse/refractory treated with alkylator, median time from diagnosis (dg) to tt: 5.9yrs, median prior tt: 2 (1–4). Randomized prospective study 2 (Leblond Blood 2001) in 92pts in first relapse after alkylator: Arm 1: F (25mg/m2 ivD1–D5) (45pts) vs Arm 2: CAP (doxorubicine 25mg/m2 IV D1, cyclophosphamide 750mg/m2 IV D1, Prednisone 40mg/m2 D1–5) (45pts), median time from dg to tt: 3.9yrs. Retrospective study N°3 (Tamburini Leukemia 2005) in first-line WM (14pts) or relapse WM (35pts): F 30mg/m2 D1–3 by oral route + Cyclophosphamide (C) 300mg/m2 D1–3 by oral route, median time from dg to tt: 2.1 yrs. The incidences of MDS/AML and RS are shown in Table 1 Discussion: the crude incidence of RS varied from 6,6% to 8% and was not statistically different in the randomized prospective study N°2 between the two groups. However, the incidence reported in pts treated with only alkylating-based regimens was lower: 3/167(1.8%) (Facon J Clin Oncol1993) and 3/217 (1.4%) (Garcia Sanz Br J Hematol 2001) and could be explained by a F use as salvage treatment in the CAP arm. The impact of fludarabine on RS needs to be confirmed in larger prospective studies. The crude incidence of MDS/AML varied from 1.4 to 8.9% in pts treated with fludarabine alone and was 6% in pts treated with F+C. The incidence reported in pts treated with alkylating based regimens varied from 1% (2/167, Facon 1993, 3/217 Garcia-Sanz 2001) to 6% (3/46, Kyle Br J Hematol 2000,) and was not different. In other low grade B-cell malignancies, a higher incidence of MDS/AML has been reported in pts treated with analog-alkylator combination compared to F or alkylator alone (Morrison J Clin Oncol 2002, Bowcock Br J Hematol 2006, Tam Hematologica 2006). In our study, the rate was the same in the two populations. The impact of late effects, particularly second malignancies, need to be better evaluated in prospective studies, especially in young patients and clinicians should discuss the risk when recommending such therapy to pts.
MDS/AML and RS incidences in the three studies Study N°, pts Median survival time from study Median follow-up time from study MDS/AML (N,%) RS (N,%) N°1 71 pts 23 mo 34 mo 1/71 (1.4%) 5/71 (7%) N°2- 92 pts 41mo( arm1), 45 mo (arm2) 34mo 4/45 (8.9%, arm1), 2/45( 4.5%, arm2) 3/45 (6.6% arm1), 2/45 (4.5%, arm2) N°3-49pts 64% at 60 mo 42 mo 3/49 (6%) 4/49 (8%)