title: Results of a randomized trial of chlorambucil versus fludarabine for patients with untreated Waldenström macroglobulinemia, marginal zone lymphoma, or lymphoplasmacytic lymphoma.
abstract: OBJECTIVE
  Treatment options for patients with Waldenström macroglobulinemia (WM) and closely related disorders include alkylating agents, purine analogs, and monoclonal antibodies. No large randomized studies have yet been reported comparing any of these approaches.
  
  
  METHODS
  The randomized WM1 study (Trial Comparing Chlorambucil to Fludarabine in Patients With Advanced Waldenström Macroglobulinemia) was undertaken in 101 centers in five countries enrolling 414 eligible patients (339 with WM, 37 with non-mucosa-associated lymphoid tissue marginal zone lymphoma, and 38 with lymphoplasmacytic lymphoma) who were randomly assigned to receive chlorambucil or fludarabine. The primary end point was the overall response rate (ORR).
  
  
  RESULTS
  On the basis of intent-to-treat analysis, the ORR was 47.8% (95% CI, 40.9% to 54.8%) in the fludarabine arm versus 38.6% (95% CI, 32.0% to 45.7%) in the chlorambucil arm (P = .07). With a median follow-up of 36 months (interquartile range, 18 to 58 months), median progression-free survival (PFS), and duration of response (DR) were significantly improved in the fludarabine arm compared with the chlorambucil arm: PFS, 36.3 versus 27.1 months (P = .012) and DR, 38.3 versus 19.9 months (P < .001). In patients with WM, median overall survival (OS) was not reached in the fludarabine arm versus 69.8 months in the chlorambucil arm (95% CI, 61.6 to 79.8 months; P = .014). Grade 3 to 4 neutropenia was significantly higher among patients treated with fludarabine (36%) compared with patients treated with chlorambucil (17.8%; P < .001). Second malignancies were significantly more frequent in the chlorambucil arm with 6-year cumulative incidence rate of 20.6% versus 3.7% in the fludarabine arm (P = .001).
  
  
  CONCLUSIONS
  In the complete intent-to-treat study population, fludarabine significantly improved PFS compared with chlorambucil, and in patients with WM, it improved OS.
authors.affiliation: Département d' Hématologie Hôpital Pitié-Salpêtrière APHP, UPMC Université Paris 06, GRC11-GRECHY, 75013, Paris, France. Veronique.leblond@psl.aphp.fr
authors.forename: Véronique
authors.initials: V
authors.lastname: Leblond
authors.forename: Steve
authors.initials: S
authors.lastname: Johnson
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevret
authors.forename: Adrian
authors.initials: A
authors.lastname: Copplestone
authors.forename: Simon
authors.initials: S
authors.lastname: Rule
authors.forename: Olivier
authors.initials: O
authors.lastname: Tournilhac
authors.forename: John Francis
authors.initials: JF
authors.lastname: Seymour
authors.forename: Russell D
authors.initials: RD
authors.lastname: Patmore
authors.forename: David
authors.initials: D
authors.lastname: Wright
authors.forename: Pierre
authors.initials: P
authors.lastname: Morel
authors.forename: Marie-Sarah
authors.initials: MS
authors.lastname: Dilhuydy
authors.forename: Sara
authors.initials: S
authors.lastname: Willoughby
authors.forename: Caroline
authors.initials: C
authors.lastname: Dartigeas
authors.forename: Marion
authors.initials: M
authors.lastname: Malphettes
authors.forename: Bruno
authors.initials: B
authors.lastname: Royer
authors.forename: Maeve
authors.initials: M
authors.lastname: Ewings
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.forename: Julie
authors.initials: J
authors.lastname: Lejeune
authors.forename: Florence
authors.initials: F
authors.lastname: Nguyen-Khac
authors.forename: Sylvain
authors.initials: S
authors.lastname: Choquet
authors.forename: Roger G
authors.initials: RG
authors.lastname: Owen
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002699:Chlorambucil / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D018442:Lymphoma, B-Cell, Marginal Zone / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy* / Q000401:mortality
chemical_list: D000970:Antineoplastic Agents; D002699:Chlorambucil; D014740:Vidarabine; C024352:fludarabine