title: Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial.
abstract: OBJECTIVE
  To determine the clinical significance of flow cytometric minimal residual disease (MRD) quantification in chronic lymphocytic leukemia (CLL) in addition to pretherapeutic risk factors and to compare the prognostic impact of MRD between the arms of the German CLL Study Group CLL8 trial.
  
  
  METHODS
  MRD levels were prospectively quantified in 1,775 blood and bone marrow samples from 493 patients randomly assigned to receive fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). Patients were categorized by MRD into low- (< 10(-4)), intermediate- (≥ 10(-4) to <10(-2)), and high-level (≥ 10(-2)) groups.
  
  
  RESULTS
  Low MRD levels during and after therapy were associated with longer progression-free survival (PFS) and overall survival (OS; P < .0001). Median PFS is estimated at 68.7, 40.5, and 15.4 months for low, intermediate, and high MRD levels, respectively, when assessed 2 months after therapy. Compared with patients with low MRD, greater risks of disease progression were associated with intermediate and high MRD levels (hazard ratios, 2.49 and 14.7, respectively; both P < .0001). Median OS was 48.4 months in patients with high MRD and was not reached for lower MRD levels. MRD remained predictive for OS and PFS in multivariate analyses that included the most important pretherapeutic risk markers in CLL. PFS and OS did not differ between treatment arms within each MRD category. However, FCR induced low MRD levels more frequently than FC.
  
  
  CONCLUSIONS
  MRD levels independently predict OS and PFS in CLL. Therefore, MRD quantification might serve as a surrogate marker to assess treatment efficacy in randomized trials before clinical end points can be evaluated.
authors.affiliation: University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany. s.boettcher@med2.uni-kiel.de
authors.forename: Sebastian
authors.initials: S
authors.lastname: Böttcher
authors.forename: Matthias
authors.initials: M
authors.lastname: Ritgen
authors.forename: Kirsten
authors.initials: K
authors.lastname: Fischer
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.forename: Raymonde M
authors.initials: RM
authors.lastname: Busch
authors.forename: Günter
authors.initials: G
authors.lastname: Fingerle-Rowson
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Fink
authors.forename: Andreas
authors.initials: A
authors.lastname: Bühler
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.forename: Michael Karl
authors.initials: MK
authors.lastname: Wenger
authors.forename: Myriam
authors.initials: M
authors.lastname: Mendila
authors.forename: Clemens-Martin
authors.initials: CM
authors.lastname: Wendtner
authors.forename: Barbara F
authors.initials: BF
authors.lastname: Eichhorst
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hallek
authors.forename: Michael
authors.initials: M
authors.lastname: Kneba
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D018450:Disease Progression; D005434:Flow Cytometry; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality*; D018365:Neoplasm, Residual / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*; D011379:Prognosis; D011446:Prospective Studies; D000069283:Rituximab; D015996:Survival Rate; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine