title: Minimal Residual Disease Assessment Improves Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Partial Response: Comprehensive Analysis of Two Phase III Studies of the German CLL Study Group.
abstract: Purpose To determine the value of minimal residual disease (MRD) assessments, together with the evaluation of clinical response in chronic lymphocytic leukemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia criteria. Patients and Methods Progression-free survival (PFS) and overall survival of 554 patients from two randomized trials of the German CLL Study Group (CLL8: fludarabine and cyclophosphamide [FC] v FC plus rituximab; CLL10: FC plus rituximab v bendamustine plus rituximab) were analyzed according to MRD assessed in peripheral blood at a threshold of 10-4and clinical response. The prognostic value of different parameters defining a partial response (PR) was further investigated. Results Patients with MRD-negative complete remission (CR), MRD-negative PR, MRD-positive CR, and MRD-positive PR experienced a median PFS from a landmark at end of treatment of 61 months, 54 months, 35 months, and 21 months, respectively. PFS did not differ significantly between MRD-negative CR and MRD-negative PR; however, PFS was longer for MRD-negative PR than for MRD-positive CR ( P = .048) and for MRD-positive CR compared with MRD-positive PR ( P = .002). Compared with MRD-negative CR, only patients with MRD-positive PR had a significantly shorter overall survival (not reached v 72 months; P = .001), whereas there was no detectable difference for patients with MRD-negative PR or MRD-positive CR ( P = 0.612 and P = 0.853, respectively). Patients with MRD-negative PR who presented with residual splenomegaly had only a similar PFS (63 months) compared with patients with MRD-negative CR (61 months; P = .354), whereas patients with MRD-negative PR with lymphadenopathy showed a shorter PFS (31 months; P < .001). Conclusion MRD quantification allows for improved PFS prediction in both patients who achive PR and CR, which thus supports its application in all responders. In contrast to residual lymphadenopathy, persisting splenomegaly does not impact outcome in patients with MRD-negative PR.
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Gabor
authors: G
authors: Kovacs
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Sandra
authors: S
authors: Robrecht
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Anna Maria
authors: AM
authors: Fink
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Jasmin
authors: J
authors: Bahlo
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Paula
authors: P
authors: Cramer
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Julia
authors: J
authors: von Tresckow
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Christian
authors: C
authors: Maurer
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Petra
authors: P
authors: Langerbeins
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Günter
authors: G
authors: Fingerle-Rowson
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Matthias
authors: M
authors: Ritgen
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Michael
authors: M
authors: Kneba
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Hartmut
authors: H
authors: Döhner
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Stephan
authors: S
authors: Stilgenbauer
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Wolfram
authors: W
authors: Klapper
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Clemens-Martin
authors: CM
authors: Wendtner
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Kirsten
authors: K
authors: Fischer
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Michael
authors: M
authors: Hallek
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Barbara
authors: B
authors: Eichhorst
authors: Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Kirsten Fischer, Michael Hallek, and Barbara Eichhorst, University of Cologne and Center of Integrated Oncology Cologne/Bonn, Cologne; Matthias Ritgen, Michael Kneba, and Sebastian Böttcher, University of Schleswig-Holstein, Lubeck; Hartmut Döhner and Stephan Stilgenbauer, University of Ulm, Ulm; Wolfram Klapper, University of Kiel, Kiel; Clemens-Martin Wendtner, Klinikum Schwabing, Munich, Germany; and Günter Fingerle-Rowson, F. Hoffmann La-Roche, Basel, Switzerland.
authors: Sebastian
authors: S
authors: Böttcher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D005260:Female; D005858:Germany; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual / Q000175:diagnosis*; D017063:Outcome Assessment, Health Care / Q000379:methods*; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D012074:Remission Induction