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J Clin Oncol. 2016 Nov 1;34(31):3758-3765. doi: 10.1200/JCO.2016.67.1305.

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.

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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.


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 10-4 and 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.

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