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Prospective MRD assessment improves prediction of patient outcomes.

Nov 15, 2016

This article was written by Associate Professor Gabor Kovacs, Professor Michael Hallekand Dr Barbara Eichhorstfrom the University of Cologne and Centre of Integrated Oncology Cologne/Bonnand other co-authors from various German centres; published in the Journal of Clinical Oncologyin August 2016.

A total of 1,378 patients were enrolled in two phase III trials of the GCLLSG; CLL8: fludarabine and cyclophosphamide vs FCR; and CLL10: FCR vs bendamustine plus rituximab. However, the impact of minimal residual disease (MRD) assessments and clinical response on progression free survival (PFS) and overall survival (OS) could be analysed only in a total of 554 patients. The role of MRD in patients with a PR who presented with residual splenomegaly, lymphadenopathy or bone marrow involvement was also analysed as one of the outcomes in this study.

The key findings of the article were as follows:

  • Median PFS for patients who achieved a MRD-negative CR, MRD-negative PR, MRD-positive CR, and MRD-positive PR was found to 61 months, 54 months, 35 months, and 21 months, respectively
  • Patients who achieved MRD negativity in PB while in CR showed a longer PFS than patients with MRD-positive CR and MRD-positive PR. PFS was also shown to be longer for patients with MRD-negative PR compared with patients with MRD-positive CR. In contrast, there was no statistical significant difference in terms of PFS between patients with MRD-negative CR and MRD-negative PR
  • Median OS was not reached in patients with MRD-negative CR, MRD-positive CR, and MRD-negative PR, nor was it shown to be different when MRD-negative CR was compared with MRD-positive CR or MRD-negative PR
  • Median PFS was not reached for either patients with a CR or a PR with MRD negativity in BM, whereas it was estimated at 36 and 25 months for patients with MRD-positive CR and MRD positive PR
  • Of 161 patients with MRD-negative PR, 48.4% showed residual splenomegaly, 15.5% residual lymphadenopathy, 11.2% residual morphologic BM involvement, and 24.8% a combination of these factors.  Patients with MRD-negative PR who presented with residual lymphadenopathy showed a significantly shorter PFS than patients with MRD negative CR
  • Patients with MRD-negative PR who presented with residual splenomegaly, residual marrow involvement, or more than one involved site showed no significant difference in PFS compared with patients with MRD-negative CR.
  • No significant difference in OS was observed between MRD-negative CR versus any of the MRD-negative PR subgroups: patients with lymphadenopathy, splenomegaly, BM involvement, and more than one involvement site.


A large patient cohort was investigated in this article which allowed an enhanced assessment of the relative prognostic impact of clinical versus MRD response evaluation. PFS did not show any significant difference between patients who were MRD negative, who achieved a PR and a CR; whereas both MRD-negative patient groups experienced a longer PFS than did patients with MRD-positive CRs. The findings in this article were consistent with a recent published study that showed that both CR and MRD negativity have an influence on PFS. The implications of MRD assessments during indefinite therapies administered until progression, remains to be investigated. Determining MRD in all patients with a clinical response will allow an early and accurate comparison of treatment efficacy in future randomized clinical trials.

Minimal Residual Disease Assessment Improves Prediction of Outcome in Patients With Chronic LymphocyticLeukemia (CLL) Who Achieve Partial Response: Comprehensive Analysis of Two Phase III Studies of the German CLL Study Group.


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.


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.


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).


MRD quantification allows for improved PFS prediction in both patients who achieve 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.

  1. Kovacs G et al., 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. J Clin Oncol.2016 Aug 29. pii: JCO671305. Epub ahead of print.