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Minimal Residual Disease

Quantitative MRD monitoring identifies distinct GVL response patterns after allogeneic stem cell transplantation for chronic lymphocytic leukemia: results from the GCLLSG CLL3X trial

Abstract

The purpose of this study was to prospectively analyze minimal residual disease(MRD) kinetics after reduced-intensity allogeneic stem cell transplantation (allo-SCT) in high-risk chronic lymphocytic leukemia (CLL). Subjects were the first 30 consecutive patients from a prospective clinical trial, and seven pilot patients treated identically. Using real-time quantitative-PCR (RQ-PCR) and/or flow-based MRD monitoring (sensitivity 10−4), five distinct patterns of MRD kinetics could be identified: patients who promptly achieved durable MRD negativity without direct evidence of graft-versus-leukemia (GVL) effects (Group 1) (n=4; no clinical relapse); patients with complete and sustained MRD response after GVL induced by immunosuppression tapering (Group 2) or donor lymphocyte infusions (Group 3) (n=18; one relapse); patients without MRD response due to lack of GVL (Group 4) (n=2; two relapses); patients with incomplete and transient MRD response to GVL (Group 5) (n=4; three relapses). In summary, this study provides a comprehensive map of possible MRD courses and their prognostic implications after T-replete allo-SCT in high-risk CLL, indicating that effective GVL activity is induced virtually in all patients who develop chronic GVHD. However, in a significant proportion of cases, this does not translate into sustained disease control due to development of secondary GVL resistance.

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Acknowledgements

We thank the German CLL Study Group CLL3X investigators for their participation in this study; a complete list of investigators appears in ‘Appendix.

This study was supported by grants from the Deutsche Jose-Carreras Leukämiestiftung e.V. Projects R02/18, R05/02 (MR, PD and MK).

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Correspondence to P Dreger.

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Presented in part in abstract form at the 9th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 2005. Authorship: MR, PD and HD designed the trial; PD, SS, DB, JS, SC and NS were involved in patient care, sample and clinical data acquisition; MR, PD and MH were responsible for data management; SS and HD performed genetic analyses; MR, SB and MK performed MRD analyses; AH performed chimerism analyses; PD performed statistical analyses; MR and PD wrote the paper; and all authors checked the final version of the manuscript.

The authors declare that no potential conflict of interest exists.

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Appendix

Appendix

CLL3X Investigators

Berlin, Charite Benjamin Franklin (Lutz Uharek); Essen, Universitätsklinikum (Dietrich Beelen); Göttingen, Universitätsklinikum (Bertram Glass); Hamburg, AK St Georg (Norbert Schmitz); Hannover, Medizinische Hochschule (Bernd Hertenstein, Michael Stadler, Matthias Eder); Heidelberg, Innere Medizin V (Peter Dreger, Manfred Hensel); Homburg, Universitätsklinikum (Jörg Schubert); Kiel, II. Medizinische Klinik (Martin Gramatzki); Köln, Universitätsklinikum (Michael Hallek); Marburg, Universitätsklinikum (Andreas Burchert); Montreal, Hopital Maisonneuve Rosemont (Sandra Cohen); Leipzig, Universitätsklinikum (Dietger Niederwieser); Regensburg, Universitätsklinikum (Ernst Holler); Ulm, III. Medizinische Klinik (Donald Bunjes, Stephan Stilgenbauer, Hartmut Döhner).

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Ritgen, M., Böttcher, S., Stilgenbauer, S. et al. Quantitative MRD monitoring identifies distinct GVL response patterns after allogeneic stem cell transplantation for chronic lymphocytic leukemia: results from the GCLLSG CLL3X trial. Leukemia 22, 1377–1386 (2008). https://doi.org/10.1038/leu.2008.96

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