Universität zu Köln

Dimier, Natalie, Delmar, Paul, Ward, Carol, Morariu-Zamfir, Rodica, Fingerle-Rowson, Guenter, Bahlo, Jasmin, Fischer, Kirsten, Eichhorst, Barbara, Goede, Valentin, van Dongen, Jacques J. M., Ritgen, Matthias, Boettcher, Sebastian, Langerak, Anton W., Kneba, Michael and Hallek, Michael (2018). A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL. Blood, 131 (9). S. 955 - 963. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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Abstract

Our objective was to evaluate minimal residual disease (MRD) at the end of induction treatment with chemoimmunotherapy as a surrogate end point for progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) based on 3 randomized, phase 3 clinical trials (ClinicalTrials.gov identifiers NCT00281918, NCT00769522, and NCT02053610). MRD was measured in peripheral blood (PB) from treatment-naive patients in the CLL8, CLL10, and CLL11 clinical trials, and quantified by 4-color flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on PB-MRD. PB-MRD levels were measured in 393, 337, and 474 patients from CLL8, CLL10, and CLL11, respectively. The model demonstrated a statistically significant relationship between treatment effect on PB-MRD and treatment effect on PFS. As the difference between treatment arms in PB-MRD response rates increased, a reduction in the risk of progression or death was observed; for each unit increase in the (log) ratio of MRD- rates between arms, the log of the PFS hazard ratio decreased by -0.188 (95% confidence interval, -0.321 to -0.055; P = .008). External model validation on the REACH trial and sensitivity analyses confirm the robustness and applicability of the surrogacy model. Our surrogacy model supports use of PB-MRD as a primary end point in randomized clinical trials of chemoimmunotherapy in CLL. Additional CLL trial data are required to establish a more precise quantitative relationship between MRD and PFS, and to support general applicability of MRD surrogacy for PFS across diverse patient characteristics, treatment regimens, and different treatment mechanisms of action.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dimier, Natalie UNSPECIFIED UNSPECIFIED UNSPECIFIED Delmar, Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED Ward, Carol UNSPECIFIED UNSPECIFIED UNSPECIFIED Morariu-Zamfir, Rodica UNSPECIFIED UNSPECIFIED UNSPECIFIED Fingerle-Rowson, Guenter UNSPECIFIED UNSPECIFIED UNSPECIFIED Bahlo, Jasmin UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Kirsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Eichhorst, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Goede, Valentin UNSPECIFIED UNSPECIFIED UNSPECIFIED van Dongen, Jacques J. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ritgen, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Boettcher, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Langerak, Anton W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kneba, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-193977
DOI:	10.1182/blood-2017-06-792333
Journal or Publication Title:	Blood
Volume:	131
Number:	9
Page Range:	S. 955 - 963
Date:	2018
Publisher:	AMER SOC HEMATOLOGY
Place of Publication:	WASHINGTON
ISSN:	1528-0020
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHRONIC LYMPHOCYTIC-LEUKEMIA; MINIMAL RESIDUAL DISEASE; IG/TCR GENE REARRANGEMENTS; TIME QUANTITATIVE PCR; INDEPENDENT PREDICTOR; CLINICAL-TRIALS; OPEN-LABEL; RITUXIMAB; THERAPY; CYCLOPHOSPHAMIDE Multiple languages Hematology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19397