Stilgenbauer, Stephan, Schnaiter, Andrea, Paschka, Peter, Zenz, Thorsten, Rossi, Marianna ORCID: 0000-0003-1661-1511, Doehner, Konstanze, Buehler, Andreas, Boettcher, Sebastian, Ritgen, Matthias, Kneba, Michael, Winkler, Dirk, Tausch, Eugen, Hoth, Patrick, Edelmann, Jennifer, Mertens, Daniel ORCID: 0000-0003-0227-7188, Bullinger, Lars, Bergmann, Manuela, Kless, Sabrina, Mack, Silja, Jaeger, Ulrich, Patten, Nancy, Wu, Lin, Wenger, Michael K., Fingerle-Rowson, Guenter, Lichter, Peter, Cazzola, Mario, Wendtner, Clemens M., Fink, Anna M., Fischer, Kirsten, Busch, Raymonde, Hallek, Michael and Doehner, Hartmut (2014). Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood, 123 (21). S. 3247 - 3255. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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Abstract

Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab(FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) >= 10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age >= 65 years, Eastern Cooperative Oncology Group performance status >= 1, beta 2-microglobulin >= 3.5 mg/L, TK >= 10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT00281918.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Stilgenbauer, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schnaiter, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paschka, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zenz, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rossi, MariannaUNSPECIFIEDorcid.org/0000-0003-1661-1511UNSPECIFIED
Doehner, KonstanzeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buehler, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boettcher, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ritgen, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kneba, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winkler, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tausch, EugenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoth, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Edelmann, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mertens, DanielUNSPECIFIEDorcid.org/0000-0003-0227-7188UNSPECIFIED
Bullinger, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bergmann, ManuelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kless, SabrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mack, SiljaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jaeger, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patten, NancyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, LinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wenger, Michael K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fingerle-Rowson, GuenterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lichter, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cazzola, MarioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wendtner, Clemens M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fink, Anna M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, KirstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Busch, RaymondeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doehner, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-437788
DOI: 10.1182/blood-2014-01-546150
Journal or Publication Title: Blood
Volume: 123
Number: 21
Page Range: S. 3247 - 3255
Date: 2014
Publisher: AMER SOC HEMATOLOGY
Place of Publication: WASHINGTON
ISSN: 1528-0020
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
INDEPENDENT PREDICTOR; GENOMIC ABERRATIONS; PROGRESSION-FREE; INITIAL THERAPY; CD38 EXPRESSION; SF3B1 MUTATIONS; POOR SURVIVAL; FLUDARABINE; CYCLOPHOSPHAMIDE; RITUXIMABMultiple languages
HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/43778

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