Gene mutations and treatment outcome in chronic lymphocytic leukemia

Results from the CLL8 trial

Stephan Stilgenbauer, Andrea Schnaiter, Peter Paschka, Thorsten Zenz, Marianna Rossi, Konstanze Döhner, Andreas Bühler, Sebastian Böttcher, Matthias Ritgen, Michael Kneba, Dirk Winkler, Eugen Tausch, Patrick Hoth, Jennifer Edelmann, Daniel Mertens, Lars Bullinger, Manuela Bergmann, Sabrina Kless, Silja Mack, Ulrich Jäger & 12 others Nancy Patten, Lin Wu, Michael K. Wenger, Günter Fingerle-Rowson, Peter Lichter, Mario Cazzola, Clemens M. Wendtner, Anna M. Fink, Kirsten Fischer, Raymonde Busch, Michael Hallek, Hartmut Döhner

Research output: Contribution to journalArticle

231 Citations (Scopus)

Abstract

Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first line therapy with flud arabine 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. NOTCH1mut and SF3B1mut virtually showed mutual exclusivity (0.6% concurrence), but TP53mut was frequently found in NOTCH1mut (16.1%) and in SF3B1mut (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. Inmultivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53mut, and SF3B1mut on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, b2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53mut 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 NOTCH1mut. In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1mut 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.

Original languageEnglish
Pages (from-to)3247-3254
Number of pages8
JournalBlood
Volume123
Issue number21
DOIs
Publication statusPublished - May 22 2014

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B-Cell Chronic Lymphocytic Leukemia
Genes
Mutation
Thymidine Kinase
Survival
Oncology
Genetic Markers
Cyclophosphamide
Disease-Free Survival
Therapeutics
Rituximab

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Stilgenbauer, S., Schnaiter, A., Paschka, P., Zenz, T., Rossi, M., Döhner, K., ... Döhner, H. (2014). Gene mutations and treatment outcome in chronic lymphocytic leukemia: Results from the CLL8 trial. Blood, 123(21), 3247-3254. https://doi.org/10.1182/blood-2014-01-546150

Gene mutations and treatment outcome in chronic lymphocytic leukemia : Results from the CLL8 trial. / Stilgenbauer, Stephan; Schnaiter, Andrea; Paschka, Peter; Zenz, Thorsten; Rossi, Marianna; Döhner, Konstanze; Bühler, Andreas; Böttcher, Sebastian; Ritgen, Matthias; Kneba, Michael; Winkler, Dirk; Tausch, Eugen; Hoth, Patrick; Edelmann, Jennifer; Mertens, Daniel; Bullinger, Lars; Bergmann, Manuela; Kless, Sabrina; Mack, Silja; Jäger, Ulrich; Patten, Nancy; Wu, Lin; Wenger, Michael K.; Fingerle-Rowson, Günter; Lichter, Peter; Cazzola, Mario; Wendtner, Clemens M.; Fink, Anna M.; Fischer, Kirsten; Busch, Raymonde; Hallek, Michael; Döhner, Hartmut.

In: Blood, Vol. 123, No. 21, 22.05.2014, p. 3247-3254.

Research output: Contribution to journalArticle

Stilgenbauer, S, Schnaiter, A, Paschka, P, Zenz, T, Rossi, M, Döhner, K, Bühler, A, Böttcher, S, Ritgen, M, Kneba, M, Winkler, D, Tausch, E, Hoth, P, Edelmann, J, Mertens, D, Bullinger, L, Bergmann, M, Kless, S, Mack, S, Jäger, U, Patten, N, Wu, L, Wenger, MK, Fingerle-Rowson, G, Lichter, P, Cazzola, M, Wendtner, CM, Fink, AM, Fischer, K, Busch, R, Hallek, M & Döhner, H 2014, 'Gene mutations and treatment outcome in chronic lymphocytic leukemia: Results from the CLL8 trial', Blood, vol. 123, no. 21, pp. 3247-3254. https://doi.org/10.1182/blood-2014-01-546150
Stilgenbauer, Stephan ; Schnaiter, Andrea ; Paschka, Peter ; Zenz, Thorsten ; Rossi, Marianna ; Döhner, Konstanze ; Bühler, Andreas ; Böttcher, Sebastian ; Ritgen, Matthias ; Kneba, Michael ; Winkler, Dirk ; Tausch, Eugen ; Hoth, Patrick ; Edelmann, Jennifer ; Mertens, Daniel ; Bullinger, Lars ; Bergmann, Manuela ; Kless, Sabrina ; Mack, Silja ; Jäger, Ulrich ; Patten, Nancy ; Wu, Lin ; Wenger, Michael K. ; Fingerle-Rowson, Günter ; Lichter, Peter ; Cazzola, Mario ; Wendtner, Clemens M. ; Fink, Anna M. ; Fischer, Kirsten ; Busch, Raymonde ; Hallek, Michael ; Döhner, Hartmut. / Gene mutations and treatment outcome in chronic lymphocytic leukemia : Results from the CLL8 trial. In: Blood. 2014 ; Vol. 123, No. 21. pp. 3247-3254.
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abstract = "Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first line therapy with flud arabine 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. NOTCH1mut and SF3B1mut virtually showed mutual exclusivity (0.6{\%} concurrence), but TP53mut was frequently found in NOTCH1mut (16.1{\%}) and in SF3B1mut (14.0{\%}) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. Inmultivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53mut, and SF3B1mut on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, b2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53mut 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 NOTCH1mut. In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1mut 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.",
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AU - Stilgenbauer, Stephan

AU - Schnaiter, Andrea

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AU - Zenz, Thorsten

AU - Rossi, Marianna

AU - Döhner, Konstanze

AU - Bühler, Andreas

AU - Böttcher, Sebastian

AU - Ritgen, Matthias

AU - Kneba, Michael

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AU - Tausch, Eugen

AU - Hoth, Patrick

AU - Edelmann, Jennifer

AU - Mertens, Daniel

AU - Bullinger, Lars

AU - Bergmann, Manuela

AU - Kless, Sabrina

AU - Mack, Silja

AU - Jäger, Ulrich

AU - Patten, Nancy

AU - Wu, Lin

AU - Wenger, Michael K.

AU - Fingerle-Rowson, Günter

AU - Lichter, Peter

AU - Cazzola, Mario

AU - Wendtner, Clemens M.

AU - Fink, Anna M.

AU - Fischer, Kirsten

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AU - Hallek, Michael

AU - Döhner, Hartmut

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