Addition of rituximab to chemotherapy overcomes the negative prognostic impact of cyclin E expression in diffuse large B-cell lymphoma

E. Frei, C. Visco, Z. Y. Xu-Monette, S. Dirnhofer, K. Dybkræ, A. Orazi, G. Bhagat, E. D. Hsi, J. H. Van Krieken, M. Ponzoni, R. S. Go, M. A. Piris, M. B. Møller, Ken H. Young, Alexander Tzankov

Research output: Contribution to journalArticle

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Abstract

Background: High levels of cyclin E (CCNE) are accompanied by shorter survival in cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP)-treated diffuse large B-cell lymphomas (DLBCL), independent of the international prognostic index (IPI). Data on the prognostic role of CCNE in the 'rituximab (R)-era' are lacking. Methods: To test reproducibility and applicability of observations from the 'pre-R era' to the 'R era', we examined the prognostic role of CCNE expression by immunohistochemistry in 1579 DLBCL on tissue microarrays (TMA); 339 patients were treated by CHOP and 635 by R-CHOP. Results: 1209 samples (77%) were evaluable; failures were due to missing TMA punches and fixation artefacts. Mean expression of CCNE was 13% (0-85%); applying a cut-off of >16%, 382 DLBCL (31%) were positive. CCNE did not correlate with any of the known variables (IPI, primary site, cell of origin, proliferation, and BCL2- or C-MYC rearrangements). We were able to reproduce data suggesting an IPI- and response to therapy independent, negative prognostic impact of CCNE in CHOP-treated DLBCL patients: CCNE-positive cases had a median survival of 16 months compared with 57 months in negative ones (p=0.012). In R-CHOP-treated patients the prognostic impact of CCNE was abrogated and only IPI, cell of origin and response to therapy had a prognostic significance. Conclusions: Addition of R to CHOP overcomes the negative prognostic impact of CCNE in DLBCL. Thus, R not only prolongs survival in DLBCL but also serves a cautionary note that prognostic factors should not be transferred into the 'R era' without proper scientific studies.

Original languageEnglish (US)
Pages (from-to)956-961
Number of pages6
JournalJournal of Clinical Pathology
Volume66
Issue number11
DOIs
StatePublished - Nov 2013
Externally publishedYes

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Cyclin E
Lymphoma, Large B-Cell, Diffuse
Vincristine
Prednisone
Drug Therapy
Cyclophosphamide
Survival
Rituximab
Artifacts
Immunohistochemistry
Cell Proliferation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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Addition of rituximab to chemotherapy overcomes the negative prognostic impact of cyclin E expression in diffuse large B-cell lymphoma. / Frei, E.; Visco, C.; Xu-Monette, Z. Y.; Dirnhofer, S.; Dybkræ, K.; Orazi, A.; Bhagat, G.; Hsi, E. D.; Van Krieken, J. H.; Ponzoni, M.; Go, R. S.; Piris, M. A.; Møller, M. B.; Young, Ken H.; Tzankov, Alexander.

In: Journal of Clinical Pathology, Vol. 66, No. 11, 11.2013, p. 956-961.

Research output: Contribution to journalArticle

Frei, E, Visco, C, Xu-Monette, ZY, Dirnhofer, S, Dybkræ, K, Orazi, A, Bhagat, G, Hsi, ED, Van Krieken, JH, Ponzoni, M, Go, RS, Piris, MA, Møller, MB, Young, KH & Tzankov, A 2013, 'Addition of rituximab to chemotherapy overcomes the negative prognostic impact of cyclin E expression in diffuse large B-cell lymphoma', Journal of Clinical Pathology, vol. 66, no. 11, pp. 956-961. https://doi.org/10.1136/jclinpath-2013-201619
Frei, E. ; Visco, C. ; Xu-Monette, Z. Y. ; Dirnhofer, S. ; Dybkræ, K. ; Orazi, A. ; Bhagat, G. ; Hsi, E. D. ; Van Krieken, J. H. ; Ponzoni, M. ; Go, R. S. ; Piris, M. A. ; Møller, M. B. ; Young, Ken H. ; Tzankov, Alexander. / Addition of rituximab to chemotherapy overcomes the negative prognostic impact of cyclin E expression in diffuse large B-cell lymphoma. In: Journal of Clinical Pathology. 2013 ; Vol. 66, No. 11. pp. 956-961.
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abstract = "Background: High levels of cyclin E (CCNE) are accompanied by shorter survival in cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP)-treated diffuse large B-cell lymphomas (DLBCL), independent of the international prognostic index (IPI). Data on the prognostic role of CCNE in the 'rituximab (R)-era' are lacking. Methods: To test reproducibility and applicability of observations from the 'pre-R era' to the 'R era', we examined the prognostic role of CCNE expression by immunohistochemistry in 1579 DLBCL on tissue microarrays (TMA); 339 patients were treated by CHOP and 635 by R-CHOP. Results: 1209 samples (77{\%}) were evaluable; failures were due to missing TMA punches and fixation artefacts. Mean expression of CCNE was 13{\%} (0-85{\%}); applying a cut-off of >16{\%}, 382 DLBCL (31{\%}) were positive. CCNE did not correlate with any of the known variables (IPI, primary site, cell of origin, proliferation, and BCL2- or C-MYC rearrangements). We were able to reproduce data suggesting an IPI- and response to therapy independent, negative prognostic impact of CCNE in CHOP-treated DLBCL patients: CCNE-positive cases had a median survival of 16 months compared with 57 months in negative ones (p=0.012). In R-CHOP-treated patients the prognostic impact of CCNE was abrogated and only IPI, cell of origin and response to therapy had a prognostic significance. Conclusions: Addition of R to CHOP overcomes the negative prognostic impact of CCNE in DLBCL. Thus, R not only prolongs survival in DLBCL but also serves a cautionary note that prognostic factors should not be transferred into the 'R era' without proper scientific studies.",
author = "E. Frei and C. Visco and Xu-Monette, {Z. Y.} and S. Dirnhofer and K. Dybkr{\ae} and A. Orazi and G. Bhagat and Hsi, {E. D.} and {Van Krieken}, {J. H.} and M. Ponzoni and Go, {R. S.} and Piris, {M. A.} and M{\o}ller, {M. B.} and Young, {Ken H.} and Alexander Tzankov",
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T1 - Addition of rituximab to chemotherapy overcomes the negative prognostic impact of cyclin E expression in diffuse large B-cell lymphoma

AU - Frei, E.

AU - Visco, C.

AU - Xu-Monette, Z. Y.

AU - Dirnhofer, S.

AU - Dybkræ, K.

AU - Orazi, A.

AU - Bhagat, G.

AU - Hsi, E. D.

AU - Van Krieken, J. H.

AU - Ponzoni, M.

AU - Go, R. S.

AU - Piris, M. A.

AU - Møller, M. B.

AU - Young, Ken H.

AU - Tzankov, Alexander

PY - 2013/11

Y1 - 2013/11

N2 - Background: High levels of cyclin E (CCNE) are accompanied by shorter survival in cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP)-treated diffuse large B-cell lymphomas (DLBCL), independent of the international prognostic index (IPI). Data on the prognostic role of CCNE in the 'rituximab (R)-era' are lacking. Methods: To test reproducibility and applicability of observations from the 'pre-R era' to the 'R era', we examined the prognostic role of CCNE expression by immunohistochemistry in 1579 DLBCL on tissue microarrays (TMA); 339 patients were treated by CHOP and 635 by R-CHOP. Results: 1209 samples (77%) were evaluable; failures were due to missing TMA punches and fixation artefacts. Mean expression of CCNE was 13% (0-85%); applying a cut-off of >16%, 382 DLBCL (31%) were positive. CCNE did not correlate with any of the known variables (IPI, primary site, cell of origin, proliferation, and BCL2- or C-MYC rearrangements). We were able to reproduce data suggesting an IPI- and response to therapy independent, negative prognostic impact of CCNE in CHOP-treated DLBCL patients: CCNE-positive cases had a median survival of 16 months compared with 57 months in negative ones (p=0.012). In R-CHOP-treated patients the prognostic impact of CCNE was abrogated and only IPI, cell of origin and response to therapy had a prognostic significance. Conclusions: Addition of R to CHOP overcomes the negative prognostic impact of CCNE in DLBCL. Thus, R not only prolongs survival in DLBCL but also serves a cautionary note that prognostic factors should not be transferred into the 'R era' without proper scientific studies.

AB - Background: High levels of cyclin E (CCNE) are accompanied by shorter survival in cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP)-treated diffuse large B-cell lymphomas (DLBCL), independent of the international prognostic index (IPI). Data on the prognostic role of CCNE in the 'rituximab (R)-era' are lacking. Methods: To test reproducibility and applicability of observations from the 'pre-R era' to the 'R era', we examined the prognostic role of CCNE expression by immunohistochemistry in 1579 DLBCL on tissue microarrays (TMA); 339 patients were treated by CHOP and 635 by R-CHOP. Results: 1209 samples (77%) were evaluable; failures were due to missing TMA punches and fixation artefacts. Mean expression of CCNE was 13% (0-85%); applying a cut-off of >16%, 382 DLBCL (31%) were positive. CCNE did not correlate with any of the known variables (IPI, primary site, cell of origin, proliferation, and BCL2- or C-MYC rearrangements). We were able to reproduce data suggesting an IPI- and response to therapy independent, negative prognostic impact of CCNE in CHOP-treated DLBCL patients: CCNE-positive cases had a median survival of 16 months compared with 57 months in negative ones (p=0.012). In R-CHOP-treated patients the prognostic impact of CCNE was abrogated and only IPI, cell of origin and response to therapy had a prognostic significance. Conclusions: Addition of R to CHOP overcomes the negative prognostic impact of CCNE in DLBCL. Thus, R not only prolongs survival in DLBCL but also serves a cautionary note that prognostic factors should not be transferred into the 'R era' without proper scientific studies.

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