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Addition of rituximab to chemotherapy overcomes the negative prognostic impact of cyclin E expression in diffuse large B-cell lymphoma
  1. E Frei1,
  2. C Visco2,
  3. Z Y Xu-Monette3,
  4. S Dirnhofer1,
  5. K Dybkær4,
  6. A Orazi5,
  7. G Bhagat6,
  8. E D Hsi7,
  9. J H van Krieken8,
  10. M Ponzoni9,
  11. R S Go10,
  12. M A Piris11,
  13. M B Møller12,
  14. K H Young3,
  15. A Tzankov1,3
  1. 1Institute of Pathology, University Hospital, Basel, Switzerland
  2. 2Department of Hematology, San Bortolo Hospital, Vicenza, Italy
  3. 3Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  4. 4Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark
  5. 5Weill Medical College of Cornell University, New York, New York, USA
  6. 6Columbia University Medical Center and New York Presbyterian Hospital, New York, New York, USA
  7. 7Cleveland Clinic, Cleveland, Ohio, USA
  8. 8Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  9. 9San Raffaele H. Scientific Institute, Milan, Italy
  10. 10Gundersen Lutheran Health System, La Crosse, Wisconsin, USA
  11. 11Hospital Universitario Marques de Valdecilla, Santander, Spain
  12. 12Odense University Hospital, Odense, Denmark
  1. Correspondence to Professor Dr Alexandar Tzankov, Institute of Pathology, University Hospital Basel, Schoenbeinstrasse 40, Basel CH-4031, Switzerland; atzankov{at} and Dr Ken H Young, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Holcombe Boulevard, Houston, TX 77030-4009, USA; khyoung{at}


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.

  • Lymphoma
  • Cell Cycle Regulation
  • Haematopathology

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