High immunohistochemical expression of p-AKT predicts inferior survival in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

Br J Haematol. 2010 May;149(4):560-8. doi: 10.1111/j.1365-2141.2010.08123.x. Epub 2010 Mar 1.

Abstract

Chemotherapy and rituximab (R) is current standard therapy in diffuse large B-cell lymphoma (DLBCL), but a substantial proportion of patients still fail to reach sustained remission. In vitro studies have indicated that rituximab resistance could be accompanied by dysregulated apoptotic pathways, such as the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, which can be constitutively activated in DLBCL. In this retrospective, immunohistochemical study on 106 patients treated with R-CHO(E)P (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab [+etoposide]), we investigated the prognostic role of proteins involved in different apoptotic pathways; phosphorylated AKT (p-AKT), bcl-2, MCL1, bcl-xL, Bax and Bak. High p-AKT expression (>108 cells/mm2, highest quartile, n=27) predicted worse progression-free (PFS) (P=0.02) and overall (OS) (P=0.01) survival, independent of International Prognostic Index and sex. Also bcl-2+ (cut-off 50%) predicted worse PFS (P=0.005) and OS (P=0.05) but after adjustment for clinical factors only the influence on PFS (P=0.03) remained significant. The prognostic impact of p-AKT overexpression was independent of bcl-2 status. MCL1, bcl-xL, Bax and Bak expression did not add any prognostic information. Our results suggest that high p-AKT expression predicts worse outcome, possibly indicating that inhibition of the activated PI3K/AKT pathway could be of clinical interest in DLBCL patients. In addition, bcl-2 status could have prognostic importance also in the era of immunochemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Murine-Derived
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / metabolism*
  • Combined Modality Therapy
  • Female
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / metabolism*
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Lymphoma, Large B-Cell, Diffuse / therapy
  • Male
  • Middle Aged
  • Neoplasm Proteins / metabolism
  • Neoplasm Staging
  • Prognosis
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Retrospective Studies
  • Rituximab
  • Survival Analysis
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Biomarkers, Tumor
  • Neoplasm Proteins
  • Rituximab
  • Proto-Oncogene Proteins c-akt