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Published year: 20104
Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL.
GLA - German Lymphoma Alliance

Abstract (Expand)

The survival of diffuse large B-cell lymphoma patients varies considerably, reflecting the molecular diversity of tumors. In view of the controversy whether cytologic features, immunohistochemical … markers or gene expression signatures may capture this molecular diversity, we investigated which features provide prognostic information in a prospective trial in the R-CHOP treatment era. Within the cohort of DLBCLs patients treated in the RICOVER-60 trial of the German High-Grade Lymphoma Study Group (DSHNHL), we tested the prognostic impact of IB morphology in 949 patients. The expression of immunohistochemical markers CD5, CD10, BCL2, BCL6, human leukocyte antigen (HLA)-DR, interferon regulatory factor-4/multiple myeloma-1 (IRF4/MUM1), and Ki-67 was assessed in 506 patients. Expression of the immunohistochemical markers tested was of modest, if any, prognostic relevance. Moreover, the Hans algorithm using the expression patterns of CD10, BCL6, and interferon regulatory factor-4/multiple myeloma-1 failed to show prognostic significance in the entire cohort as well as in patient subgroups. IB morphology, however, emerged as a robust, significantly adverse prognostic factor in multivariate analysis, and its diagnosis showed a good reproducibility among expert hematopathologists. We conclude, therefore, that IB morphology in DLBCL is likely to capture some of the adverse molecular alterations that are currently not detectable in a routine diagnostic setting, and that its recognition has significant prognostic power.

Authors: G. Ott, M. Ziepert, W. Klapper, H. Horn, M. Szczepanowski, H. W. Bernd, C. Thorns, A. C. Feller, D. Lenze, M. Hummel, H. Stein, H. K. Muller-Hermelink, M. Frank, M. L. Hansmann, T. F. Barth, P. Moller, S. Cogliatti, M. Pfreundschuh, N. Schmitz, L. Trumper, M. Loeffler, A. Rosenwald

Date Published: 2nd Dec 2010

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group.
GLA - German Lymphoma Alliance

Abstract (Expand)

To evaluate outcome and prognosis of patients with T-cell lymphoma we analyzed 343 patients treated within trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Two hundred eighty-nine … patients belonged to 1 of the 4 major T-cell lymphoma subtypes: anaplastic large cell lymphoma (ALCL), anaplastic large cell lymphoma kinase (ALK)-positive (n = 78); ALCL, ALK-negative (n = 113); peripheral T-cell lymphoma, unspecified (PTCLU; n = 70); and angioimmunoblastic T-cell lymphoma (AITL; n = 28). Treatment consisted of 6-8 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone) or etoposide plus (CHOEP). Three-year event-free survival (EFS) and overall survival were 75.8% and 89.8% (ALK-positive ALCL), 50.0% and 67.5% (AITL), 45.7% and 62.1% (ALK-negative ALCL), and 41.1% and 53.9% (PTCLU), respectively. The International Prognostic Index (IPI) was effective in defining risk groups with significantly different outcomes. For patients, </= 60 years with lactate dehydrogenase </= upper normal value (UNV), etoposide improved improved 3-year EFS: 75.4% versus 51.0%, P = .003. In patients > 60 years 6 courses of CHOP administered every 3 weeks remains the standard therapy. Patients with ALK-negative ALCL, PTCLU, or AITL presenting with IPI > 1 have a poor prognosis and should be considered candidates for novel treatment strategies.

Authors: N. Schmitz, L. Trumper, M. Ziepert, M. Nickelsen, A. D. Ho, B. Metzner, N. Peter, M. Loeffler, A. Rosenwald, M. Pfreundschuh

Date Published: 4th Nov 2010

Publication Type: Not specified

Human Diseases: mature T-cell and NK-cell lymphoma

Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era.
GLA - German Lymphoma Alliance

Abstract (Expand)

PURPOSE: The International Prognostic Index (IPI) is widely used for risk stratification of patients with aggressive B-cell lymphoma. The introduction of rituximab has markedly improved outcome, and … R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone) has become the standard treatment for CD20(+) diffuse large B-cell lymphoma. To investigate whether the IPI has maintained its power for risk stratification when rituximab is combined with CHOP, we analyzed the prognostic relevance of IPI in three prospective clinical trials. PATIENTS AND METHODS: In total, 1,062 patients treated with rituximab were included (MabThera International Trial [MInT], 380 patients; dose-escalated regimen of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (MegaCHOEP) trial, 72 patients; CHOP + rituximab for patients older than age 60 years [RICOVER-60] trial, 610 patients). A multivariate proportional hazards modeling was performed for single IPI factors under rituximab on event-free, progression-free, and overall survival. RESULTS: IPI score was significant for all three end points. Rituximab significantly improved treatment outcome within each IPI group resulting in a quenching of the Kaplan-Meier estimators. However, IPI was a significant prognostic factor in all three end points and the ordering of the IPI groups remained valid. The relative risk estimates of single IPI factors and their order in patients treated with R-CHOP were similar to those found with CHOP. CONCLUSION: The effects of rituximab were superimposed on the effects of CHOP with no interactions between chemotherapy and antibody therapy. These results demonstrate that the IPI is still valid in the R-CHOP era.

Authors: M. Ziepert, D. Hasenclever, E. Kuhnt, B. Glass, N. Schmitz, M. Pfreundschuh, M. Loeffler

Date Published: 10th May 2010

Publication Type: Not specified

Human Diseases: B-cell lymphoma

A functional polymorphism in the NAD(P)H oxidase subunit CYBA is related to gene expression, enzyme activity, and outcome in non-Hodgkin lymphoma.
GLA - German Lymphoma Alliance

Abstract (Expand)

NAD(P)H oxidase is a major endogenous source of reactive oxygen species (ROS). ROS may not only be involved in carcinogenesis but also in efficacy of chemotherapeutic agents like doxorubicin. By a … comprehensive genotyping approach covering 48 genetic polymorphisms (single-nucleotide polymorphisms) in five subunits of phagocytic NAD(P)H oxidase, we asked whether they affect gene expression, enzymatic activity, and outcome of CHO(E)P chemotherapy. A highly consistent effect was observed for the CYBA 640A>G variant. In peripheral blood granulocytes of 125 healthy volunteers, the G allele of 640A>G was associated with lower NAD(P)H oxidase activity (P = 0.006). Moreover, the G allele was associated with lower mRNA and protein expression (both P = 0.02). Of clinical importance, the outcome of patients suffering from non-Hodgkin lymphoma and treated with CHO(E)P regimen was dependent on the CYBA 640A>G polymorphism. In an exploratory study (n = 401), carriers of 640GG had an event-free survival (EFS) risk ratio of 1.95 [95% confidence interval (95% CI), 1.31-2.90; P = 0.001] compared with 640AA. In a confirmatory set (n = 477), the risk ratios were 1.53 (1.04-2.25, P = 0.03). The complete set of 878 patients showed a relative risk of 1.72 (1.30-2.26) and 1.59 (1.14-2.21) for EFS and overall survival, respectively. Further molecular-biological experiments showed lower expression and reduced stability of transcripts with the G allele in lymphoblastoid cell lines. Transfection of allele-specific plasmids into HEK293 cells elicited lower activity for the G allele in a luciferase reporter gene construct. Thus, CYBA 640A>G was shown to be a functional polymorphism with possible consequences for patients receiving CHO(E)P chemotherapy and might have further implications for other ROS-mediated modalities.

Authors: M. Hoffmann, M. A. Schirmer, M. V. Tzvetkov, M. Kreuz, M. Ziepert, L. Wojnowski, D. Kube, M. Pfreundschuh, L. Trumper, M. Loeffler, J. Brockmoller

Date Published: 15th Mar 2010

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma

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