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24 Publications visible to you, out of a total of 24
Optimization of rituximab for the treatment of DLBCL: increasing the dose for elderly male patients.
GLA - German Lymphoma Alliance

Abstract (Expand)

Male sex is associated with unfavourable pharmacokinetics and prognosis in elderly patients with diffuse large B-cell lymphoma (DLBCL). We investigated higher rituximab doses for elderly male DLBCL … patients. Elderly patients (61-80 years) received 6 cycles CHOP-14 (cyclophosphamide, doxorubicin, vincristine and prednisone at 14-day intervals) and were randomized to 8 cycles rituximab (males 500 mg/m(2) , females 375 mg/m(2) ) every 2 weeks or according to an upfront dose-dense schedule. In 268 (120 females, 148 males) no difference between the standard and the upfront dose-dense rituximab schedule was found (3-year PFS 72% vs. 74%; OS 74% vs. 77%; P = 0.651). The 500 mg/m(2) dose of rituximab for male patients was associated with serum levels and exposure times slightly better than in females and a male/female hazard ratio of 0.9 for progression-free survival (PFS) and 0.8 for overall survival. For elderly males, 500 mg/m(2) was not more toxic than 375 mg/m(2) rituximab, but improved PFS by 32.5% (P = 0.039), with a trend for a (30%) better overall survival (P = 0.076) in a planned subgroup analysis adjusting for International Prognostic Index risk factors. We conclude that the higher rituximab dose for elderly male patients abrogated the adverse prognosis of male sex without increasing toxicity. In the era of personalized medicine, sex-specific pharmacokinetics and toxicities should be investigated for all drugs where these parameters impact on outcome.

Authors: M. Pfreundschuh, N. Murawski, S. Zeynalova, M. Ziepert, M. Loeffler, M. Hanel, J. Dierlamm, U. Keller, M. Dreyling, L. Truemper, N. Frickhofen, A. N. Hunerliturkoglu, N. Schmitz, V. Poschel, T. Rixecker, C. Berdel, C. Rube, G. Held, C. Zwick

Date Published: 11th Oct 2017

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma, diffuse large B-cell lymphoma

TP53 mutation and survival in aggressive B cell lymphoma.
GLA - German Lymphoma Alliance

Abstract (Expand)

TP53 is mutated in 20-25% of aggressive B-cell lymphoma (B-NHL). To date, no studies have addressed the impact of TP53 mutations in prospective clinical trial cohorts. To evaluate the impact of TP53 … mutation to current risk models in aggressive B-NHL, we investigated TP53 gene mutations within the RICOVER-60 trial. Of 1,222 elderly patients (aged 61-80 years) enrolled in the study and randomized to six or eight cycles of CHOP-14 with or without Rituximab (NCT00052936), 265 patients were analyzed for TP53 mutations. TP53 mutations were demonstrated in 63 of 265 patients (23.8%). TP53 mutation was associated with higher LDH (65% vs. 37%; p < 0.001), higher international prognostic index-Scores (IPI 4/5 27% vs. 12%; p = 0.025) and B-symptoms (41% vs. 24%; p = 0.011). Patients with TP53 mutation were less likely to obtain a complete remission CR/CRu (CR unconfirmed) 61.9% (mut) vs. 79.7% (wt) (p = 0.007). TP53 mutations were associated with decreased event-free (EFS), progression-free (PFS) and overall survival (OS) (median observation time of 40.2 months): the 3 year EFS, PFS and OS were 42% (vs. 60%; p = 0.012), 42% (vs. 67.5%; p < 0.001) and 50% (vs. 76%; p < 0.001) for the TP53 mutation group. In a Cox proportional hazard analysis adjusting for IPI-factors and treatment arms, TP53 mutation was shown to be an independent predictor of EFS (HR 1.5), PFS (HR 2.0) and OS (HR 2.3; p < 0.001). TP53 mutations are independent predictors of survival in untreated patients with aggressive CD20+ lymphoma. TP53 mutations should be considered for risk models in DLBCL and strategies to improve outcome for patients with mutant TP53 must be developed.

Authors: T. Zenz, M. Kreuz, M. Fuge, W. Klapper, H. Horn, A. M. Staiger, D. Winter, H. Helfrich, J. Huellein, M. L. Hansmann, H. Stein, A. Feller, P. Moller, N. Schmitz, L. Trumper, M. Loeffler, R. Siebert, A. Rosenwald, G. Ott, M. Pfreundschuh, S. Stilgenbauer

Date Published: 1st Oct 2017

Publication Type: Journal article

Human Diseases: non-Hodgkin lymphoma, B-cell lymphoma

Modified BEAM with triple autologous stem cell transplantation for patients with relapsed aggressive non-Hodgkin lymphoma.
GLA - German Lymphoma Alliance

Abstract (Expand)

Treatment of relapse and primary progression in aggressive lymphoma remains unsatisfactory; outcome is still poor. Better treatment strategies are much needed for this patient population. The R1 study … is a prospective multi-center phase I/II study evaluating a dose finding approach with a triple transplant regimen in four BEAM dose levels in patients with relapsed aggressive non-Hodgkin lymphoma. The aim of the study was to determine feasibility, toxicity, and remission rate. In a total of 39 patients (pts.) enrolled in the study, 24 pts. were evaluated in the following analysis. Twenty pts. had aggressive B cell lymphoma, and two pts. had T cell lymphoma. All evaluated patients responded to DexaBEAM with a sufficient stem cell harvest. The phase I/II study was started with BEAM dose level II. Four patients were treated at dose level II, and 20 pts. were treated at dose level III. Due to the early termination of the study, dose levels I and IV were never administered. Sixteen pts. completed therapy according to protocol, and eight pts. (33.3 %) stopped treatment early. Infections (27 %) and stomatitis (13 %) were the most frequent grade III/IV non-hematologic toxicities. Thirteen percent of patients presented with severe grade III/IV lung toxicity during modified BEAM (m-BEAM). Fourteen pts. achieved a complete response (CR), one pt. achieved no change (NC), six pts. had progressive disease (PD), and two pts. died; for one pt., outcome is not known. One-year and 3-year event-free survival (EFS) was 38 and 33 %, respectively. Overall survival (OS) after 1 and 3 years was 50 and 38 %. In conclusion, dose escalation of standard BEAM is not feasible due to toxicity.

Authors: K. Hohloch, S. Zeynalova, B. Chapuy, M. Pfreundschuh, M. Loeffler, M. Ziepert, A. C. Feller, L. Trumper, D. Hasenclever, G. Wulf, N. Schmitz

Date Published: 12th May 2016

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma

Epigenetic Heterogeneity of B-Cell Lymphoma: Chromatin Modifiers.
MMML-MYC-SYS

Abstract (Expand)

We systematically studied the expression of more than fifty histone and DNA (de)methylating enzymes in lymphoma and healthy controls. As a main result, we found that the expression levels of nearly all … enzymes become markedly disturbed in lymphoma, suggesting deregulation of large parts of the epigenetic machinery. We discuss the effect of DNA promoter methylation and of transcriptional activity in the context of mutated epigenetic modifiers such as EZH2 and MLL2. As another mechanism, we studied the coupling between the energy metabolism and epigenetics via metabolites that act as cofactors of JmjC-type demethylases. Our study results suggest that Burkitt's lymphoma and diffuse large B-cell Lymphoma differ by an imbalance of repressive and poised promoters, which is governed predominantly by the activity of methyltransferases and the underrepresentation of demethylases in this regulation. The data further suggest that coupling of epigenetics with the energy metabolism can also be an important factor in lymphomagenesis in the absence of direct mutations of genes in metabolic pathways. Understanding of epigenetic deregulation in lymphoma and possibly in cancers in general must go beyond simple schemes using only a few modes of regulation.

Authors: L. Hopp, L. Nersisyan, H. Loffler-Wirth, A. Arakelyan, H. Binder

Date Published: 21st Oct 2015

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma

Epigenetic Heterogeneity of B-Cell Lymphoma: DNA Methylation, Gene Expression and Chromatin States.
MMML-MYC-SYS

Abstract (Expand)

Mature B-cell lymphoma is a clinically and biologically highly diverse disease. Its diagnosis and prognosis is a challenge due to its molecular heterogeneity and diverse regimes of biological dysfunctions, … which are partly driven by epigenetic mechanisms. We here present an integrative analysis of DNA methylation and gene expression data of several lymphoma subtypes. Our study confirms previous results about the role of stemness genes during development and maturation of B-cells and their dysfunction in lymphoma locking in more proliferative or immune-reactive states referring to B-cell functionalities in the dark and light zone of the germinal center and also in plasma cells. These dysfunctions are governed by widespread epigenetic effects altering the promoter methylation of the involved genes, their activity status as moderated by histone modifications and also by chromatin remodeling. We identified four groups of genes showing characteristic expression and methylation signatures among Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma and multiple myeloma. These signatures are associated with epigenetic effects such as remodeling from transcriptionally inactive into active chromatin states, differential promoter methylation and the enrichment of targets of transcription factors such as EZH2 and SUZ12.

Authors: L. Hopp, H. Loffler-Wirth, H. Binder

Date Published: 7th Sep 2015

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma, B-cell lymphoma

Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the german high-grade non-Hodgkin lymphoma study group.
GLA - German Lymphoma Alliance

Abstract (Expand)

PURPOSE: To study pharmacokinetics, toxicity, and efficacy of prolonged rituximab exposure in elderly patients with diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: In the SMARTE-R-CHOP-14 … trial, rituximab 375 mg/m(2) was administered, together with six cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone on a 14-day schedule (6xR-CHOP-14), on days -4, 0, 10, 29, 57, 99, 155, and 239. Pharmacokinetics and outcome were to be compared with those of patients who had received 6xR-CHOP-14 in combination with eight 2-week applications of rituximab in the RICOVER-60 (Rituximab With CHOP Over Age 60 Years) trial. RESULTS: The complete response (CR)/unconfirmed CR rate was 85% in 189 evaluable patients, 90% for 90 good-prognosis patients (International Prognostic Index [IPI], 1 or 2), and 81% for 99 poor-prognosis patients (IPI, 3 to 5); 3-year event-free survival (EFS) was 71%, 75%, and 67%, respectively; and 3-year overall survival (OS) was 84%, 88%, and 80%, respectively, with no differences between men and women. The preplanned historical comparison with 306 RICOVER-60 patients (good prognosis, n = 183; poor prognosis, n = 123) revealed no outcome differences for all and good-prognosis patients; however, the longer exposure time in SMARTE-R-CHOP-14 compared with RICOVER-60 was associated with better 3-year EFS (67% v 54%) and OS (80% v 67%) in poor-prognosis patients. CONCLUSION: Extended rituximab exposure compared with eight 2-week applications in combination with 6xR-CHOP-14 significantly improved outcome of elderly poor-prognosis patients without increasing toxicity. To our knowledge, results obtained with the SMARTE-R-CHOP-14 rituximab schedule are the best reported for elderly patients with DLBCL to date. In the subgroup of poor-prognosis patients treated with extended rituximab exposure, the outcome seemed superior to that of a similar historical cohort of patients treated with 6xR-CHOP-14 plus 2-week rituximab, with similar toxicity. A randomized comparison of the two schedules is warranted.

Authors: M. Pfreundschuh, V. Poeschel, S. Zeynalova, M. Hanel, G. Held, N. Schmitz, A. Viardot, M. H. Dreyling, M. Hallek, C. Mueller, M. H. Wiesen, M. Witzens-Harig, L. Truemper, U. Keller, T. Rixecker, C. Zwick, N. Murawski

Date Published: 20th Dec 2014

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma, diffuse large B-cell lymphoma

Excellent outcome of young adults with aggressive non-Hodgkin lymphomas treated with CHOP-like regimens.
GLA - German Lymphoma Alliance

Abstract

Not specified

Authors: K. Hohloch, S. Zeynalova, G. Held, M. Ziepert, M. Loeffler, G. Wulf, N. Schmitz, M. Pfreundschuh, L. Trumper

Date Published: 10th Jul 2014

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma

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