Showing papers by "Lorenz Trümper published in 2011"

CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group.

Abstract: Summary Background The MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen in young patients with good-prognosis diffuse large-B-cell lymphoma. Extended follow-up was needed to establish long-term effects. Methods In the randomised open-label MInT study, patients from 18 countries (aged 18–60 years with none or one risk factor according to the age-adjusted International Prognostic Index [IPI], stage II–IV disease or stage I disease with bulk) were randomly assigned to receive six cycles of a CHOP-like chemotherapy with or without rituximab. Bulky and extranodal sites received additional radiotherapy. Randomisation was done centrally with a computer-based tool and was stratified by centre, bulky disease, age-adjusted IPI, and chemotherapy regimen by use of a modified minimisation algorithm that incorporated a stochastic component. Patients and investigators were not masked to treatment allocation. The primary endpoint was event-free survival. Analyses were by intention to treat. This observational study is a follow-up of the MInT trial, which was stopped in 2003, and is registered at ClinicalTrials.gov, number NCT00400907. Findings The intention-to-treat population included 410 patients assigned to chemotherapy alone and 413 assigned to chemotherapy plus rituximab. After a median follow-up of 72 months (range 0·03–119), 6-year event-free survival was 55·8% (95% CI 50·4–60·9; 166 events) for patients assigned to chemotherapy alone and 74·3% (69·3–78·6; 98 events) for those assigned to chemotherapy plus rituximab (difference between groups 18·5%, 11·5–25·4, log-rank p vs 71·0% [65·1–76·1], log-rank p=0·005). 18 (4·4%, 95% CI 2·6–6·9) second malignancies occurred in the chemotherapy-alone group and 16 (3·9%, 2·2–6·2) in the chemotherapy and rituximab group (Fisher's exact p=0·730). Interpretation Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows a more refined therapeutic approach to these patients than does assessment by IPI alone. Funding Hoffmann–La Roche.

Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3

Abstract: Targeting the surface of malignant cells has evolved into a cornerstone in cancer therapy, paradigmatically introduced by the success of humoral immunotherapy against CD20 in malignant lymphoma. However, tumor cell susceptibility to immunochemotherapy varies, with mostly a fatal outcome in cases of resistant disease. Here, we show that lymphoma exosomes shield target cells from antibody attack and that exosome biogenesis is modulated by the lysosome-related organelle-associated ATP-binding cassette (ABC) transporter A3 (ABCA3). B-cell lymphoma cells released exosomes that carried CD20, bound therapeutic anti-CD20 antibodies, consumed complement, and protected target cells from antibody attack. ABCA3, previously shown to mediate resistance to chemotherapy, was critical for the amounts of exosomes released, and both pharmacological blockade and the silencing of ABCA3 enhanced susceptibility of target cells to antibody-mediated lysis. Mechanisms of cancer cell resistance to drugs and antibodies are linked in an ABCA3-dependent pathway of exosome secretion.

β-catenin-independent WNT signaling in basal-like breast cancer and brain metastasis

Abstract: A role of WNT signaling for primary breast cancers of the basal-like subtype and as a predictor of brain metastasis has been described. However, a responsible WNT ligand has not been identified. To further clarify this question, we comparatively investigated 22 human breast cancer brain metastases as well as the highly invasive human breast cancer cell line MDA-MB-231 and the weakly motile MCF-7 as models for the basal-like and the luminal A subtype. WNT5A and B were found overexpressed in MDA-MB-231 cells as compared with MCF-7. This corresponded to reduction of MDA-MB-231 invasiveness by WNT inhibitors, whereas MCF-7 invasion was enhanced by recombinant WNT5B and abolished by WNT and Jun-N-terminal kinase antagonists. Expression and subcellular distribution of β-catenin remained uninfluenced. Consistently, β-catenin was not localized in the nuclei of brain metastases while there was strong nuclear c-Jun staining. Similar to MDA-MB-231, metastases showed expression of WNT5A/B and the alternative WNT receptors ROR1 and 2. These findings were validated using external gene expression datasets (Gene Expression Omnibus) of different breast cancer subtypes and brain metastases. Hierarchical cluster analysis yielded a close relation between basal-like cancers and brain metastases. Gene set enrichment analyses confirmed WNT pathway enrichment not only in basal-like primaries but also in cerebral metastases of all subtypes. In conclusion, WNT signaling seems highly relevant for basal-like and other subtypes of breast cancers metastasizing into the brain. β-catenin-independent WNT signaling, presumably via ROR1-2, plays a major role in this context.

Radioimmunotherapy Confers Long-Term Survival to Lymphoma Patients with Acceptable Toxicity: Registry Analysis by the International Radioimmunotherapy Network

Abstract: The Radioimmunotherapy Network (RIT-N) is a Web-based, international registry collecting long-term observational data about radioimmunotherapy-treated patients with malignant lymphoma outside randomized clinical studies. The RIT-N collects unbiased data on treatment indications, disease stages, patients' conditions, lymphoma subtypes, and hemato- logic side effects of radioimmunotherapy treatment. Methods: RIT-N is located at the University of Gottingen, Germany, and collected data from 14 countries. Data were entered by inves- tigators into a Web-based central database managed by an independent clinical research organization. Results: Patients (1,075) were enrolled from December 2006 until November 2009, and 467 patients with an observation time of at least 12 mo were included in the following analysis. Diagnoses were as follows: 58% follicular lymphoma and 42% other B-cell lym- phomas. The mean overall survival was 28 mo for follicular lym- phoma and 26 mo for other lymphoma subtypes. Hematotoxicity was mild for hemoglobin (World Health Organization grade II), with a median nadir of 10 g/dL, but severe (World Health Organ- ization grade III) for platelets and leukocytes, with a median nadir of 7,000/mL and 2.2/mL, respectively. Conclusion: Clinical usage of radioimmunotherapy differs from the labeled indications and can be assessed by this registry, enabling analyses of outcome and toxicity data beyond clinical trials. This analysis proves that radioimmunotherapy in follicular lymphoma and other lymphoma subtypes is a safe and efficient treatment option.

Tandem high-dose therapy in relapsed and refractory B-cell lymphoma: results of a prospective phase II trial of myeloablative chemotherapy, followed by escalated radioimmunotherapy with (131)I-anti-CD20 antibody and stem cell rescue.

Abstract: A phase II trial evaluated safety, feasibility and efficacy of a sequential tandem approach combining myeloablative BEAM chemotherapy and autologous stem cell transplantation (ASCT) with myeloablative radioimmunotherapy (HD-RIT), with (131)I-anti-CD20 antibody ((131)I-rituximab), followed by a second ASCT in patients with relapsed or refractory CD20+ B-cell lymphoma. According to protocol, 16 patients with relapsed (n = 14) and refractory (n = 2) CD20+ B-cell lymphoma received salvage therapy with rituximab and Dexa-BEAM, followed by BEAM (HD chemotherapy) and high-dose myeloablative radioimmunotherapy 2-6 months after BEAM. Nine of 16 patients received HD-RIT; seven patients were excluded before HD-RIT because of toxicity or progressive disease. Disease histologies were follicular lymphoma (FL) grades 1 and 2 (n = 4), transformed follicular (FL 3b; n = 6), diffuse large B-cell (DLBCL; n = 4), mantle cell (n = 1) and marginal zone lymphoma (n = 1). After a median follow-up of 50.4 months for OS and 39.7 months for progression-free survival (PFS), estimated 4-year OS and PFS were 67% and 64%, respectively. The estimated 4-year OS and PFS for patients with FL were 80% and 78%, respectively. Toxicity was significant, including one fatal outcome due to pneumonitis. Tandem transplants consisting of HD chemotherapy followed by HD-RIT with (131)I-coupled anti-CD20 are manageable and effective but toxic treatment modalities for relapsed poor prognosis CD20+ B-NHL.

Lymphatische Neoplasien bei jungen Patienten

Abstract: gig sind. Innerhalb padiatrischer Studien zeigt sich bereits eine Abnahme der Uberlebensraten mit zunehmendem Alter. So nahm in der padiatrischen BFM-95-Studie (BFM = Berlin-Frankfurt-Munster) die Gesamtuberlebensrate mit zunehmendem Lebensalter der Kinder ab und war bei den Jugend lichen uber 15 Jahren am niedrigsten [3]. An diese Entwicklung schliesen sich nahtlos die Erwachsenen-ALLStudien an. Hier sind die Gesamtuberlebensraten fur die AYA am gunstigsten und nehmen dann kontinuierlich ab. Die Grunde dafur sind vielfaltig. Zum einen nehmen mit zunehmendem Alter ungunstige Prognosefaktoren zu. Zum anderen hangt der Therapieerfolg bei der ALL entscheidend von der zeitnahen Durchfuhrung einer intensiven Chemotherapie ab. Die Therapiedurchfuhrbarkeit und -vertraglichkeit nehmen mit dem Alter kontinuierlich ab und daraus resultiert das schlechtere Therapieansprechen bei erwachsenen Patienten insgesamt und bei alteren Patienten im Besonderen. In den vergangenen Jahren wurde eine Reihe von Studien an jungen Erwachsenen, die nach padiatrischen Protokollen oder nach Protokollen fur Erwachsene behandelt wurden, publiziert. Es zeigte sich, dass die Eingangskriterien fur den Studieneinschluss vergleichbar waren und sich auch die Raten an Komplettremissionen nicht wesentlich voneinander unterschieden, jedoch war in den Padiatrie-Studien das ereignisfreie Uberleben (EFS) bzw. das krankheitsfreie Uberleben (DFS) zum Teil deutlich langer [4]. Es fallt auf, dass die zum Vergleich herangezogenen Erwachsenen-Studien unterdurchschnittliche Ergebnisse erbracht hatten und zum Teil auf Therapieprinzipien beruhten, die nicht zeitgemas sind. In neueren Vergleichen von Studien auf Basis innovativer Protokolle lassen sich keine deutlichen Unterschiede zwischen Padiatrieund Erwachsenen-Studien zeigen. Es lohnt sich deshalb der Blick auf moderne ALL-Protokolle, wie sie etwa in der deutschen Studiengruppe fur die ALL des Erwachsenen (GMALL) verwendet werden. Die aktuelle Studie GMALL 07/2003 wurde fur Erwachsene und Adoleszente konzipiert und wird in 146 internistisch-onkologischen deutschen Zentren durchgefuhrt. Die Studien der Die AYA-Problematik am Beispiel der akuten lymphatischen Leukamie Verantwortliche Autorin: Nicola Gokbuget, Frankfurt/Main