Showing papers by "Lorenz Trümper published in 2016"

Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial

Abstract: Summary Background Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, showed activity in many single-group studies in relapsed or refractory mantle cell lymphoma. The aim of this randomised study was to examine the efficacy and safety of lenalidomide versus best investigator's choice of single-agent therapy in relapsed or refractory mantle cell lymphoma. Methods The MCL-002 (SPRINT) study was a randomised, phase 2 study of patients with mantle cell lymphoma aged 18 years or older at 67 clinics and academic centres in 12 countries who relapsed one to three times, had Eastern Cooperative Oncology Group performance status of 0–2, at least one measurable lesion to be eligible, and who were ineligible for intensive chemotherpy or stem-cell transplantation. Using a centralised interactive voice response system, we randomly assigned (2:1) patients in a permuted block size of six to receive lenalidomide (25 mg orally on days 1–21 every 28 days) until progressive disease or intolerability, or single-agent investigator's choice of either rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine. Randomisation was stratified by time from diagnosis, time from last anti-lymphoma therapy, and previous stem-cell transplantation. Individual treatment assignment between lenalidomide and investigator's choice was open label, but investigators had to register their choice of comparator drug before randomly assigning a patient. Patients who progressed on investigator's choice could cross over to lenalidomide treatment. We present the prespecified primary analysis results in the intention-to-treat population for the primary endpoint of progression-free survival, defined as the time from randomisation to progressive disease or death, whichever occurred first. Patient enrolment is complete, although treatment and collection of additional time-to-event data are ongoing. This study is registered with ClinicalTrials.gov, number NCT00875667. Findings Between April 30, 2009, and March 7, 2013, we enrolled 254 patients in the intention-to-treat population (170 [67%] were randomly assigned to receive lenalidomide, 84 [33%] to receive investigator's choice monotherapy). Patients had a median age of 68·5 years and received a median of two previous regimens. With a median follow-up of 15·9 months (IQR 7·6–31·7), lenalidomide significantly improved progression-free survival compared with investigator's choice (median 8·7 months [95% CI 5·5–12·1] vs 5·2 months [95% CI 3·7–6·9]) with a hazard ratio of 0·61 (95% CI 0·44–0·84; p=0·004). In the 167 patients in the lenalidomide group and 83 patients in the investigator's choice group who received at least one dose of treatment the most common grade 3–4 adverse events included neutropenia (73 [44%] of 167 vs 28 [34%] of 83) without increased risk of infection, thrombocytopenia (30 [18%] vs 23 [28%]), leucopenia (13 [8%] vs nine [11%]), and anaemia (14 [8%] vs six [7%]). Interpretation Patients with relapsed or refractory mantle cell lymphoma ineligible for intensive chemotherapy or stem-cell transplantation have longer progression-free survival, with a manageable safety profile when treated with lenalidomide compared with monotherapy investigator's choice options. Funding Celgene Corporation.

USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma

Abstract: The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC-induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X-linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B-cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression. We show that high USP9X/XIAP expression is associated with shorter event-free survival in patients treated with spindle poison-containing chemotherapy. Accordingly, aggressive B-cell lymphoma lines with USP9X and associated XIAP overexpression exhibit increased chemoresistance, reversed by specific inhibition of either USP9X or XIAP. Moreover, knockdown of USP9X or XIAP significantly delays lymphoma development and increases sensitivity to spindle poisons in a murine Eμ-Myc lymphoma model. Together, we specify the USP9X-XIAP axis as a regulator of the mitotic cell fate decision and propose that USP9X and XIAP are potential prognostic biomarkers and therapeutic targets in aggressive B-cell lymphoma.

Alterations of microRNA and microRNA-regulated messenger RNA expression in germinal center B-cell lymphomas determined by integrative sequencing analysis.

Abstract: MicroRNA are well-established players in post-transcriptional gene regulation However, information on the effects of microRNA deregulation mainly relies on bioinformatic prediction of potential targets, whereas proof of the direct physical microRNA/target messenger RNA interaction is mostly lacking Within the International Cancer Genome Consortium Project "Determining Molecular Mechanisms in Malignant Lymphoma by Sequencing", we performed miRnome sequencing from 16 Burkitt lymphomas, 19 diffuse large B-cell lymphomas, and 21 follicular lymphomas Twenty-two miRNA separated Burkitt lymphomas from diffuse large B-cell lymphomas/follicular lymphomas, of which 13 have shown regulation by MYC Moreover, we found expression of three hitherto unreported microRNA Additionally, we detected recurrent mutations of hsa-miR-142 in diffuse large B-cell lymphomas and follicular lymphomas, and editing of the hsa-miR-376 cluster, providing evidence for microRNA editing in lymphomagenesis To interrogate the direct physical interactions of microRNA with messenger RNA, we performed Argonaute-2 photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation experiments MicroRNA directly targeted 208 messsenger RNA in the Burkitt lymphomas and 328 messenger RNA in the non-Burkitt lymphoma models This integrative analysis discovered several regulatory pathways of relevance in lymphomagenesis including Ras, PI3K-Akt and MAPK signaling pathways, also recurrently deregulated in lymphomas by mutations Our dataset reveals that messenger RNA deregulation through microRNA is a highly relevant mechanism in lymphomagenesis

Alemtuzumab added to CHOP for treatment of peripheral T-cell lymphoma (pTNHL) of the elderly: Final results of 116 patients treated in the international ACT-2 phase III trial.

Abstract: 7500Background: Standard treatment in pTNHL pts is unsatisfactory due to a high rate of early progression. Alemtuzumab (A), a monoclonal anti-CD52 antibody, has demonstrated efficacy in relapsed pTNHL pts, and phase II trials have shown feasibility of concomitant A+CHOP application. We report the final analysis of the international ACT-2 phase III randomized trial in elderly pts comparing standard CHOP to A-CHOP. Methods: Between 2007 and 2013, 116 pts from 52 centers were randomized to receive either 6 cycles of CHOP or A-CHOP at 14-day intervals with G-CSF support. Pts were to receive a total of 360 mgs A (until pt 39) or 120 mg. The protocol demanded stringent CMV / EBV monitoring and anti-infective prophylaxis. The study was powered to detect a 15% increase in EFS with the addition of A to CHOP. Results: 116 pts (median age 69 yrs, 58% male) were randomized (58/58). Histologies were 41% AITL, 39% pTNHL NOS , 6% ALCL , 14% other subtypes. Complete treatment as planned was applied in 79% (CHOP) resp 57%...

Novel IGH and MYC Translocation Partners in Diffuse Large B-Cell Lymphomas.

Abstract: Chromosomal translocations involving an immunoglobulin (IG) locus and a proto-oncogene play a major role in diffuse large B-cell lymphoma (DLBCL) pathogenesis. Recurrent IG translocation partners in DLBCL are the BCL6, BCL2, and MYC genes, but other rare translocation partners are also known. We studied 20 DLBCL with fluorescence in situ hybridization-based evidence for IG heavy chain (IGH) locus-associated translocations not involving BCL6, BCL2, MALT1, or MYC by long distance inverse PCR to identify the translocation partners. Moreover, we studied eight DLBCL with MYC translocations not involving IG or known non-IG loci as translocation partner to search for novel MYC translocations. We identified three novel IGH-associated translocations. Chromosomal breakpoints involved the IMMP2L gene in 7q31, the BCAS2 gene in 1p13, and the PVRL2 gene in 19q13. The latter gene, which is recurrently translocated in T-cell lymphomas, is significantly higher expressed in the biopsy with the translocation compared to cases without this genetic aberration, indicating a pathogenetic role of PVRL2 also in DLBCL. In one case with a MYC break we obtained a novel MYC-SOCS1 translocation representing an unusual translocation of a proto-oncogene with a tumor suppressor gene. Indeed, we demonstrate that the oncogene was deregulated and the tumor suppressor gene inactivated. As both genes undergo aberrant somatic hypermutation in the region of the chromosomal breakpoints, this translocation likely happened as a byproduct of the hypermutation process. Overall, our study suggests that chromosomal translocations in DLBCL are more heterogeneous than previously known. © 2016 Wiley Periodicals, Inc.

Radioimmunotherapy in relapsed/refractory mantle cell lymphoma patients: final results of a European MCL Network Phase II Trial

Abstract: Radioimmunotherapy in relapsed/refractory mantle cell lymphoma patients: final results of a European MCL Network Phase II Trial

Partial Response to First-Line Crizotinib in an Elderly Male Patient with ROS1 Translocation-Positive Lung Cancer.

Abstract: We report on a 90-year-old male patient with a ROS1-translocated adenocarcinoma of the lung who was treated with crizotinib as first-line therapy. After 11 months of treatment, we noticed complete metabolic response as measured by (18)F-FDG-PET/CT scan and a partial response according to RECIST criteria. This patient indicates that ROS1 translocations are not restricted to young age, female gender and low stage. Furthermore, this case illustrates exemplarily that crizotinib therapy is effective and manageable even as first-line treatment in elderly patients with comorbidities. Based on our findings, we recommend to include elderly patients with advanced pulmonary adenocarcinomas in molecular screening approaches for ROS1 translocations.

Osteolytic lesions occur rarely in patients with B-CLL and may respond well to ibrutinib

Abstract: Therapeutic regimens in chronic lymphocyte leukemia/small lymphocytic lymphoma (CLL/SLL) are undergoing tremendous changes. In 2014, the Bruton tyrosine kinase inhibitor (TKI) ibrutinib was approve...

Modified BEAM with triple autologous stem cell transplantation for patients with relapsed aggressive non-Hodgkin lymphoma

Abstract: 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.

Age-dependent analysis of toxicity, mortality, and implementation of an anti-infective prophylaxis in 1171 elderly patients (pts) with aggressive B-cell lymphoma (aNHL): Data from consecutive phase II and III trials of the DSHNHL.

Abstract: 7539Background: In elderly pts with aggressive B-cell lymphoma, the feasibility of full dose curative chemotherapy is limited by comorbidities and subsequent higher treatment related mortality (TRM...

Partielles Ansprechen auf Crizotinib als Erstlinientherapie bei einem älteren männlichen Patienten mit ROS1-Translokations-positivem Bronchialkarzinom

Abstract: Wir berichten hier uber einen 90-jahrigen mannlichen Patienten mit ROS1-transloziertem Adenokarzinom der Lunge, der eine Erstlinientherapie mit Crizotinib erhielt. Nach 11-monatiger Behandlung waren ein vollstandiges metabolisches Ansprechen laut 18F-FDG-PET/CT-Scan sowie ein partielles Ansprechen nach RECIST-Kriterien zu verzeichnen. Dieser Fall deutet darauf hin, dass ROS1-Translokationen sich nicht auf junges Alter, weibliches Geschlecht und niedrige Tumorstadien beschranken. Auserdem zeigt der Fall exemplarisch, dass die Crizotinib-Therapie auch als Erstlinientherapie bei alteren, komorbiden Patienten wirksam und beherrschbar sein kann. Auf Grundlage unserer Ergebnisse empfehlen wir, altere Patienten mit fortgeschrittenem Adenokarzinom der Lunge in molekulare Screenings fur ROS1-Translokationen einzuschliesen.