Showing papers by "Lorenz Trümper published in 2019"

Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma

Abstract: Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.

Randomized Phase III Study of Alisertib or Investigator's Choice (Selected Single Agent) in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma.

Abstract: PURPOSEThe aim of this open-label, first-in-setting, randomized phase III trial was to evaluate the efficacy of alisertib, an investigational Aurora A kinase inhibitor, in patients with relapsed/re...

A modular transcriptome map of mature B cell lymphomas

Abstract: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt’s lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt’s lymphoma and particularly on ‘double-hit’ MYC and BCL2 transformed lymphomas. The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.

Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV.

Abstract: Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.

The impact of SOCS1 mutations in diffuse large B-cell lymphoma.

Abstract: Mutations in SOCS1 are frequent in primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma. In the latter, SOCS1 mutations affect the length of the encoded protein (major mutations) and are associated with shorter patient survival. Two independent studies examined the prognostic impact of SOCS1 mutations in diffuse large B-cell lymphoma (DLBCL) and showed differing results. This may be due to the small number of included patients, the heterogeneity of patients' demographics and the distinct treatment schemes in these studies. To overcome the size limitations of these previous studies, we assessed SOCS1 mutations in the RICOVER-60 cohort. The cohort uniformly consists of elderly patients (aged 61-80 years) treated with the CHOP-14 scheme (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisolone at 14-day intervals) with or without an additional rituximab treatment. Patient outcomes were analysed with regard to overall SOCS1 mutation frequency, major and minor mutations and a novel impact-based classifier - against the treatment modalities. Patients harbouring putative pathogenic SOCS1 mutations showed significant reduced overall survival within the CHOP plus rituximab group. Hence, putative pathogenic SOCS1 mutations seem to efface the beneficial effect of the therapeutic CD20 antibody. Comparing published data of whole exome and transcriptome sequencing of a large DLBCL cohort confirmed that predicted deleterious SOCS1 mutations forecast pre-eminent survival in early onset DLBCL.

Allogeneic stem cell transplantation for patients with relapsed or refractory T-cell lymphoma: efficacy of lymphoma-directed conditioning against advanced disease.

Abstract: Salvage chemotherapy induces disease remissions in patients with relapsed or refractory (r/r) T-cell lymphomas, but fails to provide lasting tumor control. We analyzed the outcome after peripheral blood stem and bone marrow transplantation (PBSCT, n = 80; BMT, n = 4) from matched related (MRD, n = 22) or matched and unmatched unrelated donors (MUD and MMD, n = 53 and n = 9, respectively) following conditioning with fludarabine, busulfan, and cyclophosphamide (FBC) for 84 consecutive patients with r/r T-cell malignancies. At start of conditioning LDH was elevated in 50% of cases, and residual tumor (PD, SD, PR) was detectable in 84% of patients. In total, 38% (95% CI 33–44) of the patients were alive and disease-free after a median observation time of 14.5 (range 1.8 to 114) months. Univariate and multivariate analyses identified low ECOG status, as well as occurrence of acute GvHD as favorable factors for outcome. Lymphoma-directed conditioning with fludarabin, busulfan and cyclophosphamid (FBC-12), and allogeneic stem cell transplantation resulted in long-term survival for a proportion of patients with r/r peripheral T-cell lymphoma, including those with PR and SD only after salvage therapy.

MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma

Abstract: Oncogenic MYC activation promotes proliferation in Burkitt lymphoma, but also induces cell-cycle arrest and apoptosis mediated by p53, a tumor suppressor that is mutated in 40% of Burkitt lymphoma cases. To identify molecular dependencies in Burkitt lymphoma, we performed RNAi-based, loss-of-function screening in eight Burkitt lymphoma cell lines and integrated non-Burkitt lymphoma RNAi screens and genetic data. We identified 76 genes essential to Burkitt lymphoma, including genes associated with hematopoietic cell differentiation (FLI1, BCL11A) or B-cell development and activation (PAX5, CDKN1B, JAK2, CARD11) and found a number of context-specific dependencies including oncogene addiction in cell lines with TCF3/ID3 or MYD88 mutation. The strongest genotype-phenotype association was seen for TP53. MDM4, a negative regulator of TP53, was essential in TP53 wild-type (TP53wt) Burkitt lymphoma cell lines. MDM4 knockdown activated p53, induced cell-cycle arrest, and decreased tumor growth in a xenograft model in a p53-dependent manner. Small molecule inhibition of the MDM4-p53 interaction was effective only in TP53wt Burkitt lymphoma cell lines. Moreover, primary TP53wt Burkitt lymphoma samples frequently acquired gains of chromosome 1q, which includes the MDM4 locus, and showed elevated MDM4 mRNA levels. 1q gain was associated with TP53wt across 789 cancer cell lines and MDM4 was essential in the TP53wt-context in 216 cell lines representing 19 cancer entities from the Achilles Project. Our findings highlight the critical role of p53 as a tumor suppressor in Burkitt lymphoma and identify MDM4 as a functional target of 1q gain in a wide range of cancers that is therapeutically targetable. SIGNIFICANCE: Targeting MDM4 to alleviate degradation of p53 can be exploited therapeutically across Burkitt lymphoma and other cancers with wild-type p53 harboring 1q gain, the most frequent copy number alteration in cancer.

Critical evaluation of current molecular MRD strategies including NGS for the management of AML patients with multiple mutations

Abstract: Current follow‐up procedures in patients with acute myeloid leukemia (AML) comprise cytomorphology, multiparameter flow cytometry (MFC), and molecular genetics by polymerase chain reaction (PCR)– based methods, Sanger, and, increasingly, next‐generation sequencing (NGS). Commercial myeloid NGS panels identify multiple mutations in most AML patients at diagnosis. Before NGS, follow‐up strategies using highly sensitive quantitative real‐time PCR (qPCR) were limited to a few reciprocal rearrangements or hotspot mutations such as NPM1. NGS offers follow‐up monitoring to virtually all AML patients, including clonal and subclonal changes. However, interpretation of NGS MRD results for individual patients remains challenging. Clinicians face uncertainty on how to proceed in patients with persisting mutation load by NGS, how to interpret divergent kinetics of various markers by NGS, and how to weigh the different sensitivities of NGS and qPCR.

Safety and efficacy of PD-L1 inhibitor durvalumab with R-CHOP or R2-CHOP in subjects with previously untreated, high-risk DLBCL.

Abstract: 7520Background: We report results of a phase 2, open-label study of durvalumab (durva) in combination with R-CHOP or R2-CHOP (R-CHOP + lenalidomide) in previously untreated, high-risk diffuse large...

9 Periphere T-Zell-Lymphome

Abstract: Als periphere T‑Zell-Lymphome (PTCL) wird eine heterogene Gruppe klinisch aggressiver Erkrankungen mit dem Phanotyp reifer T‑Zellen und schlechter Prognose zusammengefasst. Neue Therapien werden intensiv untersucht und konnen die Behandlung fur einige Subtypen schon in naher Zukunft verbessern. Der aktuelle Wissenstand zu PTCL mit Fokus auf moderne Therapiestandards und neue therapeutische Optionen wird dargestellt. Basierend auf einer selektiven Literaturreche werden Grundlagenarbeiten und Leitlinien diskutiert. Aktueller Konsens fur die Erstlinientherapie von PTCL sind anthrazyklinhaltige Kombinationschemotherapien, abhangig vom Subtyp und Erkrankungsstadium gefolgt von autologer Stammzelltransplantation. Darunter ist fur etwa 50 % der Patienten eine langfristige Erkrankungsfreiheit zu erwarten; bei 30 % der PTCL-Patienten sind die Lymphome primar refraktar. Im Rezidiv ist die Prognose bei alleinigem Einsatz von Zytostatika sehr ungunstig. Fur geeignete Patienten stellt die allogene Stammzelltransplantation ein Verfahren mit der Chance auf eine langfristige Erkrankungskontrolle dar. Fur Patienten mit anaplastischen groszelligen T‑Zell-Lymphomen steht mit dem gegen CD30 gerichteten Antikorper-Chemotherapie-Konjugat Brentuximab Vedotin im Rezidiv eine effektive Therapie zur Verfugung. Auch in der Erstlinientherapie wurde fur Brentuximab Vedotin in Kombination mit Chemotherapie ein erhohter Nutzen bei CD30-positiven PTCL nachgewiesen. Das zunehmend vertiefte Verstandnis der Biologie und Pathogenese von PTCL fuhrt zur Testung weiterer zielgerichteter Therapien als Monotherapie und in Kombinationen. So wurde in den letzten Jahren die Inhibition von Histondeacetylase (HDAC) auf Ebene der epigenetischen Regulation gepruft. Unter den innovativen Therapieprinzipien wurden vor allem mit der Inhibition der Phosphoinositid-3-Kinasen (PI3K) auf Ebene der Signaltransduktion ermutigende Ansprechraten fur Patienten mit rezidivierter oder refraktarer Erkrankung erreicht. Die aktuelle Behandlung der PTCL basiert auf Chemotherapie- und Transplantationskonzepten. Aktuell werden fur viele PTCL-Subtypen potenziell effektivere Therapien entwickelt.