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ZusammenfassungDer Onko-Nexus („Kümmererprojekt“), gefördert vom Bayerischen Staatsministerium für Gesundheit und Pflege, widmet sich der Verbesserung der ambulanten/stationären Schnittstellenproblematik für Patienten mit hochkomplexen malignen Erkrankungen, die einen Aufenthalt an einem universitären Zentrum benötigten. Die Patienten wurden von einer ambulanten und einer stationären „Kümmerin“ (medizinische Fachangestellte) mitbetreut. Zusätzlich wurde vom universitären Zentrum eine Spezialsprechstunde in der heimatnahen onkologischen Praxis angeboten. Während der 3-jährigen Laufzeit konnten 26 Patienten in das Projekt eingeschlossen werden. Nach Abschluss des Projektes wurden 9 Patienten und die 2 „Kümmerinnen“ mittels qualitativer Leitfadeninterviews befragt. Die Patienten profitierten v. a. von der intensivierten Betreuung, der Vermeidung von Fahrstrecken und dem engen Kontakt zwischen Klinik und Praxis. Das Projekt wirkte sich deutlich positiv auf die Lebensqualität der Patienten aus.

The aim was to assess the incremental costs of chimeric antigen receptor (CAR) T-cell therapy (axicabtagene ciloleucel, tisagenlecleucel) compared with standard of care in adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) from the German third-party payer perspective. A budget impact model was established over a 6-year period. Estimation of the third-line population: partitioned survival model based on outcome data from peer-reviewed literature, a top-down approach based on population forecasts, and age-standardized incidences. Cost data were derived from the controlling department of a tertiary hospital and a German cost-of-illness study. In the scenario analysis, the budget impact of treating second-line DLBCL patients was calculated. One-way deterministic sensitivity analyses were conducted to test the robustness of the model. For the period 2021-2026, 788-867 (minimum population, min) and 1,068-1,177 (maximum population, max) adult third-line r/r DLBCL patients were estimated. The budget impact ranged from €39,419,562; €53,426,514 (min; max) in year 0 to €122,104,097; €165,763,001 (min; max) in year 5. The scenario analysis resulted in a budget impact of €65,987,823; €89,558,611 (min; max) and €204,485,031; €277,567,601 (min; max) for years 0 and 5, respectively. This budget impact analysis showed a significant but reasonable financial burden associated with CAR T-cell therapy for a limited number of patients requiring individualized care. Further, this study presents challenges and future needs in data acquisition associated with cost analysis in personalized medicine. For comprehensive economic discussions, complementary cost-effectiveness analyses are required to determine the value of innovative therapies for r/r DLBCL.

BACKGROUND The successful initiation of enteral nutrition is frequently hampered by various complications occurring in patients treated in the intensive care unit (ICU). Successful placement of a nasojejunal tube by CORTRAK enteral access system (CEAS) has been reported to be a simple bedside tool for placing the postpyloric (PP) feeding tube. METHODS We evaluated the efficacy and side effects using CEAS to establish EN in patients with critical illness, thrombocytopenia, and/or anticoagulation. RESULTS Fifty-six mechanically ventilated patients were analyzed. Twenty-four of them underwent prior hematopoietic stem cell transplantation (SCT). Sixteen patients received extracorporeal membrane oxygenation treatment because of acute respiratory distress syndrome. The median platelet count at PP placement was 26 g/L (range, 4-106 g/L); 16 patients received therapeutic anticoagulation (activated partial thromboplastin time, 50-70 s). CEAS-assisted placement of a PP nasojejunal tube was performed successfully in all patients. The most frequent adverse event was epistaxis in 27 patients (48.2%), which was mostly mild (Common Terminology Criteria for Adverse Events grade 1, n = 21 [77.8%], and grade 2, n = 6). A significant association between a low platelet count and bleeding complications was observed (P

​​Since its recent zoonotic spill-over severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is constantly adapting to the human host as illustrated by the emergence of variants of concern with increased transmissibility and immune evasion. Prolonged replication in immunosuppressed individuals and evasion from spike-specific antibodies is known to drive intra-host SARS-CoV-2 evolution. Here we show for the first time the major role of CD8 T cells in SARS-CoV-2 evolution. In a patient with chronic, ultimately fatal infection, we observed three spike mutations that prevented neutralisation by convalescent plasma therapy. Moreover, at least four mutations in non-spike proteins emerged that hampered CD8 T-cell recognition of mutant epitopes, two of these occurred before spike mutations. A comparison with worldwide sequencing data showed that several of these T-cell escape mutations had emerged independently as homoplasies in multiple circulating lineages. We propose that human leukocyte antigen class I contributes to shaping the evolutionary landscape of SARS-CoV-2.

Prolonged shedding of infectious SARS-CoV-2 has recently been reported in a number of immunosuppressed individuals with COVID-19. Here, we describe the detection of high levels of replication-competent SARS-CoV-2 in specimens taken from the respiratory tract of a B-cell depleted patient up to 154 days after initial COVID-19 diagnosis concomitant with the development of high mutation rate. In this patient, a total of 11 nonsynonymous mutations were detected in addition to the Y144 deletion in the spike protein of SARS-CoV-2.Virus evolution studies revealed a dramatic diversification in viral population coinciding with treatment with convalescent plasma and clinical respiratory deterioration. Our findings highlight the urgent need for continuous real-time surveillance of genetic changes of SARS-CoV-2 adaptation alongside immunological investigations in patients with severely compromised humoral responses who may shed infectious virus over prolonged periods of time.

The clinical and immunological impact of B-cell depletion in the context of coronavirus disease 2019 (COVID-19) is unclear. We conducted a prospectively planned analysis of COVID-19 in patients who received B-cell depleting anti-CD20 antibodies and chemotherapy for B-cell lymphomas. The control cohort consisted of age- and sex-matched patients without lymphoma who were hospitalized because of COVID-19. We performed detailed clinical analyses, in-depth cellular and molecular immune profiling, and comprehensive virological studies in 12 patients with available biospecimens. B-cell depleted lymphoma patients had more severe and protracted clinical course (median hospitalization 88 versus 17 d). All patients actively receiving immunochemotherapy (n = 5) required ICU support including long-term mechanical ventilation. Neutrophil recovery following granulocyte colony stimulating factor stimulation coincided with hyperinflammation and clinical deterioration in 4 of the 5 patients. Immune cell profiling and gene expression analysis of peripheral blood mononuclear cells revealed early activation of monocytes/macrophages, neutrophils, and the complement system in B-cell depleted lymphoma patients, with subsequent exacerbation of the inflammatory response and dysfunctional interferon signaling at the time of clinical deterioration of COVID-19. Longitudinal immune cell profiling and functional in vitro assays showed SARS-CoV-2-specific CD8+ and CD4+ T-effector cell responses. Finally, we observed long-term detection of SARS-CoV-2 in respiratory specimens (median 84 versus 12 d) and an inability to mount lasting SARS-CoV-2 antibody responses in B-cell depleted lymphoma patients. In summary, we identified clinically relevant particularities of COVID-19 in lymphoma patients receiving B-cell depleting immunochemotherapies.

The Onko-Nexus ("Caretaker-Project"), sponsored by the Bavarian Ministry for Health and Nursing, is dedicated to improving the outpatient/hospitalized care interface issue for patients with highly complex malignant diseases requiring inpatient care in a university hospital. A total of 26 patients were recruited during the 3-year period of the project. The patients were managed and supported by 2 "Caretakers" (physician assistants), one from the outpatient unit and one working in the wards. Additionally, the university hospital provided a special consultation hour in an oncological private practice close to patient's home. After completion of the project, 9 patients and the 2 "Caretakers" were interviewed via guided qualitative interviews. The main benefits for the patients were intensive support, avoiding long journeys and the close contact between hospital and private practice. The project had a clear positive effect on the patients' quality of life.Der Onko-Nexus („Kümmererprojekt“), gefördert vom Bayerischen Staatsministerium für Gesundheit und Pflege, widmet sich der Verbesserung der ambulanten/stationären Schnittstellenproblematik für Patienten mit hochkomplexen malignen Erkrankungen, die einen Aufenthalt an einem universitären Zentrum benötigten. Die Patienten wurden von einer ambulanten und einer stationären „Kümmerin“ (medizinische Fachangestellte) mitbetreut. Zusätzlich wurde vom universitären Zentrum eine Spezialsprechstunde in der heimatnahen onkologischen Praxis angeboten. Während der 3-jährigen Laufzeit konnten 26 Patienten in das Projekt eingeschlossen werden. Nach Abschluss des Projektes wurden 9 Patienten und die 2 „Kümmerinnen“ mittels qualitativer Leitfadeninterviews befragt. Die Patienten profitierten v. a. von der intensivierten Betreuung, der Vermeidung von Fahrstrecken und dem engen Kontakt zwischen Klinik und Praxis. Das Projekt wirkte sich deutlich positiv auf die Lebensqualität der Patienten aus.

Die Uberwachung der Adharenz fur orale antineoplastische Therapien hamatologischer und onkologischer Erkrankungen stellt ein groses Problem insbesondere bei alteren und immobilen Patienten im landlichen Raum dar. Das Projekt „Mobiler Onkologischer Dienst“ (MOD) wurde zur Verbesserung der Versorgungssituation in der Region Landshut eingefuhrt. Die vorliegende Untersuchung dient der Evaluation dieses innovativen Versorgungsmodells bezuglich Patientenadharenz, okonomischer Aspekte und Patientenzufriedenheit. Fur jeden Besuch wurden allgemeine Kennzahlen, Medikation, Nebenwirkungen und Krankenhausaufenthalte durch die jeweilige MOD-Assistentin registriert. Die Patientenzufriedenheit wurde durch Fragebogen ermittelt. Durchschnittlich 32 Patienten wurden im Mittel 4‑ bis 5‑mal pro Quartal besucht. Der durchschnittliche zeitliche Aufwand pro Besuch und Patient betrug 63 min, der durchschnittliche Anfahrtsweg 20 km. Die Umfrage belegte eine sehr hohe Patientenzufriedenheit. Krankenhausaufenthalte durch therapieassoziierte Toxizitaten konnten weitestgehend vermieden werden. Die durch den MOD verabreichten und uberwachten Therapien verursachten Kosten von teilweise mehreren Tausend Euro pro Monat. Der MOD erreichte eine Reduktion der Fahrtkosten von 10–15 % gegenuber Taxen oder Fahrdiensten und um bis zu 60 % gegenuber Krankentransporten. Der zeitliche Aufwand fur die Patienten oder deren Angehorige konnte auf ein Viertel reduziert werden. Der MOD stellt ein effektives und kostensparendes Instrument zur Uberwachung der Patientenadharenz, Vermeidung von schwerwiegenden Nebenwirkungen und Krankenhausaufenthalten dar und fuhrt zu einer hohen Patientenzufriedenheit.

Der Onko-Nexus („Kummererprojekt“), gefordert vom Bayerischen Staatsministerium fur Gesundheit und Pflege, widmet sich der Verbesserung der ambulanten/stationaren Schnittstellenproblematik fur Patienten mit hochkomplexen malignen Erkrankungen, die einen Aufenthalt an einem universitaren Zentrum benotigten. Die Patienten wurden von einer ambulanten und einer stationaren „Kummerin“ (medizinische Fachangestellte) mitbetreut. Zusatzlich wurde vom universitaren Zentrum eine Spezialsprechstunde in der heimatnahen onkologischen Praxis angeboten. Wahrend der 3-jahrigen Laufzeit konnten 26 Patienten in das Projekt eingeschlossen werden. Nach Abschluss des Projektes wurden 9 Patienten und die 2 „Kummerinnen“ mittels qualitativer Leitfadeninterviews befragt. Die Patienten profitierten v. a. von der intensivierten Betreuung, der Vermeidung von Fahrstrecken und dem engen Kontakt zwischen Klinik und Praxis. Das Projekt wirkte sich deutlich positiv auf die Lebensqualitat der Patienten aus.

Das Onkologische und Palliativmedizinische Netzwerk Landshut ist ein Losungsansatz fur strukturschwache landliche Regionen, um eine adaquate Versorgung schwerstkranker Patienten zu verbessern, vor allem durch eine enge Verquickung der ambulanten und stationaren Leistungserbringer. Diese Netzwerke optimieren nicht nur die Patientenversorgung, sondern konnen auch kosteneffektiv arbeiten.

The mammalian target of rapamycin (mTOR) is a protein kinase involved in the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway. It plays a pivotal role in the control of cell proliferation, survival, and angiogenesis with multiple and frequent dysregulations of this pathway in human tumors. Temsirolimus is an intravenous drug, specifically inhibiting the mTOR pathway. Bendamustine is well known for its clinical activity in indolent non-Hodgkin-lymphoma (NHL) and has lately shown clinical activity in mantle cell lymphoma (MCL). Here, we present a case report of temsirolimus in combination with bendamustine and rituximab leading to a CR in a pretreated male. In addition, our in vitro data underlines the additive and synergistic efficacy in cell growth reduction of temsirolimus combined with bendamustine in MCL cell lines and in DLBCL cell lines. Furthermore, as an underlying mechanism of this additive, effects on cell cycle inhibition and apoptosis induction could be identified.

e20549 Background: According to recent studies, Germany will face 14% more cases of cancer in 2020 than in 2008. Especially rural areas will have severe further problems due to the already existent...

Abstract 4781 Background Mantle cell lymphoma (MCL) responds only transiently to conventional chemotherapy resulting in a dismal long-term prognosis. At a molecular level it is characterised by the chromosomal translocation t(11;14)(q13;q32), which leads to constitutive over-expression of the cell cycle regulatory protein cyclin D1. GA101 is a third generation, glycoengineered type II IgG1 anti-CD20 monoclonal antibody with superior direct cell death induction by targeting a type II epitope and enhanced antibody dependent cellular cytotoxicity (ADCC). High efficacy in lymphoma cell lines has led to combination experiments with various chemotherapeutic compounds or the CDK-inhibitor Flavopiridol. Methods Using a MCL cell line panel (Granta-519, HBL-2, Jeko-1, Rec-1 and Z-138) and a Diffuse Large B-Cell Lymphoma cell line (Karpas-422) we determined the effect of GA101 (1 μg/ml) monotherapy as well as in combination with Fludarabine (0,25 μg/ml), Bendamustine (5 μg/ml), Mitoxantrone (0,25 and 0,5 μg/ml) and Flavopiridol (100nM) on cell proliferation and viability. Trypan-blue exclusion tests were used to analyze cell viability at 0h, 24h, 48h and 72h. The panel of MCL cell lines was treated to determine potential synergism of agent combinations. Accordingly, fractional product was calculated: synergism > 0,1; additive effect -0,1 Results After mono-exposure with GA101 (1 μg/ml), Granta-519 and Rec-1 showed the highest sensitivity (Granta: 65-75% cell reduction, Rec-1: 30-45%). Intermediate results were achieved for HBL-2 (20-30%), Z-138 and Karpas-422 (10-15%), Jeko-1 (5%). Fludarabine alone resulted in a 20-40% cell reduction. Bendamustine showed a higher efficacy in Jeko-1, Rec-1 and Z-138 (40-90%) than in Granta-519, Karpas-422 and HBL-2 (10%). Mitoxantrone treatment demonstrated a high impact on all cell lines (80-95% cell reduction). Flavopiridol induced a 65-85% cell reduction in Jeko-1, Rec-1 and Karpas-422in comparison to 30-45% in Granta-519, HBL-2 and Z-138. Additional experiments showed additive effects of all GA101 combinations resulting in 40-80% cell reduction (Fludarabine), 30-90% (Bendamustine), 85-95% (Mitoxantrone) and 60-80% (Flavopiridol). Conclusions These in vitro results demonstrate that the anti-CD20 monoclonal antibody GA101 alone or in combination with various chemotherapeutical compounds or the CDK-inhibitor (Flavopiridol) show a promising efficacy in MCL cell lines (additive in combination), supporting the clinical evaluation of such an innovative immuno-chemotherapy in mantle cell lymphoma. Disclosures: Klein: Roche (Glycart): Employment, Equity Ownership, Patents & Royalties. Weinkauf:Lilly Deutschland GmbH: Research Funding. Hutter:Lilly Deutschland GmbH: Research Funding. Zimmermann:Lilly Deutschland GmbH: Research Funding. Dreyling:Roche: Honoraria, Research Funding.

Abstract 2704 Poster Board II-680 Background: Mantle cell lymphoma (MCL) is characterized by a poor long-term prognosis with a median survival of 3–5 years. Type I anti-CD20 antibody rituximab has demonstrated a clear anti-proliferative effect in MCL and achieves increased response rates in combination with chemotherapy. GA101, a third-generation IgG1 anti-CD20 antibody displays improved ADCC and superior direct cell death induction by virtue of glycoengineering compared to rituximab and its targeting a type II epitope on CD20, respectively. Methods: Using a panel of MCL cell lines (Rec-1, HBL-2, Jeko-1, Granta-519, JVM-2 and Z-138) we determined the effect of GA101 alone as well as in combination with rituximab on cell viability and proliferation. Karpas-422 (Diffuse Large B-Cell Lymphoma) was used as a control cell line. MCL and Karpas-422 cells were treated with GA101 or rituximab at concentrations of 1 – 20μg/ml and rituximab. Cell viability was analyzed by trypan-blue exclusion tests at 0h, 24h, 48h and 72h. The panel of MCL cell lines and Karpas-422 were then treated with GA101 and rituximab each at 1 and 10 μg/ml to determine potential synergism of antibody combinations. Accordingly, a fractional product calculation was performed: synergism > 0,1; antagonism < −0,1. In addition, Western-blot and RNA-array-analyses were performed to elucidate potential intra-cellular downstream pathway mechanisms. Results: After mono-exposure with GA101 (1 μg/ml), Granta-519 and Rec-1 showed the highest sensitivity (65–75% cell reduction in Granta-519 and 35–40% in Rec-1). Intermediate results were gained for Z-138, HBL-2, Jeko-1 and JVM-2 and Karpas-422 (15–20%). rituximab mono-exposure at 12,5 μg/ml showed a 25% reduction of cell count in Granta-519, 20% in HBL-2 and < 5% in Rec-1, Jeko-1 and Z-138. Combination experiments suggested the competitive binding of the two antibodies. Thus, GA101 plus rituximab combination experiments resulted in a lower cytotoxicity than GA101 alone, according to fractional product calculations. Conclusions: Although GA101 is competitively displaced by rituximab, GA101 demonstrates higher efficacy in MCL cell lines than rituximab, even at a more than 10-fold lower concentration. Currently RNA-array- and Western blot analysis are being performed to identify the critical pathways responsible for the superior cytotoxicity of GA101. Disclosures: Klein: Discovery Oncology, Roche Diagnostics GmbH: Employment. Weinkauf:Lilly Deutschland GmbH: Research Funding. Hutter:Lilly Deutschland GmbH: Research Funding. Zimmermann:Lilly Deutschland GmbH: Research Funding. Dreyling:Roche: Honoraria, Research Funding.

Introduction: Mantle cell lymphoma (MCL) is an aggressive form of B-cell non-Hodgkin’s lymphoma (NHL). It is characterized by the t(11;14)(q13;q32) translocation, which results in the overexpression of cyclinD1, a cyclin regulated by the PI3K/AKT pathway. Activation of the PI3K/AKT pathway has been shown to be involved in the pathogenesis of MCL. In addition overexpression of the protein kinase C beta (PKCβ) has been described for most cases of MCL, inhibited by enzastaurin which in turn induces apoptosis and reduces proliferation through the PKCβ/PI3K/AKT pathways. 4EBP1 is described as one of the downstream targets of PI3K/mTOR pathway linking translation initiation with PI3K/mTOR signalling as a EIF4E binding protein and playing therefore critical role in the control of protein synthesis, survival and cell growth. Targeting 4EBP1 and/or EIF4E via the PI3K/AKt/mTOR signalling or directly will affect tumor tissue. Aim of the study: The aim of the study was to determine the functional impact of PKCβ/PI3K/AKt/mTOR signaling on the translation initiation factor EIF4E, its binding protein and regulated proteins in MCL cell lines. Methods: MCL cell lines were treated with inhibitors of the PKCβ/PI3K/AKt/mTOR pathways (enzastaurin, LY294002, rapamycin) for up to 48h.The impact of the drugs on the proliferation rate of the cells was accessed after 48h by WST-assay and/or cell count. mRNA expression levels were determined using Taqmanassays. Protein phosphorylation status and protein expression were identified by westernblot. For downregulation of EIF4E in the cells sodium arsenite was used. Specific silencing of EIF4E was achieved by transfection of cells with siRNA against EIF4E. Results: The MCL celllines (5) responded to the treatment with the inhibitors of the PI3K/AKt/mTOR pathway at a IC50 for rapamycin between 5nM-50nM and for the PI3Kinhibitor between 0,31μM-5μM. Treatment of the cells with the PI3K/AKt/mTOR inhibitors induced dephosphorylation of 4EBP1 in a time-and dosedependent manner while a potential effect of the PI3K and mTOR inhibitors on the EIF4E expression and its target genes (cyclinD1, BCL2) could not be shown consistently. 4 out of 5 MCL cell lines were susceptible to enzastaurin with an IC50 between 2μM-5μM. In the not responding to enzastaurin and most resistant to rapamycin cell line (Rec-1) no 4EBP1 proteinexpression was detectable. Dephosphorylation of 4EBP1 achieved by treatment of the cells with sodium arsenit was accompanied by downregulation of EIF4E, cyclinD1 and BCL2 proteins but also stop of proliferation. The potential involvement of eIF4E gene expression in the NaAsO2-induced cytotoxicity and cell death in MCL cell lines was shown by silencing the expression of the eIF4E gene by transfection with siRNA specifically targeting the eIF4E gene expression leading to downregulation of cyclinD1, 4EBP1 proteins and cell proliferation. Conclusion: Eventhough treatment of the cells with the PI3K/AKt/mTOR inhibitors induced dephosphorylation of 4EBP1 a potential effect of the PI3K and mTOR inhibitors on the EIF4E expression and its target genes (cyclinD1, BCL2) could not be shown consistently. Instead dephosphorylation of 4EBP1 accomponied by downregulation of EIF4E or targeted downregulation of eIF4E gene expression lead to downregulation of cyclinD1 and BCL2 proteins as well as cell death in MCL. Therefore targeting the downstream targets of the PI3K/AKt/mTOR signalling 4EBP1 and/or EIF4E directly seems to be a promising anticancer strategy.