Publications by authors named "Richard Greil"

378 Publications

CD44 loss of function sensitizes AML cells to the BCL-2 inhibitor venetoclax by decreasing CXCL12-driven survival cues.

Blood 2021 Jun 3. Epub 2021 Jun 3.

Karlsruhe Institute for Technology, Eggenstein-Leopoldshafen, Germany.

Acute myeloid leukemia (AML) has a poor prognosis under the current standard of care. In recent years, venetoclax, a BCL-2 inhibitor, was approved to treat patients, ineligible for intensive induction chemotherapy. Complete remission rates with venetoclax-based therapies are, however, hampered by minimal residual disease (MRD) in a proportion of patients, leading to relapse. MRD is due to leukemic stem cells retained in bone marrow protective environments; activation of the CXCL12/CXCR4 pathway was shown to be relevant to this process. An important role is also played by cell adhesion molecules such as CD44, which has been shown to be crucial for AML development. Here we show that CD44 is involved in CXCL12 promotion of resistance to venetoclax-induced apoptosis in human AML cell lines and AML patient samples which could be abrogated by CD44 knockdown, knockout or blocking with an anti-CD44 antibody. Split-Venus biomolecular fluorescence complementation showed that CD44 and CXCR4 physically associate at the cell membrane upon CXCL12 induction. In the venetoclax-resistant OCI-AML3 cell line, CXCL12 promoted an increase in the proportion of cells expressing high levels of embryonic-stem-cell core transcription factors (ESC-TFs: Sox2, Oct4, Nanog), abrogated by CD44 knockdown. This ESC-TF-expressing subpopulation which could be selected by venetoclax treatment, exhibited a basally-enhanced resistance to apoptosis, and expressed higher levels of CD44. Finally, we developed a novel AML xenograft model in zebrafish, showing that CD44 knockout sensitizes OCI-AML3 cells to venetoclax treatment in vivo. Our study shows that CD44 is a potential molecular target to sensitize AML cells to venetoclax-based therapies.
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http://dx.doi.org/10.1182/blood.2020006343DOI Listing
June 2021

AID Contributes to Accelerated Disease Progression in the TCL1 Mouse Transplant Model for CLL.

Cancers (Basel) 2021 May 26;13(11). Epub 2021 May 26.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, Austria.

Adaptive somatic mutations conferring treatment resistance and accelerated disease progression is still a major problem in cancer therapy. Additionally in CLL, patients receiving novel, efficient drugs frequently become treatment refractory and eventually relapse. Activation-induced deaminase (AID) is a cytosine deaminase that catalyzes somatic hypermutation of genomic DNA at the immunoglobulin locus in activated B cells. As considerable off-target mutations by AID have been discerned in chronic lymphocytic leukemia, it is essential to investigate to which extent these mutations contribute to disease progression to estimate whether AID inhibition could counteract drug resistance mechanisms. In this study, we examined the TCL1 mouse model for CLL on an AID pro- and deficient background by comparing disease development and mutational landscapes. We provide evidence that AID contributes to the acquisition of somatic cancer-specific mutations also in the TCL1 model and accelerates CLL development particularly in the transplant setting. We conclude that AID is directly determining the fitness of the CLL clone, which prompts further studies to assess the effect of AID inhibition on the occurrence of drug resistance.
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http://dx.doi.org/10.3390/cancers13112619DOI Listing
May 2021

Prognostic and Predictive Factors in Advanced Head and Neck Squamous Cell Carcinoma.

Int J Mol Sci 2021 May 7;22(9). Epub 2021 May 7.

Oncologic Center, Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Paracelsus Medical University, 5020 Salzburg, Austria.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease arising from the mucosa of the upper aerodigestive tract. Despite multimodality treatments approximately half of all patients with locally advanced disease relapse and the prognosis of patients with recurrent or metastatic HNSCC is dismal. The introduction of checkpoint inhibitors improved the treatment options for these patients and pembrolizumab alone or in combination with a platinum and fluorouracil is now the standard of care for first-line therapy. However, approximately only one third of unselected patients respond to this combination and the response rate to checkpoint inhibitors alone is even lower. This shows that there is an urgent need to improve prognostication and prediction of treatment benefits in patients with HNSCC. In this review, we summarize the most relevant risk factors in the field and discuss their roles and limitations. The human papilloma virus (HPV) status for patients with oropharyngeal cancer and the combined positive score are the only biomarkers consistently used in clinical routine. Other factors, such as the tumor mutational burden and the immune microenvironment have been highly studied and are promising but need validation in prospective trials.
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http://dx.doi.org/10.3390/ijms22094981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125786PMC
May 2021

Cytotoxic Compounds of Two Demosponges ( and sp.) from the Aegean Sea.

Biomolecules 2021 May 12;11(5). Epub 2021 May 12.

Institute of Pharmacy/Pharmacognosy, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.

The class of demosponges is the biggest and most diverse of all described sponge species and it is reported to produce a plethora of chemically different metabolites with interesting biological activities. The focus of the present study was to investigate the chemical composition of two Mediterranean demosponges, targeting their brominated compounds and prenylated hydroquinones, compounds with interesting cytotoxic and anti-microbial properties. In order to gain a deeper insight into the chemical diversity of their metabolites and their activities, 20 pure secondary metabolites including new natural products were isolated from two different species ( and sp.) using various chromatographic techniques. Their structures were confirmed by NMR and HRMS, revealing molecules with various chemical scaffolds, mainly prenylated hydroquinones from sp. and halogenated compounds from including 5 novel natural products. The isolated compounds were investigated for their cytotoxic properties using 9 different cell lines, and especially one compound, 2,6-dibromo-4-hydroxy-4-methoxycarbonylmethylcyclohexa-2,5-dien-1-one showed good activities in all tested models.
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http://dx.doi.org/10.3390/biom11050723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151441PMC
May 2021

Two Cases of Pancytopenia with Coombs-Negative Hemolytic Anemia after Chimeric Antigen Receptor T-Cell Therapy.

Int J Mol Sci 2021 May 21;22(11). Epub 2021 May 21.

Oncologic Center, Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Paracelsus Medical University, 5020 Salzburg, Austria.

Background: Chimeric antigen receptor (CAR) T-cells are changing the therapeutic landscape of hematologic malignancies. Severe side effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but prolonged cytopenia has also been reported. The underlying mechanism for prolonged cytopenia is poorly understood so far.

Cases: Severe pancytopenia with grade 2-3 anemia was marked 2-3 months after treatment. Laboratory evaluation revealed undetectable levels of haptoglobin with increased reticulocyte counts. Coomb's tests were negative, no schistocytes were detected on blood smear, and infectious causes were ruled out. Increased erythropoiesis without lymphoma infiltration was noted on bone marrow biopsy. A spontaneous increase in haptoglobin and hemoglobin levels was observed after several weeks. For one patient, peripheral CAR-T levels were monitored over time. We observed a decline at the same time as hemoglobin levels began to rise, implying a potential causality.

Conclusion: To our knowledge, we describe the first two cases of Coombs-negative hemolytic anemia after CAR-T treatment for B-cell lymphoma. We encourage routine monitoring for hemolytic anemia after CAR-T treatment and also encourage further investigations on the underlying mechanism.
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http://dx.doi.org/10.3390/ijms22115449DOI Listing
May 2021

Pharmacokinetics and safety of capmatinib with food in patients with MET-dysregulated advanced solid tumors.

Clin Ther 2021 May 27. Epub 2021 May 27.

Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.

Purpose: In the Phase II GEOMETRY mono-1 study, the potent and selective mesenchymal-epithelial transition (MET) inhibitor capmatinib exhibited considerable efficacy in MET exon 14 skipping (METex14)-mutated metastatic non-small cell lung cancer at a dose of 400 mg BID. The current recommended dose is 400 mg BID in tablet formulation, with or without food. This article reports the pharmacokinetic (PK) profile, safety, and tolerability of capmatinib 300 and 400 mg BID given with food in MET-dysregulated advanced solid tumors.

Methods: This multicenter, open-label, Phase I study enrolled adult patients with MET-dysregulated advanced solid tumors. In the dose escalation phase, capmatinib tablets were orally administered at a dose of 300 mg BID with food; if tolerated, the dose escalation cohort of 400 mg BID was to be opened to enrollment. In the expansion phase, patients were to be enrolled at the higher of the tolerated doses. Tablets were taken within 30 minutes of an unrestricted meal type, except on cycle 1 day 1 (C1D1) and cycle 1 day 7 (C1D7), when they were given with a high-fat meal. The primary objectives were to determine the higher of the tolerated study doses and assess PK variables, with a secondary objective of safety.

Findings: Overall, 35 patients (300 mg BID, n = 8; 400 mg BID, n = 27) with MET-dysregulated advanced solid tumors were enrolled; all patients had received prior antineoplastic therapy, and the most common primary site was lung (45.7%). Among PK-evaluable patients, the median T for capmatinib after administration with a high-fat meal (on C1D1/C1D7) was 4.0 to 5.6 hours across doses. At steady state (C1D7), capmatinib accumulation was low across dose levels (geometric mean of accumulation ratios, 1.29-1.69), with an increase in exposure (AUC and C) from 300 to 400 mg BID. There were no occurrences of dose-limiting toxicity. All patients experienced at least 1 adverse event, and treatment-related adverse events occurred in 28 patients (80%; 300 mg BID, n = 6; 400 mg BID, n = 22), the most frequent of which were fatigue (37.1%) and nausea (34.3%).

Implications: Capmatinib tablet formulation at a dose of up to 400 mg BID with food is well tolerated in patients with MET-dysregulated advanced solid tumors, with safety observations consistent with the existing profile under fasted conditions. These findings support the capmatinib dosing recommendation of 400 mg BID with or without food. ClinicalTrials.gov identifier: NCT02925104.
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http://dx.doi.org/10.1016/j.clinthera.2021.04.006DOI Listing
May 2021

PET-guided eBEACOPP treatment of advanced-stage Hodgkin lymphoma (HD18): follow-up analysis of an international, open-label, randomised, phase 3 trial.

Lancet Haematol 2021 Jun;8(6):e398-e409

German Hodgkin Study Group, Department I of Internal Medicine and Center of Integrated Oncology Aachen, Bonn, Cologne, Düsseldorf, German Hodgkin Study Group, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.

Background: The German Hodgkin Study Group's HD18 trial established the safety and efficacy of PET-guided eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) for the treatment of advanced-stage Hodgkin lymphoma. However, because of a protocol amendment during the enrolment period (June 1, 2011) that changed standard treatment from eight to six cycles, the results of the HD18 trial have been partially immature. We report a prespecified 5-year follow-up analysis of the completed HD18 trial.

Methods: HD18 was an international, open-label, randomised, phase 3 trial done in 301 hospitals and private practices in five European countries. Patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited. After receiving an initial two cycles of eBEACOPP (1250 mg/m intravenous cyclophosphamide [day 1], 35 mg/m intravenous doxorubicin [day 1], 200 mg/m intravenous etoposide [day 1-3], 100 mg/m oral procarbazine [day 1-7], 40 mg/m oral prednisone [day 1-14], 1·4 mg/m intravenous vincristine [day 8], and 10 mg/m intravenous bleomycin [day 8]), patients underwent a contrast-enhanced CT and PET scan (PET-2). Patients with positive PET-2 were randomly assigned to receive standard therapy (an additional six cycles of eBEACOPP; ie, eight cycles in total) or experimental therapy (an additional six cycles of eBEACOPP plus 375 mg/m intravenous rituximab; ie, eight cycles in total) until June 1, 2011. After June 1, 2011, all patients with positive PET-2 were assigned to the updated standard therapy with an additional four cycles of eBEACOPP (ie, six cycles in total). Patients with negative PET-2 were randomly assigned (1:1) to receive standard therapy (an additional six cycles of eBEACOPP [ie, eight cycles in total] until June 1, 2011; an additional four cycles of eBEACOPP [ie, six cycles in total] after June 1, 2011) or experimental therapy (an additional two cycles of eBEACOPP; ie, four cycles in total). Randomisation was done centrally with the minimisation method, including a random component, stratified by centre, age, stage, international prognostic score, and sex. The primary endpoint was progression-free survival. HD18 aimed to improve 5-year progression-free survival by 15% in the PET-2-positive intention-to-treat cohort and to exclude inferiority of 6% or more in 5-year progression-free survival in the PET-2-negative per-protocol population. This study is registered with ClinicalTrials.gov, NCT00515554, and is completed.

Findings: Between May 14, 2008, and July 18, 2014, 2101 patients were enrolled and 1945 were assigned to a treatment group according to their PET-2 result. In the PET-2-positive cohort, with a median follow-up of 73 months (IQR 59 to 94), 5-year progression-free survival was 89·9% (95% CI 85·7 to 94·1) in 217 patients assigned to eight cycles of eBEACOPP before the protocol amendment and 87·7% (83·1 to 92·4) in 217 patients assigned to eight cycles of rituximab plus eBEACOPP (p=0·40). Among 506 patients who received six cycles of eBEACOPP after the protocol amendment, 5-year progression-free survival was 90·1% (95% CI 87·2 to 92·9), with a median follow-up of 58 months (IQR 39 to 66). In the PET-2-negative cohort, with a median follow-up of 66 months (IQR 54 to 85) in the combined pre-amendment and post-amendment groups, 5-year progression-free survival was 91·2% (95% CI 88·4 to 93·9) in 446 patients who received eight or six cycles of eBEACOPP and 93·0% (90·6 to 95·4) in 474 patients who received four cycles of eBEACOPP (difference 1·9% [95% CI -1·8 to 5·5]). In the subgroup of PET-2-negative patients randomly assigned after protocol amendment, 5-year progression-free survival was 90·9% (95% CI 86·8 to 95·1) in 202 patients assigned to receive six cycles of eBEACOPP and 91·0% (86·6 to 95·5) in 200 patients assigned to receive four cycles of eBEACOPP (difference 0·1% [-5·9 to 6·2]).

Interpretation: Long-term follow-up confirms the efficacy and safety of PET-2-guided eBEACOPP in patients with advanced-stage Hodgkin lymphoma. The reduction from eight to four cycles of eBEACOPP represents a benchmark in the treatment of early-responding patients, who can now be potentially cured with a short and safe treatment approach.

Funding: Deutsche Krebshilfe, Swiss State Secretariat for Education, Research and Innovation SERI (Switzerland), and Roche Pharma.

Translation: For the German translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S2352-3026(21)00101-0DOI Listing
June 2021

Docetaxel, cisplatin and 5-FU compared with docetaxel, cisplatin and cetuximab as induction chemotherapy in advanced squamous cell carcinoma of the head and neck: Results of a randomised phase II AGMT trial.

Eur J Cancer 2021 Jul 19;151:201-210. Epub 2021 May 19.

Paracelsus Medical University, Internal Medicine III, Hematology & Medical Oncology, Mu¨llner Hauptstraße 48, A-5020 Salzburg, Austria; Salzburg Cancer Research Institute-CCCIT and Cancer Cluster Salzburg, Austria.

Purpose: Induction chemotherapy (ICT) with cisplatin (P), 5-FU (F) and taxanes (T) is a therapeutical option in patients suffering from locally advanced or unresectable stage III or IV squamous cell carcinoma of the head and neck (SCCHN). The role of ICT is controversial, and toxicity and/or delay of radiotherapy (RT) may reduce the potential benefit of this treatment regimen. Here, we report the results of a randomised phase II trial comparing TPF with TP + cetuximab (C).

Patients And Methods: In this trial, 100 patients with locally advanced stage III or IV SCCHN were included in the analysis. Patients were randomly assigned to either TPF-ICT (N = 49) or TPC-ICT (N = 51), both followed by RT + C. The primary end-point of the study was overall response rate (ORR) three months after RT + C was finished.

Results: On an intention-to-treat basis, the ORR (complete remission + partial remission) was 74.5% in the TPC arm compared with 63.3% in the TPF arm (p = 0.109). OS was similar in both arms 400 days after treatment was initiated (86.1% [95% confidence interval {CI}, 73.0-93.1%] in the TPC arm and 78.5% [95% CI, 63.7-87.8%] in the TPF arm). TPC resulted in slightly less serious adverse events and in less haematological, but more skin toxicities. Two patients randomised in the TPC arm died during ICT and RT. Four patients in the TPF arm died after completion of RT. No delay from the end of ICT to RT + C was observed. A total of 83.1% of patients (80% in the TPC arm; 86% in the TPF arm) received RT without dose reduction and/or modification.

Conclusion: TPC-containing ICT for patients with locally advanced SCCHN was found to be an effective and tolerable one-day regimen. Further prospective evidence from larger trials is warranted.
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http://dx.doi.org/10.1016/j.ejca.2021.03.051DOI Listing
July 2021

Pretreatment with ibrutinib reduces cytokine secretion and limits the risk of obinutuzumab-induced infusion-related reactions in patients with CLL: analysis from the iLLUMINATE study.

Ann Hematol 2021 Jul 20;100(7):1733-1742. Epub 2021 May 20.

Department of Hematology, Dokuz Eylül University, Izmir, Turkey.

Anti-CD20 antibody treatments, such as obinutuzumab, have been associated with infusion-related reactions (IRRs). In the phase 3 iLLUMINATE study of ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab in first-line chronic lymphocytic leukemia/small lymphocytic lymphoma, IRRs were substantially reduced with ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab. We prospectively analyzed inflammatory cytokines to evaluate the impact of ibrutinib on circulating cytokine levels following obinutuzumab infusion. In iLLUMINATE, ibrutinib or chlorambucil was given approximately 30-120 min before the first obinutuzumab infusion. Cytokines evaluated were IFNγ, IL-6, IL-8, IL-10, IL-18, MCP-1, MIP-1α, MIP-1β, and TNFα. Changes in peak cytokine levels from baseline (immediately before obinutuzumab) to post-obinutuzumab infusion were compared between arms and between patients with versus without IRRs using Wilcoxon rank sum test. Of 228 treated patients, 95 on ibrutinib-obinutuzumab (15 with IRRs, 80 without) and 88 on chlorambucil-obinutuzumab (45 with IRRs, 43 without) with cytokine data were included. Irrespective of IRR occurrence, median increase in cytokines was lower with ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab for all cytokines (P < 0.01) except MIP-1β. Across treatment arms, post-obinutuzumab median increase in all cytokines except MIP-1β was greater in patients with versus without IRRs (P < 0.001). IL-6 and IL-8 elevations were associated with IRRs in both treatment arms. Among patients with IRRs, those receiving ibrutinib-obinutuzumab had lower post-obinutuzumab increases in IL-6, IL-8, IL-10, and MCP-1 (P < 0.04) than patients receiving chlorambucil-obinutuzumab. For patients in the ibrutinib-treatment arm, we observed a reduction in both the rate of clinically apparent IRRs and the levels of IRR-related cytokines and chemokines. This observation supports an immunomodulatory mechanism of action for ibrutinib. Clinical Trial Registration: NCT02264574.
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http://dx.doi.org/10.1007/s00277-021-04536-6DOI Listing
July 2021

Ramucirumab plus FOLFIRI or irinotecan as second-line therapy in advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.

J Gastrointest Oncol 2021 Apr;12(2):906-909

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology, and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute, Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University Salzburg, Salzburg, Austria.

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http://dx.doi.org/10.21037/jgo-20-230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107630PMC
April 2021

Gemcitabine/nab-Paclitaxel versus FOLFIRINOX for palliative first-line treatment of advanced pancreatic cancer: A propensity score analysis.

Eur J Cancer 2021 Jul 2;151:3-13. Epub 2021 May 2.

Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. Electronic address:

Background: Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX are standard first-line treatment options for advanced pancreatic ductal adenocarcinoma (aPDAC), but currently no prospective randomised head-to-head comparison between these treatments has yet been performed.

Methods: We conducted a comparative propensity score (PS) analysis of overall (OS) and progression-free survival (PFS) in a tri-centre cohort of patients with aPDAC undergoing palliative first-line treatment with either GN or FOLFIRINOX.

Results: In unadjusted analysis, OS and PFS were highly similar between patients treated with GN (n = 297) and FOLFIRINOX (n = 158). In detail, median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 11.2 months, 45% and 12% in the FOLFIRINOX group, respectively (log-rank p = 0.783). Accordingly, median (4.6 versus 4.8 months), 6-month (40% versus 43%) and 1-year (9% versus 9%) PFS estimates did not significantly differ (log-rank p = 0.717). However, patients treated with FOLFIRINOX were significantly younger, had fewer comorbidities, and a better Eastern Cooperative Oncology Group performance status. These imbalances were accounted for by weighting the data with the PS. In PS analysis of survival outcomes, OS and PFS remained comparable between the two treatment groups. In detail, PS-weighted median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 10.1 months, 40% and 13% in the FOLFIRINOX group (PS-weighted log-rank p = 0.449). PS-weighted PFS estimates again did not differ (PS-weighted log-rank p = 0.329).

Conclusion: This real-world comparative effectiveness study indicates that FOLFIRINOX and GN have similar effectiveness in the palliative first-line treatment of aPDAC.
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http://dx.doi.org/10.1016/j.ejca.2021.03.040DOI Listing
July 2021

Results of a hospitalization policy of asymptomatic and pre-symptomatic COVID-19-positive long-term care facility residents in the province of Salzburg-a report from the AGMT COVID-19 Registry.

Geroscience 2021 Apr 10. Epub 2021 Apr 10.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.

COVID-19-associated case fatality rates up to 48% were reported among nursing facility residents. During the first wave of the COVID-19 pandemic, routine SARS-CoV-2 testing in long-term care facilities in the Province of Salzburg and centralized hospitalization in the COVID-19 unit of the Paracelsus Medical University Salzburg (Austria) irrespective of symptoms was implemented. Baseline characteristics and the course of COVID-19 disease were assessed among hospitalized long-term care facility residents within the COVID-19 Registry of the Austrian Group Medical Tumor Therapy (AGMT; NCT04351529). Between the 24 of March and the 20 of April 2020, 50 COVID-19-positive residents were hospitalized. The median age was 84.5 years (range: 79-88) and the median number of comorbidities and baseline medication classes was 6 (IQR: 4-7) and 5 (IQR: 3-6), respectively. At admission, 31 residents (62%) were symptomatic, nine residents (18%) pre-symptomatic whereas ten residents (20%) remained asymptomatic. The 30-day mortality rate from hospitalization was 32% and significantly higher in symptomatic residents at admission when compared to asymptomatic residents including pre-symptomatic residents (48% [95% CI: 27-63%] versus 5% [95% CI: 0-15%], p=0.006). The Early Warning Score (EWS) at admission was associated with 30-day mortality: high risk: 100%, intermediate risk: 50% (95% CI: 0-78%), and low risk: 21% (95% CI: 7-32%) (p<0.001). In light of comparably low mortality rates between asymptomatic and pre-symptomatic hospitalized COVID-19-positive residents, we suggest the supply of comparable intensity and quality of monitoring and care in long-term care facilities as an alternative to immediate hospitalization upon a positive COVID-19 test in asymptomatic residents.
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http://dx.doi.org/10.1007/s11357-021-00352-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035610PMC
April 2021

Intensified treatment of patients with early stage, unfavourable Hodgkin lymphoma: long-term follow-up of a randomised, international phase 3 trial of the German Hodgkin Study Group (GHSG HD14).

Lancet Haematol 2021 Apr;8(4):e278-e288

German Hodgkin Study Group, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, University of Cologne, Germany; Department of Hematology and Stem Cell Transplantation and Cancer Center Cologne Essen-Partner Site Essen, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address:

Background: To improve the long-term tumour control in early, unfavourable Hodgkin Lymphoma, the German Hodgkin Study Group (GHSG) HD14 trial compared four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with an intensified chemotherapy regimen consisting of two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) plus two cycles of ABVD. The final analysis of the trial showed a significant advantage in terms of freedom from treatment failure (difference 7·2% [95% CI 3·8-10·5] at 5 years) for patients who received two cycles of escalated BEACOPP and two cycles of ABVD. However, there was no difference in overall survival between the two groups. To evaluate long-term efficacy and toxicity of this strategy, we did a follow-up analysis.

Methods: Patients aged 18-60 years with performance status of 2 or less and primary diagnosis of early, unfavourable Hodgkin lymphoma (all histologies) were included in an international, randomised, open-label, phase 3 trial. Patients were randomly assigned to receive four cycles of ABVD (ABVD group) or two cycles of escalated BEACOPP and two cycles of ABVD (2 + 2 group), both groups also received 30 Gy involved field radiotherapy. The ABVD dosing regimen was doxorubicin 25 mg/m (days 1 and 15), bleomycin 10 mg/m (days 1 and 15), vinblastine 6 mg/m (days 1 and 15), and dacarbazine 375 mg/m (days 1 and 15), repeated on day 29. The escalated BEACOPP dosing regimen was cyclophosphamide 1250 mg/m (day 1), doxorubicin 35 mg/m (day 1), etoposide 200 mg/m (days 1-3), procarbazine 100 mg/m (days 1-7), prednisone 40 mg/m (days 1-14), vincristine 1·4 mg/m (day 8; maximum 2 mg), and bleomycin 10 mg/m (day 8), repeated on day 22. After closure of the ABVD group according to prespecified rules, patients were assigned to receive two cycles of escalated BEACOPP and two cycles of ABVD (non-randomised 2 + 2 group), which continued until the end of the predefined 5-year recruitment period. In this prespecified long-term follow-up analysis, we aimed to evaluate the secondary endpoints progression-free survival, overall survival, and long-term toxicity. To this end, we did a descriptive intention-to-treat analysis of all qualified HD14 patients and on the predefined subsets of randomised qualified HD14 patients and patients in the non-randomised 2 + 2 group. The trial was registered on the International Standard Randomised Controlled Trial database, 04761296.

Findings: Between Jan 28, 2003, and Dec 29, 2009, 1686 patients were randomly assigned to the ABVD group (847 [50·2%] patients) and the 2 + 2 group (839 [49·8%] patients). 370 additional patients were recruited to the non-randomised 2 + 2 group. 1550 (92%) randomly assigned patients (median observation time 112 months [IQR 80-132]) and 339 (92%) patients in the non-randomised 2 + 2 group (median observation time 74 months [58-100]) were included in the qualified analysis set. 10-year overall survival in the randomly assigned patients was 94·1% (95% CI 92·0-95·7) for the ABVD group and 94·1% (91·8-95·7) for the 2 + 2 group (HR 1·0 [95% CI 0·6-1·5]; p=0·88). 8-year overall survival in the non-randomised 2 + 2 group was 95·1% (95% CI 91·6-97·2). 10-year progression-free survival in the randomly assigned patients was 85·6% (95% CI 82·6-88·1) for the ABVD group and 91·2% (88·4-93·3) for the 2 + 2 group (HR 0·5% [95% CI 0·4-0·7]; p=0·0001), accounting for a significant difference of 5·6% (95% CI 1·9-9·2) favouring the 2 + 2 group (p=0·0001). In the non-randomised 2 + 2 group, 8-year progression-free survival was 94·5% (95% CI 91·1-96·6). Standardised incidence ratios of second primary malignancies were similar between the ABVD group (2·3 [95% CI 1·6-3·1]) and the 2 + 2 group (2·5 [1·8-3·4]; Gray's p=0·80). Standardised incidence ratio of second primary malignancies was 3·1 (95% CI 1·7-5·0) in the non-randomised 2 + 2 group.

Interpretation: This long-term analysis confirms superior tumour control in the 2 + 2 group compared with the ABVD group without translating into an overall survival difference. At longer follow-up, there is no difference regarding second primary malignancies between groups. In conclusion, the 2 + 2 regimen spares a significant number of patients from the burden of relapse and additional treatment without increased long-term toxicity.

Funding: Deutsche Krebshilfe eV and Swiss Federal Government.
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http://dx.doi.org/10.1016/S2352-3026(21)00029-6DOI Listing
April 2021

Conventional versus reverse sequence of neoadjuvant epirubicin/cyclophosphamide and docetaxel: sequencing results from ABCSG-34.

Br J Cancer 2021 May 24;124(11):1795-1802. Epub 2021 Mar 24.

Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.

Background: Preoperative chemotherapy containing anthracyclines and taxanes is well established in early-stage breast cancer. Previous studies have suggested that the chemotherapy sequence may matter but definitive evidence is missing. ABCSG trial 34 evaluated the activity of the MUC1 vaccine tecemotide when added to neoadjuvant treatment; the study provided the opportunity for the second randomisation to compare two different anthracycline/taxane sequences.

Methods: HER2-negative early-stage breast cancer patients were recruited to this randomised multicentre Phase 2 study. Patients in the chemotherapy cohort (n = 311) were additionally randomised to a conventional or reversed sequence of epirubicin/cyclophosphamide and docetaxel. Residual cancer burden (RCB) with/without tecemotide was defined as primary study endpoint; RCB in the two chemotherapy groups was a key secondary endpoint.

Results: No significant differences in terms of RCB 0/I (40.1% vs. 37.2%; P = 0.61) or pathologic complete response (pCR) rates (24.3% vs. 25%, P = 0.89) were observed between conventional or reverse chemotherapy sequence. No new safety signals were reported, and upfront docetaxel did not result in decreased rates of treatment delay or discontinuation.

Conclusion: Upfront docetaxel did not improve chemotherapy activity or tolerability; these results suggest that upfront neoadjuvant treatment with anthracyclines remains a valid option.
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http://dx.doi.org/10.1038/s41416-021-01284-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144560PMC
May 2021

Vinorelbine as substitute for vincristine in patients with diffuse large B cell lymphoma and vincristine-induced neuropathy.

Support Care Cancer 2021 Feb 24. Epub 2021 Feb 24.

Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Background: A combination of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line therapy for diffuse large B cell lymphoma (DLBCL), the most common aggressive lymphoma in adults. One of the major adverse effects of this regimen is vincristine-induced polyneuropathy which leads to discontinuation of vincristine in up to 30% of DLBCL-patients. Dose reduction of vincristine might worsen treatment outcomes of DLBCL but identification of treatment alternatives for patients exhibiting peripheral neuropathy during R-CHOP is an unmet need in hematology.

Methods: In this retrospective cohort study, comprising 987 patients with de novo DLBCL, we delineated the role of vinorelbine as a substitute for vincristine in R-CHOP by measuring improvements in neuropathy and outcome variables.

Results: Five-year overall survival (OS) and progression-free survival (PFS) were 72.6% and 63.1% in patients who received regular doses of vincristine, as compared to 60.6% and 51.7% in patients who received reduced doses of vincristine (p = 0.022 and p = 0.003, respectively). Of 199 patients who switched to vinorelbine, the majority experienced an improvement of neuropathy Furthermore, vinorelbine-switched patients showed favorable oncologic outcomes.

Conclusion: Replacement of vincristine by vinorelbine due to neuropathy is effective and safe, and results in a significant improvement in neuropathy as compared to treatment with R-CHOP.
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http://dx.doi.org/10.1007/s00520-021-06059-2DOI Listing
February 2021

SAMHD1 restrains aberrant nucleotide insertions at repair junctions generated by DNA end joining.

Nucleic Acids Res 2021 03;49(5):2598-2608

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria.

Aberrant end joining of DNA double strand breaks leads to chromosomal rearrangements and to insertion of nuclear or mitochondrial DNA into breakpoints, which is commonly observed in cancer cells and constitutes a major threat to genome integrity. However, the mechanisms that are causative for these insertions are largely unknown. By monitoring end joining of different linear DNA substrates introduced into HEK293 cells, as well as by examining end joining of CRISPR/Cas9 induced DNA breaks in HEK293 and HeLa cells, we provide evidence that the dNTPase activity of SAMHD1 impedes aberrant DNA resynthesis at DNA breaks during DNA end joining. Hence, SAMHD1 expression or low intracellular dNTP levels lead to shorter repair joints and impede insertion of distant DNA regions prior end repair. Our results reveal a novel role for SAMHD1 in DNA end joining and provide new insights into how loss of SAMHD1 may contribute to genome instability and cancer development.
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http://dx.doi.org/10.1093/nar/gkab051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969033PMC
March 2021

Spatial Heterogeneity in Large Resected Diffuse Large B-Cell Lymphoma Bulks Analysed by Massively Parallel Sequencing of Multiple Synchronous Biopsies.

Cancers (Basel) 2021 Feb 6;13(4). Epub 2021 Feb 6.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Müllner Hauptstraße 48, 5020 Salzburg, Austria.

Diffuse large B-cell lymphoma (DLBCL) usually needs to be treated immediately after diagnosis from a single lymph node biopsy. However, several reports in other malignancies have shown substantial spatial heterogeneity within large tumours. Therefore, we collected multiple synchronous biopsies of twelve patients that had diagnostic or therapeutic resections of large lymphoma masses and performed next-generation sequencing of 213 genes known to be important for lymphoma biology. Due to the high tumour cell content in the biopsies, we were able to detect several mutations which were present with a stable allelic frequency across all the biopsies of each patient. However, ten out of twelve patients had spatially discordant mutations and similar results were found by the analysis of copy number variants. The median Jaccard similarity coefficient, a measure of the similarity of a sample set was 0.77 (range 0.47-1), and some of the involved genes such as , , , and have a known prognostic or therapeutic relevance in DLBCL. This shows that single biopsies underestimate the complexity of the disease and might overlook possible mechanisms of resistance and therapeutic targets. In the future, the broader application of liquid biopsies will have to overcome these obstacles.
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http://dx.doi.org/10.3390/cancers13040650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914762PMC
February 2021

Randomized Phase III Study of FOLFOX Alone or With Pegilodecakin as Second-Line Therapy in Patients With Metastatic Pancreatic Cancer That Progressed After Gemcitabine (SEQUOIA).

J Clin Oncol 2021 Apr 8;39(10):1108-1118. Epub 2021 Feb 8.

Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Purpose: SEQUOIA compared efficacy and safety of adding pegilodecakin (PEG), a pegylated recombinant human interleukin (IL)-10, with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) in patients following progression on first-line gemcitabine-containing therapy with metastatic pancreatic ductal adenocarcinoma (PDAC).

Patients And Methods: SEQUOIA, a randomized, global phase III study, compared FOLFOX with PEG + FOLFOX as second line in gemcitabine-refractory PDAC. Patients were randomly assigned 1:1 (PEG + FOLFOX:FOLFOX) and stratified by prior gemcitabine and region. Eligible patients had only one prior gemcitabine-containing treatment. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), response evaluation per Response Evaluation Criteria in Solid Tumor (RECIST) 1.1, and safety. Exploratory analyses included biomarkers related to immune activation.

Results: Between March 1, 2017, and September 9, 2019, 567 patients were randomly assigned PEG + FOLFOX (n = 283) or FOLFOX (n = 284). Most (94.7%) patients received prior gemcitabine plus nab paclitaxel. OS was similar comparing PEG + FOLFOX versus FOLFOX (median: 5.8 6.3 months; hazard ratio = 1.045; 95% CI, 0.863 to 1.265). Also, PFS (median 2.1 2.1 months; hazard ratio = 0.981; 95% CI, 0.808 to 1.190) and objective response rate (4.6% 5.6%) were similar between the treatment arms. Most common (≥ 35%) treatment-emergent adverse events in PEG + FOLFOX versus FOLFOX were thrombocytopenia (55% 20%), anemia (40% 16%), fatigue (61% 45%), neutropenia (39% 28%), abdominal pain (37% 29%), nausea (45% 41%), neuropathy (37% 38%), and decreased appetite (35% 31%). Exploratory analyses revealed increases in total IL-18, interferon (IFN)-γ, and granzyme B and decreases in transforming growth factor (TGF)-β with the addition of PEG.

Conclusion: PEG added to FOLFOX did not improve efficacy in advanced gemcitabine-refractory PDAC. Safety findings were consistent as previously observed from PEG with chemotherapy; toxicity was manageable and tolerable. Exploratory pharmacodynamic results were consistent with immunostimulatory signals of the IL-10R pathway.
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http://dx.doi.org/10.1200/JCO.20.02232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078437PMC
April 2021

PET-guided omission of radiotherapy in early-stage unfavourable Hodgkin lymphoma (GHSG HD17): a multicentre, open-label, randomised, phase 3 trial.

Lancet Oncol 2021 02;22(2):223-234

Department of Radiotherapy, University Hospital Münster, Münster, Germany.

Background: Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavourable Hodgkin lymphoma. However, the use of radiotherapy can have long-term sequelae, which is of particular concern, as Hodgkin lymphoma is frequently diagnosed in young adults with a median age of approximately 30 years. In the German Hodgkin Study Group HD17 trial, we investigated whether radiotherapy can be omitted without loss of efficacy in patients who have a complete metabolic response after receiving two cycles of escalated doses of etoposide, cyclophosphamide, and doxorubicin, and regular doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2).

Methods: In this multicentre, open-label, randomised, phase 3 trial, patients (aged 18-60 years) with newly diagnosed early-stage unfavourable Hodgkin lymphoma (all histologies) and an Eastern Cooperative Oncology Group performance status of 2 or less were enrolled at 224 hospitals and private practices in Germany, Switzerland, Austria, and the Netherlands. Patients were randomly assigned (1:1) to receive either standard combined-modality treatment, consisting of the 2 + 2 regimen (eBEACOPP consisted of 1250 mg/m intravenous cyclophosphamide on day 1, 35 mg/m intravenous doxorubicin on day 1, 200 mg/m intravenous etoposide on days 1-3, 100 mg/m oral procarbazine on days 1-7, 40 mg/m oral prednisone on days 1-14, 1·4 mg/m intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m intravenous bleomycin on day 8; ABVD consisted of 25 mg/m intravenous doxorubicin, 10 mg/m intravenous bleomycin, 6 mg/m intravenous vinblastine, and 375 mg/m intravenous dacarbazine, all given on days 1 and 15) followed by 30 Gy involved-field radiotherapy (standard combined-modality treatment group) or PET4-guided treatment, consisting of the 2 + 2 regimen followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy (PET4; PET4-guided treatment group). Randomisation was done centrally and used the minimisation method and seven stratification factors (centre, age, sex, clinical symptoms, disease localisation, albumin concentration, and bulky disease), and patients and investigators were masked to treatment allocation until central review of the PET4 examination had been completed. With the final analysis presented here, the primary objective was to show non-inferiority of the PET4-guided strategy in a per-protocol analysis of the primary endpoint of progression-free survival. We defined non-inferiority as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01356680.

Findings: Between Jan 13, 2012, and March 21, 2017, we enrolled and randomly assigned 1100 patients to the standard combined-modality treatment group (n=548) or to the PET4-guided treatment group (n=552); two patients in each group were found ineligible after randomisation. At a median follow-up of 46·2 months (IQR 32·7-61·2), 5-year progression-free survival was 97·3% (95% CI 94·5-98·7) in the standard combined-modality treatment group and 95·1% (92·0-97·0) in the PET4-guided treatment group (hazard ratio 0·523 [95% CI 0·226-1·211]). The between-group difference was 2·2% (95% CI -0·9 to 5·3) and excluded the non-inferiority margin of 8%. The most common grade 3 or 4 acute haematological adverse events were leucopenia (436 [83%] of 528 patients in the standard combined-modality treatment group vs 443 [84%] of 529 patients in the PET4-guided treatment group) and thrombocytopenia (139 [26%] vs 176 [33%]), and the most frequent acute non-haematological toxic effects were infection (32 [6%] vs 40 [8%]) and nausea or vomiting (38 [7%] vs 29 [6%]). The most common acute radiotherapy-associated adverse events were dysphagia (26 [6%] in the standard combined-modality treatment group vs three [2%] in the PET4-guided treatment group) and mucositis (nine [2%] vs none). 229 serious adverse events were reported by 161 (29%) of 546 patients in the combined-modality treatment group, and 235 serious adverse events were reported by 164 (30%) of 550 patients in the PET4-guided treatment group. One suspected unexpected serious adverse reaction (infection) leading to death was reported in the PET4-guided treatment group.

Interpretation: PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavourable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy.

Funding: Deutsche Krebshilfe.
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http://dx.doi.org/10.1016/S1470-2045(20)30601-XDOI Listing
February 2021

A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma.

Blood 2021 02;137(5):600-609

Memorial Sloan Kettering Cancer Center, New York, NY.

The phase 2 CAVALLI (NCT02055820) study assessed efficacy and safety of venetoclax, a selective B-cell lymphoma-2 (Bcl-2) inhibitor, with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line (1L) diffuse large B-cell lymphoma (DLBCL), including patients demonstrating Bcl-2 protein overexpression by immunohistochemistry (Bcl-2 IHC+). Eligible patients were ≥18 years of age and had previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2 to 5. Venetoclax 800 mg (days 4-10, cycle 1; days 1-10, cycles 2-8) was administered with rituximab (8 cycles) and cyclophosphamide, doxorubicin, vincristine, and prednisone (6-8 cycles) in 21-day cycles. Primary end points were safety, tolerability, and research_plete response (CR) at end of treatment (EOT). Secondary end points were progression-free survival (PFS) and overall survival. Comparative analyses used covariate-adjusted R-CHOP controls from the GOYA/BO21005 study, an appropriate contemporary benchmark for safety and efficacy. Safety and efficacy analyses included 206 patients. CR rate at EOT was 69% in the overall population and was maintained across Bcl-2 IHC+ subgroups. With a median follow-up of 32.2 months, trends were observed for improved investigator-assessed PFS for venetoclax plus R-CHOP in the overall population (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.43-0.87) and Bcl-2 IHC+ subgroups (HR, 0.55; 95% CI, 0.34-0.89) vs R-CHOP. Despite a higher incidence of grade 3/4 hematologic adverse events (86%), related mortality was not increased (2%). Chemotherapy dose intensity was similar in CAVALLI vs GOYA. The addition of venetoclax to R-CHOP in 1L DLBCL demonstrates increased, but manageable, myelosuppression and the potential of improved efficacy, particularly in high-risk Bcl-2 IHC+ patient subgroups.
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http://dx.doi.org/10.1182/blood.2020006578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869186PMC
February 2021

miRNA-Based Therapeutics in the Era of Immune-Checkpoint Inhibitors.

Pharmaceuticals (Basel) 2021 Jan 26;14(2). Epub 2021 Jan 26.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, 5020 Salzburg, Austria.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by binding to complementary target regions on gene transcripts. Thus, miRNAs fine-tune gene expression profiles in a cell-type-specific manner and thereby regulate important cellular functions, such as cell growth, proliferation and cell death. MiRNAs are frequently dysregulated in cancer cells by several mechanisms, which significantly affect the course of the disease. In this review, we summarize the current knowledge on how dysregulated miRNAs contribute to cancer and how miRNAs can be exploited as predictive factors and therapeutic targets, particularly in regard to immune-checkpoint inhibitor therapies.
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http://dx.doi.org/10.3390/ph14020089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911012PMC
January 2021

Outcomes of patients with chronic myelomonocytic leukaemia treated with non-curative therapies: a retrospective cohort study.

Lancet Haematol 2021 Feb;8(2):e135-e148

Hematology Department, Vall d'Hebron Hospital Universitari, Experimental Hematology, Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.

Background: Approval of hypomethylating agents in patients with chronic myelomonocytic leukaemia is based on trials done in patients with myelodysplastic syndromes. We aimed to investigate whether hypomethylating agents provide a benefit in subgroups of patients with chronic myelomonocytic leukaemia compared with other treatments.

Methods: For this retrospective cohort study, data were retrieved between Nov 30, 2017, and Jan 5, 2019, from 38 centres in the USA and Europe. We included non-selected, consecutive patients diagnosed with chronic myelomonocytic leukaemia, who received chronic myelomonocytic leukaemia-directed therapy. Patients with acute myeloid leukaemia according to 2016 WHO criteria at initial diagnosis (ie, ≥20% blasts in the bone marrow or peripheral blood) or with unavailability of treatment data were excluded. Outcomes assessed included overall survival, time to next treatment, and time to transformation to acute myeloid leukaemia. Analyses were adjusted by age, sex, platelet count, and Chronic myelomonocytic leukaemia-Specific Prognostic Scoring System (CPSS). Patients were grouped by first received treatment with either hydroxyurea, hypomethylating agents, or intensive chemotherapy, and stratified by risk according to blast count, French-American-British subtype, CPSS, WHO 2016 subtype, and the eligibility criteria of the DACOTA trial (NCT02214407).

Findings: 949 patients diagnosed with chronic myelomonocytic leukaemia between April 13, 1981, and Oct 26, 2018, were included. Median follow-up was 23·4 months (IQR 11·5-42·3) from diagnosis and 16·2 months (6·6-31·6) from start of first-line treatment. 412 (43%) of 949 patients received hypomethylating agents as first treatment, 391 (41%) hydroxyurea, and 83 (9%) intensive chemotherapy. Adjusted median overall survival for patients treated with hydroxyurea versus hypomethylating agents was 15·6 months (95% CI 13·1-17·3) versus 20·7 months (17·9-23·4); hazard ratio (HR) 1·39 (1·17-1·65; p=0·0002) and 14·0 months (9·8-17·2) versus 20·7 months (17·9-23·4; HR 1·55 [1·16-2·05]; p=0·0027) for those treated with intensive chemotherapy versus hypomethylating agents. In patients with myeloproliferative chronic myelomonocytic leukaemia (myeloproliferative CMML), median overall survival was 12·6 months (10·7-15·0) versus 17·6 months (14·8-21·5; HR 1·38 [1·12-1·70]; p=0·0027) for patients treated with hydroxyurea versus hypomethylating agents, and 12·3 months (8·4-16·6) versus 17·6 months (14·8-21·5; HR 1·44 [1·02-2·03]; p=0·040) for intensive chemotherapy versus hypomethylating agents. Hypomethylating agents did not confer an overall survival advantage for patients classified as having lower-risk disease (ie, myelodysplastic chronic myelomonocytic leukaemia with <10% blasts, CMML-0, or lower-risk CPSS).

Interpretation: These data suggest hypomethylating agents as the preferred therapy for patients with higher-risk chronic myelomonocytic leukaemia and those with myeloproliferative CMML. Our findings also suggest that CPSS is a valuable tool to identify patients who are most likely to benefit from hypomethylating agents. Further evidence from prospective cohorts would be desirable.

Funding: The Austrian Group for Medical Tumor Therapy.
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http://dx.doi.org/10.1016/S2352-3026(20)30374-4DOI Listing
February 2021

Overcoming negative predictions of microRNA expressions to gemcitabine response with FOLFIRINOX in advanced pancreatic cancer patients.

Future Sci OA 2020 Nov 30;7(2):FSO644. Epub 2020 Nov 30.

IIIrd Medical Department with Hematology & Medical Oncology, Hemostaseology, Rheumatology & Infectious Diseases, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstrasse 48, Salzburg 5020, Austria.

FOLFIRINOX is superior to gemcitabine in patients with pancreatic cancer, but this regimen is associated with toxicity and biomarkers for response are warranted. MicroRNAs can mediate drug resistance and could provide predictive information. Altered expressions of several microRNAs including miR-21-5p, miR-10b-5p and miR-34a-5p have been previously linked to a worse response to gemcitabine. We investigated the influence of expression levels in tumor tissue of those three microRNAs on outcome to FOLFIRINOX. Twenty-nine patients with sufficient formalin-fixed paraffin-embedded tumor tissue were identified. There was no significant association between high and low expression groups for these three microRNA. We conclude that polychemotherapy combination can overcome intrinsic negative prognostic factors.
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http://dx.doi.org/10.2144/fsoa-2020-0128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787156PMC
November 2020

Re-Sensitizing Tumor Cells to Cancer Drugs with Epigenetic Regulators.

Curr Cancer Drug Targets 2021 ;21(4):353-359

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, Salzburg, Austria, Cancer Cluster Salzburg, 5020Salzburg, Austria.

Cancer drug resistance is a major problem for cancer therapy. While many drugs can be effective in first-line treatments, cancer cells can become resistant due to genetic (mutations and chromosomal aberrations) but also epigenetic changes. Hence, many research studies addressed epigenetic drugs in circumventing resistance to conventional therapeutics in different tumor entities and in increasing the efficiency of immune checkpoint therapies. Furthermore, repositioning of already approved drugs in combination with epigenetic modifiers could potentiate their efficacy and thus could be an attractive strategy for cancer treatment. Summarizing, we recapitulate current data on epigenetic drugs and their targets in modulating sensitivity towards conventional and immune therapies, providing evidence that altering expression profiles by epigenetic modifiers holds great potential to improve the clinical outcome of cancer patients.
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http://dx.doi.org/10.2174/1568009620666210108102723DOI Listing
January 2021

Treatment Landscape for Patients with HER2-Positive Metastatic Breast Cancer: A Review on Emerging Treatment Options.

Cancer Manag Res 2020 27;12:10615-10629. Epub 2020 Oct 27.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University Salzburg, Salzburg, Austria.

The prognosis of HER2-positive metastatic breast cancer (MBC) has radically changed in recent years and continues to improve due to the broad application of effective therapies like monoclonal antibodies and small molecules targeting HER2. Persistent dependency of tumor cells on the oncogene HER2, on one hand, as well as low expression levels in healthy tissue, on the other hand, make this protein an ideal target for anti-cancer therapy. New HER2 targeting strategies including targeted delivery of cytotoxic drugs via HER2 receptor have been developed. Recently, the US Food and Drug Administration (FDA) approved three new drugs for the treatment of HER2-positive MBC: the antibody-drug conjugate trastuzumab deruxtecan and the two tyrosine kinase inhibitors neratinib and tucatinib. Here, we summarize recent publications and developments of novel anti-HER2 therapies like monoclonal antibodies with improved properties compared to trastuzumab and bispecific antibodies, which bind two different HER-epitopes or bring T cells closer to tumor cells. Furthermore, novel antibody-drug conjugates and small molecules against HER2 are discussed. These developments coupled with new combination strategies (eg, with CDK4/6 inhibitors or immunotherapy) will change the treatment landscape for patients with HER2-positive MBC very soon and will hopefully further improve clinical outcomes.
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http://dx.doi.org/10.2147/CMAR.S235121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602897PMC
October 2020

Hospitalizations and Clinical Outcome in Metastatic Colorectal Cancer During Regorafenib or TAS-102 Therapy.

Cancers (Basel) 2020 Sep 30;12(10). Epub 2020 Sep 30.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Center for Clinical Cancer and Immunology Trials (CCCIT), Paracelsus Medical University, 5020 Salzburg, Austria.

Current National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO) guidelines recommend regorafenib or trifluridine/tipiracil (TAS-102) for the third-line therapy of metastatic colorectal cancer (mCRC). In this analysis, we evaluated hospitalizations during regorafenib or TAS-102 treatment and the impact of hospitalizations on overall survival (OS). This retrospective analysis was based on unselected, consecutive mCRC patients treated with regorafenib and/or TAS-102 at the tertiary cancer centers in Salzburg and Wels-Grieskirchen, Austria. Between January 2013 and May 2019, 93 patients started third- or fourth-line therapy with regorafenib or TAS-102. Tumor therapy (regorafenib versus TAS-102, HR: 1.95 [95% CI: 1.07-3.54], = 0.03) and the Eastern Cooperative Oncology Group (ECOG) performance status (2-3 versus 0-1, HR: 4.04 [95% CI: 2.11-7.71], < 0.001) showed a statistically significant association with hospitalization risk in multivariate analysis. The corresponding hospitalization probability from initiation of third- or fourth-line was 30% with regorafenib versus 18% with TAS-102 at five weeks and 41% versus 28% at ten weeks, respectively. Hospitalizations irrespective of cause during regorafenib or TAS-102 therapy did neither impact median survival in patients undergoing only third-line therapy (never-hospitalized: 5.7 months [95% CI: 3.9-10.5] versus hospitalized: 5.4 months [95% CI: 2.8-9.6], = 0.45), nor in patients receiving third- and fourth-line therapy (12.2 months [95% CI: 10.6-28.8] versus 18.6 months [95% CI: 6.3-not reached], = 0.90). In conclusion, apart from poor ECOG performance status, regorafenib therapy was associated with an increased hospitalization probability during palliative systemic third- and fourth-line therapy in mCRC. However, hospitalizations during regorafenib or TAS-102 therapy did not impact OS beyond second-line therapy.
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http://dx.doi.org/10.3390/cancers12102812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599669PMC
September 2020

Adjuvant MUC vaccination with tecemotide after resection of colorectal liver metastases: a randomized, double-blind, placebo-controlled, multicenter AIO phase II trial (LICC).

Oncoimmunology 2020 08 23;9(1):1806680. Epub 2020 Aug 23.

Medical Department 1, Johannes Gutenberg University, Mainz, Germany.

Resection of colorectal liver metastases (CRLM) is a potential curative treatment for patients with metastatic colorectal cancer (mCRC) with liver-limited disease (LLD). Although long-term survival improved considerably within the last decades, high recurrence rates of 50-75% after resection remain a major challenge.Tecemotide (L-BLP25) is an antigen-specific cancer vaccine inducing immunity against mucin-1 (MUC1). The LICC trial aimed to improve survival in patients with mCRC after R0/R1 resection of CRLM. LICC was a binational, randomized, double-blind, placebo-controlled, multicenter phase 2 study including patients with R0/R1 resected CRLM without evidence of metastatic disease outside the liver. Co-primary endpoints were recurrence-free survival (RFS) and 3-year overall survival (OS) rate, secondary endpoints were RFS and OS in subgroups with different MUC1 expression and safety. In total, 121 patients were 2:1 randomized between Oct 2011 and Dec 2014to receive tecemotide (N=79) or placebo (N=42). Baseline characteristics were well balanced. Median RFS was 6.1 months (95% CI 4.5-8.9) and 11.4 months (95% CI 3.7-21.2) ( = .1754), 3-year OS rate 69.1% and 79.1%, median OS 62.8 months and not reached in the tecemotide vs. placebo arm ( = .2141), respectively. Cox regression models revealed no dependence of RFS or OS on MUC1 expression. The most common tecemotide-related grade 3/4 adverse events were diarrhea, injection site reaction, intestinal perforation, peritonitis and tinnitus (1.3% each). The LICC trial failed to meet its primary endpoints of significantly improving RFS and OS with tecemotide. However, both arms showed unexpectedly long OS. MUC1 expression was not associated with outcome.EudraCT No: 2011-000218-20Clinical Trial Information: NCT01462513Financial Support: Merck KGaA, Darmstadt, Germany.

Abbreviations: AE: adverse event; CP: cyclophosphamide; CRC: colorectal cancer; CT: computed tomography; ECOG: Eastern Cooperative Oncology Group; FU: follow-up; HR: hazard ratio; IHC: immunohistochemical staining; ITT: intention-to-treat; DSMB: Data Safety Monitoring Board; LLD: liver-limited disease; mCRC: metastatic colorectal cancer; MPLA: monophosphoryl lipid; AMRI: magnetic resonance imaging; MUC1: mucin 1; NA: not applicable; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; NS: normal saline; NSCLC: non-small-cell lung carcinoma; OS: overall surviva; lPP: per protocol; RAS: Rat sarcoma; RFS: recurrence-free survival; TEAE: treatment-emergent adverse event; UICC: Union for International Cancer Control; US: ultrasound; vs.: versus.
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http://dx.doi.org/10.1080/2162402X.2020.1806680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458621PMC
August 2020

Impact of PD-L1 Scores and Changes on Clinical Outcome in Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiotherapy.

J Clin Med 2020 Aug 27;9(9). Epub 2020 Aug 27.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, Austria.

Reports on the prognostic role of programmed death-ligand 1 (PD-L1) expression in rectal cancer are controversial. We investigated expression patterns and changes of PD-L1 in rectal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Seventy-two patients diagnosed with rectal cancer and/or treated with fluorouracil-based neoadjuvant CRT at the Department of Internal Medicine III of the Paracelsus Medical University Salzburg (Austria) between January 2003 and October 2012 were included. PD-L1 scoring was performed according to the tumor proportion score (TPS), combined positive score (CPS), and immune cell score (IC). PD-L1 TPS prior to neoadjuvant CRT had a statistically significant impact on survival (median: ≤1%: 95.4 months (95% CI: 51.8-not reached) vs. >1%: not reached, = 0.03, log-rank). Patients with a PD-L1 TPS ≤1% prior to and after CRT showed an inferior survival compared to all other patients (median: 56.7 months (95% CI: 51.4-not reached) vs. not reached, = 0.005, log-rank). In multivariate analysis, PD-L1 TPS prior to neoadjuvant CRT (>1% vs. ≤1%, hazard ratio: 0.29 (95% CI: 0.11-0.76), = 0.01) remained independently associated with survival. In conclusion, low PD-L1 TPS was associated with inferior survival in rectal cancer patients undergoing neoadjuvant CRT. A prospective validation of the prognostic value of PD-L1 expression in rectal cancer patients within a clinical trial is necessitated.
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http://dx.doi.org/10.3390/jcm9092775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563312PMC
August 2020

Dabrafenib plus trametinib in patients with BRAF-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial.

Lancet Oncol 2020 09 17;21(9):1234-1243. Epub 2020 Aug 17.

Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA.

Background: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAF-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAF-mutated biliary tract cancer.

Methods: This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAF-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAF-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting.

Findings: Between March 12, 2014, and July 18, 2018, 43 patients with BRAF-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6-15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36-67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31-62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported.

Interpretation: Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAF-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAF mutations should be considered in patients with biliary tract cancer.

Funding: GlaxoSmithKline and Novartis.
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http://dx.doi.org/10.1016/S1470-2045(20)30321-1DOI Listing
September 2020

A phase 1 study to evaluate the feasibility and efficacy of the addition of ropeginterferon alpha-2b to imatinib treatment in patients with chronic phase chronic myeloid leukemia (CML) not achieving a deep molecular response (molecular remission 4.5)-AGMT_CML 1.

Hematol Oncol 2020 Dec 19;38(5):792-798. Epub 2020 Aug 19.

Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria.

The goal of current management of patients with chronic phase chronic myeloid leukemia (CML) is to reach treatment-free remission with sustained deep molecular remission (DMR) being the prerequisite therefor. Second-generation tyrosine kinase inhibitors can induce deeper and faster remission than imatinib, but are often associated with severe adverse events (AEs). The combination of pegylated interferon (IFN) with imatinib was shown to induce higher molecular remissions than imatinib alone in two studies. Treatment discontinuation rates due to IFN induced AEs were high in both studies. To investigate safety, tolerability (primary objective), and efficacy (secondary objective) of the combination of imatinib with ropeginterferon alpha-2b this phase I study was initiated. Twelve patients were planned to be enrolled. Nine patients completed the study according to protocol. Three patients terminated the study early, one due to occurrence of a dose-limiting toxicity (neutropenia grade 3), one due to an AE (panic attacks grade 2) and one due to the patient's decision. Tolerability was good, non-hematologic AEs were mainly grade 1/2, hematologic AEs were mainly neutropenias. No new AEs were reported for the combination of imatinib and ropeginterferon alpha-2b. In a nondose-dependent manner the addition of ropeginterferon alpha-2b led to the achievement of a DMR in four out of nine patients after a treatment duration of 18 months. The combination of imatinib and ropeginterferon alpha-2b is safe and showed in this phase I study the ability to deepen the molecular response in patients with chronic phase CML not achieving a DMR with imatinib alone.
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http://dx.doi.org/10.1002/hon.2786DOI Listing
December 2020