Search

Introduction: The CLL2-BCG trial is a prospective, open-label, multicenter phase-II study based on the "sequential triple-T" (tailored, targeted, total eradication of CLL) concept proposed earlier [Hallek M., Blood 2013; 122(23): 3723-34]. This concept consists of sequentially applied combinations of targeted agents and aims for achieving undetectable minimal residual disease (MRD). It uses a sequential application of bendamustine (Ben) for debulking, followed by obinutuzumab (Obi) plus idelalisib (Ide) as induction and maintenance therapy for an all-comer population of physically fit and unfit, treatment-naïve (t-n) and relapsed/refractory (r/r) CLL patients (pts) irrespective of high-risk genetic markers. Methods: Pts with an absolute lymphocyte count ≥ 25.000/µl and/or lymph nodes ≥ 5 cm were to receive 2 cycles of Ben as debulking (70 mg/m² d1&2 q28 d), unless contraindicated. In the induction phase Obi 1000 mg was administered on d 1, 8 and 15 of cycle 1 and d1 of cycles 2-6; Ide was added in cycle 2 (150 mg twice daily). In the maintenance phase, daily dosing of Ide was continued and Obi was administered every 3 months until achieving a MRD-negative complete response or for up to 24 months. The primary endpoint was the overall response rate (ORR) at the end of induction therapy, secondary endpoints included MRD assessment, safety and survival. Due to an increased incidence of opportunistic infections in other Ide trials, amendment 2 in March 2016 limited the recruitment to r/r CLL pts with high-risk features such as presence of a deletion 17p/TP53 mutation and/or ineligibility for ibrutinib treatment (refractoriness, intolerance or contraindications). Slow enrolment led to recruitment stop in September 2019. Results: Between May 2015 and September 2019, 48 pts were enrolled. Sixteen pts were t-n and 32 had r/r CLL with a median of 2 prior lines (range: 1-10); most common were BR and FCR, 6 pts each had received ibrutinib and venetoclax containing therapies. Median age was 66 (range 41-83) years, median CIRS score was 2 (0-13). Twenty-three pts (48%) were defined unfit by a CIRS score >6 (7 pts) and/or an impaired renal function with a Creatinine Clearance Thirty-eight patients (79%, 16 t-n and 22r/r) received Ben debulking. However, 8 pts never started the induction phase due to protocol amendment 2. Forty pts (10 t-n, 30 r/r) received induction treatment (FAS [full analysis set]), 33 completed the full 6 cycles (PP [per protocol] collective). Twenty-seven (7 t-n, 20 r/r) continued in a maintenance phase. At the end of induction, 32 of 40 pts (FAS) and 28 of 33 pts with 6 induction cycles (PP) responded (ORR 80% and 85%, respectively); undetectable MRD levels ( As of June 8th 2020, 603 adverse events (AEs) were reported in the entire cohort; 313 (52%) were related to study drug and 127 (21%) were serious adverse events. 286 (47%) occurred in the induction treatment (see table 1). Of these, 69 (24%) were CTC grade 3 and 18 (6%) CTC grade 4, 4 had a fatal outcome. Most common AEs in the induction were infusion-related reactions, neutropenia, thrombocytopenia, anemia, nasopharyngitis, headache, and fatigue [Table 2]. Summary/Conclusion: Sequential treatment with Ben debulking, followed by Obi and Ide induction and maintenance achieved responses and even undetectable MRD levels in CLL patients with high-risk disease and extensive prior therapy. However, the study also confirmed the known toxicities of Ide. In light of the current, alternative therapeutic options, the BCG regimen reported here should be used with caution, but represents an alternative treatment option if ibrutinib and venetoclax have failed. Disclosures Cramer: Gilead: Other: travel support, Research Funding; F. Hoffmann-LaRoche: Honoraria, Other: travel support, Research Funding; Acerta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Beigene: Research Funding; AbbVie: Honoraria, Other: travel support; Novartis: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding. Von Tresckow:Celgene: Other: travel grants; AbbVie: Honoraria; Janssen-Cilag: Honoraria, Other: travel grants, Research Funding; F. Hoffmann-LaRoche: Honoraria, Other: travel grants, Research Funding. Fink:AbbVie: Other: travel grants; Janssen: Honoraria; Celgene: Research Funding. Tausch:Janssen-Cilag: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Knauf:Janssen-Cilag: Honoraria; AbbVie: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Mundipharma: Honoraria. Al-Sawaf:BeiGene: Research Funding; AbbVie: Consultancy, Honoraria, Other: personal fees, Research Funding; Roche: Consultancy, Honoraria, Other: personal fees, Research Funding; Gilead: Consultancy, Honoraria, Other: personal fees; Janssen: Consultancy, Honoraria, Other: personal fees, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: personal fees. Langerbeins:AbbVie: Honoraria, Other: travel grants, Research Funding; F. Hoffmann-LaRoche: Honoraria, Other: travel grants, Research Funding; Janssen-Cilag: Honoraria, Other: travel grants, Research Funding; Mundipharma: Honoraria, Other: travel grants, Research Funding. Fischer:F. Hoffmann-La Roche: Honoraria, Other: travel grants; AbbVie: Honoraria. Kreuzer:Hoffmann-La Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Ritgen:Gilead: Other: travel grants; BMS: Consultancy, Honoraria, Other: travel grants; F. Hoffman-La Roche: Consultancy, Honoraria, Other: travel grants, Research Funding; Pfizer: Consultancy, Honoraria. Kneba:AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding. Wendtner:Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding. Stilgenbauer:Pharmacyclics: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Honoraria, Other, Research Funding; Mundipharma: Consultancy, Honoraria, Other, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genzyme: Consultancy, Honoraria, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding. Eichhorst:Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding. Hallek:F. Hoffmann-LaRoche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.

Fifty-one of 189 evaluable patients from 3 prospective phase 2 trials evaluating a sequential targeted treatment had high-risk chronic lymphocytic leukemia (CLL) with a 17p deletion, TP53 mutation, or both. Twenty-seven patients started treatment with bendamustine debulking before induction and maintenance treatment, which was ibrutinib/ofatumumab (IO) in 21 patients, ibrutinib/obinutuzumab (IG) in 13, and venetoclax/obinutuzumab (AG) in 17. The primary end point was overall response rate after 8 months of induction treatment, which was 81%, 100%, and 94% for IO, IG, and AG, respectively. Minimal residual disease (MRD) was undetectable (uMRD) in peripheral blood (

Autonomous migration is a central characteristic of immune cells, and changes in this function have been correlated to the progression and severity of diseases. Hence, the identification of pathologically altered leukocyte migration patterns might be a promising approach for disease surveillance and prognostic scoring. However, because of the lack of standardized and robust assays, migration patterns have not been clinically exploited so far. In this study, we introduce an easy-to-use and cross-laboratory, standardized two-dimensional migration assay for neutrophil granulocytes from peripheral blood. By combining time-lapse video microscopy and automated cell tracking, we calculated the average migration of neutrophils from 111 individual participants of the German Heinz Nixdorf Recall MultiGeneration study under steady-state, formyl-methionyl-leucyl-phenylalanine–, CXCL1-, and CXCL8-stimulated conditions. Comparable values were obtained in an independent laboratory from a cohort in Belgium, demonstrating the robustness and transferability of the assay. In a double-blinded retrospective clinical analysis, we found that neutrophil migration strongly correlated with the Revised International Prognostic Scoring System scoring and risk category of myelodysplastic syndrome (MDS) patients. In fact, patients suffering from high-risk subtypes MDS with excess blasts I or II displayed highly significantly reduced neutrophil migration. Hence, the determination of neutrophil migration patterns might represent a useful tool in the surveillance of MDS. Taken together, we suggest that standardized migration assays of neutrophils and other leukocyte subtypes might be broadly applicable as prognostic and surveillance tools for MDS and potentially for other diseases.

Vaccination is one of the most useful preventive interventions in healthcare. The purpose of our study was to gain overview of the opinions, knowledge, and engagement in vaccination practices among medical students (MS) and junior doctors (JD) in Europe. The survey was distributed from March 2016 until August 2016 via the e-mail and social media of the European Medical Students’ Association. In total, 1821 responses from MS and JD from 34 countries in the European region were analysed. The majority of respondents agreed that vaccines are useful (98.7%) and effective (97.2%). Although the necessity of revaccination was supported by 99.2%, only 68.0% of the respondents went through with it. Even though the potential benefit of the flu vaccination seems to be acknowledged by our participants, only 22.1% of MS and JD declared getting the flu shot every or every other season. MS and JD were in favour of specific mandatory vaccination for medical staff (86.0%) and medical students (82.7%). Furthermore, we analysed the self-reported vaccination coverage of our participants regarding 19 vaccines. Of the respondents, 89.5% claimed to provide advice about vaccination to their friends and family. In conclusion, European MS and JD have a very positive attitude towards vaccination. However, their behaviour and knowledge demonstrate certain gaps which should be further addressed in medical education.

We determined the 10-year progression rate of light chain monoclonal gammopathy of undetermined significance (LCMGUS) and investigated potential associations with cancer utilizing the German population-based Heinz Nixdorf Recall Study. The Heinz Nixdorf Recall Study comprises 4814 men and women aged 45–75 years. Serum samples from baseline (2000–2003) and five-year (2006–2008) and 10-year (2011–2015) follow-up examinations were screened for monoclonal free light chains (FLC). LCMGUS was defined as abnormal FLC ratio, increase of involved FLC with complete loss of immunoglobulin heavy chain, and absence of a history of lymphoproliferative disease (LPD). Seventy-five individuals with LCMGUS were identified across all three evaluation time points (median age 64 years; 43 (57%) male; FLCR > 1.65 65 (87%); FLCR ≤ 0.65 10 (13%)). After a median observation time of 11.5 years, none of the LCMGUS cases had progressed to overt LPD; in particular, we did not observe incident light chain multiple myeloma. On serial analysis 17/31 (55%), LCMGUS could not be confirmed and disappearance of the monoclonal protein was associated with low concentrations of the involved FLC. Individuals with LCMGUS had a 1.5-fold increased risk of cancer but did not show differences in overall survival or renal function as compared to individuals with normal FLC. In conclusion, LCMGUS represents a relatively benign condition with a high disappearance rate of the monoclonal protein on longitudinal analysis and normal overall survival at least in the population-based setting.