Abstract: Background Venetoclax (VEN)-based combination therapy with hypomethylating agents (HMA) has been approved for first-line treatment in patients ineligible for intensive treatment based on two randomized trials. There is some evidence for efficacy also in the in relapsed/ refractory setting (R/R), but comparative controlled data is lacking. Here, we report our experience of VEN-Azacitidine (AZA) in R/R AML salvage treatment and bridge to allogeneic cell transplantation (allo-HCT) in fit patients compared to historical data from the Study Alliance Leukemia (SAL) registry (ClinicalTrials.gov Identifier: NCT03188874). Design/Methods We analyzed all patients with R/R AML after initial intensive therapy, who started VEN-AZA salvage treatment at the University Hospital Heidelberg, between October 2018 and October 2020. Patients, who were bridged to allo-HCT were compared in a multivariable analysis to data of R/R AML patients from the SAL registry receiving an allo-HCT. Results: A total of 26 patients (median age 60 years, range 23 to 79) were included. All patients initially received intensive therapy, 16 patients (62%) had been refractory to intensive induction therapy with DA (daunorubicin, cytarabine) (11 patients)/ CPX-351 (2 patients) or to an intensive salvage therapy regime with HAM (2 patients)/ Cytarabin-Bortezomib (1 patient). Ten patients (38%) had morphologic (7 patients) or molecular relapse (3 patients) after intensive first line therapy. The distribution of AML according to WHO-2016 classification was n=10 recurrent genetic abnormalities (n= 7, mutated NPM1; n=1, biallelic CEBPA mutations; n=1, mutated RUNX1; n=1, CBFB-MYH11), n=10 AML with MRC, n=6 AML NOS. According to the 2017 ELN classification, 9 patients (34,5%) had low risk, 8 (31%) intermediate risk and 9 (34,5%) adverse risk disease. All patients received AZA 75mg/m² for 7 days combined with VEN 400mg/day after initial ramp up or a reduced dose of 100mg/day in case of co-medication with azoles in 28 days cycles. Best response was CR/CRi in 58% (n=15), PR in 23% (n=6) patients. Day 30-mortality was 0%, day 60-mortality was 4% (n=1). Allo-HCT was performed in 20 patients (77%). Pre-Allo-HCT remission status was CR/CRi in 11 (55%), PR in 4 (20%) patients and MLFS in 1 patient and 4 patients had active disease (n=3, relapse after achieving CR/CRi on VEN-AZA, n=1 refractory to VEN-AZA.). At the time of analysis 15 (75%) of the 20 bridged patients were alive and 11 (55%) are still in CR resulting in a median relapse-free survival in bridged patients of 406 days, whereas all patients not proceeding to allo-HCT died after a median of 139 days. In total, 63 patients with R/R AML were identified in the SAL-registry proceeding to allo-HCT with non VEN-based salvage attempt. Pre-Allo-HCT remission status was CR/CRi in 18 (28%), PR in 15 (24%), unknown in 13 patients (21%) and 17 (27%) patients had active disease (n=9 relapsed, n=8 refractory). Patients of the SAL registry were younger (median, 55 years; range, 22-75 years) and more patients were ELN-int (low risk, 32%, n=20; int, 52%, n=33, adv, 16%, n=10). Median follow-up in the VEN-AZA and the SAL cohorts were 1.4 years and 4.6 years, respectively. Cox-regression modeling of survival measured from the date of being refractory/relapsed revealed a non-significant effect of the cohorts favoring the VEN-AZA salvage therapy (HR, 0.87, p=0.73). However, stratified univariable survival analysis revealed in trend better survival (p=0.10) in the VEN-AZA compared to the SAL cohort with 77% (95%-CI, 62-95%) and 74% (95%-CI, 57-97%) as well as 84% (95%-CI, 76-94%) and 52% (95-CI, 41-68%) 1- and 2-years survival, respectively. Conclusion: Our data confirms the efficacy of VEN-AZA in patients with R/R AML and underlines its potential as an effective strategy for bridging to successful allo-HCT. Disclosures Unglaub: JazzPharma: Consultancy, Other: travel costs/ conference fee; Novartis: Consultancy, Other: travel costs/ conference fee. Schlenk: Boehringer Ingelheim: Research Funding; AstraZeneca: Research Funding; Roche: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria; Neovio Biotech: Honoraria; Hexal: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Celgene: Honoraria; Astellas: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria; Agios: Honoraria. Middeke: Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy; Abbvie: Consultancy, Honoraria; Jazz: Consultancy; Pfizer: Consultancy, Honoraria; Sanofi: Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Novartis: Consultancy; Glycostem: Consultancy; UCB: Honoraria. Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Haenel: GSK: Consultancy; Jazz: Consultancy, Honoraria; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Crysandt: Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria. Fransecky: Medac: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Seggewiss-Bernhardt: Astra-Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; ipsen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; EusaPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Platzbecker: AbbVie: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Geron: Honoraria; Takeda: Honoraria. Baldus: Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Novartis: Honoraria. Dreger: Bluebird Bio: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; BMS: Consultancy; AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Müller-Tidow: Pfizer: Research Funding; Janssen: Consultancy, Research Funding; Bioline: Research Funding. Sauer: Takeda: Consultancy, Other: DSMB/SAB Member; Matterhorn Biosciences AG: Consultancy, Other: DSMB/SAB Member; Abbvie: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. OffLabel Disclosure: off-label use of Venetoclax-based combination therapy in relapsed or refractory AML

Abstract: Die Digitalisierung findet längst auch im Gesundheitswesen und mithin in seiner herausragenden Subinstitution, dem Krankenhaus, statt. Konkrete Digitalisierungsprojekte sind dabei häufig von Mehrdeutigkeiten und Widerständen begleitet, die auf die komplexen soziotechnischen Herstellungszusammenhänge verweisen, in denen sie realisiert werden. Dieser Artikel arbeitet anhand einer empirischen Fallstudie die Ge- bzw. Misslingensbedingungen für die Integration multipler Interessen in eine digitale Überwachungsplattform heraus und geht den strukturellen Effekten des Entwicklungsprozesses für das beteiligte Universitätskrankenhaus nach. Dabei zeigt sich: Erwartungs-, Deutungs- und Konstellationsstrukturen der organisierten Krankenbehandlung können insbesondere dann verändert werden, wenn auch die mehrdimensionale Kontrolle der ökonomischen Übersetzung, die Herstellung zeitlicher Kohärenz und die Kongruenz von digitaltechnischer und sozialer Konstellationsstruktur gelingen. Diese Momente situativer Schließung lassen sich ausgehend von den empirischen Übersetzungen einer digitalen Plattform rekonstruieren und als Bedingung der Möglichkeit für strukturelle Effekte aus dem Plattformentwicklungsprozess behandeln.

Abstract: BCL-2 inhibition has been shown to be effective in acute myeloid leukemia (AML) in combination with hypomethylating agents or low-dose cytarabine. However, resistance and relapse represent major clinical challenges. Therefore, there is an unmet need to overcome resistance to current venetoclax-based strategies. We performed high-throughput drug screening to identify effective combination partners for venetoclax in AML. Overall, 64 antileukemic drugs were screened in 31 primary high-risk AML samples with or without venetoclax. Gilteritinib exhibited the highest synergy with venetoclax in FLT3 wild-type AML. The combination of gilteritinib and venetoclax increased apoptosis, reduced viability, and was active in venetoclax-azacitidine–resistant cell lines and primary patient samples. Proteomics revealed increased FLT3 wild-type signaling in specimens with low in vitro response to the currently used venetoclax-azacitidine combination. Mechanistically, venetoclax with gilteritinib decreased phosphorylation of ERK and GSK3B via combined AXL and FLT3 inhibition with subsequent suppression of the antiapoptotic protein MCL-1. MCL-1 downregulation was associated with increased MCL-1 phosphorylation of serine 159, decreased phosphorylation of threonine 161, and proteasomal degradation. Gilteritinib and venetoclax were active in an FLT3 wild-type AML patient-derived xenograft model with TP53 mutation and reduced leukemic burden in 4 patients with FLT3 wild-type AML receiving venetoclax-gilteritinib off label after developing refractory disease under venetoclax-azacitidine. In summary, our results suggest that combined inhibition of FLT3/AXL potentiates venetoclax response in FLT3 wild-type AML by inducing MCL-1 degradation. Therefore, the venetoclax-gilteritinib combination merits testing as a potentially active regimen in patients with high-risk FLT3 wild-type AML.

Abstract: Patients with hematological malignancy or other cancers as well as immunosuppression bear a high risk for severe COVID-19. Monoclonal antibodies (mAb) are efficient at early stages of the disease but may lose potency with new variants. Trials on plasma from convalescent donors in unselected patients have not shown clinical benefit. No randomized trials focussing on patients with underlying disease have been published. Methods We conducted an open-label, multicenter, randomized controlled trial to evaluate efficacy of plasma (CVP - convalescent or after vaccination) in patients with COVID-19 at high risk for adverse outcome in Germany. We assessed the effect of high-titer CVP (2 units from different donors, 238-337 ml each, on subsequent days). Patients with hematological or other malignancy (group 1), immunosuppression (group 2), age & gt;50 and ≤75 years and lymphopenia and/or high D-dimers (group 3) or age & gt;75 years (group 4) who were hospitalized with confirmed SARS-CoV-2 infection and with an oxygen saturation ≤94% were included. Primary outcome measure was time to clinical improvement on a seven-point ordinal scale, secondary outcome was mortality (Janssen et al. Trials 2020 Oct 6;21(1):828). Results Overall, 133 patients were randomized, 68 received CVP with an additional 10 patients as a crossover on day 10. Median age (range) was 68 years (39-95) in the CVP group and 70 (38-90) in controls. For the entire cohort, no significant difference was seen in time to improvement (median days: CVP 12.5 vs. control 18; HR 1.24 (95% confidence interval (CI) 0.83-1.85), p=0.29). Subgroup analysis (group 1+2) revealed shortened time to improvement (median days CVP 13 vs. control 32; HR 2.03 (95%CI 1.17-3.6), p=0.01) and mortality was reduced (mortality CVP n=6 (18%) vs. control n=10 (29%). No significant differences in time to improvement were observed in group 3 or 4 (HR 0.72 (95%CI 0.41-1.28), p=0.26). No relevant adverse events were observed. Conclusion CVP improves time to clinical improvement and mortality for COVID-19 patients with underlying hematological disease/cancer or other reasons of impaired immune response. Even with new variants, high-titer CVP may offer a widely available and inexpensive therapy option in high-risk groups. Funding BMBF FKZ 01KI20152; EudraCT 2020-001632-10. Disclosures Uta Merle, MD, Gilead: Sponsored congress travel and accommodation Markus Weigand, MD, Bbraun: Speakers fee/ad boards fee|Biotest: Speakers fee/ad boards fee|Eumedica: Speakers fee/ad boards fee|Gilead: Speakers fee/ad boards fee|MSD: Speakers fee/ad boards fee|Pfizer: Speakers fee/ad boards fee|Shionogi: Speakers fee/ad boards fee|SOBI: Speakers fee/ad boards fee Martin Bornhäuser, MD, Alexion: Honoraria|Jazz Pharmaceuticals: Honoraria|MSD: Honoraria|Novartis: Honoraria Nael Alakel, MD, Amgen: personal fee, travel grant|Gilead: personal fee, travel grant|MSD Sharp and Dohme GmbH: personal fee, travel grant|Pfizer: personal fee, travel grant Timo Wolf, MD, Gilead Sciences: Lecture fee, travel grant|Janssen Pharmaceuticals: Lecture fee, travel grant|Merck Sharp Dome: Lecture fee, travel grant Maria Vehreschild, Prof. Dr., 3M: speaker fee|Astellas: Advisor/Consultant|Astellas: speaker fee|biologische heilmittel heel gmbh: Grant/Research Support|BioNtech: Grant/Research Support|EUMEDICA: Advisor/Consultant|Farmak International Holding: Advisor/Consultant|Ferring: Advisor/Consultant|Ferring: Speaker fee|Gilead Sciences: Advisor/Consultant|Immunic AG: Advisor/Consultant|MaaT: Advisor/Consultant|Merck: Advisor/Consultant|Merck: speaker fee|MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: speaker fees|Pfizer: speaker fee|Roche Molecular Systems: Grant/Research Support|Roche Molecular Systems: speaker fees|SocraRTec R & D GmbH: Advisor/Consultant|Takeda California: Grant/Research Support Hanns-Martin Lorenz, MD, Abbvie: Advisor/Consultant|Abbvie: Honoraria|Actelion: Advisor/Consultant|Actelion: Honoraria|Alexion: Advisor/Consultant|Alexion: Honoraria|Amgen: Advisor/Consultant|Amgen: Grant/Research Support|Astra Zeneca: Advisor/Consultant|Astra Zeneca: Honoraria|Baxter: Advisor/Consultant|Baxter: Advisor/Consultant|Baxter: Honoraria|Baxter: Honoraria|Bayer Vital: Advisor/Consultant|Bayer Vital: Honoraria|Biogen: Advisor/Consultant|Biogen: Honoraria|BMS: Advisor/Consultant|BMS: Honoraria|Boehringer Ingelheim: Advisor/Consultant|Boehringer Ingelheim: Honoraria|Celgene: Advisor/Consultant|Celgene: Honoraria|Fresenius: Advisor/Consultant|Fresenius: Honoraria|Genzyme: Advisor/Consultant|Genzyme: Honoraria|Gilead/Galapagos: Advisor/Consultant|Gilead/Galapagos: Honoraria|GSK: Advisor/Consultant|GSK: Honoraria|Hexal: Advisor/Consultant|Hexal: Honoraria|Janssen-Cilag: Advisor/Consultant|Janssen-Cilag: Honoraria|Lilly: Advisor/Consultant|Lilly: Honoraria|Medac: Advisor/Consultant|Medac: Honoraria|MSD: Advisor/Consultant|MSD: Honoraria|Mundipharm: Advisor/Consultant|Mundipharm: Honoraria|Mylan: Advisor/Consultant|Mylan: Honoraria|Novartis: Advisor/Consultant|Novartis: Honoraria|octapharm: Advisor/Consultant|octapharm: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Roche/Chugai: Advisor/Consultant|Roche/Chugai: Honoraria|Sandoz: Advisor/Consultant|Sandoz: Honoraria|Sanofi: Advisor/Consultant|Sanofi: Honoraria|Shire: Advisor/Consultant|Shire: Honoraria|SOBI: Advisor/Consultant|SOBI: Honoraria|Thermo Fisher: Advisor/Consultant|Thermo Fisher: Honoraria|UCB: Advisor/Consultant|UCB: Honoraria.

Abstract: The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional, and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined the therapy outcome. LSCs of 5-AZA/VEN-refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based “Mediators of apoptosis combinatorial score” (MAC-Score) linking the ratio of protein expression of BCL2, BCL-xL, and MCL1 in LSCs. MAC scoring predicts initial response with a positive predictive value of more than 97% associated with increased event-free survival. In summary, combinatorial levels of BCL2 family members in AML-LSCs are a key denominator of response, and MAC scoring reliably predicts patient response to 5-AZA/VEN. Significance: Venetoclax/azacitidine treatment has become an alternative to standard chemotherapy for patients with AML. However, prediction of response to treatment is hampered by the lack of clinically useful biomarkers. Here, we present easy-to-implement MAC scoring in LSCs as a novel strategy to predict treatment response and facilitate clinical decision-making. This article is highlighted in the In This Issue feature, p. 1275

Abstract: Although we know that HRM practices can have a huge impact on employees’ innovative work behaviour (IWB), we do not know exactly which practices make the difference and how they affect IWB. Thus, the purpose of this paper is to determine the best HRM practices for boosting IWB, to understand the theoretical reasons for this, and to discover mediators and moderators in the relationship between HRM practices and IWB. Design/methodology/approach Based on a systematic review of the literature, the authors carried out a content analysis on 27 peer-reviewed journal articles. Findings Working with the definitions and items provided in the articles, the authors were able to cluster HRM practices according to the ability-motivation-opportunity framework. The best HRM practices for enhancing IWB are training and development, reward, job security, autonomy, task composition, job demand, and feedback. Practical implications The results of this study provide practical information for HRM professionals aiming to develop an HRM system that generates innovative employee behaviours that might help build an innovative climate. Originality/value A framework is presented that aggregates the findings and clarifies which HRM practices influence IWB and how these relationships can be explained.