Abstract: Purpose: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and key epigenetic regulator involved in transcriptional repression and embryonic development. Loss of EZH2 activity by inactivating mutations is associated with poor prognosis in myeloid malignancies such as MDS. More recently, EZH2 inactivation was shown to induce chemoresistance in acute myeloid leukemia (AML) (Göllner et al., 2017). Data on the frequency and prognostic role of EZH2-mutations in AML are rare and mostly confined to smaller cohorts. To investigate the prevalence and prognostic impact of this alteration in more detail, we analyzed a large cohort of AML patients (n = 1604) for EZH2 mutations. Patients and Methods: All patients analyzed had newly diagnosed AML, were registered in clinical protocols of the Study Alliance Leukemia (SAL) (AML96, AML2003 or AML60+, SORAML) and had available material at diagnosis. Screening for EZH2 mutations and associated alterations was done using Next-Generation Sequencing (NGS) (TruSight Myeloid Sequencing Panel, Illumina) on an Illumina MiSeq-system using bone marrow or peripheral blood. Detection was conducted with a defined cut-off of 5% variant allele frequency (VAF). All samples below the predefined threshold were classified as EZH2 wild type (wt). Patient clinical characteristics and co-mutations were analyzed according to the mutational status. Furthermore, multivariate analysis was used to identify the impact of EZH2 mutations on outcome. Results: EZH2-mutations were found in 63 of 1604 (4%) patients, with a median VAF of 44% (range 6-97%; median coverage 3077x). Mutations were detected within several exons (2-6; 8-12; 14-20) with highest frequencies in exons 17 and 18 (29%). The majority of detected mutations (71% missense and 29% nonsense/frameshift) were single nucleotide variants (SNVs) (87%), followed by small indel mutations. Descriptive statistics of clinical parameters and associated co-mutations revealed significant differences between EZH2-mut and -wt patients. At diagnosis, patients with EZH2 mutations were significantly older (median age 59 yrs) than EZH2-wt patients (median 56 yrs; p=0.044). In addition, significantly fewer EZH2-mut patients (71%) were diagnosed with de novo AML compared to EZH2-wt patients (84%; p=0.036). Accordingly, EZH2-mut patients had a higher rate of secondary acute myeloid leukemia (sAML) (21%), evolving from prior MDS or after prior chemotherapy (tAML) (8%; p=0.036). Also, bone marrow (and blood) blast counts differed between the two groups (EZH2-mut patients had significantly lower BM and PB blast counts; p=0.013). In contrast, no differences were observed for WBC counts, karyotype, ECOG performance status and ELN-2017 risk category compared to EZH2-wt patients. Based on cytogenetics according to the 2017 ELN criteria, 35% of EZH2-mut patients were categorized with favorable risk, 28% had intermediate and 37% adverse risk. No association was seen with -7/7q-. In the group of EZH2-mut AML patients, significantly higher rates of co-mutations were detected in RUNX1 (25%), ASXL1 (22%) and NRAS (25%) compared to EZH2-wt patients (with 10%; 8% and 15%, respectively). Vice versa, concomitant mutations in NPM1 were (non-significantly) more common in EZH2-wt patients (33%) vs EZH2-mut patients (21%). For other frequently mutated genes in AML there was no major difference between EZH2-mut and -wt patients, e.g. FLT3ITD (13%), FLT3TKD (10%) and CEBPA (24%), as well as genes encoding epigenetic modifiers, namely, DNMT3A (21%), IDH1/2 (11/14%), and TET2 (21%). The correlation of EZH2 mutational status with clinical outcomes showed no effect of EZH2 mutations on the rate of complete remission (CR), relapse free survival (RFS) and overall survival (OS) (with a median OS of 18.4 and 17.1 months for EZH2-mut and -wt patients, respectively) in the univariate analyses. Likewise, the multivariate analysis with clinical variable such as age, cytogenetics and WBC using Cox proportional hazard regression, revealed that EZH2 mutations were not an independent risk factor for OS or RFS. Conclusion EZH mutations are recurrent alterations in patients with AML. The association with certain clinical factors and typical mutations such as RUNX1 and ASXL1 points to the fact that these mutations are associated with secondary AML. Our data do not indicate that EZH2 mutations represent an independent prognostic factor. Disclosures Middeke: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Scholl:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbivie: Other: Travel support; Alexion: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding. Brümmendorf:Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Merck: Consultancy; Pfizer: Consultancy, Research Funding. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Eisai: Research Funding; Novartis: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

Abstract: Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas ( n  = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2 , NBN , and CHEK2 . A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.

Abstract: Most adult gastrointestinal stromal tumors (GIST) are driven by activating KIT or PDGFRA mutations. The remaining 10-15% of cases, often referred to as wildtype (WT) GIST, display either alterations of the succinate dehydrogenase complex (SDH) or RAS pathway mutations. To gain additional insight into the biology of GIST, we performed whole-exome or genome and RNA sequencing in 38 GIST patients (WT, n=15; KIT-mutant, n=21; PDGFRA-mutant, n=2) enrolled in a prospective molecular stratification trial of NCT Heidelberg/Dresden and the German Cancer Consortium (DKTK) designed for younger adults with advanced-stage cancer across histologies and patients with rare tumors (NCT/DKTK MASTER). Of the 15 patients with WT GIST, 3 had pathogenic germline mutations in NF1 and 9 harbored SDH alterations (germline, n=5; somatic, n=4). In the 3 patients with quadruple-negative GIST - defined by the absence of KIT, PDGFRA, SDH, or RAS pathway alterations - we detected novel gene fusions affecting RET, FGFR2, and FGF4, respectively. To delineate biologically relevant subgroups of GIST based on RNA sequencing data from the entire cohort (n=34), we used 3 different clustering methods and 4 different measures of stability and consistency. Despite the underlying clinical and molecular heterogeneity, we identified 3 distinct transcriptional subgroups that were characterized by (i) SDH deficiency, (ii) recurrent somatic RB1 alterations and mutational signatures associated with defective homologous recombination DNA repair, and (iii) elevated PDGFRA expression, respectively. Furthermore, we used random forest analysis to identifiy genes that are significantly (p & lt;0.005) differentially expressed between the 3 subgroups. Interestingly, quadruple-negative cases did not form a separate cluster or clustered within a specific subgroup. Collectively, our data illustrate the molecular heterogeneity of advanced-stage GIST and support comprehensive molecular profiling approaches to capture the entire spectrum of clinically actionable genetic alterations, such as diverse fusion genes affecting kinase signaling pathways in quadruple-negative cases or pathogenic germline mutations in patients with inconspicuous family histories. The finding of two separate transcriptional clusters among patients with SDH-proficient GIST may be reflective of distinct regulatory pathways whose molecular underpinnings and clinical actionability warrant further study. Citation Format: Peter Horak, Matea Hajnic, Laura Gieldon, Mario Hlevnjak, Susan Richter, Barbara Hutter, Johanna Falkenhorst, Sebastian Uhrig, Gregor Warsow, Nagarajan Paramasivam, Stefan Gröschel, Barbara Klink, Simon Kreutzfeldt, Christoph Heining, Christoph E. Heilig, Martina Fröhlich, Stephan Richter, Christian Brandts, Wilko Weichert, Philipp Jost, Olaf Neumann, Marc Zapatka, Albrecht Stenzinger, Alexander Marx, Benedikt Brors, Evelin Schröck, Sebastian Bauer, Peter Hohenberger, Hanno Glimm, Claudia Scholl, Stefan Fröhling. Comprehensive genomic and transcriptomic profiling of gastrointestinal stromal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1686.

Abstract: Co-senior authors Andrew Brunner and Andrew H. Wei contributed equally to this work Background: MBG453 is a high-affinity humanized anti-TIM-3 (T-cell immunoglobulin domain and mucin domain-3) IgG4 antibody in development for the treatment of MDS, AML, and other malignancies. TIM-3 is an immune checkpoint with a complex regulatory role in both adaptive and innate immune responses and is also preferentially expressed on leukemic stem and progenitor cells, making it a potential target in MDS and AML. MBG453 has been shown to enhance immune cell-mediated killing of AML cells in vitro. Hypomethylating agents (HMAs) have been shown to increase immune checkpoint expression in MDS and AML, providing rationale to study the combination of HMAs with MBG453. Methods: Patients with Revised International Prognostic Scoring System (IPSS-R) high or very high-risk (HR) MDS and newly diagnosed, or relapsed/refractory (R/R), AML following ≥ 1 prior therapy who were not candidates for standard chemotherapy and who were HMA naive were enrolled in this multi-center, open label phase Ib dose-escalation study (NCT03066648). Escalating doses of MBG453 were administered i.v. every 2 weeks (Q2W; days 8, 22) or every four weeks (Q4W; day 8) in combination with decitabine (20 mg/m2; i.v. days 1-5). The primary objectives were to characterize the safety and tolerability of MBG453 in combination with decitabine and to identify recommended doses for future studies. Secondary objectives included assessing preliminary efficacy and pharmacokinetics of the combination. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs). Adverse events (AEs) were graded using NCI-CTCAE v4.03. The International Working Group criteria for MDS (Cheson et al, 2006) or AML (Cheson et al, 2003) were used to assess efficacy. Results: As of March 25, 2019, 17 HR-MDS, 4 chronic myelomonocytic leukemia (CMML), and 38 AML patients have received decitabine and MBG453 at 240 mg Q2W (n=22), 400 mg Q2W (n=21), or 800 mg Q4W (n=16). MTD has not been reached. Median age was 70 years (range 23-87 years). 24 patients are ongoing (duration of exposure 1.1 to 18.6 months) with 35 patients discontinued (disease progression [n=19, 32%], AE [n=1, 2%] , patient/physician decision [n=13, 22%], death [n=2, 3%] ). There was one DLT consisting of a grade 3 ALT elevation that was corticosteroid responsive. The most common treatment emergent grade 3/4 AEs were febrile neutropenia (39%), neutropenia (34%), thrombocytopenia (31%), and anemia (29%). A total of 8 patients (14%) developed ≥ grade 2 suspected immune related AEs (irAEs) considered to be MBG453 related; 4 of whom (7%) presented with grade 3/4 events: ALT elevation (n=2), arthritis (n=1), and GGT increase (n=1). No study treatment-related deaths were observed. 16 HR-MDS and 31 AML patients have had post-baseline disease response assessments. Median duration of decitabine and MBG453 is 3.9 months (range 0.7-18.6 months). Evidence of activity with MBG453 in combination with decitabine has been seen at doses ranging from 240 mg Q2W to 800 mg Q4W. 8 of 16 (50%) HR-MDS patients achieved mCR or CR. None of the responding HR-MDS patients has had disease recurrence with exposure durations currently ranging from 3.4 to 18.6 months; two patients in mCR underwent allogeneic stem cell transplant. 4 of 14 (29%) newly diagnosed AML patients have achieved a response of PR or better (2 PR, 2 CR), with 3 additional patients exhibiting ≥ 50% bone marrow blast reduction, and 10 of 14 (71%) continuing on study. 5 of 17 (29%) R/R AML patients have achieved a response of CRi, with 5 additional patients exhibiting ≥ 50% bone marrow blast reduction. Exposure durations for all AML responders currently range from 2.1 to 17.9 months. Median onset of response among all patients was 2.0 months. TIM-3 expression was detected on leukemic cells, with modulation of TIM-3 expression following treatment with decitabine. Conclusions: In this ongoing study in patients with HR-MDS and AML, the combination of MBG453 and decitabine was safe and well tolerated, and exhibited evidence of anti-leukemic activity with encouraging preliminary response rates occurring at a median of 2 cycles, with durability in both HR-MDS and AML. These findings validate TIM-3 as a promising therapeutic target in MDS and AML and support further clinical development of MBG453 in combination with HMAs in patients with MDS and AML. Disclosures Borate: AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Esteve:Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau; Pfizer: Consultancy. Porkka:Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Knapper:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Tolero: Consultancy; Daiichi Sankyo: Honoraria; Pfizer: Consultancy. Vey:Janssen: Honoraria; Novartis: Consultancy, Honoraria. Scholl:Novartis: Other: Project funding; Pfizer: Other: Advisory boards; Gilead: Other: Project funding; AbbVie: Other: Advisory boards; Daiichi Sankyo: Other: Advisory boards. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Wermke:Novartis: Honoraria, Research Funding. Janssen:Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands: Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Other: Founder of the HematologyApp which is supported by BMS, among others, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Pfizer, among others; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Incyte, among others; AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Founder of the HematologyApp which is supported by Janssen, among others; MSD: Other: Founder of the HematologyApp which is supported by MSD, among others; Daiichi-Sankyo: Other: Founder of the HematologyApp which is supported by Daiichi-Sankyo, among others; Roche: Other: Founder of the HematologyApp which is supported by Roche, among others; Takeda: Other: Founder of the HematologyApp which is supported by Takeda, among others. Traer:AbbVie: Consultancy; Notable Labs: Equity Ownership; Agios: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy. Chua:Alfred Hospital, Melbourne, Australia: Employment. Narayan:Takeda: Other: Employment (spouse); Merck: Other: Equity ownership (spouse); Genentech: Other: Equity ownership (spouse). Tovar:Hospital Clinic Barcelona: Employment. Kontro:Amgen: Consultancy; Astellas: Consultancy; AbbVie: Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ottmann:Roche: Honoraria; Pfizer: Honoraria; Fusion Pharma: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Sun:Novartis Institutes for BioMedical Research: Employment; Novartis: Other: Novartis stock owner (stock share as long-term employee incentive). Longmire:Novartis Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Szpakowski:Novartis Institutes for Biomedical Research: Employment, Other: Novartis Stock. Liao:Novartis: Employment. Patel:Novartis Pharmaceuticals: Employment. Rinne:Novartis: Employment; N-Of-One, Inc: Consultancy. Brunner:Astra Zeneca: Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Wei:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: 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, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: MBG453 is an investigational anti-TIM-3 antibody that is being evaluated in hematological malignancies and solid tumors

Abstract: Introduction: Outcome of patients (pts) with refractory AML or following relapse is considered dismal and usually reported as refractory/relapsed. Here we analyzed long term outcome of refractory and relapsing pts separately over a 10 year (y) period from two prospective, non-age-limited, adult AML studies. Results have been published or presented previously as part of the German AML Intergroup studies1,2. However, incidence, characteristics, treatment and outcome of refractory and relapsed pts have not been evaluated. Patients and Methods: A total of 1621 pts from the OSHO 2002 ≤60 y (n=740) and 2004 & gt;60 y (n=881) with newly diagnosed AML (except acute promyelocytic leukemia) and eligible for chemotherapy were analyzed. The gender was male in 51.7% of pts. AML type was de novo in 66.6%, followed by secondary AML in 25.8% and therapy related in 7.6%. Cytogenetic risk status was normal in 47.9%, intermediate in 16.3%, unfavorable in 15.3%, monosomal in 12.6% and favorable in 7.9%. Molecular analysis revealed wildtype (wt) FLT3 in 80.9% and FLT3 ITD mutated (mut) in 19.1% of pts. NPM was mutated in 30.2% of 1124 pts. In the AML 2002 and 2004 studies (NCT 01414231; NCT 01497002; NCT00266136), pts were randomly (9:1) assigned to remission induction by cytarabine (1 g/m2 bid d 1, 3, 5, 7) and Idarubicin (AML 2002) 12 mg/m2/d d 1-31 or mitoxantrone (AML 2004) 10 mg/m2/d iv d 1 - 32 or to a common arm consisting of a 3+7 scheme 3. Pts in complete remission (CR) received consolidation and stem cell transplantation (HSCT) according to cytogenetic risk and donor availability1,2. Pts with partial remission (PR) or non-response (NR) to two induction cycles were considered refractory. Pts achieving CR and relapsing thereafter were considered relapses and treated with MitoFlag or Flag-Ida4. Results: The majority of pts [median age 62 (range 17-87) y] entered CR or CRi after one or two induction cycles (n=1144; 70.6%). OS was 31.9 (29.5-34.4) % @5y and 26.0 (23.4-28.9) % @10y. Results were age dependent and superior in younger pts with an OS of 46.8 (43.1-50.7) % @5y compared to 19.3 (16.7-22.4) % @ 5y in elderly. Age, cytogenetics and NPM1 were determinants for CR and WBC (p & lt;0,001), gender (p & lt;0,05) and AML type (p & lt;0,01) for OS. FLT3-ITD mut was an important determinant for relapse free survival in pts ≤60y. A total of 238 (14.7%) of 1621 pts, 23.5% in the younger and 76.5% in the elderly study, were refractory (PR 60.1%, NR 39.9%). Pts had a median age of 66 (range 23-83)y. OS of refractory pts was 11.4 (7.9-16.6)% @5y, and dependent upon PR [(13.1 (8.1-21.1) % @10y] and NR [5.2 (2.1-12.6) % @5y; p=0.0003] . Intensive chemotherapy ± HSCT and hypomethylating agents (HMA) were able to induce CR in 24.8% of pts. CR and non-CR pts had an OS of 42.7 (31.4-58.2) % @5y and an OS of 3.7 (1.7-8.0) % @2y, respectively. Risk factors for OS in refractory pts were age and type of therapy (p & lt;0.0001). Almost all long term survivors were treated with HSCT. Of the 1144 CR/CRi pts, 582 relapsed 1-121 months (mts) after CR. Relapse occurred in 34.0% ≤6 mts, in 38,8% between 7-18 mts and in 12,2% & gt;18 mts. Age, cytogenetic risk, type of AML, interval CR to relapse and HSCT were the dominant factors for relapse. CR2 was achieved after intensive chemotherapy ± HSCT, ± DLI and HMA in 227 pts (39.0%), 54.5% in the AML 2002 and 28.4% in the AML 2004. OS of relapsed pts was 13.8 (11.1 - 17.3) % @5y and 10.9 (7.4 - 16.2) % @10y and was higher in the younger with 23.4 (18.2-29.9) % @5y as compared to elderly pts 6.9 (4.4 - 11.0) % @5y. Pts with CR2 had a LFS of 24.9 (19.5-31.7) % @5y and was highest in patients & lt;60y when intensive chemotherapy followed by HSCT was involved. Independent risk factors for OS in relapsed pts were age, cytogenetic risk, interval CR1 to relapse and type of therapy. Relapsed pts with HSCT in CR1 showed a trend for reduced survival. Conclusions Outcome of pts with refractory and relapsed AML is unsatisfactory but consistent & gt;10% @5y. A differential response is observed in refractory and relapsed pts and is dependent upon PR, NR and the achievement of CR. Increase of CR rate in younger but especially in elderly pts with second generation TKI, reduction of TRM using FLT3-inhibitor monotherapy and the option to treat pts ineligible to chemotherapy promise better outcome in refractory and relapsed AML. 1Büchner et al. JCO 2012; 2Niederwieser et al Blood 2016; 3Mayer et al. NEJM 1994; 4Thiel et al. Ann Oncology 2015 Disclosures Niederwieser: Daichii: Speakers Bureau; Cellectis: Consultancy. Scholl:Gilead: Other: Project funding; Daiichi Sankyo: Other: Advisory boards; AbbVie: Other: Advisory boards; Pfizer: Other: Advisory boards; Novartis: Other: Project funding. Zojer:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sayer:Novartis: Other: none. Schwind:Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding. Maschmeyer:Gilead, Janssen Cilag, Astra Zeneca; BMS, Merk-Serono: Honoraria. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Al-Ali:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria.

Abstract: Ultrasound renal denervation (uRDN) was shown to lower blood pressure (BP) in patients with uncontrolled hypertension (HTN). Establishing the magnitude and consistency of the uRDN effect across the HTN spectrum is clinically important. Objective To characterize the effectiveness and safety of uRDN vs a sham procedure from individual patient-level pooled data across uRDN trials including either patients with mild to moderate HTN on a background of no medications or with HTN resistant to standardized triple-combination therapy. Data Sources A Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN SOLO and TRIO) and A Study of the ReCor Medical Paradise System in Stage II Hypertension (RADIANCE II) trials. Study Selection Trials with similar designs, standardized operational implementation (medication standardization and blinding of both patients and physicians to treatment assignment), and follow-up. Data Extraction and Synthesis Pooled analysis using individual patient-level data using linear regression models to compare uRDN with sham across the trials. Main Outcomes and Measures The primary outcome was baseline-adjusted change in 2-month daytime ambulatory systolic BP (dASBP) between groups. Results A total of 506 patients were randomized in the 3 studies (uRDN, 293; sham, 213; mean [SD] age, 54.1 [9.3] ; 354 male [70.0%]). After a 1-month medication stabilization period, dASBP was similar between the groups (mean [SD] , uRDN, 150.3 [9.2] mm Hg; sham, 150.8 [10.5] mm Hg). At 2 months, dASBP decreased by 8.5 mm Hg to mean (SD) 141.8 (13.8) mm Hg among patients treated with uRDN and by 2.9 mm Hg to 147.9 (14.6) mm Hg among patients treated with a sham procedure (mean difference, −5.9; 95% CI, −8.1 to −3.8 mm Hg; P   & amp;lt; .001 in favor of uRDN). BP decreases from baseline with uRDN vs sham were consistent across trials and across BP parameters (office SBP: −10.4 mm Hg vs −3.4 mm Hg; mean difference, −6.4 mm Hg; 95% CI, −9.1 to –3.6 mm Hg; home SBP: −8.4 mm Hg vs −1.4 mm Hg; mean difference, −6.8 mm Hg; 95% CI, −8.7 to −4.9 mm Hg, respectively). The BP reductions with uRDN vs sham were consistent across prespecified subgroups. Independent predictors of a larger BP response to uRDN were higher baseline BP and heart rate and the presence of orthostatic hypertension. No differences in early safety end points were observed between groups. Conclusions and Relevance Results of this patient-level pooled analysis suggest that BP reductions with uRDN were consistent across HTN severity in sham-controlled trials designed with a 2-month primary end point to standardize medications across randomized groups. Trial Registration ClinicalTrials.gov Identifier: NCT02649426 and NCT03614260

Abstract: CMV associated tissue-invasive disease is associated with a considerable risk of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Recently, the terminase inhibitor letermovir (LMV) has been approved for prophylaxis of CMV infection in HSCT. We hereby report a 60-year-old female experiencing CMV reactivation after HSCT in a CMV seronegative donor-constellation. Due to ongoing elevated CMV viral load and drug-associated myelosuppression, which prevented ganciclovir therapy, treatment was replaced by foscarnet. Due to nephrotoxicity, foscarnet was switched to LMV. The patient developed skin GvHD and prednisolone was started. Subsequently, CMV viremia worsened despite LMV therapy. Genotyping revealed the mutation C325Y of the CMV UL56 terminase being associated with high-level resistance against LMV. Prolonged uncontrolled low-level viremia due to prednisolone treatment may have favored the selection of drug-resistant CMV. Despite the excellent toxicity profile of LMV, physicians should be aware of risk factors for the emergence of resistance.

Abstract: Myelodysplastic syndrome ( MDS ) comprises a heterogeneous group of clonal disorders of haematopoietic stem cells, characterised by dysplastic haematopoiesis and dysregulated apoptosis resulting in various degrees of cytopenia, whereas canonical cytologic, cytogenetic and histopathologic findings guiding the diagnosis MDS are widely accepted, the MDS ‐phenotype can be masked by coexisting/paraneoplastic immunologic disease. Autoimmune disorders have an estimated incidence of 10% among patients suffering from MDS and are causally related to increased morbidity and mortality, younger age at diagnosis and more complex genetics. Conversely, systemic inflammatory disorders may be an early manifestation of MDS , show good response to immunosuppressive therapy and frequently disappear during the course of specific haematologic therapy. Objective Monocentric report on clinical phenotypes found in MDS or bone marrow failure with paraneoplastic inflammatory disease. Methods Clinical case reports and systematic review about MDS pathophysiology and treatment. Results We report eight patients diagnosed with MDS or bone marrow failure, who presented with paraneoplastic autoimmune diseases. Six of eight patients were treated with the hypomethylating agent 5‐azacytidine, three of which achieved meaningful response with regard to inflammation control and haematologic recovery. Conclusions As paraneoplastic syndromes are often mistakenly diagnosed as idiopathic autoimmune disorders, we propose that coexistence of an underlying myelodysplastic syndrome should be considered early in the diagnostic work up. 5‐Azacytidine is effective in controlling paraneoplastic inflammation.