Abstract: High CD33 expression in acute myeloid leukemia (AML) with mutated NPM1 provides a rationale for the evaluation of gemtuzumab ozogamicin (GO) in this AML entity. We conducted a randomized trial to evaluate GO in combination with intensive induction and consolidation therapy in NPM1-mutated AML. PATIENTS AND METHODS Between May 2010 and September 2017, patients ≥ 18 years old and considered eligible for intensive therapy were randomly assigned up front for induction therapy with idarubicin, cytarabine, etoposide, and all- trans-retinoic acid with or without GO. The early ( P = .02) primary end point of event-free survival (EFS) was evaluated 6 months after completion of patient recruitment. RESULTS Five hundred eighty-eight patients were randomly assigned (standard arm, n = 296; GO arm, n = 292). EFS in the GO arm was not significantly different compared with that in the standard arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.04; P = .10). The early death rate during induction therapy was 10.3% in the GO arm and 5.7% in the standard arm ( P = .05). Causes of death in both arms were mainly infections. The cumulative incidence of relapse (CIR) in patients achieving a complete remission (CR) or CR with incomplete hematologic recovery (CRi) was significantly reduced in the GO arm compared with the standard arm ( P = .005), with no difference in the cumulative incidence of death ( P = .80). Subgroup analysis revealed a significant beneficial effect of GO in female, younger (≤ 70 years), and FLT3 internal tandem duplication–negative patients with respect to EFS and CIR. CONCLUSION The trial did not meet its early primary end point of EFS, mainly as a result of a higher early death rate in the GO arm. However, in patients achieving CR/CRi after induction therapy, significantly fewer relapses occurred in the GO compared with the standard arm.

Abstract: Background: Relapsed (REL) & refractory (REF) r/r AML pts unsuitable for intensive therapy (IT) due to age or co-morbidities, have limited treatment options. Low-dose cytarabine (LDAC) demonstrated limited survival benefit (mOS ≤6 months), highlighting the significant unmet need for new treatments in this patient population. Bemcentinib (BEM) is an orally bioavailable, highly selective AXL-inhibitor. AXL is a receptor tyrosine kinase conferring poor prognosis, resistance to chemotherapy and decreased antitumor immune response. AXL is overexpressed on leukemic cells, especially in the stem cell compartment, thus representing an important novel target in AML. Aims: The ongoing BGBC003 PhII trial cohorts receiving BEM+LDAC (B+L) include newly diagnosed (ND) and r/r AML pts unfit for IT. Based on the initial efficacy signal observed, the r/r AML patient sub-group was selected for an expansion cohort, to further explore safety and efficacy and to pursue translational biomarker analysis. Here, we present preliminary efficacy data in r/r pts, with a safety overview for all pts treated with B+L. We additionally include translational plasma biomarker and multiomics data from bone marrow mononuclear cells (BMMNC). Methods: Pts received the combination of BEM at the RP2D (200mg PO/d) and LDAC SoC schedule. Efficacy endpoints were objective response (OR) and clinical benefit (OR+unchanged [UC]+stable disease [SD=UC for at least 3 BEM cycles] ). Secondary objectives looked at overall survival (OS) and exploratory biomarker analyses. Longitudinal BMMNC samples (n=36) from 15 patients were subjected to scRNA-seq and CiteSeq (Chromium 10x genomics; TotalSeq, Biolegend). For scRNA-seq data analyses, Cell Ranger (v3.1.0) and the Seurat (v.4.0.1) in R (v.4.0) were used. Pts were stratified by best response: CR, CRi, PR for Responders; SD, UC, PD for Non-Responders. Cell type annotations were based on the identified clusters and inferred from the expression of known markers at both RNA and protein level. Results: As of 15 July 2021, the B+L cohorts comprised 27 r/r (20 REL, 7 REF) AML pts. Median prior lines of therapy: 1 [1-8] in REL, 3 [1-4] in REF. Median age: 75.5yrs [66-86] for REL, 75yrs [71-81] for REF. Adverse cytogenetic risk profile: 6/18 (33%) in REL; 2/7 (29%) in REF. 17/20 REL pts were evaluable for efficacy (BM assessment post-baseline). 4/17 (24%) achieved remission (4 CR/CRi) between wk13(C5)-wk19(C7); 4 pts had SD, 6 pts were UC; observed clinical benefit rate was 82%. Late onset responses may reflect immunological mechanism of action targeting AXL + innate immune cells in REL pts and may also contribute to a longer time-on-treatment (ToT) and survival. Median ToT was 36.9 wks for CR/CRi pts; mDOR 33wks [12.0-69.9]; 4 pts remain on treatment. Median OS currently 13.3 months (historical controls suggest 4.5 months mOS in this population) continues to mature. In contrast, REF pts showed no response (0/7), with 4/7 (57%) demonstrating clinical benefit; mToT 12.0wks for benefitting patients and mOS 5.3 months; no pts ongoing on treatment. Overall, the safety of B+L (compared with previously published BEM monotherapy) is comparable with the known safety profile of LDAC. TRAEs of ≥G3 observed in ≥10% of pts were anaemia (21% B+L; 4% BEM), and ECG QT prolonged (12% B+L; 7% BEM). No G5 TRAEs reported. scRNA and multiomic analysis of longitudinal samples reflect differences in the immune compartment, underscoring the clinical impression of an immune-mediated MOA associated with response to BEM. CD8+ effector T-cells of responding patients demonstrated enhanced pro-inflammatory signatures involving TNF-alpha and IFN-gamma as compared with non-responders. Furthermore, increased activation of B plasma cells was observed in correlation with response to BEM confirming that BEM mediates an anti-AML immune response through activation of the two major adaptive immune cell populations. Conclusion: B+L is well tolerated and offers promising survival benefit to older unfit REL AML patients. Translational research including scRNA and multiomics, identified specific activation of CD8+ T cells and B plasma cells associated with response to treatment, indicating that BEM elicits activation of the two major adaptive immune cell populations responsible for anti-AML immune responses. B+L warrants evaluation in a randomized pivotal trial in this population. Disclosures Loges: BerGenBio ASA: Honoraria, Research Funding, Speakers Bureau; BMS: Research Funding; Eli Lilly: Research Funding; Roche Pharma: Research Funding; ADC Therapeutics: Research Funding; BMS: Honoraria, Speakers Bureau; Boehringer Ingelheim: Honoraria, Speakers Bureau; Eli Lilly: Honoraria, Speakers Bureau; Roche Pharma: Honoraria, Speakers Bureau; Medac GmbH and Sanofi Aventis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau. Heuser: Astellas: Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees. Kapp-Schwoerer: BerGenBio ASA: Research Funding. Lemoli: Celgene: Other: Support for attending meetings and/or travel; Jazz, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Daiichi Sankyo, Servier: Honoraria, Speakers Bureau. Ben Batalla: BerGenBio ASA: Research Funding. Hellesøy: BerGenBio ASA: Research Funding. Rayford: BerGenBio ASA: Current Employment. Nautiyal: BerGenBio ASA: Current Employment. Berkman-Gottlieb: BerGenBio ASA: Consultancy, Ended employment in the past 24 months. Micklem: BerGenBio ASA: Current Employment, Current equity holder in publicly-traded company. Gabra: BerGenBio ASA: Current Employment, Current equity holder in publicly-traded company. Gorcea-Carson: BerGenBio ASA: Current Employment. Lorens: BerGenBio ASA: Current equity holder in publicly-traded company, Ended employment in the past 24 months, Patents & Royalties. Fiedler: Servier: Consultancy, Other: support for meeting attendance; Amgen: Consultancy, Other: support for meeting attendance, Patents & Royalties, Research Funding; ARIAD/Incyte: Consultancy; Daiichi Sankyo: Consultancy, Other: support for meeting attendance; Stemline: Consultancy; Abbvie: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Other: support for meeting attendance; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Celgene: Consultancy; Morphosys: Consultancy. Alvarado: Jazz Pharmaceuticals: Research Funding; BerGenBio: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; CytomX Therapeutics: Consultancy; Astex Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Consultancy, Research Funding. Gjertsen: BerGenBio: Consultancy; Pfizer Inc.: Consultancy; Alden Cancer Therapy: Current holder of stock options in a privately-held company; KinN Therapeutics: Current holder of stock options in a privately-held company; Novartis: Consultancy.

Abstract: Background: FLT3-ITD occurs in ~25% of adult AML patients (pts) and is associated with poor prognosis. MRD monitoring is of high prognostic relevance, but restricted to certain AML subtypes. FLT3-ITD represents an attractive target for MRD monitoring in particular in pts treated with a tyrosine kinase inhibitor. FLT3-ITD MRD monitoring is hampered by the broad heterogeneity of ITD length and insertion site (IS). NGS may overcome these limitations offering the opportunity for MRD monitoring in FLT3-ITD+ AML. Aims: To validate our recently established NGS-based FLT3-ITD MRD assay in a defined cohort of FLT3-ITD+ AML pts treated within the AMLSG16-10 trial (NCT01477606) combining intensive chemotherapy with midostaurin followed by midostaurin maintenance and to evaluate the prognostic impact of FLT3-ITD MRD monitoring. Methods: Using FLT3-ITD paired-end NGS (Illumina MiSeq) with a variant allele frequency (VAF) sensitivity of 10-4-10-5 (Blätte et al., Leukemia 2019), 227 bone marrow (BM) and 17 peripheral blood samples from 61 FLT3-ITD+ AML pts were analyzed at diagnosis (Dx), after two cycles of chemotherapy (Cy2), at the end of treatment (EOT), and during 3-6 months follow-up (FU). All pts achieved complete remission (CR) after Cy2. Allogeneic hematopoietic cell transplantation in first CR was performed in 40 (66%) pts. Mutational status for NPM1 and DNMT3A was available for all pts (NPM1mut, n=48; DNMT3Amut, n=33; NPM1mut/DNMT3Amut, n=31), and NPM1mut MRD data for 41 pts. Results: At Dx we identified 191 ITDs; median length was 45 nucleotides (range, 9-194) and median VAF 0.279% (range, 0.006-90.21). Of the 191 ITDs, 133 (70%) located in the juxtamembrane domain (JMD) and 58 (30%) in the tyrosine kinase domain-1 (TKD1). There was no correlation of VAF with length or IS, whereas ITD size correlated with IS: the more C-terminal the IS, the longer the ITD (Rho=0.51; p & lt;.001). Total ITD VAF per pt was in median 34.3% (range, 0.007-90.21) and correlated positively with white blood cell count (WBC, Rho=0.314; p=.021) and lactate dehydrogenase serum level (LDH, Rho=0.274; p=.04), and inversely with the number of ITDs (Rho=-0.265; p=.04). Most pts (67%) exhibited & gt;1 ITD at Dx (median 2; range, 1-16). Categorizing pts according to IS as JMDsole (46%), JMD/TKD1 (34%), and TKD1sole (20%) revealed that JMD/TKD1 pts exhibited more ITD subclones (p & lt;.001) and a lower total VAF at Dx (p=.03). There were no correlations with any other clinical or genetic features. Pts' total ITD VAF significantly decreased after Cy2 and at EOT (median log10 reduction: 4.4 and 4.7; p & lt;.001, each), and MRD negativity (MRD-) was achieved in 67% and 87% of pts, respectively. According to subgroups, pts with JMDsole or TKD1sole showed deeper MRD reduction compared to JMD/TKD1 pts after Cy2 (4.6 vs 4.7 vs 3.7 log10; p=.06) and at EOT (4.8 vs 4.8 vs 4.0 log10; p=.02) but this did not result in a significant difference in achievement of MRD-. Concurrent NPM1mut was of favorable impact for log10 VAF reduction (median, 4.7 for DNMT3Amut/NPM1mut vs 4.6 for NPM1mut vs 2.8 others; p=.003) and MRD- (77 vs 76 vs 31%; p=.01) after Cy2, but exerted no impact at EOT. Correlating NPM1mut and FLT3-ITD MRD course revealed a positive correlation after Cy2 (Rho=0.327; p=.03), but not at EOT (Rho=0.250; p=.10), likely due to the higher sensitivity of the real-time quantitative PCR-based NPM1mut MRD assay. Median follow-up was 3.4 years (95% CI, 2.6-4.6). Survival analyses with respect to cumulative incidence of relapse (CIR; n=60) and overall survival (OS; n=61) revealed significantly lower CIR for total VAF at Dx & gt;34.3% (p=.03), a VAF reduction & gt;4.7 log10 (MR4.7) at EOT (p=.001), and for MRD- pts at EOT (p=.001). There was no impact on OS. In preliminary exploratory Cox regression (n=48), including BM blasts, WBC, LDH, age, and NPM1mut as covariables, MRD- at EOT was the only consistent favorable variable for CIR (HR, 0.1; p=.001) and OS (HR, 0.27; p=.03). During FU, 5/8 (63%) MRD+ pts at EOT became MRD- and 4/53 (8%) MRD- pts converted to MRD+ resulting in consecutive relapse in 2 pts. Conclusion: In this first cohort of FLT3-ITD+ AML pts treated with intensive chemotherapy and midostaurin in the prospective AMLSG16-10 trial we could demonstrate that FLT3-ITD NGS-based MRD monitoring is feasible and represents a promising tool to evaluate therapy response and identification of pts at a higher risk of relapse. Further analysis of the study cohort is ongoing. Disclosures Kapp-Schwoerer: Jazz Pharmaceuticals: Honoraria, Research Funding. Paschka:Sunesis Pharmaceuticals: Consultancy; BerGenBio ASA: Research Funding; Novartis: Consultancy, Speakers Bureau; Otsuka: Consultancy; Pfizer: Consultancy, Speakers Bureau; Astellas Pharma: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, accommodations or expenses; Astex Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Agios Pharmaceuticals: Consultancy, Speakers Bureau; Amgen: Other; Janssen Oncology: Other; AbbVie: Other: Travel, accommodation or expenses, Speakers Bureau. Fiedler:Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Daiichi Sankyo Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; Morphosys: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Servier: Honoraria, Other; BerGenBio ASA: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations, support in medical writing, Research Funding; Gilead: Honoraria. Salih:Novartis: Consultancy; Pfizer: Consultancy; Philogen: Consultancy; Medigene: Consultancy; Synimmune: Consultancy, Research Funding. Salwender:Bristol-Myers Squibb/Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Oncopeptides: Honoraria; Sanofi: Honoraria; GlaxoSmithKline: Honoraria; AbbVie: Honoraria. Götze:Celgene: Research Funding. Luebbert:Janssen: Research Funding. Schlenk:PharmaMar: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Roche: Research Funding; AstraZeneca: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Thol:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Heuser:Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding; Abbvie: Consultancy; PriME Oncology: Honoraria; Amgen: Research Funding; Astellas: Research Funding; Roche: Research Funding; Stemline Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; BerGenBio ASA: Research Funding; Bayer: Consultancy, Research Funding. Ganser:Novartis: Consultancy; Celgene: Consultancy. Döhner:AstraZeneca: Consultancy, Honoraria; Sunesis: Research Funding; Roche: Consultancy, Honoraria; Pfizer: Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; AROG: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria. Bullinger:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Döhner:Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Celgene: Consultancy, Honoraria; Sunesis Pharmaceuticals: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Arog: Research Funding; Roche: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Astellas Pharma: Consultancy; Agios: Consultancy; Abbvie: Consultancy.

Abstract: Background: Deletion of the long arm of chromosome 9, del(9q), is a recurrent genomic abnormality, which occurs at a frequency of ~2% in AML. Interestingly, deletions of 9q are mainly found in t(8;21)-positive AML, as well as in AML with NPM1 (NPM1mut) or CEBPA (CEBPAmut) gene mutation, thereby suggesting that del(9q) can act as cooperating event in these prognostically favorable AML subgroups. Aims: In order to dissect the biology of AML with del(9q), we comprehensively characterized a large cohort of 9q21 deleted cases (n=45) at the molecular level. Methods: We performed SNP 6.0 microarray analysis to delineate the minimally deleted region on 9q, and we analyzed gene expression in selected cases to determine whether 9q21 deletions are displaying a characteristic expression pattern. Potential candidate genes were further studied by shRNA based knock-down experiments in cell line models. Finally, we performed whole exome sequencing (WES) of paired diagnostic and remission samples from n=20 del(9q) patients with NPM1mut (n=7), NPM1wt/CEBPAmut (n=7), and t(8;21) (n=6) to identify additional aberrations cooperating with 9q loss in leukemogenesis. Results: By SNP microarray analysis, we could confirm a minimally deleted region (MDR) on 9q21 encompassing seven genes (GKAP1, KIF27, C9orf64, HNRNPK, RMI1, SLC28A3, NTRK2). By targeted resequencing in n=50 non-9q deleted cases, we detected a mutation in HNRNPK, which was recently confirmed to be recurrently mutated by The Cancer Genome Atlas (TCGA) project. These findings point to HNRNPK as the most important candidate gene of the MDR. HNRNPK encodes for a ubiquitously expressed heterogeneous nuclear ribonucleoprotein (hnRNP), which influences pre-mRNA processing and other aspects of mRNA metabolism, and it is thought to play a role during cell cycle progression. To further evaluate the biology underlying 9q deleted/HNRNPK haploinsufficient cases, gene expression data were generated by microarray technology comparing NPM1mut cases with and without del(9q) (n=11 vs n=119, respectively). These analyses showed deregulated expression of genes involved in splicing and mRNA processing, and there was an overlap with gene expression changes following shRNA-mediated HNRNPK knock-down in AML cell lines, which also suggested a growth advantage for haploinsufficient cells. While these data further support that HNRNPK might play a cooperating role in AML, we were eager to see whether there are additional mutations commonly linked to del(9q). By WES, we detected on average 7.8 somatic protein altering point mutations per sample (missense and nonsense SNVs) and 2.5 frameshift insertions or deletions affecting genes known to play a role in AML as well as genes not yet linked to AML. In accordance with the general mutational spectrum of t(8;21), NPM1 or CEBPA mutant AML, we identified mutations in known epigenetic regulators such as ASXL1, ASXL2, TET2 or DNMT3A, but we also could find novel somatic mutations in additional genes involved in the regulation of the chromatin structure such as BRD3 or BRWD3. Furthermore, we identified mutations in genes associated with mRNA processing and RNA splicing,as well as mutations affecting the RAS- signaling pathway and DNA repair mechanisms. Conclusions: While ongoing analyses are likely to identify additional gene mutations in del(9q) AML, first results suggest HNRNPK haploinsufficiency as a potential "driver" mutation playing a role in the pathomechanism of 9q deleted AML. A better understanding of the HNRNPK function in normal hematopoietic cells as well as leukemia cells without del(9q), and studying the impact of HNRNPK mutations in AML might enable novel therapeutic approaches for del(9q)/HNRNPKmut AML. These authors contributed equally to the work: AD and SRC as well as KD and LB. Supported by: FP7 NGS-PTL project, and DFG SFB 1074 B3 project. Disclosures No relevant conflicts of interest to declare.

Abstract: Recent improvements in alveolar echinococcosis (AE) therapy can provide long-term disease control, and even allow structured treatment interruption in selected cases. Imaging has a pivotal role in monitoring disease activity, with 18-fluoro-deoxyglucose positron emission and computed tomography (18F-FDG-PET/CT) in particular having proven beneficial for assessing disease activity. Repetitive regular examinations to monitor therapy response, however, can lead to substantial radiation burden. Therefore, by combining metabolic information and excellent tissue contrast in magnetic resonance imaging (MRI), PET/MR appears ideally suited for this task. Here, we retrospectively analyzed 51 AE patients that underwent 18F-FDG-PET/MR. Patients had a ‘confirmed/probable’ diagnosis in 22/29 cases according to the WHO classification. FDG uptake, diffusion restriction, and MRI morphology were evaluated. We found significant differences in FDG uptake between responders to benzimidazole therapy and progressive manifestations (SUVavg 2.7 ± 1.3 vs. 5.4 ± 2.2, p 〈 0.001) as well as between Kodama Types 1 and 3 (F = 9.9, p 〈 0.003). No significant differences were detected for ADC values or MRI morphology concerning response and no correlations were present between FDG uptake and ADC values. The mean radiation dose was 5.9–6.5 mSv. We conclude that the combination of metabolic information and MRI morphology at a low radiation dose proposes PET/MR as a suitable imaging modality for AE assessment. Longitudinal studies are needed to define the role of this imaging modality.

Abstract: Background: Mutations of the NPM1 gene are one of the most frequent genetic aberrations in adult AML. AML with mutated NPM1 is categorized as a disease entity according the WHO-2016 classification and clinically associated with female sex, high white blood cells at diagnosis, normal karyotype and high CD33 antigen expression. We recently showed that patients with NPM1-mutated AML benefit from all-trans retinoic acid (ATRA) as adjunct to intensive induction therapy (Ann Hematol. 2016; 95:1931-1942; Haematologica. 2009;94:54-60). Based on the regular high CD33 expression in AML with mutated NPM1 we hypothesized that gemtuzumab ozogamicin (GO) added to intensive therapy with ATRA may further improve clinical outcome in AML with mutated NPM1. Aim: To evaluate GO in combination with intensive induction and consolidation therapy and ATRA in NPM1 mutated AML within the randomized AMLSG 09-09 trial (NCT00893399) Methods: Between May 2010 and September 2017, patients ≥18 years of age and considered eligible for intensive therapy were randomized up-front for open-label treatment with GO. Induction therapy consisted of two cycles of A-ICE (idarubicin 12mg/m² iv, day 1,3,5 [in induction II and for patients 〉 60 years reduced to d 1, 3]; cytarabine 100mg/m² continuous iv, day 1 to 7; etoposide 100mg/m² iv, day 1-3 [in induction II and for patients 〉 60 years reduced to d 1, 3]; ATRA 45 mg/m²/day po on days 6-8 and 15mg/m² days 9-21, +/- GO 3mg/m² iv day 1). Consolidation therapy consisted of 3 cycles of high-dose cytarabine (HiDAC; 3g/m² [reduced to 1g/m² in patients 〉 60 years] bid, days 1-3; Pegfilgrastim 6mg sc, day 10; ATRA 15 mg/m²/day po, days 4-21; +/- GO 3mg/m² on day 1 [first consolidation only] ). The primary endpoints of the study were event-free survival (EFS) as early endpoint tested 6 months and overall survival (OS) tested 4 years after study completion with sequential testing according the fallback procedure described by Wiens (Statistics 2003;2:211-215). This report focusses on the early EFS endpoint. Further secondary endpoints were response to induction therapy, cumulative incidence of relapse (CIR) and cumulative incidence of death (CID). Results: In total 588 patients were evaluable for analysis (n=296, standard-arm; n=292 GO-arm). Median age was 58.7 years (range, 18.4-82.3 years), ECOG performance status was 0 in 34.1% and 1 in 55.1%, and FLT3-ITD was present in 16.8% of the patients, with baseline characteristics well balanced between the two arms. After first induction therapy death rates were significantly higher in the GO-arm (7.5%) (p=0.02) compared to the standard-arm (3.4%); in both study-arms causes of death were mainly infections. Following induction therapy complete remission (CR) and CR with incomplete count recovery (CRi) were 88.5% and 85.3% (p=0.28), refractory disease (RD) 6.1% and 5.1% (p=0.72), death 5.4% and 9.6% (p=0.06) in the standard- and GO-arm, respectively. Due to prolonged thrombocytopenia after second induction therapy in the GO-arm, the protocol was amended in that GO was omitted in second induction and first consolidation cycles, if prolonged cytopenias were observed during first induction therapy. The study treatment was completed in 197 and 171 patients (p=0.11), allogeneic hematopoietic cell transplantation in first CR was performed in 18 and 21 patients (p=0.51) in the standard- and GO-arm, respectively. Median follow-up was 2.6 years (95%-CI, 2.4-3.1 years). Two- and 4-year EFS were 53% (95%-CI, 48-60%) and 58% (95%-CI, 52%-64%), and 44% (95%-CI, 38-52%) and 52% (95%-CI, 46%-59%) in the standard- and GO-arm, respectively. According to the pre-specified significance level of 0.025, EFS in the GO-arm was not different to that in the standard-arm (p=0.21). In patients achieving CR/CRi after induction therapy, CIR was significantly reduced in the GO-arm compared to the standard-arm (p=0.018), whereas no difference in CID was noted between both arms (p=0.89). Conclusion: The addition of GO to intensive induction therapy with ICE plus ATRA was associated with a higher death rate. In patients achieving a CR/CRi after induction therapy significantly less relapses occurred in the GO- compared to the standard-arm. Disclosures Schlenk: Pfizer: Research Funding, Speakers Bureau. Paschka:Astex: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees, Travel support; Otsuka: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Other: Travel support, Speakers Bureau; Jazz: Speakers Bureau; Amgen: Other: Travel support; Janssen: Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Travel support. Fiedler:Amgen: Other: support for meetíng attendance; Gilead: Other: support for meeting attendance; Pfizer: Research Funding; Amgen: Research Funding; Amgen: Patents & Royalties; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees, support for meeting attendance; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSO: Other: support for meeting attendance; Teva: Other: support for meeting attendance; JAZZ Pharmaceuticals: Other: support for meeting attendance; Daiichi Sankyo: Other: support for meeting attendance. Lübbert:Cheplapharm: Other: Study drug; Celgene: Other: Travel Support; Janssen: Honoraria, Research Funding; TEVA: Other: Study drug. Götze:Novartis: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017; JAZZ Pharmaceuticals: Honoraria; Celgene: Honoraria, Research Funding. Schleicher:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Ipsen: Membership on an entity's Board of Directors or advisory committees; Eissai: Other: Investigator; Astra Zeneca: Other: Investigator; Pfizer: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau. Greil:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Honoraria, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Heuser:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; BergenBio: Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Research Funding; Sunesis: Research Funding; Tetralogic: Research Funding; Bayer Pharma AG: Consultancy, Research Funding; StemLine Therapeutics: Consultancy; Janssen: Consultancy. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Döhner:Agios: Consultancy, Honoraria; Pfizer: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Celator: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Jazz: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Abstract: Background: Acute myeloid leukemia (AML) with t(8;21)(q22;q22.1) resulting in the RUNX1-RUNX1T1 gene fusion is considered favorable in the 2017 genetic risk stratification by the European LeukemiaNet (ELN). After intensive chemotherapy most patients (pts) achieve complete remission (CR), but relapse occurs in about 50% and is associated with poor prognosis. In this AML subgroup monitoring of measurable residual disease (MRD) has been shown to identify pts at higher risk of relapse. Aims: To assess the prognostic impact of MRD monitoring in bone marrow (BM) and peripheral blood (PB) in a large cohort of 155 clinically well-annotated t(8;21)-AML pts enrolled in one of six AMLSG treatment trials. Methods: RT-qPCR was used to quantify RUNX1-RUNX1T1 transcript levels (TL) reported as normalized RUNX1-RUNX1T1 values per 106 transcripts of the housekeeping gene B2M. Samples were analyzed in triplicate, the sensitivity was up to 10-6. Results: While pretreatment RUNX1-RUNX1T1 TL did not impact prognosis, both reduction of RUNX1-RUNX1T1 TL and achievement of MRD negativity (MRDneg) at end of treatment (EOT) were of significant prognostic importance in BM as well as in PB: MR2.5 ( 〉 2.5 log reduction) after treatment cycle 1 and MR3.0 after cycle 2 were significantly associated with a reduced relapse risk (MR2.5, BM: P=.034; PB: P=.008 and MR3.0, BM: P=.028; PB: P=.036, respectively). After completion of therapy, MRDneg was an independent favorable prognostic factor for cumulative incidence of relapse (CIR) (4-year CIR BM: 17% vs 36%, P=.021; PB: 23% vs 55%; P=.001) and overall survival (OS) (4-year OS rate BM: 93% vs 70%, P=.007; PB: 87% vs 47%; P 〈 .0001). Moreover, maximally selected Gray´s statistic defined specific MRD cut-offs at EOT associated with a lower relapse risk: 〈 83 RUNX1-RUNX1T1 TL in BM and 〈 5 in PB predicted for superior 4-year CIR (BM: 18% vs 61%; P 〈 .0001; PB: 23% vs 65%; P 〈 .0001). During follow-up serial MRD analyses allowed prediction of relapse in 77% of pts exceeding an arbitrary cut-off of 150 RUNX1-RUNX1T1 TL in BM and in 84% of pts with 〉 50 TL in PB, respectively. KIT mutation observed in 28% of pts predicted for lower CR rate and inferior outcome, but its prognostic impact was outweighed by RUNX1-RUNX1T1 TL during treatment. To determine whether PB could provide similar prognostic information as BM, we compared 680 paired samples (diagnosis, n=125; after cycle 1, n=80; after cycle 2, n=86; at EOT, n=78; during follow-up, n=311). At diagnosis RUNX1-RUNX1T1 TL tended to be slightly higher in BM than in PB (P=.072), but were significantly higher after cycle 1 (P=.008), cycle 2 (P 〈 .001), at EOT (P=.002), and during follow-up (P 〈 .001). RUNX1-RUNX1T1 TL in BM and PB correlated well (r=.87; P 〈 .0001) with on average 1-log lower values in PB. However, 2.5%, 26.7%, 26.9%, and 24.8% of all pairs were discrepant (BMpos/PBneg or BMneg/PBpos) after cycle 1, cycle 2, at EOT, and during follow-up. Of 104 PBneg samples obtained during treatment, 46 (44%) were still BMpos. In the post-treatment period, this fraction decreased to 28% (77 BMpos/276 PBneg pairs) (P=.003). Of note, RUNX1-RUNX1T1 TL in all but four of the 77 (5.2%) BMpos samples were below the cut-off of 150 TL. Virtually all relapses occurred within one year after EOT with a very short latency from molecular to morphologic relapse strongly suggesting to perform MRD assessment at short intervals during this period. Based on our data we refined the practical guidelines for MRD assessment in RUNX1-RUNX1T1-positive AML: i) along with the current ELN MRD recommendations, BM and PB should be analyzed after each treatment cycle; ii) during the follow-up period, in particular the first year after EOT, MRD monitoring in PB should be performed monthly; in pts with TL 〉 50 in PB, increase of MRD TL 〉 1-log, and/or conversion from MRDneg to MRDpos a complementary BM samples should be analyzed timely. Summary: RUNX1-RUNX1T1 MRD monitoring allows for the discrimination of pts at high and low risk of relapse. MRDneg in both BM and PB after completion of therapy was the most valuable independent favorable prognostic factor for relapse risk and OS. During follow-up, serial MRD analyses allowed the definition of cut-offs predicting relapse. Moreover, considering that virtually all relapses occurred within the first year after EOT with a very short latency from molecular to morphologic relapse MRD assessment in PB at shorter intervals during this period is indispensable. Disclosures Weber: Celgene Corporation: Research Funding. Schroeder:Celgene Corporation: Consultancy, Honoraria, Research Funding. Götze:AbbVie: Membership on an entity's Board of Directors or advisory committees. Fiedler:Amgen, Pfizer, Abbvie: Other: Support in medical writing; Amgen, Pfizer, Novartis, Jazz Pharmaceuticals, Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Amgen, Jazz Pharmaceuticals, Daiichi Sanchyo Oncology, Servier: Other: Support for meeting attendance. Greil:Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Sandoz: Honoraria. Krauter:Pfizer: Honoraria. Bullinger:Amgen: Honoraria; Astellas: Honoraria; Gilead: Honoraria; Daiichi Sankyo: Honoraria; Hexal: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; Menarini: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; Bayer: Other: Financing of scientific research; Sanofi: Honoraria; Seattle Genetics: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria. Paschka:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Jazz: 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, Speakers Bureau; BMS: Other: Travel expenses, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel expenses; Otsuka: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Travel expenses; Janssen: Other: Travel expenses; Abbvie: Other: Travel expenses; Sunesis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Astex: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Astellas: Membership on an entity's Board of Directors or advisory committees. Döhner:AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; Celgene, Novartis, Sunesis: Honoraria, Research Funding; AROG, Bristol Myers Squibb, Pfizer: Research Funding. Döhner:Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria; Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria.