Abstract: Background In newly diagnosed acute myeloid leukemia (AML), the general recommendation is to start treatment immediately after the diagnosis has been made. This paradigm is based both on the observation that untreated acute leukemia has a poor prognosis and on retrospective analyses demonstrating a shorter survival in younger AML patients (pts) in whom treatment was delayed by more than 5 days (Sekeres et al., 2009). A more recent single-center analysis came to a different conclusion, showing no prognostic effect for the time from diagnosis to treatment (TDT; Bertoli et al., 2013). We explored the relationship between TDT and prognosis on a large set of real-world data from the AML registry of the Study Alliance Leukemia (SAL) and compared it to the published cohorts. Methods The SAL runs a transregional AML registry in 46 treatment centers across Germany (NCT03188874). All registered patients with an intensive induction treatment, a minimum follow-up time of 12 months and no acute promyelocytic leukemia were selected (n=2,200). Treatment start was defined by the first day of cytarabine, whereas single agent hydroxyurea (HU) was labeled as pretreatment. We analyzed the influence of TDT on complete remission (CR), early death (ED) and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0-5, 6-10, 11-15 and & gt;15 days of TDT, and by using the restricted cubic spline (RCS) method for data modelling. In order to adjust for the influence of established prognostic variables on the outcomes, we used multivariable regression models and propensity score weighting. The influence of HU pretreatment on outcomes was investigated by introducing an interaction term between TDT and the presence of HU pretreatment. Results The median age was 59 years (y) (IQR 50-68), the proportion of pts with favorable, intermediate and adverse genetic risk according to ELN was 27%, 53%, and 20%; & gt;95% of pts received induction treatment with standard 7+3. HU pretreatment was administered in 4% of pts. The median TDT was 3 days (IQR 2-6). Descriptive statistics after grouping of pts showed the highest median age and the lowest proportion of NPM1 mutated and favorable risk in the TDT group 11-15. Of all pts, 79% achieved a CR/CRi; unadjusted CR rates for the patient groups with TDT of 0-5, 6-10, 11-15 and & gt;15 days were 80%, 77%, 74% and 76%, respectively (p=0.317). In multivariable analysis accounting for the influence of ELN risk, age, WBC, LDH, de novo versus secondary AML and ECOG, the OR for each additional day of TDT was 0.99 (95%-CI, 0.97-1.00; p=0.124). Four percent of pts died within the first 30 days from treatment start. The respective rates in the four TDT categories were 4.0%, 3.8%, 5.1% and 4.1% (p=0.960). In multivariable analysis, the OR for TDT was 1.01 (95%-CI, 0.98-1.05; p=0.549). After a median follow-up of 40 months, the 2-y OS of all pts was 51%. The unadjusted 2-y OS rates stratified by TDT of 0-5, 6-10, 11-15, & gt;15 days were 52, 49, 46, and 51% (see Table 1 and Figure 1). The hazard ratio (HR) for each day of treatment delay was 1.00 (95%-CI; 0.99-1.01; p=0.317). In multivariable Cox regression analysis, the HR for TDT as continuous variable was 1.00 (95%-CI, 0.99-1.01; p=0.689). When OS was analyzed separately stratified for age ≤60 and & gt;60 ys and for high versus lower initial WBC defined by a threshold of 50 x 109/L, no significant differences between TDT groups were observed. Multivariable models using TDT as a grouped variable or with RCS did not provide evidence for a significant influence of TDT on outcomes. Propensity score matching of pts in the four TDT groups did not reveal an influence on outcomes. The use of HU was not associated with CR, ED nor OS. Conclusion Our study on 2,200 newly diagnosed registry pts receiving consistent intensive induction with standard-dose cytarabine plus daunorubicin (7+3) suggests that TDT is not related to response or survival, neither in younger nor in older pts. Despite multivariable analyses, a bias towards longer TDT intervals in pts judged to be clinically stable by the treating physician cannot be excluded entirely. As treatment stratification in intensive first-line treatment of AML evolves, the TDT data suggests that it may be a safe and reasonable approach to wait for genetic and other laboratory test results in order to assign clinically stable pts to the best available treatment option before the start of intensive treatment. Disclosures Krämer: Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; BMS: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hänel:Roche: Honoraria; Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board. Jost:Daiichi: Honoraria; Sanofi: Honoraria; Gilead: Other: travel grants; Jazz Pharmaceuticals: Honoraria. Brümmendorf:Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; University Hospital of the RWTH Aachen: Employment; Ariad: Consultancy. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. Scholl:Novartis: Other: Project funding; Pfizer: Other: Advisory boards; Gilead: Other: Project funding; Daiichi Sankyo: Other: Advisory boards; AbbVie: Other: Advisory boards. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Kiani:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Middeke:Sanofi: Research Funding, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau; MSD: Consultancy. Thiede:AgenDix GmbH: Employment, Equity Ownership; Novartis: Research Funding, Speakers Bureau; Bayer: Research Funding; Daiichi-Sankyo: Speakers Bureau. Stoelzel:JAZZ Pharmaceuticals: Consultancy; Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding. Platzbecker:Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

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: 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: Overall survival remains poor in older patients with acute myeloid leukemia (AML) with less than 10% being alive after 5 years. In recent studies, a significant improvement in event-free, relapse-free and overall survival was shown by adding gemtuzumab ozogamicin (GO), a humanized antibody-drug conjugate directed against CD33, to intensive induction therapy once or in a sequential dosing schedule. Glasdegib, the small-molecule inhibitor of smoothened (SMO), also showed improved overall survival in patients not eligible for intensive chemotherapy when combined with low-dose cytarabine compared to low-dose cytarabine alone. These findings warrant further investigations in the phase III GnG trial. Methods/Design This is a randomized phase III trial with measurable residual disease (MRD) after induction therapy and event-free survival (EFS) as primary endpoints. The two research questions are addressed in a 2 by 2 factorial design. Patients age 60 years and older are upfront randomized 1:1 in one of the two induction arms: GO administered to intensive induction therapy on days 1,4, and 7 versus GO administered once on day 1 (GO-147 versus GO-1), and double-blinded 1:1 in one of the subsequent treatment arms glasdegib vs. placebo as adjunct to consolidation therapy and as single-agent maintenance therapy for six months. Chemotherapy backbone for induction therapy consists of standard 7 + 3 schedule with cytarabine 200 mg/m 2 continuously days 1 to 7, daunorubicin 60 mg/m 2 days 1, 2, and 3 and high-dose cytarabine (1 g/m 2 , bi-daily, days 1, 2, and 3) for consolidation therapy. Addressing two primary endpoints, MRD-negativity after induction therapy and event-free survival (EFS), 252 evaluable patients are needed to reject each of the two null hypotheses at a two-sided significance level of 2.5% with a power of at least 85%. Ethics and dissemination Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. Trial status Protocol version: 1st version 20.10.2020, no amendments yet. Study initiation on February 16, 2021. First patient was recruited on April 1st. Trial registration ClinicalTrials.gov NCT04093505 ; EudraCT 2019-003913-32. Registered on October 30, 2018.

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: Abstract 497 Background: The ratio of the FLT3-ITD mutation to the wt-FLT3 allele has significant prognostic importance in FLT3-ITD mutated acute myeloid leukemia (AML). Patients with a high mutant/wt ratio above 0.78 have significantly shorter overall (OS) and disease-free survival (DFS), whereas survival in patients with ratios below 0.78 did not differ from those without FLT3 aberrations (Thiede C et al, Blood 2002). There is still uncertainty about the role of allogeneic transplantation (allo-SCT) in the treatment of patients with FLT-ITD mutations (FLT3-ITD+). In order to prove the presence of an allogeneic effect, we compared the survival after allo-SCT in first remission in patients with a mutant rate 〈 0.8 with those ≥ 0.8. For comparison, the results in patient cohorts treated with chemotherapy alone were analyzed. Patients and Methods: Patients diagnosed with AML, aged 18–60 years, and treated in the AML-2003 trial of the SAL Study Alliance Leukemia were analyzed. According to the risk-adapted treatment strategy of the trial, cytogenetically intermediate-risk (IR) and adverse-risk (AR) patients should receive an allo SCT as consolidation treatment if an HLA-matched-sibling donor (IR) or HLA-matched related or unrelated donor (AR) was available. Patients with no available donor received high-dose cytarabine-based consolidation or autologous SCT. Survival analyses were performed using the Kaplan-Meier method including log-rank tests for significance testing. Results: Of 1182 patients enrolled in the AML-2003 trial between December 2003 and November 2009, 257 were FLT3-ITD+ (22%). The ratio of the FLT3-ITD mutation to the wt-FLT3 allele was 〈 0.8 in 182 patients (low-ratio) and ≥ 0.8 in 75 patients (high-ratio). 47 (26%) of the low-ratio group and 30 (40%) of the high-ratio group received an allogeneic transplantation. In the cohorts having received an allogeneic transplantation, the 3-year DFS in the low- and high-ratio groups was 58% and 50%, respectively (p=0.53). The 3-year OS was 61% and 59%, respectively (p=0.47). In the cohorts having chemotherapy as consolidation, the 3-year DFS in the low- and high-ratio groups was 36% and 10%, respectively (p 〈 0.001). The 3-year OS was 43% and 11%, respectively (p 〈 0.001). Conclusions: According to our results, allo-SCT in patients with a high allelic ratio of FLT3-ITD mutation led to an overall and event-free survival comparable with those with a low allelic ratio. In patients who received chemotherapy as consolidation and no allogeneic transplantation significant differences in DFS and OS could be shown between patients with a high vs. low ratio confirming our results obeserved in the previous AML96 study. These data point towards a strong graft versus leukemia effect after transplantation thus abrogating the negative impact of a high allelic ratio seen after conventional therapeutic appoaches. Disclosures: No relevant conflicts of interest to declare.

Abstract: Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are among the most frequent alterations in acute myeloid leukemia (AML) and can be found in ∼20% of patients at diagnosis. Among 4930 patients (median age, 56 years; interquartile range, 45-66) with newly diagnosed, intensively treated AML, we identified IDH1 mutations in 423 (8.6%) and IDH2 mutations in 575 (11.7%). Overall, there were no differences in response rates or survival for patients with mutations in IDH1 or IDH2 compared with patients without mutated IDH1/2. However, distinct clinical and comutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with increased age, lower white blood cell (WBC) count, less frequent comutation of NPM1 and FLT3 internal tandem mutation (ITD) as well as with lower rate of complete remission and a trend toward reduced overall survival (OS) compared with other IDH1 mutation variants and wild-type (WT) IDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC count, more karyotype abnormalities, and less frequent comutations of NPM1 and/or FLT3-ITD. Among patients within the European LeukemiaNet 2017 intermediate- and adverse-risk groups, relapse-free survival and OS were significantly better for those with IDH2-R172K compared with WT IDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific comutation pattern and favorable outcome. In summary, the presented data from a large cohort of patients with IDH1/2 mutated AML indicate novel and clinically relevant findings for the most common IDH mutation subtypes.