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.

Abstract: The presence of a mutated nucleophosmin-1 gene (NPM1 mut ) in acute myeloid leukemia (AML) is associated with a favorable prognosis. To assess the predictive value with regard to allogeneic stem-cell transplantation (SCT), we compared the clinical course of patients with NPM1 mut AML eligible for allogeneic SCT in a donor versus no-donor analysis. Patients and Methods Of 1,179 patients with AML (age 18 to 60 years) treated in the Study Alliance Leukemia AML 2003 trial, we identified all NPM1 mut patients with an intermediate-risk karyotype. According to the trial protocol, patients were intended to receive an allogeneic SCT if an HLA-identical sibling donor was available. Patients with no available donor received consolidation or autologous SCT. We compared relapse-free survival (RFS) and overall survival (OS) depending on the availability of a suitable donor. Results Of 304 eligible patients, 77 patients had a sibling donor and 227 had no available matched family donor. The 3-year RFS rates in the donor and no-donor groups were 71% and 47%, respectively (P = .005); OS rates were 70% and 60%, respectively (P = .114). In patients with normal karyotype and no FLT3 internal tandem duplication (n = 148), the 3-year RFS rates in the donor and no-donor groups were 83% and 53%, respectively (P = .004); and the 3-year OS rates were 81% and 75%, respectively (P = .300). Conclusion Allogeneic SCT led to a significantly prolonged RFS in patients with NPM1 mut AML. The absence of a statistically significant difference in OS is most likely a result of the fact that NPM1 mut patients who experienced relapse responded well to salvage treatment. Allogeneic SCT in first remission has potent antileukemic efficacy and is a valuable treatment option in patients with NPM1 mut AML with a sibling donor.

Abstract: Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPAbi and 109 CEBPAsm (60 affecting the N-terminal transactivation domains [CEBPAsmTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPAsmbZIP] ). Interestingly, patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 109/L and 35.7 × 109/L) than patients with CEBPAsmTAD (median age, 63 years, median WBC 13.1 × 109/L; P & lt; .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs 6.7% CEBPAsmTAD; P & lt; .001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs 38.3% CEBPAsmTAD; P & lt; .001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf). When patients were classified according to CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and non-CEBPAbZIP-inf), only patients bearing CEBPAbZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation.

Abstract: Background Double induction using two subsequent 7+3 regimens of cytarabine plus anthracycline is commonly performed in AML patients with an adequate performance status in order to maximize dose intensity upfront. However, for patients with a good early response at day 15 of first induction, there is no prospective randomized evidence on the necessity or value of a second induction cycle. Aims In order to answer the question if good responders of the first 7+3 induction could be spared a second induction cycle, we set up randomized-controlled SAL DaunoDouble trial. The study prospectively assesses the outcome of patients with a good early response with respect to the number of induction cycles (single versus double). We assumed non-inferiority of single induction in terms of complete remission (CR/CRi) rate, based on a margin of 7.5%. Here, we present the results of the planned interim analysis. Methods Patients (pts) 18-65 years with newly diagnosed AML, normal cardiac and organ function received a first induction cycle with seven days of cytarabine plus three days of daunorubicin ("7+3"). Response assessment in bone marrow was done on day 15 after the initiation of chemotherapy and confirmed by central review. A blast count & lt;5% was defined as good response. Pts with good response were randomized to receive a second induction cycle (arm D) or no second induction cycle (arm S). Primary endpoint was CR/CRi after completion of induction, secondary endpoints were RFS, and OS. Results Between 2014 and 2020, 624 evaluable pts were enrolled and received the first induction cycle with 7+3. A marrow blast clearance below 5% on day 15 was achieved in 298 pts (48%), providing eligibility for randomization. Of these patients, 150 were randomized into arm S and 148 into arm D, respectively. Median age was 52 years, 92% had de novo AML, NPM1 mutation was present in 53%, FLT3-ITD in 25% of pts. Favorable, intermediate and adverse risk (ELN 2017) were present in 56%, 34% and 10% of pts, respectively. CR/CRi rates at the end of induction were 86% after single induction and 85% after double induction. The CR/CRi rates in 224 pre-defined per-protocol pts were 88% versus 91%, resulting in a CR difference of 3% (95%-CI -0.047-0.111; p for non-inferiority test 0.145). After a median follow-up time of 24 months, RFS was slightly but not significantly lower after single induction with a 3-year RFS of 53% versus 64% (HR 1.4, p=0.125), whereas no differences were seen in 3-year OS, with a of rate of 74% versus 75% (HR 1.1, p=0.645) after single versus double induction. Conclusion The interim analysis results show that in good responders, the difference between CR rates after single versus double induction was even smaller than the predefined 7.5% margin, suggesting a trend for non-inferiority of single induction, although statistical significance was not reached. The trial continued recruitment. These findings suggest that in good responders, it may be safe to omit a second induction cycle if a second cycle poses a high risk. Figure. CR + CRi, RFS and OS after randomization to single versus double induction. Disclosures Alakel: Pfizer: Consultancy. Jost:Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; JAZZ: Other: travel support; Celgene: Other: travel support. Novak:Roche: Consultancy; Janssen: Other: Travel expenses; Takeda: Consultancy; Amgen: Consultancy, Other: Travel expenses; Pfizer: Consultancy; Novartis: Consultancy. Krause:Takeda: Honoraria; Celgene: Other: Travel Support; MSD: Honoraria; Pfizer: Honoraria; Siemens: Research Funding; Gilead: Other: Travel Support. Held:Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; MSD: Consultancy; Acrotech: Research Funding; Spectrum: Research Funding; Amgen: Research Funding. Platzbecker:AbbVie: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Thiede:AgenDix GmbH: Other: Co-owner and CEO. Müller-Tidow:Daiichi Sankyo: Research Funding; Pfizer: Research Funding, Speakers Bureau; BiolineRx: Research Funding; Janssen-Cilag GmbH: Speakers Bureau.

Abstract: Background: Measurable residual disease (MRD) can identify patients (pts) with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in complete hematological remission (CR) at high risk of relapse even after allogeneic hematopoietic stem cell transplantation (HSCT). We have recently shown in 53 pts treated within the first cohort of the RELAZA2 trial that pre-emptive therapy with azacitidine (AZA) at the time of MRD-positivity (MRDpos) can successfully prevent imminent hematological relapse (Platzbecker et al. Lancet Oncol. 2018). We now report on the results of the second cohort of 41 pts undergoing MRD-guided treatment in the RELAZA2 trial (ClinicalTrials.gov NCT01462578) by the Study Alliance Leukemia (SAL). Methods: Between 2015 and 2018, 166 MDS/AML pts were screened and centrally monitored for MRD in bone marrow or peripheral blood at monthly intervals for a period of 2 years prospectively in 9 centers in Germany. Of these 166, 41 pts with either advanced MDS (n=6) or AML (n=35) in CR after either conventional chemotherapy only (n=13) or consecutive allogeneic HSCT (n=28) developed MRD above a threshold defining imminent hematological relapse. Still being in morphological CR, these pts pre-emptively received 6 cycles of AZA (75mg/m2, s.c. days 1-7), which was followed by a risk-adapted AZA-maintenance therapy based on MRD-response for up to 18 additional months. Pts developing a hematological relapse went off study. MRD was detected by either the quantification of NPM1 mutation level (n=19), leukemia-specific fusion genes DEK-NUP214 (n=1) or RUNX1/RUNX1T1 (n=2) or a sensitive donor chimerism analysis of sorted CD34(+)/CD117(+) peripheral blood cells (n=28) in pts undergoing allogeneic HSCT. Here, we report the analysis of the primary endpoint of the 41 pts in the second cohort as well as the data for the entire 94 pts who entered the treatment phase of the RELAZA-2 study. Results: At a median of 110 days (range 28-476) after start of screening, 41 (25%) out of 166 prospectively screened pts became MRDpos as defined by either a decrease of CD34(+)/CD117(+) donor chimerism to & lt;80% (n=23) or a detectable mutation level & gt;1% (NPM1 n=18) while being still in hematological CR. All of these MRDpos pts started AZA-based pre-emptive treatment to prevent imminent hematological relapse. Six months after start of MRD-guided therapy, 25 out of 41 pts were still in CR (61%, 95%-CI 45-76%, p & lt;0.001, one-sided binomial test for H0: pexp≤0.3) while a total of 15 pts (37%) developed hematologic relapse after median of 3 AZA cycles. In fact, 19 pts (46%) responded with either a decline of MRD below a predefined threshold (increasing CD34(+) donor chimerism to ≥80% or mutation level & lt;1%), while a stabilization in the absence of relapse was achieved in 6 pts (15%). Overall response rate was not statistically different between pts with (57%) or without (69%) antecedent allogeneic HSCT (p=0.5). After 6 months of initiation of MRD-guided treatment, 21 pts (51%) continued to receive a median of 6 (range 1-15) subsequent AZA cycles. Eventually, hematologic relapse occurred in 6 of those pts (29%), but was delayed until a median of 320 days (range 219-375 days) after initial MRD detection. With a median follow-up of 9 months after start of MRD-guided pre-emptive treatment the 12-months overall and progression free survival rate is 94% and 44%, respectively. When combining results for the primary endpoint with the first cohort, the 6 months relapse free survival for all 94 pts was 60% (56/94 pts.; 49-70%; p & lt;.001 one-sided binomial test for H0: pexp≤0.3; Fig. 1). Conclusion: These multicenter prospective data provide further strong evidence that continuous MRD monitoring is feasible and can identify MDS/AML pts at high risk of hematological relapse. Pre-emptive MRD-guided therapy with AZA is an effective treatment to prevent or at least substantially delay hematologic relapse in these pts. Disclosures Platzbecker: Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Wolf:Celgene: Honoraria, Research Funding; Abbvie: Honoraria. Krämer:Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding. Bug:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Hexal: Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Sanofi: Other: travel grants; Celgene Neovii: Other: travel grant. Götze:AbbVie: Membership on an entity's Board of Directors or advisory committees. Stelljes:Novartis: Honoraria; Amgen: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; MDS: Consultancy. Subklewe:AMGEN: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Miltenyi: Research Funding; Oxford Biotherapeutics: Research Funding; Janssen: Consultancy; Roche: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Morphosys: Research Funding. Hänel:Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Amgen: Honoraria; Roche: Honoraria. Dührsen:Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Alexion: Honoraria; Takeda: Consultancy, Honoraria; Teva: Honoraria; Celgene: Research Funding; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Janssen: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; CPT: Consultancy, Honoraria. Müller-Tidow:MSD: Membership on an entity's Board of Directors or advisory committees. Thiede:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; AgenDix GmbH: Employment, Equity Ownership.

Abstract: Background: Most patients (pts) diagnosed with Acute Myeloid Leukemia (AML) are older than 60 years. Although intensive induction chemotherapy in medically fit pts is still the standard practice and a prerequisite for long-term survival, elderly pts have a higher risk of treatment related morbidity and lower remission rates than younger AML pts. An optimized induction treatment would combine high complete remission (CR) rates with tolerable toxicity. The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) has been reported to result in high CR rates (73.5%) with acceptable toxicity in 86 elderly AML pts (Niederwieser et al., Blood 2002, abstr. 1337). We present the mature final results of a randomized-controlled trial comparing efficacy and tolerability of IMA with the standard 7+3 induction regimen consisting of daunorubicin plus cytarabine (DA). Patients and Methods: In the 60+ trial of the Study Alliance Leukemia (SAL), AML pts 〉 60 years and medically fit for chemotherapy were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 BID days 1,3,5,7) plus mitoxantrone (10 mg/m2 days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1-7) plus daunorubicin (45 mg/m2 days 3-5) (DA). All pts in CR after DA received intermediate-dose cytarabine plus amsacrine (MAMAC) as consolidation treatment, whereas pts in CR after IMA were consolidated with standard-dose cytarabine plus mitoxantrone (2+5). Primary study endpoint was the CR rate with an expected difference of 15% in favor of IMA. Secondary endpoints were the incidence of serious adverse events (SAEs), time to relapse (TTR), relapse-free survival (RFS), and overall survival (OS). Results: Between February 2005 and October 2009, 852 pts were screened for study inclusion and 485 pts started study treatment, of which 241 pts were randomized for treatment arm A (DA) and 244 for treatment arm B (IMA). The median age was 69 years. Pt characteristics were equally distributed between the two arms. According to a strict definition, all patients with early death, study drop-out, or failed remission assessment were categorized as being not in CR. The CR rate amongst all 485 pts treated in the study was 47%. The CR rate after DA was 39% (95%-CI; 33-45) versus 55% (95%-CI; 49-61) after IMA (OR 1.89, p=0.001). If all first CRs were taken into account including those achieved after trial discontinuation, the CR rates after DA versus IMA induction were 55% versus 64% (p=0.043). Separate analyses addressing age, cytogenetics, de novo AML, NPM1 and FLT3-ITD confirmed higher CR rates after IMA induction throughout these subgroups. Six-week mortality was 14% in both arms. The median duration of ≥ grade 3 neutropenia was 23 days after DA I and 25 days after IMA (p=0.031). The median duration of thrombocytopenia ≥ grade 3 was 16 versus 20 days after DA I and IMA I, respectively (p 〈 0.001). The incidences of non-hematologic toxicities were not significantly different except for a higher incidence of liver toxicity (odds ratio IMA/DA = 0.52; p=0.001) and gastrointestinal symptoms (OR IMA/DA = 0.62; p=0.041) after DA. In the course of treatment, 11 pts in each arm (5%) received allogeneic stem cell transplantation. After a median follow-up of 66 months, RFS curves are superimposable in the first year with a similar median RFS of 11 months and 10 months after DA and IMA, respectively. However, a separation of RFS curves developed with longer follow up, resulting in 1-year RFS rates of 45% versus 46%, but 3-year RFS rates of 29% versus 14% in the DA versus IMA arms, respectively (p=0.042). The median OS for all randomized pts was 10 months in both arms; 1-year and 3-year OS rates were 45% and 19% after DA versus 44% and 19% after IMA (p=0.513). Conclusion: The results indicate that elderly AML pts benefit from a dose escalation of cytarabine in induction therapy by significantly higher CR rates and similar toxicity compared to a standard 7+3 approach. In our trial, this did not translate into a survival advantage, most likely due to differences in consolidation treatment of the respective treatment arms. In combination with an effective consolidation strategy such as high-dose cytarabine or allogeneic transplantation, our current results favor the use of intermediate dose cytarabine in induction for pts with a curative AML treatment approach. Figure 1. CR rates depending on induction treatment Figure 1. CR rates depending on induction treatment Disclosures Einsele: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership. Platzbecker:Amgen, Inc.: Honoraria; GlaxoSmithKline: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Honoraria. Ehninger:Cellex GmbH: Equity Ownership.

Abstract: Mutations of the key myeloid transcription factor CCAAT/enhancer binding protein alpha (C/EBPa) are found in 5-10% of patients with acute myeloid leukemia (AML). Two mutational clusters exist, in the aminoterminal transcription activation domains (TAD1 or 2) and in the basic leucine zipper domain (bZIP) located at the carboxyterminal-part of the protein. Biallelic mutations (biCEBPA) have been found to be associated with improved outcome and are now included as an independent entity in the WHO-classification. In contrast, monoallelic CEBPA-mutations (moCEBPA) do not appear to provide prognostic information. We characterized a large cohort of AML patients for CEBPA mutations and further analyzed the mutational spectrum of mono- and biallelic CEBPA-mutant AML patients to better understand potential differences in the biology of these groups. Patients and Methods: Patients (including all age groups) analyzed had a newly diagnosed AML and were registered in clinical protocols of the Study Alliance Leukemia (SAL)(AML96, AML2003 or AML60+, SORAML) or the SAL-register. Screening for CEBPA mutations was done using PCR and capillary electrophoresis. All identified CEBPA mutations were confirmed using conventional Sanger sequencing and the samples were further analyzed using next generation sequencing (Trusight Myeloid Panel, Illumina) for the presence of associated alterations. Results: In the 4578 patients analyzed, 228 (5%) with CEBPA-mutations were identified. An initial analysis revealed substantial clinical differences between the different mutation subtypes. Patients with biCEBPA (n=111) were significantly younger (median age 46 yrs) than wt-CEBPA patients (median 57 yrs; p 〈 .001). Interestingly, single bZIP mutant patients (n=64) had a similar median age (50 yrs.) as biCEBPA, whereas single TAD mutant patients (n=53) were significantly older (median 63 yrs.). In addition, WBC counts, CD34 positivity as well as the history of prior MDS differed between the subgroups (single TAD mutant had significantly lower WBC counts, lower rate of CD34 positivity and had a higher rate of prior MDS than biCEBPA and single bZIP mutant patients). Along with this, the distribution of co-mutations differed significantly between the subgroups, especially GATA2 mutations were more common in biCEBPA and single bZIP mutant patients (37% and 34%, respectively) compared to only 3% (single TAD)(p=.001). A similar pattern was seen for mutations in DNMT3A (8% biCEBPA, 20% single bZIP vs. 36% single TAD; p=.001), and NPM1 (3% biCEBPA, 8% single bZIP, 32% single TAD; p 〈 .001). In 2897 patients, the different CEBPA mutations were correlated with outcome. This analysis indicated a differential effect of the individual mutations on outcome, with an improved rate of complete remission (CR), overall survival (OS) and event free survival (EFS) for biCEBPA and single bZIP mutations in univariate and multivariate analyses (shown for OS in Figure 1a). Given the similarity of single bZIP and biCEBPA mutations, it appears reasonable to speculate on a common mechanistical background, since most of the biCEBPA mutants include a bZIP alteration. Recent experimental evidence generated by several groups indeed supports a specific role of these bZIP missense mutations. To address this in the clinical context, we regrouped patients with mutant CEBPA into patients with (n=157) or without bZIP mutations (n=71), irrespective of the biallelic status. As illustrated in Figure 1b, the bZIP mutant group had a significantly better OS, similar results were obtained for EFS and CR. In multivariate analysis, the presence of a bZIP mutation was the strongest indicator for achievement of CR (HR 7.5, 95% CI: 3-19; p 〈 .001), and together with favorable cytogenetics the factor associated with best OS (HR: .48; 95% CI .36-.64; p 〈 .001). In conclusion, our results obtained in one of the largest cohorts of AML patients analyzed for CEBPA mutations indicate that especially the presence of a missense bZIP mutation is associated with a favorable outcome in AML patients. These data point to substantial differences in prognostic implications of individual CEBPA mutations and support the major functional divergence of these alterations. If confirmed, these results might necessitate further refinement of their use in AML-classification. Disclosures Middeke: Sanofi: Honoraria. Platzbecker:Janssen-Cilag: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Thiede:AgenDix: Employment, Other: Ownership.

Abstract: Background: So called triple-negative acute myeloid leukemias (AML) form a heterogeneous subgroup of intermediate-risk AML according to ELN criteria. Molecularly this group can be defined by the absence of internal tandem duplications (ITDs) in the fms related tyrosine kinase 3 gene (FLT3), wild type (wt) nucleophosmin gene (NPM1) and wt or single (homozygously or heterozygously) mutated CCAAT/enhancer binding protein α gene (CEBPA). To date, it remains unclear whether this group of patients benefits from allogeneic stem cell transplantation (alloSCT) as consolidation strategy in first complete remission (CR1). Aims: To evaluate the impact of alloSCT on the overall (OS) and relapse free survival (RFS) in patients with triple negative AML in first remission in comparison to post remission chemotherapy (PRT). Methods: We performed a subgroup analysis of 3041 AML patients aged 16-60 years who were enrolled into the AML 96 and the AML 2003 trials of the Study Alliance Leukemia (SAL). Selection criteria for this subgroup were NPM1 wt, negativity for FLT3-ITD and CEPBA double mutations, a karyotype that does not define the AML as favorable or adverse according to ELN criteria and the accomplishment of CR1. Status of molecular markers was evaluated with standard PCR techniques. Within the AML2003 trial, donor status was evaluated at study entry, making these data eligible for a donor-versus-no-donor analysis. Kaplan-Meier estimates were used to report on point estimates for survival probabilities. Multivariate Cox models were fitted to analyze the impact of alloSCT as time-dependent covariate. Age, gender, white blood cell count, lactate dehydrogenase, AML type (de novo, secondary AML following MDS or MPN, or therapy-related myeloid neoplasms) and ECOG performance status at diagnosis were selected as adjusting covariables. As-treated analyses used data from both trials, AML96 and AML2003. For these analyses alloSCT or PRT were entered as time-dependent covariates into extended Cox regression models. Survival outcomes were displayed with Simon-Makuch-plots. Results: In total, 497 patients (AML96: 217, AML2003: 280) with a median age of 47 years were evaluable for the analysis of OS from diagnosis. A total of 302 patients had reached CR1 and could be evaluated for RFS. In a multivariate donor-versus-no-donor analysis, OS of patients with a sibling donor was not significantly different to patients without a donor (HR 0.79, 95%CI 0.53 to 1.16, p=.2). Irrespective of whether the patient actually received alloSCT in CR1, the probability of OS at 5 years from study enrollment was 55% (95%CI, 45% to 67%) for patients with a sibling donor and 47% (95%CI, 40% to 54%) for patients without a donor. For RFS, the hazard ratio was 0.72 (95%CI, 0.5 to 1.05, p=0.09), with a trend in favor of better remission-control for patients with a sibling donor. At five years from CR1, RFS of patients with sibling donor was 48% (95%CI, 38% to 61%) compared to 36% (95%CI, 30% to 44%). However, the transplantation rate in the donor group was only 53% and 15% of patients in the no-donor group actually received alloSCT. Therefore, 'cross-over' effects lowered the power of donor-versus-no-donor analysis. In the multivariable as-treated analysis including patients from AML96 and AML 2003, OS and RFS of patients with alloSCT were significantly longer (OS: HR 0.58, 95%CI, 0.37 to 0.9, p=.02, RFS: 0.51, 95%CI, 0.34 to 0.76, p=0.001) compared to the PRT group. The probability of OS at 5 years from initiation of consolidation treatment (alloSCT vs. PRT) was 66% (95%CI, 57% to 76%) for patients who received alloSCT compared to 46% (95%CI, 38% to 55%) for PRT patients. The probability of RFS at 5 years from initiation of consolidation treatment was 55% (95%CI, 46% to 67%) for alloSCT patients and 31% (95%CI, 24% to 39%) for PRT patients. Conclusions: Due to cross-over effects which limit the power of the donor-versus-no-donor analysis we give more weight to the results of the as-treated analysis. This analysis suggests that eligible intermediate-risk AML patients with NPM1 wt and absent FLT3-ITD benefit from alloSCT in CR1. However, bias introduced by selection and confounding factors cannot be excluded for this type of analysis and could only be circumvented in randomized controlled trials. Disclosures Thiede: AgenDix: Employment, Other: Ownership. Rösler:Janssen: Consultancy, Other: Travel/Accommodation/Expenses. Middeke:Sanofi: Honoraria. Schetelig:Sanofi: Honoraria.

Abstract: Background: Monitoring of measurable residual disease (MRD) in patients (pts) with advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who achieve complete remission (CR) can predict hematological relapse. Recently published data from the first cohort of the RELAZA2-trial have shown that pre-emptive therapy with azacitidine (AZA) can prevent or substantially delay an overt relapse in MRD-positive pts with MDS or AML (Platzbecker et al. Lancet Oncol. 2018). Aims: To evaluate outcome of the entire patient cohort of the RELAZA2-trial and determine whether MRD-guided pre-emptive AZA treatment could prevent relapse in molecularly defined cohorts. Methods: Between 12/2011 and 07/2018 380 pts with advanced MDS or AML, who had achieved CR after conventional chemotherapy or allogeneic hematopoietic stem-cell transplantation (allo-HCT) were prospectively screened for MRD in monthly intervals either in bone marrow (BM) or peripheral blood (PB). A total of 94 pts (AML, n=83; MDS, n=11) became MRD positive during 24 months from baseline by either quantitative PCR (qPCR) or analysis of CD34+ donor-chimerism and entered the treatment phase. Preemptive MRD-triggered treatment consisted of AZA 75 mg/m2 per day subcutaneously on days 1-7 of a 29-day cycle for up to 24 cycles. After six cycles, MRD status was reassessed and pts with MRD negativity were eligible for treatment de-escalation. Primary endpoint was relapse-free survival (RFS) six months after start of pre-emptive treatment. For mutational analysis next generation sequencing (NGS) with a panel of 54 genes was performed (Illumina Trusight Myeloid). Results: Median age was 60 yrs (range: 22-80 yrs); 52 (55%) of the pts were female. Prior therapy consisted of chemotherapy in 42 (45%) and allo-HCT in 52 (55%) of the pts. Cytogenetics could be analyzed in 93 (99%) of the 94 pts. Risk categorization according to ELN 2017 was favorable in 30 (37%), intermediate in 31 (38%) and adverse in 21 (26%) of the AML pts, respectively. Type of MDS was advanced in all 11 pts and all were previously transplanted. Fifty-two (61%) of 85 pts with available NPM1 status were positive. NGS on 64 (68%) pts with available DNA at the time of first diagnosis revealed additional mutations in DNMT3A (n=25), TET2 (n=15), FLT3-ITD (n=12), IDH1 (n=9), FLT3-TKD (n=8), ASXL1, NRAS, TP53 (n=7, each), IDH2 (n=6), PTPN11, WT1 (n=5, each), GATA2, U2AF1 (n=4, each), CBL (n=3), CEBPA, CSFR3, CUX1, EZH2, KIT, RAD21, RUNX1, SF3B, STAG2, ZRSR2 (n=2, each), and KRAS (n=1). MRD data were correlated with outcome in 45 pts for NPM1, in 3 for RUNX1-RUNX1T1, whereas CD34-donor-chimerism was analyzed in 39 pts (missing, n=7). There was a significant faster and deeper decline of MRD in PB as compared to BM (P=0.03). The same held true with regard to the increase of donor-chimerism, which was achieved faster in PB as compared to BM (P=0.05). Secondary molecular abnormalities (MAs) had no impact on MRD response as measured by qPCR, which was also true if MAs were categorized functionally. Similarly, additional chromosomal abnormalities had no impact on MRD response in both MRD methods. However, in pts with measurement of donor-chimerism ASXL1 mutations were a negative factor for MRD response (P & lt;0.001). At hematological relapse, only 1 (2%) of 45 pts with NPM1 measurement was not congruently MRD positive. Six months after start of MRD-guided therapy, 56 (60%) of 94 pts were still in CR while a total of 38 pts (40%) developed a hematological relapse after median of 3 AZA cycles. 38 (40%) pts responded with either a decline of MRD below a predefined threshold (increasing donor-chimerism to ≥80% or PCR MRD & lt;1%), while a stabilization in the absence of relapse was achieved in 18 (19%) pts. Overall response rate was not statistically different between pts with (63%) or without (55%) antecedent allo-HCT (P=0.5). RFS rate at 6 months was 60% (56/94 pts). With a median follow-up of 9 months after start of MRD-guided pre-emptive treatment 12-months overall and progression-free survival rates were 94% and 44%, respectively. Conclusions: AZA as a pre-emptive therapy was effective in delaying hematological relapse of advanced MDS or AML pts, regardless of the underlying genetic signature. Based on these encouraging results, intensifying treatment with AZA in combination with pembrolizumab is currently investigated as MRD-guided treatment in NPM1 positive AML (PEMAZA; ClinicalTrials.gov Identifier: NCT03769532). Disclosures Wolf: Celgene: Honoraria, Research Funding. Bug:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hexal: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Eurocept: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Jazz: Honoraria; Neovii: Other: Travel; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Sanofi: Other: Travel. Götze:Celgene: Research Funding. Stelljes:Amgen: Consultancy, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Subklewe:Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Morphosys: Research Funding; Janssen: Consultancy; AMGEN: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding. Haenel:Amgen, Novartis, Roche, Celgene, Takeda, Bayer: Honoraria. Rollig:Amgen, Astellas, BMS, Daiichi Sankyo, Janssen, Roche: Consultancy; Abbvie, Novartis, Pfizer: Consultancy, Research Funding. Müller-Tidow:Pfizer: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; BiolineRx: Research Funding; Janssen-Cilag GmbH: Speakers Bureau. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria. Thiede:AgenDix GmbH: Other: Co-owner and CEO. OffLabel Disclosure: Off-label: treatment with azacitidine to prevent or substantially delay an overt relapse in MRD-positive patients with MDS or AML

Abstract: Not available.