Abstract: Abstract 255 Introduction: Standard treatment of acute myeloid leukemia (AML) comprises one or two cycles of chemotherapy to induce complete remission (CR) followed by postremission treatment in order to prevent relapse of the disease (consolidation therapy). In 2003, we initiated a prospective multicenter randomized trial to investigate the impact of different consolidation strategies on long-term outcome in AML patients ≤ 60 years. Consolidation options comprised upfront allogeneic stem cell transplantation (allo SCT) in aplasia after induction therapy, autologous SCT, and three cycles of standard high-dose-cytarabine-based consolidation. For patients receiving high-dose cytarabine, the main study aim was to evaluate the benefit of adding additional mitoxantrone and amsacrine to cytarabine consolidation. Design: From 2003 to 2009, 1182 patients (median age, 48 years; range 16–60 years) with untreated AML were randomly assigned at diagnosis to different consolidation strategies after classical 7+3 induction. According to the risk-adapted treatment strategy of the trial, cytogenetically or molecular intermediate-risk (IR) and adverse-risk (AR) patients should receive an allo SCT as consolidation treatment if an HLA-identical-sibling donor (IR) or HLA-matched related or unrelated donor (AR) was available. IR and AR patients with no available donor should receive autologous SCT. All favorable risk patients and patients with no available donor were scheduled for high-dose cytarabine based consolidation. Half of the patients were randomized for high dose cytarabine based consolidation. Half of the patients were randomized for high dose cytarabine alone while the other half received high dose cytarabine with the addition of amsacrine and mitoxantrone. Standard chemotherapy consisted of three cycles with high dose cytarabine (2 × 3 g/m2, day 1,3,5) whereas combined consolidation contained two cycles of MAC (cytarabine 2 × 1g/m2, day 1–6, mitoxantrone 10 mg/m2, day 4–6) plus one cycle of MAMAC (cytarabine 2 × 1 g/m2, day 1–5, amsacrine 100 mg/m2, day 1–5). In order to evaluate the effect of the two cytarabine based consolidation strategies, we determined overall survival (OS) and event free survival (EFS) using the method of Kaplan Meyer. Survival distributions were compared using the log rank test. Results: 1182 patients were randomized for further intervention (Arm A+B: n=582, 49.3%; Arm C+D: n=600, 50.7 %). Median follow-up was 41.4 months (95%-CI 39.3–43.6). A total number of 375 patients received allogeneic (n=322) or autologous SCT (n=53) and 807 patients were consolidated with cytarabine. Of these patients, 407 were randomized for cytarabine alone and 400were randomized to receive cytarabine plus mitoxantrone and amsacrine (MAC/MAC/MAMAC). Complete remission rate (CR) after second induction therapy was 59.1% (n=698). Between the four arms, there were no significant differences of the CR rates. Five-year OS of patients receiving high dose cytarabine alone was 47.1% (95%-CI 42.0–52.2%), for patients receiving MAC/MAMAC as consolidation therapy it was 46.8% (95%-CI 42.3–51.3%; p = 0.610). Three-year event free survival (EFS) was also not significant with 30.5% (95%-CI 26.6–34.4%) for patients receiving high dose cytarabine alone and 35.6% (95%-CI 31.7–39.5%; p = 0.059) for patients receiving MAC/MAMAC. Conclusions: According to our data, the addition of mitoxantrone and amsacrine to high dose cytarabine consolidation confers no benefit for treatment outcome in younger AML patients. Disclosures: No relevant conflicts of interest to declare.

Abstract: Purpose Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are one of the most frequent alterations in acute myeloid leukemia (AML) and can be found in ~20% of patients at diagnosis. Several IDH inhibitors are currently in late stage clinical development with Enasidenib, an IDH2 inhibitor, being recently approved by the FDA. Previous analyses have reported differential impact on response to chemotherapy and outcome, depending on the IDH-mutation type, co-occurring mutations and cytogenetic abnormalities, as well as the variant allele frequency (VAF) of IDH mutations. In order to better understand its prognostic role, we analyzed newly diagnosed AML patients enrolled in prospective trials of the Study Alliance Leukemia (SAL) to investigate the impact of IDH1/2 mutations on outcome. Patients and Methods All AML patients consecutively enrolled into intensive AML treatment protocols of the SAL or into the SAL registry were included in this analysis. Next-generation sequencing (NGS) on an Illumina MiSeq-system was performed to detect IDH1/2 mutations using pre-treatment samples. Overall survival (OS) and response to therapy were analyzed for all patients with intensive treatment and according to the mutational status. Results Overall, samples of 3898 patients were analyzed. The median follow-up was 91 months (95% CI 87.2 - 93.9). Patients' characteristics are shown in Tbl.1. Three-hundred twenty-nine patients (8.4%) had IDH1 mutations and 423 (11%) had IDH2 mutations; both mutations were found in 12 pts, so the overall mutation rate in IDH1 and 2 was 19% (740/3898 patients). Of the IDH1 variants, the most common ones were the R132C found in 143 patients (43%) and R132H in 137 patients (42%). For IDH2, 324 patients had the R140Q (77%) and 80 patients the R172K (19%) variant. According to the two main variants of the more common IDH2 mutations, as reported before, the IDH2 R172K was mutually exclusive with NPM1 and/or FLT3-ITD mutations. Overall, there was a trend for increased OS for patients with IDH2 R172K (26 vs. 15 months) as compared to those with R140Q. Considering only patients with a normal karyotype and no NPM1/FLT3-ITD mutation, these patients (n=27) had a highly significant better OS than patients with IDH2 R140Q (46.3 vs. 13.1 months, p=.012), supporting the findings published by Papaemmanuil et al. (NEJM 2016). In IDH1-mutated patients, we observed statistically significant differences in baseline characteristics between the two most common mutation types, IDH1 R132C and R132H. Patients carrying the R132C mutation were older (62 vs. 55 years, p=.001), had lower WBC (3.6 vs. 21 Gpt/L, p≤.001) and were less likely to have a normal karyotype (43% vs. 66%, p=.002), NPM1 (23% vs. 66%, p= 〈 .001), and FLT3-ITD mutations (8% vs. 27%, p 〈 .001) than those with the R132H variant. In univariate testing, the CR rate was also statistically significant lower in patients with IDH1 R132C (53% vs. 72%, p≤.001), with a median OS of 12.9 months compared to 17.4 months for patients with R132H variant (p=.08). In multivariate analysis including age, WBC, NPM1 and FLT3 status, and ELN risk, the CR rate was significantly lower in patients with the IDH1 R132C variant (p=.038). The median IDH VAF was 38% (range, 0.1 - 58) with no difference according to the different types of mutation. Patients with a VAF 〉 30% had a significantly higher BM blast count (73% vs 40% for VAF≤5%) and WBC (21.2 Gpt/L vs. 3.7 Gpt/L) at baseline, but there was no clear impact on CR rate or OS found in multivariate analysis. Conclusion In this large cohort of AML patients with IDH1/2 mutations, we found significant and so far not reported differences for one of the two most prominent mutations types of IDH1. The R132C variant was associated with increased age, lower WBC, and lower NPM1 and/or FLT3 co-mutation rate. Further, these patients had lower CR rates and a trend for shorter OS. For IDH2 we were able to reproduce findings on co-mutations and showed a favorable outcome for intensively treated patients with a normal karyotype and no NPM1/FLT3-ITD mutation and the IDH2 R172K variant, providing additional evidence for classification as a separate AML entity. Disclosures Middeke: Roche: Membership on an entity's Board of Directors or advisory committees; 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. Rollig:Bayer: Research Funding; Janssen: Research Funding. Kramer:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Daiichi Sankyo: Consultancy. Scholl:Alexion: Other: Travel support; Abbivie: 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; MDS: Other: Travel support; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Incyte: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Brümmendorf:Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Novartis: Consultancy, Research Funding. Burchert:Novartis: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Takeda: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Johnson & Johnson: Research Funding; Roche: Research Funding; Eisai: Research Funding; Affimed: Research Funding; Novartis: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Schetelig:Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Consultancy, Honoraria; Roche: Honoraria; Sanofi: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Stoelzel:Neovii: Speakers Bureau.

Abstract: Abstract 144 Background: Sorafenib is a multi-kinase inhibitor with activity against several oncogenic kinases, which may play a role in the pathogenesis of acute myeloid leukemia (AML). In-vitro data and results from non-randomized clinical trials suggest that sorafenib might be an effective drug for the treatment of AML. So far, no randomized-controlled data are available for treatment of newly diagnosed AML patients up to the age of 60 years. We present the first results from the randomized placebo-controlled SORAML trial of the Study Alliance Leukemia (SAL). Patients and Methods: Between March 2009 and October 2011, 276 patients from 25 centers were enrolled in the SORAML trial (NCT00893373). The main eligibility criteria were: newly diagnosed AML, age from 18 to 60 years and suitability for intensive therapy. The treatment plan for all patients included two cycles of induction with DA (daunorubicin 60 mg/m2 days 3–5 plus cytarabine 100 mg/m2 cont. inf. days 1–7), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 b.i.d. days 1, 3, 5). Patients without response after DA I received second induction with HAM (cytarabine 3 g/m2 b.i.d. days 1–3 plus mitoxantrone 10 mg/m2 days 3–5). Allogeneic stem cell transplantation was scheduled for all intermediate-risk patients in first complete remission with a family donor and for all high-risk patients with a matched donor. At study inclusion, patients were randomized to receive either sorafenib (800 mg/day) or placebo as add-on to standard treatment. Block randomization at a ratio of 1:1 was performed within cytogenetic and molecular risk strata, allocation was concealed and treatment was double blinded. Study medication was given on days 10–19 of DA I+II or HAM, from day 8 of each consolidation until 3 days before the start of the next consolidation and as maintenance for 12 months after the end of consolidation. The primary endpoint of the trial is event-free survival (EFS) with an event being defined as either failure to achieve a complete remission (CR) after induction, relapse or death. Secondary endpoints were overall survival (OS), CR rate and incidence of adverse events (AE). We present the results of the planned interim analysis (intent to treat) after the occurrence of 50% of EFS events. The O'Brien/Fleming adjusted significance level was set at p=0.0052. Results: Out of 276 randomized patients, 264 were evaluable for EFS, 132 in each arm. Demographic and disease characteristics were equally distributed between the two arms; the FLT3-ITD incidence was 16%. The median cumulative dose of administered study medication was equal in both arms. The CR rates were 56% versus 60% in the placebo versus sorafenib arm (p=0.622). By the time of analysis, a total number of 100 events had occurred. After a median observation time of 18 months, the median EFS was 12.2 months in the placebo arm and was not reached in the sorafenib arm, corresponding to a 1-year EFS of 50% versus 64% (p=0.023). The median OS had not been reached in both arms, the 2-year OS was 66% versus 72% in placebo and sorafenib arms, respectively (p=0.367). The most common reported AEs CTC Grade ≥3 were infectious complications including fever and pneumonia, followed by bleeding events, cardiac and hepatic toxicity, hypertension, skin toxicity and headache. The risk for hepatic toxicity (relative risk 6.2, p=0.025) and bleeding events (relative risk 3.6, p=0.016) was significantly higher in the sorafenib arm while the incidence of all other AEs showed no significant differences. Conclusions: In younger AML patients, the addition of sorafenib to standard chemotherapy is feasible but associated with a higher risk of liver toxicity and bleeding events. Sorafenib treatment resulted in a marked EFS prolongation; this difference is not significant according to the adjusted significance level of this interim analysis. Results from the final analysis including post-hoc exploration of molecularly defined subgroups are necessary for drawing final conclusions on the efficacy of sorafenib. Disclosures: Off Label Use: sorafenib for the treatment of acute myeloid leukemia. Serve:Bayer: Research Funding. Ehninger:Bayer: Research Funding.

Abstract: Background: Standard therapy of acute promyelocytic leukemia has long relied on the combination of All-trans-retinoic acid (ATRA) and chemotherapy. The introduction of arsenic trioxide (ATO) in APL treatment has allowed achievement of similarly high remission and survival rates coupled with significantly reduced myelosuppression. Recent results of the APL0406 trial by the GIMEMA-AMLSG-SAL study groups showed that the combination of ATRA and arsenic trioxide (ATO) is superior to standard ATRA and chemotherapy (CHT) in front-line therapy of low/intermediate risk acute promyelocytic leukemia (APL). The implications of these results for the clinical practice of APL patients in Germany have been uncertain given the fact that ATO is not formally licensed for front-line therapy of APL. Aim:In order to provide evidence and a reflection of the clinical reality of APL patient care in Germany an intergroup APL registry (National acute promyelocytic leukemia (APL) observational study, NAPOLEON) was recently initiated by several AML study groups. Methods:Eligible patients are adults at least 18 years of age with newly diagnosed or relapsed APL not beyond the first year of diagnosis. Here we report the first analysis on the series of patients prospectively enrolled into this registry. The study was conducted in accordance with the Declaration of Helsinki, received IRB approval by all participating centers and was registered at ClinicalTrials.gov (NCT02192619). Results: As of August 1st 2016, 88 patients have been included into the study with a median age of 57 years (range 22-87). All had newly diagnosed APL (100%) with 66% (n=58) being of low/intermediate risk according to the Sanz score. Out of those patients 76% (n=44) received an ATO-ATRA based induction regimen followed by a median of 4 courses of consolidation (according to the APL 0406 study).Of 41 patients evaluable for response to induction, 40/41 (98%) patients achieved complete remission (CR) with the ATRA-ATO arms. Early death rate within 30 days of therapy was 2% (1/44). After a median follow-up of 12 months, the event-free survival, cumulative incidence of relapse and overall survival at 12 months for these patients were 97%, 0% and 97%, respectively. Therapy was well tolerated and no new safety signals have been obtained. Conclusion:These real life data from a prospective German registry provide further evidence for the safety and sustained anti-leukemic efficacy of ATRA-ATO in low/intermediate risk APL. These results further support ATRA-ATO as the new standard of care in this clinical setting. Table Demographic, clinical and laboratory characteristics of the eligible patients. Table. Demographic, clinical and laboratory characteristics of the eligible patients. Disclosures Platzbecker: TEVA: Honoraria, Research Funding. Greiner:BMS: Research Funding. Thiede:AgenDix: Employment, Other: Ownership. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding.

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: Acute myeloid leukemia (AML) is characterized by a high relapse rate, indicating insufficient clearance of leukemia-initiating cells. Depending on genetic risk stratification, consolidating chemotherapy proves to significantly reduce the risk of relapse. In particular, in younger AML patients higher dosage of cytarabine appears to improve long-term outcome, while there is no apparent benefit of multiagent combination, compared to cytarabine monotherapy. However, to this end the optimal dosage of single agent cytarabine in consolidation therapy after 7+3 remission induction remains elusive. Methods: Here, we retrospectively assessed the impact of different dosages of cytarabine consolidation on outcome in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. Patients below 65 years of age, registered between April 2005 and September 2020 with non-acute promyelocytic leukemia, who attained complete remission after intensive induction and received at least one consolidation cycle with intermediate (IDAC) or high dose cytarabine (HiDAC) were selected. To account for differences in patient and disease characteristics between both groups, the average treatment effect was estimated by propensity score weighting. Results: 642 patients received HiDAC consolidation with a median dosage of 5794.88 (IQR, 4745.48-5971.56) mg/m 2/d with a median number of 3 cycles (IQR, 2-3), whereas 178 patients received IDAC consolidation with 1946.16 (IQR, 1869.51-2469.15) mg/m 2/d with a median of 2 cycles (IQR, 1-3). IDAC-treated patients showed in average a higher age (median (IQR) 58.5 (49-62) years vs. 50 (41-56) years) and more comorbidities with 43.8% having an HCT-CI score of 2-4, compared to 22.3% among HiDAC-treated patients. Alongside, significantly more secondary (5.1% vs. 3.1%) and therapy-related (12.4% vs. 4.1%) AML as well as more adverse (14.5% vs. 6.5%) and less favorable (40.6% vs. 56%) genetic risk features according to ELN 2017 risk classification were found among IDAC-treated patients. After propensity score weighting for differences in patient and disease characteristics, overall survival after 5 years was comparable between HiDAC-treated (71.1 %) and IDAC-treated (67.7%) patients. Moreover, no significant differences in relapse-free survival were observed after 5 years (47.4 vs. 45.2%). Notably, more patients treated with IDAC received allogeneic stem cell transplantation in first remission (37.6 vs. 19.8%) while significantly more HiDAC-treated patients underwent allogeneic stem cell transplantation in relapse (30.8 vs. 20.2%). Censoring for allogeneic stem cell transplantation in first remission revealed no significant survival difference with regard to cytarabine dosage. Considering only ELN favorable risk AML patients, there was no difference in 5-years overall (80.5% vs. 83.9%) nor relapse-free (57.7% vs. 56.8%) survival. Of note, significantly more patients treated with HiDAC suffered from ≥3 CTCAE infectious complications (56.7 vs. 44.1%), which was more striking in patients above 50 years of age. The rate of other ≥3 CTCAE non-hematological toxicities and secondary malignancies was comparable in both treatment groups. Conclusion: This retrospective analysis suggests no significant benefit of high dose cytarabine compared to intermediate dosages in consolidation for AML patients under 65 years of age, independent of ELN risk group. Disclosures 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: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Brummendorf: Takepart Media: Honoraria; Repeat Diagnostics: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Patents & Royalties, Research Funding; Janssen: Honoraria; Bristol Myers: Research Funding. Fransecky: Abbvie: Honoraria, Research Funding; Medac: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Held: MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Roche: Research Funding; Acortech Biopharma: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; AbbVie: Honoraria; Geron: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Baldus: Amgen: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; Jazz: Honoraria. Mueller-Tidow: Janssen Cilag: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bioline: Consultancy, Research Funding.

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.