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: 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: Acute myeloid leukemia (AML) is a hematologic malignancy that is treated in medically fit patients with intensive induction chemotherapy (IT) and postremission therapy to achieve a complete and long-term remission. The incidence of obesity in the general population is steadily increasing and has been identified as a major risk factor for all-cause mortality. Despite previous studies assessing the role of obesity in AML patients undergoing IT, there is an ongoing debate on the impact of obesity on patient outcome as well as the optimal dosing strategy in obese AML patients. We conducted a retrospective registry study assessing 1677 AML patients who were treated with IT for newly diagnosed AML. The primary endpoint was overall survival (OS) while event-free survival (EFS), the rate of first complete remission (CR1), relapse/refractory disease and non-relapse/refractory-related mortality (NRRrM), treatment-related toxicities, patient comorbidities and chemotherapy dosing strategies were analyzed as secondary endpoints. Obese patients (body mass index, BMI ≥ 30) displayed a significant inferior median OS (29.44 vs. 47.94 months, p = 0.015) without a significant difference in median EFS (7.8 vs. 9.89 months, p = 0.3) compared to non-obese patients (BMI & lt; 30). The cumulative incidence (CI) of NRRrM was significantly increased in obese patients compared to non-obese patients while no differences could be observed regarding the CI of relapsed or refractory disease. Obesity was identified as an independent risk factor for death (HR 1.27, [95% CI 1.07-1.51], p = 0.005) in a multivariable Cox regression analysis. When the cohort was stratified by age (≥/ & lt; 60 years), the difference in OS as well as the significantly increased CI of NRRrM was only observed in patients ≥ 60 years. Notably, obese patients demonstrated higher rates of cardiovascular and metabolic comorbidities regardless of their age. No disparities for OS, EFS, CR1 rate or treatment-related toxicities were observed when the entire study population was stratified for the used dosing strategy (dose calculation using total body weight, idealized body weight, adjusted idealized body weight or capped at body surface area of 2 m 2). In conclusion, the present study identifies obesity as a major independent risk factor for worse overall survival and increased CI of non-relapse/refractory-related mortality in older (≥60 years) AML patients undergoing curative IT. These findings may be most likely attributed to obesity related comorbidities and not to dose adaption of chemotherapy in obese AML patients. Disclosures Schliemann: Boehringer-Ingelheim: Research Funding; Abbvie: Consultancy, Other: travel grants; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Fransecky: Amgen: Honoraria; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Medac: Honoraria; Takeda: Honoraria. Burchert: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Pfizer: Honoraria; Incyte: Honoraria; Gilead: Honoraria; BMS: Honoraria. Crysandt: Incyte: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Müller-Tidow: Janssen: Consultancy, Research Funding; Bioline: Research Funding; Pfizer: Research Funding. Platzbecker: Celgene/BMS: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Geron: Honoraria. Baldus: Jazz: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria.

Abstract: Functional perturbations of the cohesin complex with subsequent changes in chromatin structure and replication are reported in a multitude of cancers including acute myeloid leukemia (AML). Mutations of its STAG2 subunit may predict unfavorable risk as recognized by the 2022 European Leukemia Net recommendations, but the underlying evidence is limited by small sample sizes and conflicting observations regarding clinical outcomes, as well as scarce information on other cohesion complex subunits. We retrospectively analyzed data from a multi-center cohort of 1615 intensively treated AML patients and identified distinct co-mutational patters for mutations of STAG2 , which were associated with normal karyotypes (NK) and concomitant mutations in IDH2 , RUNX1, BCOR, ASXL1 , and SRSF2 . Mutated RAD21 was associated with NK, mutated EZH2, KRAS, CBL , and NPM1 . Patients harboring mutated STAG2 were older and presented with decreased white blood cell, bone marrow and peripheral blood blast counts. Overall, neither mutated STAG2, RAD21, SMC1A nor SMC3 displayed any significant, independent effect on clinical outcomes defined as complete remission, event-free, relapse-free or overall survival. However, we found almost complete mutual exclusivity of genetic alterations of individual cohesin subunits. This mutual exclusivity may be the basis for therapeutic strategies via synthetic lethality in cohesin mutated AML.

Abstract: Tandem-duplication mutations of the UBTF gene ( UBTF -TDs) coding for the upstream binding transcription factor have recently been described in pediatric patients with acute myeloid leukemia (AML) and were found to be associated with particular genetics (trisomy 8 (+8), FLT3 -internal tandem duplications ( FLT3 -ITD), WT1 -mutations) and inferior outcome. Due to limited knowledge on UBTF- TDs in adult AML, we screened 4247 newly diagnosed adult AML and higher-risk myelodysplastic syndrome (MDS) patients using high-resolution fragment analysis. UBTF -TDs were overall rare ( n  = 52/4247; 1.2%), but significantly enriched in younger patients (median age 41 years) and associated with MDS-related morphology as well as significantly lower hemoglobin and platelet levels. Patients with UBTF -TDs had significantly higher rates of +8 (34% vs. 9%), WT1 (52% vs. 7%) and FLT3 -ITD (50% vs. 20.8%) co-mutations, whereas UBTF -TDs were mutually exclusive with several class-defining lesions such as mutant NPM1 , in-frame CEBPA bZIP mutations as well as t(8;21). Based on the high-variant allele frequency found and the fact that all relapsed patients analyzed ( n  = 5) retained the UBTF -TD mutation, UBTF -TDs represent early clonal events and are stable over the disease course. In univariate analysis, UBTF -TDs did not represent a significant factor for overall or relapse-free survival in the entire cohort. However, in patients under 50 years of age, who represent the majority of UBTF -mutant patients, UBTF -TDs were an independent prognostic factor for inferior event-free (EFS), relapse-free (RFS) and overall survival (OS), which was confirmed by multivariable analyses including established risk factors such as age and ELN2022 genetic risk groups (EFS [HR: 2.20; 95% CI 1.52–3.17, p   〈  0.001], RFS [HR: 1.59; 95% CI 1.02–2.46, p  = 0.039] and OS [HR: 1.64; 95% CI 1.08–2.49, p  = 0.020]). In summary, UBTF -TDs appear to represent a novel class-defining lesion not only in pediatric AML but also younger adults and are associated with myelodysplasia and inferior outcome in these patients.