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

Abstract: We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR] , 0.55; P & lt; .001); both in younger (HR, 0.59; P & lt; .001) and older patients (HR, 0.42; P & lt; .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P & lt; .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.

Abstract: Core-binding factor (CBF) acute myeloid leukemia (AML) encompasses AML with inv(16)(p13.1q22) and AML with t(8;21)(q22;q22.1). Despite sharing a common pathogenic mechanism involving rearrangements of the CBF transcriptional complex, there is growing evidence for considerable genotypic heterogeneity. We comprehensively characterized the mutational landscape of 350 adult CBF-AML [inv(16): n = 160, t(8;21): n = 190] performing targeted sequencing of 230 myeloid cancer-associated genes. Apart from common mutations in signaling genes, mainly NRAS, KIT, and FLT3, both CBF-AML entities demonstrated a remarkably diverse pattern with respect to the underlying cooperating molecular events, in particular in genes encoding for epigenetic modifiers and the cohesin complex. In addition, recurrent mutations in novel collaborating candidate genes such as SRCAP (5% overall) and DNM2 (6% of t(8;21) AML) were identified. Moreover, aberrations altering transcription and differentiation occurred at earlier leukemic stages and preceded mutations impairing proliferation. Lasso-penalized models revealed an inferior prognosis for t(8;21) AML, trisomy 8, as well as FLT3 and KIT exon 17 mutations, whereas NRAS and WT1 mutations conferred superior prognosis. Interestingly, clonal heterogeneity was associated with a favorable prognosis. When entering mutations by functional groups in the model, mutations in genes of the methylation group (ie, DNMT3A, TET2) had a strong negative prognostic impact.

Abstract: Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1-mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TLs) by quantitative reverse-transcription polymerase chain reaction and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TLs and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase 3 AMLSG 09-09 trial. A total of 3733 bone marrow (BM) samples and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥ 3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after 2 treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity was consistently revealed to be a poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TLs were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly greater proportion of patients achieving MRD negativity at EOT (56% vs 41%; P = .01). The better reduction in NPM1mut TLs after 2 treatment cycles in MRD positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR, 29.3% vs 45.7%, P = .009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction in NPM1mut TLs across all treatment cycles, leading to a significantly lower relapse rate.

Abstract: BACKGROUND: Midostaurin is a first-generation, type I multi-targeted kinase inhibitor with inhibitory activity against FLT3-ITD and -TKD mutations. Midostaurin is approved by FDA and EMA in combination with intensive induction and consolidation chemotherapy for adult patients with AML exhibiting an activating FLT3 mutation; the EMA label also includes single-agent maintenance therapy following consolidation chemotherapy. We conducted a phase-II trial (AMLSG 16-10) to evaluate midostaurin with induction chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a one-year midostaurin maintenance therapy in younger and older patients with acute myeloid leukemia (AML) and FLT3 internal tandem duplication (ITD). METHODS: Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free (EFS) and overall survival (OS); results were compared to those of a historical control cohort of 415 patients with FLT3-ITD AML. Statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Major differences in trial design compared to the pivotal CALGB 10603/RATIFY trial were: i) only AML with FLT3-ITD were eligible; ii) AML with FLT3 tyrosine kinase domain mutations (only) and core-binding factor AML were not eligible; iii) older patients 60-70 years of age were eligible; iv) all patients were assigned to allogeneic HCT; v) a one-year maintenance treatment with midostaurin was included also after allogeneic HCT; vi) a continuous dosing schedule of midostaurin was applied with the aim to achieve a better target inhibition. Results: The trial accrued 440 patients, including 312 younger (18-60 yrs) and 128 older (61-70 yrs) patients. Complete remission (CR)/CR with incomplete hematologic recovery rate, median EFS and OS of the 440 patients were 74.9%, 13.6 and 36.2 months, respectively. Multivariate analysis of EFS showed a highly significant hazard reduction for an event for patients treated within AMLSG 16-10 trial compared to the historical controls (HR 0.55; 95%-confidence interval [CI], 0.47, 0.65; P & lt;0.001); this effect was significant in the younger (HR 0.59; 95%-CI, 0.49, 0.71; P & lt;0.001) and the older patient cohort (HR 0.42; 95%-CI, 0.30, 0.60; P & lt;0.001). Multivariate analysis also showed a highly significant beneficial effect on OS (HR 0.57; 95%-CI, 0.47, 0.68; P & lt;0.001), again for both age subgroups. Allogeneic HCT in first CR/CRi was performed according to protocol in 199 of 440 (45%) patients (48% and 38% in younger and older patients, respectively), and an additional 60 patients received allogeneic HCT in firstline therapy (n=33 pts. in CR/CRi after salvage therapy and 27 pts. with active disease); the treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT (n=259) as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. Conclusions: In comparison to a historical control cohort, the addition of midostaurin to intensive therapy led to a significant improvement in EFS and OS in both younger and older adult patients with AML and FLT3-ITD. Figure: Survival distribution for the primary endpoint event-free survival (EFS) and key secondary endpoint overall survival (OS) according to study population and age group. A EFS by cohort and age group (≤60 versus & gt;60 years) B OS by cohort and age group (≤60 versus & gt;60 years) Figure 1 Figure 1. Disclosures Döhner: Astellas: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Berlin-Chemie: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Pfizer: Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Ulm University Hospital: Current Employment. Fiedler: Servier: Consultancy, Other: Meeting attendance, Preparation of information material; Stemline: Consultancy; Daiichi Sanyko: Consultancy, Other: Meeting attendance, Preparation of information material; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; MorphoSys: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material; Celgene: Consultancy, Honoraria; Ariad/Incyte: Honoraria; Amgen: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material, Patents & Royalties, Research Funding; Abbvie: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material. Wulf: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Clinigen: Consultancy, Honoraria. Salih: BMS: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Synimmune GmbH: Honoraria; Novartis: Honoraria. Lübbert: Imago BioSciences: Honoraria; Janssen: Honoraria, Research Funding; Pfizer: Honoraria; Syros: Honoraria; Aristopharm: Research Funding; Cheplapharm: Research Funding; Janssen: Research Funding; Teva: Research Funding; Hexal: Honoraria; Astex: Honoraria; Abbvie: Honoraria. Kühn: Abbvie: Honoraria; Kura Oncology: Honoraria, Research Funding; Pfizer: Honoraria. Schroeder: Abbvie: Honoraria; Astellas: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Pfizer: Honoraria. Salwender: Oncopeptides: Honoraria; GlaxoSmithKline: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Takeda: Honoraria; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Chugai: Honoraria; AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen-Cilag: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Pfizer: Honoraria. Götze: Abbvie: Honoraria; Celgene/BMS: Honoraria, Research Funding. Westermann: Amgen: Consultancy, Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Stem Cell Line: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Astellas: Honoraria. Fransecky: Abbvie: Honoraria, Research Funding; Takeda: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Medac: Honoraria. Mayer: Novartis: Other: Travel support; Celgene: Other: Travel support; Roche: Other: Travel support; Amgen: Other: Travel support; BMS: Other: Travel support; Pfizer: Other: Travel support; Jazz: Other: Travel support; Astellas: Other: Travel support. Hertenstein: Sanofi: Honoraria; Novartis: Honoraria; Celgene: Honoraria; BMS: Honoraria. Tischler: AstraZeneca: Other: Travel support; Novartis: Other: Travel support; Janssen: Honoraria; GSK: Other: Travel support; Sanofi-Aventis: Other: Travel support; Abbvie: Other: Travel support. Paschka: Abbvie: Honoraria, Other: Travel support; Agios: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Astex: Honoraria; Celgene: Honoraria, Other: Travel support; Jazz: Honoraria; Novartis: Honoraria, Other: Travel support; Otsuka: Honoraria; Pfizer: Honoraria; Sunesis: Honoraria; BMS: Other, Speakers Bureau; Celgene: Honoraria; Janssen: Other; Takeda: Other. Gaidzik: Janssen: Speakers Bureau; Pfizer: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Thol: Abbvie: Honoraria; Astellas: Honoraria; BMS/Celgene: Honoraria, Research Funding; Jazz: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Heuser: Tolremo: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; BergenBio: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schlenk: Astellas: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Hexal: Honoraria; Neovio Biotech: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding; AstraZeneca: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Honoraria; Agios: Honoraria. Bullinger: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Astellas: Honoraria; Bristol-Myers Squibb / Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner: Amgen: Honoraria; BMS/Celgene: Honoraria, Research Funding; Janssen: Honoraria; Jazz: Honoraria; Novartis: Honoraria, Research Funding; Roche: Honoraria; Daiichi Sankyo: Honoraria; Agios: Research Funding; Astex: Research Funding; Astellas: Research Funding. Ganser: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria. OffLabel Disclosure: Midostaurin as single-agent maintenance therapy following allogeneic hematopoietic cell transplantation

Abstract: Background: CPX-351, a liposomal formulation of daunorubicin and cytarabine in the fixed molar ratio (1:5), is approved for the treatment of adult patients (pts) with newly diagnosed acute myeloid leukemia (AML) with myelodysplasia-related changes and therapy-related AML (t-AML). To explore the potential benefit of CPX-351 in a broader indication, we initiated a randomized phase III study of CPX-351 vs "3+7" in pts ≥18 years (yrs) of age with AML and intermediate or adverse genetics according to 2017 European LeukemiaNet (ELN) risk categorization (AMLSG 30-18, NCT03897127). In the younger pts (18-60 yrs) we sought to investigate a higher dose of CPX-351. We here report data from an interim safety analysis for this higher CPX-351 dose. Methods: Pts are randomized to receive first induction cycle (ind 1) with either CPX-351 or daunorubicin + cytarabine ("3+7": daunorubicin 60 mg/m2 on days 1, 2, 3 + cytarabine 200 mg/m2 on days 1-7); in pts aged 18-60 yrs (performance status 0-1) CPX-351 is given at a dose of 55 mg/m2 daunorubicin/125 mg/m2 cytarabine (125 U/m²; 1 U/m2=0.44 mg/m2 daunorubicin/1 mg/m2 cytarabine; days 1, 3, 5); pts & gt;60 yrs receive the standard dose CPX-351 100 U/m² (days 1, 3, 5). There was no age-adapted dosing in the control arm. For induction cycle 2 (ind 2), pts on the CPX-351 arm receive the same dosage on day 1+2 only; pts on the control arm receive intermediate-dose cytarabine + daunorubicin (both in age-adapted dosing). Continuous assessment for safety is performed for two endpoints: 60-day mortality with a maximally tolerated rate (MTR) of 15%; and hematologic recovery times with i) neutropenia 4° and / or ii) thrombocytopenia 3° or 4° after each ind lasting longer than day 42 after start of treatment cycle (without evidence of persistent leukemia) with a MTR of 25%. Median hematologic recovery times were analyzed using Kaplan-Meier estimates, p-values are mentioned in a descriptive manner (log-rank test). Results: As of July 20, 2020, 36 patients have been randomized to the study (CPX-351, n=19; "3+7", n=17) with following characteristics: de novo AML, n=27, secondary or t-AML, n=9; median age 60.5 yrs (range 47-75; ≤60 yrs, n=18; & gt;60 yrs, n=18); intermediate and adverse risk genetics were found in 7 and 10 pts, respectively (not available yet, n=19). On the CPX-351 arm, 9 of 19 pts were ≤60 yrs of age and received the higher CPX-351 dose. So far, 36 pts received ind 1, 25 pts ind 2. Overall, the median time to neutrophil recovery with absolute neutrophil count (ANC) & gt;0.5 G/l was longer in the CPX-351 arm compared to the "3+7" arm: 39 vs 28 days (p=0.07) after ind 1, and 26.5 vs 19 days after ind 2 (p=0.06; table 1). Time to platelet recovery & gt;50 G/l was significantly prolonged in the CPX-351 arm after ind 1 (40 vs 26 days; p & lt;0.0001), currently not after ind 2 (33 and 18 days; p=0.35). When comparing the higher dose (125 U/m²; pts 18-60 yrs) with the standard CPX-351 dose (100 U/m², pts & gt;60 yrs), the median time to neutrophil recovery after ind 1 was significantly longer with the higher dose (40 and 31 days, respectively; p=0.03); after ind 2 median times were 38 and 20.5 days (p=0.26); platelet recovery ( & gt;50 G/l) was also significantly delayed after ind 1 with the higher compared to the standard CPX-351 dose (median 43 vs 32 days; p=0.002); platelet recovery after ind 2 was after a median of 38.5 and 26.5 days, respectively (p=0.17). There was no treatment-related death (60-day mortality 0%) in both arms. So far, 6 of the 9 pts (67%) treated with the higher CPX-351 dose reached the safety endpoint of persisting neutropenia (n=4) or thrombocytopenia (n=5) during ind beyond day 42. The MTR was exceeded for thrombocytopenia (0.63; 95% confidence interval (CI) [0.31; 0.86]), but not for neutropenia (0.50; 95% CI [0.22; 0.78] ). Overall, there were 18 serious adverse events (SAEs); among the most frequent SAEs were infections and fever in neutropenia (n=10). Conclusion: The higher dose of CPX-351 administered in pts 18-60 yrs of age led to significantly prolonged hematologic recovery times during ind 1 and 2 exceeding the MTR for thrombocytopenia without treatment-related death. Based on the prolonged hematologic recovery, the protocol will be amended, in that the CPX-351 dose for ind in pts 18-60 yrs of age is reduced to the current Package Insert for CPX-351 44 mg/m2 daunorubicin / 100 mg/m2 cytarabine (100 U/m²). Data on hematologic response as well as on measurable residual disease using multi-parameter flow cytometry will be presented. Disclosures Kapp-Schwoerer: Jazz Pharmaceuticals: Honoraria, Research Funding. Thol:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Heuser:Karyopharm: Research Funding; Abbvie: Consultancy; Astellas: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Research Funding; BerGenBio ASA: Research Funding; Janssen: Consultancy; Stemline Therapeutics: Consultancy; Bayer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Amgen: Research Funding; PriME Oncology: Honoraria. Faderl:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Wagner:JAZZ Pharmaceuticals: Current Employment; JAZZ Pharmaceuticals: Current equity holder in publicly-traded company. Ganser:Celgene: Consultancy; Novartis: Consultancy. Döhner:Abbvie: Consultancy; Daiichi Sankyo: Honoraria; Celgene: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Amgen: Consultancy, Research Funding; Astellas Pharma: Consultancy; Janssen: Consultancy, Honoraria; Sunesis Pharmaceuticals: Research Funding; Agios: Consultancy; Arog: Research Funding. Paschka:BerGenBio ASA: Research Funding; Janssen Oncology: Other; Amgen: Other; Otsuka: Consultancy; Novartis: Consultancy, Speakers Bureau; Sunesis Pharmaceuticals: Consultancy; Pfizer: Consultancy, Speakers Bureau; Astellas Pharma: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, accommodations or expenses; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Agios Pharmaceuticals: Consultancy, Speakers Bureau; Astex Pharmaceuticals: Consultancy; AbbVie: Other: Travel, accommodation or expenses, Speakers Bureau. Döhner:Abbvie: Consultancy, Honoraria; Sunesis: Research Funding; Roche: Consultancy, Honoraria; Pfizer: Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AROG: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: CPX-351 is approved for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) with myelodysplasia-related changes and therapy-related AML (t-AML). To explore the potential benefit of CPX-351 in a broader indication, a randomized phase III study of CPX-351 vs 3+7 in patients older than 18 years of age with AML and intermediate or adverse genetics according to 2017 European LeukemiaNet (ELN) risk categorization (AMLSG 30-18, NCT03897127) was initiated. In the younger patients (18-60 yrs) a higher dose of CPX-351 is evaluated.