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Background: Acute myeloid leukaemia with mutated NPM1 is associated with high CD33 expression and intermediate-risk cytogenetics. The aim of this study was to evaluate intensive chemotherapy with or without the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin in participants with newly diagnosed, NPM1-mutated acute myeloid leukaemia., Methods: This open-label, phase 3 trial was conducted at 56 hospitals in Germany and Austria. Eligible participants were 18 years or older and had newly diagnosed NPM1-mutated acute myeloid leukaemia and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned, using age as a stratification factor (18-60 years vs >60 years), 1:1 to the two treatment groups using allocation concealment; there was no masking of participants and investigators to treatment groups. Participants received two cycles of induction therapy (idarubicin, cytarabine, and etoposide) plus all-trans retinoic acid (ATRA) followed by three consolidation cycles of high-dose cytarabine (or an intermediate dose for those older than 60 years) and ATRA, without or with gemtuzumab ozogamicin (3 mg/m 2 administered intravenously on day 1 of induction cycles 1 and 2, and consolidation cycle 1). The primary endpoints were short-term event-free survival and overall survival in the intention-to-treat population (overall survival was added as a co-primary endpoint after amendment four of the protocol on Oct 13, 2013). The secondary endpoints were event-free survival with long-term follow-up, rates of complete remission, complete remission with partial haematological recovery (CRh), and complete remission with incomplete haematological recovery (CRi), cumulative incidences of relapse and death, and number of days in hospital. This trial is registered with ClinicalTrials.gov (NCT00893399) and has been completed., Findings: Between May 12, 2010, and Sept 1, 2017, 600 participants were enrolled, of which 588 (315 women and 273 men) were randomly assigned (296 to the standard group and 292 to the gemtuzumab ozogamicin group). No difference was found in short-term event-free survival (short-term event-free survival at 6-month follow-up, 53% [95% CI 47-59] in the standard group and 58% [53-64] in the gemtuzumab ozogamicin group; hazard ratio [HR] 0·83; 95% CI 0·65-1·04; p=0·10) and overall survival between treatment groups (2-year overall survival, 69% [63-74] in the standard group and 73% [68-78] in the gemtuzumab ozogamicin group; 0·90; 0·70-1·16; p=0·43). There was no difference in complete remission or CRi rates (n=267 [90%] in the standard group vs n=251 [86%] in the gemtuzumab ozogamicin group; odds ratio [OR] 0·67; 95% CI 0·40-1·11; p=0·15) and complete remission or CRh rates (n=214 [72%] vs n=195 [67%]; OR 0·77; 0·54-1·10; p=0·18), whereas the complete remission rate was lower with gemtuzumab ozogamicin (n=172 [58%] vs n=136 [47%]; OR 0·63; 0·45-0·80; p=0·0068). Cumulative incidence of relapse was significantly reduced by gemtuzumab ozogamicin (2-year cumulative incidence of relapse, 37% [95% CI 31-43] in the standard group and 25% [20-30] in the gemtuzumab ozogamicin group; cause-specific HR 0·65; 0·49-0·86; p=0·0028), and there was no difference in the cumulative incidence of death (2-year cumulative incidence of death 6% [4-10] in the standard group and 7% [5-11] in the gemtuzumab ozogamicin group; HR 1·03; 0·59-1·81; p=0·91). There were no differences in the number of days in hospital across all cycles between treatment groups. The most common treatment-related grade 3-4 adverse events were febrile neutropenia (n=135 [47%] in the gemtuzumab ozogamicin group vs n=122 [41%] in the standard group), thrombocytopenia (n=261 [90%] vs n=265 [90%]), pneumonia (n=71 [25%] vs n=64 [22%]), sepsis (n=85 [29%] vs n=73 [25%]). Treatment-related deaths were documented in 25 participants (4%; n=8 [3%] in the standard group and n=17 [6%] in the gemtuzumab ozogamicin group), mostly due to sepsis and infections., Interpretation: The primary endpoints of the trial of event-free survival and overall survival were not met. However, an anti-leukaemic efficacy of gemtuzumab ozogamicin in participants with NPM1-mutated acute myeloid leukaemia is shown by a significantly lower cumulative incidence of relapse rate, suggesting that the addition of gemtuzumab ozogamicin might reduce the need for salvage therapy in these participants. The results from this study provide further evidence that gemtuzumab ozogamicin should be added in the standard of care treatment in adults with NPM1-mutated acute myeloid leukaemia., Funding: Pfizer and Amgen., Competing Interests: Declaration of interests HD declares being in an advisory role for Abbvie, Agios, Amgen, Astellas, AstraZeneca, Berlin-Chemie, Bristol Myers Squibb, Celgene, Daiichi Sankyo, GEMoaB, Gilead, Janssen, Jazz Pharmaceuticals, Novartis, Servier, Stemline, and Syndax; and research funding from Abbvie, Agios, Amgen, Astellas, Bristol Myers Squibb, Jazz Pharmaceuticals, Kronos-Bio, Novartis, and Pfizer. WF declares a membership on an entity's board of directors or advisory committee for AbbVie, Amgen, ARIAD/Incyte, Celgene, Jazz Pharmaceuticals, MorphoSys, Stemline, Clinigen, Novartis, and Pfizer; patents and royalties from Amgen; support for meeting attendance from Amgen, Daiichi Sankyo, Gilead, Jazz Pharmaceuticals, and Servier; and research funding from Amgen and Pfizer. MWMK declares being in an advisory role for Abbvie, Bristol Myers Squibb, Jazz Pharmaceuticals, Kura-Oncology, and Pfizer; speakers honoraria from Abbvie and Gilead; travel support from Abbvie, Celgene, and Daiichi Sankyo; and research funding from Kura-Oncology. TS declares being in an advisory role for Abbvie, Astellas, Celgene, Janssen, Jazz Pharmaceuticals, Novartis, Takeda, Pfizer Bristol Myers Squibb, and Telix Pharma; speakers honoraria from Abbvie, Astellas, Celgene, Janssen, Jazz Pharmaceuticals, and Novartis; research funding from Jazz Pharmaceuticals and Bristol Myers Squibb; and travel support from Jazz Pharmaceuticals and Medac. KM declares being on an advisory role and paid for lectures for Bristol Myers Squibb; and travel support from Amgen, Astellas, Bristol Myers Squibb, Celgene, Jazz Pharmaceuticals, Novartis, Pfizer, and Roche. ML declares being in an advisory role for AbbVie, Astex Pharmaceuticals, Janssen, Pfizer, Otsuka, and Syros; and research funding from Aristopharm, Cheplapharm, Janssen, and TEVA. KG declares being in an advisory role for Abbvie, BMS, and Servier. LF declares being in an advisory role for AbbVie, Amgen, Medac, Novartis, and Takeda; and research funding from Abbvie, Kite, and Speaker's Bureau for Celgene. EK reports speaker honoraria from Abbvie, Astellas, Celgene/BMS, Jazz, Novartis, and Servier; and being in an advisory or consultancy role for Abbvie, Astellas, Celgene/BMS, Jazz, and Servier. GW reports consultancy for Clinigen and Novartis; and honoraria from Novartis, Gilead, and Takeda. JS reports being in an advisory role and honoraria from AbbVie, Bayer, BMS, Janssen, Novartis, Pfizer, and Sanofi. RG reports being in an advisory role for Abbvie, Astra Zeneca, BMS, Celgene, Daiichi Sankyo, Gilead, Janssen, Merck, MSD, Novartis, Roche, Sanofi, and Takeda. BH reports being in an advisory role for Bristol Myers Squibb, Celgene, Novartis, and Sanofi. UMM reports being in an advisory role for BMS and Sanofi. SM-S reports being in an advisory role for Amgen, BMS/Celgene, Jazz Pharmaceuticals, and Novartis. SK-S reports consultancy for Abbvie, Jazz Pharmaceuticlas, and Pfizer. LB reports being in an advisory role for Abbvie, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Sanofi, and Seattle Genetics; and research funding from Bayer and Jazz Pharmaceuticals. FT reports being in an advisory role for Abbvie, Astellas, Bristol Myers Squibb/Celgene, Jazz Pharmaceuticals, Novartis, and Pfizer. MH reports being in an advisory role for Abbvie, BMS/Celgene, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, Pfizer, Roche, and Tolremo; honoraria from Jazz Pharmaceuticals, Janssen, and Novartis; and research funding to institution from Astellas, Bayer Pharma, BergenBio, Daiichi Sankyo, Jazz Pharmaceuticals, Karyopharm, Novartis, Pfizer, and Roche. PP reports being in an advisory role for Abbvie, Agios, Astellas, Astex Pharmaceuticals, Bristol Myers Squibb, Celgene, Jazz Pharmaceuticals, Novartis, Otsuka Pharma, Pfizer, and Sunesis; speakers bureau for Abbvie, Agios, Astellas, Bristol Myers Squibb, Celgene, Jazz Pharmaceuticals, Novartis, and Pfizer; and travel support for Abbvie, Bristol Myers Squibb, Celgene, Janssen, Novartis, and Takeda. VIG reports being in an advisory role for Abbvie and Pfizer; and speakers bureau for Pfizer and Janssen. RFS reports consulting for or an advisory board membership with Astellas, Daiichi Sankyo, Novartis, and Pfizer; research funding from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, PharmaMar, and Roche; and travel, accommodations, and expenses covered by Daiichi Sankyo. KD reports being in an advisory role for Amgen, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Janssen, Jazz Pharmaceuticals, Novartis, and Roche; and research funding from Agios, Astex, Astellas, Bristol Myers Squibb, Celgene, and Novartis. AG reports being in an advisory role for Celgene, JAZZ Pharmaceuticals, and Novartis. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)