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Abstract Introduction MECOM rearrangements (MECOM::r) account for just 1-2% of adult AML, their outcomes are extremely poor, with high rates of resistance to chemotherapy and relapse post treatment. Despite advances in the biological understanding of disease evolution there has been no significant progress in the development of new therapies. Intensive chemotherapy and allogeneic transplant in first remission remain the standard of care, although long term survival is poor. From our earlier studies in AML patients with t(3;3)/inv(3) the overall response rate (ORR) was just 36%, with 10-year overall survival (OS) of 3% (Grimwade 2010). Therefore, some clinicians believe this current approach is futile. We sought to investigate the response and survival of MECOM::r patients in two more recent large prospective randomised trials. Methods NCRI AML17 (2009-2014) and AML19 (2015-2020) enrolled younger adults with newly diagnosed AML. Results from diagnostic karyotype, FISH and RNA sequencing were reviewed to identify all patients with MECOM::r. OS was calculated with the Kaplan-Meier method, and cumulative incidence of relapse (CIR) considered death as a competing risk. The impact of CR1 transplant was assessed using time-dependent Cox regression. Results 82 patients (AML17 n=48, AML19 n=34) were identified from 5672 trial subjects. Median age was 48y (range 16 – 64). 33 (40%) were female and 49 (60%) were male. 8 (10%) had a prior myeloid disorder and 1 (1%) were prior therapy related. 57 (70%) were inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2) / GATA2::MECOM, 25 (30%) were t(3q26.2;v)/MECOM::r. 32 (39%) also had monosomy 7 while 30 (37%) had MECOM::r as their sole abnormality. FLT3 ITD mutations were present in 7 (9%) and TKD in 3 (4%). Treatment was with DA in 48 (59%), FLAG-Ida in 14 (17%), ADE in 14 (17%) and CPX-351 in 6 (7%). 34 (41%) received GO. All randomisation allocations contained a double induction schedule. The ORR (CR/CRi) was 57% (n=47), with 27 (35%) in CR/CRi after course 1, indicating that 22% of responses are only achieved with the second induction course. Response was higher in the 30 patients with an isolated MECOM::r, with ORR 70% (n=21), with 46% after C1. The type of MECOM::r did not alter response. Higher rates of refractory disease were seen in patients with additional high risk cytogenetic abnormalities (monosomy 7, del 5q, del 17p and complex karyotype), with ORR 42% (n=16) patients after second induction. Median follow-up was 5.17 years. Day 30 and 60 mortality was 6.1% and 9.8% respectively. Median overall survival (OS) was 1.01y (95CI 0.83 – 1.18) and 3-year OS was 22%. No survival differences were seen between GATA2::MECOM and other MECOM::r (3-yr OS 21% vs 25%). The presence of monosomy 7 (HR 1.88, 95CI 1.14- 3.12), deletion 17p (HR 4.59, 95CI 1.39-15.2) or complex karyotype (HR 2.74, 95CI 1.35-5.56) were associated with worse survival. Outcomes were poor for patients with any of monosomy 7, del 5q, del 17p and complex karyotype, with median OS 0.75y and no survivors at 3 years in all but the -7 group. No difference in survival was seen by induction schedule or whether remission was achieved after C1 or C2. The 3-year cumulative incidence of relapse was 49.4% (95CI 34-63%), predominantly within the first year. The cumulative incidence of death in remission at 3 years was 19.6% (95CI 10-32). Of the 47 patients achieving remission, 30 (64%) were transplanted in CR1. An additional 10 patients were transplanted at other stages. CR1 transplant was associated with improved OS in all patients (HR 0.24, 95CI 0.11 - 0.54), and in GATA2::MECOM and MECOM::r other subgroups. OS 3 years after allo transplant was 38% (95CI 25-58%). For those transplanted in CR1 it was 45% (95CI 29-69%), and 20% for those transplanted at other stages (95CI 5.8-69%). Conclusion Here we demonstrate meaningful survival for MECOM::r patients who received intensive double induction chemotherapy followed by an allograft in first complete remission. Optimal response is achieved after double induction and potentially sustained by transplant consolidation. Survival is exceptionally poor in MECOM::r patients with additional high risk cytogenetics abnormalities. These data are important to identify MECOM::r patients with a prospect of longer-term survival and those who should be considered for investigational therapy as first line treatment.