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• W4306873721 abstract "Overall survival (OS) after a diagnosis of acute myeloid leukaemia (AML) in adults has improved over the last three decades.1-4 The improvement has been most pronounced in patients aged 50–70 years, which correlates with, but is not necessarily caused by, an increase in the proportion of patients aged 50–70 years who were treated with intensive chemotherapy and who were subsequently referred to allogeneic haematopoietic cell transplantation (HCT),1-3 especially after introducing non-myeloablative conditioning.5 In parallel, allogeneic HCT protocols and supportive care have improved.6 Correspondingly, several studies found a continuously improved survival after allogeneic HCT for AML from the 1980s to the 2010s.7-12 However, studies in more recent years in a population-based setting are lacking. We therefore aimed to investigate trends in OS, cure rates, and other outcomes after allogeneic HCT for AML from 2000 to 2020 in a Danish population-based cohort study. We studied all adult (>18 years) patients who underwent a first allogeneic HCT for AML in Denmark between 2000 and 2020. Until 2009, all transplants were performed at Rigshospitalet, Copenhagen University Hospital; thereafter, Aarhus University Hospital transplanted patients from Western Denmark. Allogeneic HCT was indicated as consolidation treatment for AML in patients in first complete remission (CR) with intermediate or adverse cytogenetic risk or with secondary AML, patients in second CR regardless of cytogenetic risk, and selected patients with primary induction failure. Transplant procedures are outlined in the Supplementary Information. Data were collected from local registers and the Danish National Acute Leukaemia Registry.13 The statistical analyses are described in the Supplementary Information. A total of 659 patients were included (Table 1, Table S1), corresponding to 13% of the 5241 adults who were diagnosed with AML in Denmark from 2000 to 2020. The number of transplants increased over time, with 239 (36%) patients transplanted from 2016 to 2020. With a median follow-up of 7.5 years, the median OS was 7.9 years [95% confidence interval (CI): 6.1, 14.1 years]. The estimated two- and five-year OS was 66% (CI: 63%, 70%) and 57% (CI: 53%, 61%) respectively (Figure S1). Main causes of death (Table S2) were relapse (54% of deaths) and infection (13% of deaths). Patients with adverse and intermediate cytogenetics respectively had a two-year OS of 53% (CI: 45%, 63%) and 68% (CI: 65%, 73%) (Figure S2A); unadjusted estimates of OS according to conditioning intensity, donor type, and disease state at HCT are shown in Figure S2B–S2D. [Correction added on 07 October 2022, after first online publication: ‘Figure S3–S5’ was corrected to ‘Figure S2B-S2D’ in the preceding sentence’.] OS differed significantly between 2000 and 2020 (p value for overall effect of calendar year of HCT = 0.02). Figure 1 shows the unadjusted and adjusted (for age, disease state, cytogenetic risk, donor type, Karnofsky score, and conditioning intensity) estimates of two-year OS according to calendar year of HCT. The unadjusted two-year OS was 75% (CI: 57%, 89%) in year 2000, 59% (CI: 52%, 66%) in year 2010, and 71% (CI: 63%, 78%) in year 2020. The five-year OS showed similar trends (Figure S3). The trend in OS was most pronounced in patients who received myeloablative conditioning (Figure S4), but the interaction between calendar year of HCT and conditioning regimen was not statistically significant (p = 0.32). The overall two-year relapse risk was 28% (CI: 23%, 31%). Median time to relapse was 161 days (min, Q1, Q3, max: 21, 96, 414, 5370 days). The estimated two-year relapse risk (Figure S5A) was 20% (CI: 9%, 39%) in year 2000 and 29% (CI: 23%, 38%) in year 2020, but this increase was not statistically significant (p = 0.10). The overall two-year non-relapse mortality (NRM) was 13% (CI: 11%, 16%). NRM differed over time (p < 0.001). The estimated two-year NRM (Figure S5B) was 10% (CI: 3%, 27%) in year 2000, 21% (CI: 15%, 28%) in year 2010, and 10% (CI: 6%, 16%) in year 2020. For grade II–IV acute graft-versus-host disease (GVHD), the incidence decreased over time (p = 0.01). The cumulative incidence at day +180 (Figure S6A) was 41% (CI: 25%, 62%) in year 2000 and 24% (CI: 17%, 32%) in year 2020. However, after adjusting for conditioning intensity, the overall effect of calendar year was no longer statistically significant (p = 0.12), indicating that the decrease in acute GVHD over time was related to the increasing use of non-myeloablative conditioning. The incidence of grade III–IV acute GVHD also decreased over time (Figure S6B), but this increase was not statistically significant (p = 0.21). We found no support for a difference over time for overall chronic GVHD (p = 0.54, Figure S7A), whereas the incidence of extensive chronic GVHD decreased over time (p < 0.001, Figure S7B). The estimated fraction of patients achieving ‘statistical cure’ (i.e., the fraction of patients with no excess mortality compared to the Danish general population matched by calendar year, age and sex) was 53% (CI: 48%, 58%). This cure fraction differed over time (p = 0.03, Figure S8), being 67% (CI: 46%, 81%) in year 2000, 44% (CI: 36%, 52%) in year 2010, and 65% (CI: 46%, 79%) in year 2020. The relative survival of patients compared to the general population plateaued after approximately eight years post-transplantation (Figure S9), indicating that patients could on average be considered statistically cured when having survived eight years. However, later, after 14 years post-transplantation, some excess mortality was observed, the causes of death being late complications (infection, chronic GVHD, organ failure, secondary malignancy and unknown, each N = 1) or relapse (N = 3). Our results echo previous findings that changes in OS after allogeneic HCT for AML were mainly driven by changes in NRM rather than relapse rates.7, 9, 10 In contrast to most reports of allogeneic HCTs for AML in earlier years, the survival trend was not continuously improving in our study. Nevertheless, despite the patients being notably older and having lower performance score at transplant in later years, the estimated survival in 2020 matched that in 2000, when the transplanted patients were younger, had less comorbidity, and more often received an allogeneic HCT from an HLA-matched related donor. We would have liked to explore changes in the degree of pre-transplant minimal residual disease (MRD), which may guide the indication for allogeneic HCT in AML,14 and mutational status, but we were limited by a lack of data. In conclusion, OS and cure rates after allogeneic HCT for AML in adults in Denmark decreased from 2000 to 2010 but improved again from 2010 to 2020, mainly driven by changes in NRM rather than in the relapse rate. The incidence of acute GVHD decreased over time, but not that of chronic GVHD. Future efforts to improve outcomes should focus on reducing the risks of relapse and chronic GVHD. Lars K. Gjærde designed the study, collected and analysed data, and wrote the paper. Lasse H. Jakobsen designed the study and revised the paper. Caroline Juhl-Christensen, Gitte Olesen, and Irma Petruskevicius collected data and revised the paper. Marianne T. Severinsen, Claus W. Marcher, and Kim Theilgaard-Mönch revised the paper. Niels S. Andersen, Lone S. Friis, Brian Kornblit, Søren L. Petersen, and Ida Schjødt collected data and revised the paper. Henrik Sengeløv designed the study, collected data, and revised the paper. The authors thank Camilla Roepstorff and Heidi Petersen for their excellent work as data managers and the Danish National Acute Leukaemia Registry for providing data for our study. The authors have no competing interests. Data S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W4306873721 date "2022-10-20" @default.
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• W4306873721 title "Trends in survival and cure after allogeneic haematopoietic cell transplantation for acute myeloid leukaemia from 2000 to 2020: A Danish population‐based cohort study" @default.
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• W4306873721 doi "https://doi.org/10.1111/bjh.18511" @default.
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