DDX41 germline mutations (DDX41MutGL) are the most common genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia (AML). Recent reports suggest that DDX41MutGL myeloid malignancies could be considered as a distinct entity, even if their specific presentation and outcome remain to be defined. We described here the clinical and biological features of 191 patients with DDX41MutGL AML. Baseline characteristics and outcome of 86 of them, treated with intensive chemotherapy in 5 prospective ALFA/FILO trials were compared with those of 1604 DDX41 wild-type (DDX41WT) AML patients, representing a prevalence of 5%. DDX41MutGL AML patients were mostly males (75%) in their seventh decade, with low leukocyte count (median, 2x109/L), low bone marrow blast infiltration (median, 33%), normal cytogenetics (75%) and few additional somatic mutations (median, 2). A second somatic DDX41 mutation (DDX41MutSom) was found in 82% of patients and clonal architecture inference suggested that it could be the main driver for AML progression. DDX41MutGL patients displayed higher complete remission (CR) rates (94% vs. 69%, p<0.0001) and longer restricted mean overall survival (OS) censored at hematopoietic stem cell transplantation (HSCT) than ELN-2017 intermediate/adverse (Int/Adv) DDX41WT patients (5-year ΔRMST of 13.6 months, p < 0.001). Relapse rates censored at HSCT were lower at 1 year in DDX41MutGL patients (15% vs. 44%) but later increased to join that of Int/Adv DDX41WT patients at 3 years (82% vs 75%). HSCT in first CR was associated with prolonged relapse-free survival (RFS; HR, 0.43 [95%CI, 0.21-0.88]; p = 0.02) but not with longer OS (HR=0.77 [95%CI, 0.35-1.68], p=0.5).

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5’-KMT2A, two patients had a 5’-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.