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 describe here the clinical and biological features of 191 patients with DDX41MutGL AML. Baseline characteristics and outcome of 86 of these patients, treated with intensive chemotherapy in 5 prospective Acute Leukemia French Association/French Innovative Leukemia Organization trials, were compared with those of 1604 patients with DDX41 wild-type (DDX41WT) AML, representing a prevalence of 5%. Patients with DDX41MutGL AML were mostly male (75%), in their seventh decade, and with low leukocyte count (median, 2 × 109/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 rates (94% vs 69%; P < .0001) and longer restricted mean overall survival censored at hematopoietic stem cell transplantation (HSCT) than 2017 European LeukemiaNet intermediate/adverse (Int/Adv) DDX41WT patients (5-year difference in restricted mean survival times, 13.6 months; P < .001). Relapse rates censored at HSCT were lower at 1 year in DDX41MutGL patients (15% vs 44%) but later increased to be similar to Int/Adv DDX41WT patients at 3 years (82% vs 75%). HSCT in first complete remission was associated with prolonged relapse-free survival (hazard ratio, 0.43; 95% confidence interval, 0.21-0.88; P = .02) but not with longer overall survival (hazard ratio, 0.77; 95% confidence interval, 0.35-1.68; P = .5).

In recent years, through whole genome analyses, convincing evidence for the contribution of genetic predisposition to childhood B-cell precursor - acute lymphoblastic leukemia (BCP-ALL) due to altered PAX5 has been provided. A recurrent mutation p.Gly183Ser affecting the octapeptide domain has been described in three unrelated families and a p.Arg38His mutation affecting the DNA-binding paired domain reported in another one. We strengthen here the assumption of the inherited character of familial BCP-ALL by identifying the PAX5 p.Arg38His mutation in a family in which the three children developed BCP-ALL. One relapsed two years after his initial diagnosis and was allografted with his brother's cells before the latter developed BCP-ALL. The patient allografted relapsed later from donor-related cells. By syngeneic transplantations in mice, we showed that p.Arg38His expression does not abrogate the engraftment capacity of transduced Pax5^-/- pro-B cells unlike wild type PAX5-rescued Pax5^-/- pro-B cells and can predispose to BCP-ALL. Through functional and molecular analyses, we demonstrated that p.Arg38His acts as a hypomorphic variant altering the pattern of expression of PAX5 target genes. Our data highlight the importance of transcriptional deregulation, particularly of genes involved in B cell differentiation in familial BCP-ALL. We demonstrated that inherited genetic basis of susceptibility to BCP-ALL has been underestimated and should be considered before any familial allograft.

A multistage model instructed by a large dataset (knowledge bank [KB] algorithm) has recently been developed to improve outcome prediction and tailor therapeutic decision, including hematopoietic stem cell transplantation (HSCT) in AML. We assessed the performance of the KB in guiding HSCT decision in first complete remission (CR1) in 656 AML patients younger than 60 years from the ALFA-0702 trial (NCT00932412). KB predictions of Overall Survival (OS) were superior to those of European LeukemiaNet (ELN) 2017 risk stratification (C-index 68.9 versus 63.0). Among patients reaching CR1, HSCT in CR1, as a time-dependent covariate was detrimental in those with favorable ELN 2017 risk and those with negative NPM1 MRD (interaction tests P=0.01 and P=0.02, respectively). Using KB simulations of survival at 5 years in a scenario without HSCT in CR1 (KB score), we identified in a similar time-dependent analysis a significant interaction between the KB score and HSCT, with HSCT in CR1 being detrimental only in patients with a good prognosis based on KB simulations (KB score ≥40, interaction test P=0.01). We could finally integrate ELN 2017, NPM1 MRD and KB scores to sort 545 CR1 patients into 278 (51.0%) HSCT candidates and 267 (49.0%) chemo-only candidates. In both time-dependent and 6-month landmark analyses, HSCT significantly improved OS in HSCT candidates while it significantly shortened OS in chemo-only candidates. Integrating KB predictions with ELN 2017 and MRD may thus represent a promising approach to optimize HSCT timing in younger AML patients.

Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIP^InDel), frameshift InDel or nonsense mutations inducing translational stop (bZIP^STOP) or single base-pair missense alterations (bZIP^ms), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIP^InDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups. Moreover, co-mutations in bZIP^InDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIP^InDel patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIP^InDel mutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPA and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIP^ms).

Tandem duplications (TDs) of theUBTFgene have been recently described as a recurrent alteration in pediatric acute myeloid leukemia (AML). Here, by screening 1946 newly diagnosed adult AML, we found thatUBTF-TDs occur in about 3% of patients aged 18–60 years, in a mutually exclusive pattern with other known AML subtype-defining alterations. The characteristics of 59 adults withUBTF-TD AML included young age (median 37 years), low bone marrow (BM) blast infiltration (median 25%), and high rates ofWT1mutations (61%),FLT3-ITDs (51%) and trisomy 8 (29%). BM morphology frequently demonstrates dysmyelopoiesis albeit modulated by the co-occurrence ofFLT3-ITD.UBTF-TD patients have lower complete remission (CR) rates (57% after 1 course and 76% after 2 courses of intensive chemotherapy [ICT]) thanUBTF-wild-type patients. In patients enrolled in the ALFA-0702 study (n = 614 patients including 21 withUBTF-TD AML), the 3-year disease-free survival (DFS) and overall survival ofUBTF-TD patients were 42.9% (95%CI: 23.4–78.5%) and 57.1% (95%CI: 39.5–82.8%) and did not significantly differ from those of ELN 2022 intermediate/adverse risk patients. Finally, the study of paired diagnosis and relapsed/refractory AML samples suggests thatWT1-mutated clones are frequently selected under ICT. This study supports the recognition ofUBTF-TD AML as a new AML entity in adults.