Prognostic impact ofDDX41germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study

Abstract

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).

Adult-onset hereditary myeloid malignancy and allogeneic stem cell transplantation

“…Targeted therapy can also be administered when adequate molecular target is available, although specific data for HMMs are not yet available. Whether chemosensitivity in patients with HMMs is different from that in sporadic cases is unclear, except that CR rate of patients with AML having germline DDX41 mutations after induction chemotherapy was higher than that of patients with wild-type DDX41 (94% vs. 69%) (16). More vigorous studies to explore the suitable initial treatment strategies are warranted.…”

“…Germline mutations in DEAD/H-box helicase gene (DDX41) were reported for the first time in 2015 (15). Despite being a recent discovery, DDX41 mutation is the most common genetic predisposition to MDS/AML, representing 1-5% of myeloid malignancies (11,16,17). Many HMMs cases with germline DDX41 mutations were accompanied by somatic DDX41 mutations (16,47).…”

“…Despite being a recent discovery, DDX41 mutation is the most common genetic predisposition to MDS/AML, representing 1-5% of myeloid malignancies (11,16,17). Many HMMs cases with germline DDX41 mutations were accompanied by somatic DDX41 mutations (16,47). In addition, remarkable ethnic deviation was found in the mutation sites in DDX41; however, second hit was predominantly R525H, irrespective of ethnicity (47)(48)(49).…”

“…Since the prevalence of patients with germline DDX41 mutations is relatively high among patients with HMMs, retrospective comparison of patients with and without germline DDX41 mutations using large-scale data of some clinical trials was recently reported by Duployez et al;191 patients with AML having DDX41 germline mutations and 1,604 DDX41 wild-type patients with AML were compared (16). Interestingly, AML with germline DDX41 mutation displayed a specific relapse kinetics, with a lower short-term relapse rate and higher late relapse risk.…”

“…Some previous reports had suggested apparently favorable outcomes in AML with germline DDX41 mutations (11, 51, 80); however, long-term follow up may be necessary to evaluate the genuine prognosis of AML with germline DDX41 mutations. Regarding the role of HSCT, Duployez et al showed that HSCT in first CR for AML with germline DDX41 mutation may contribute to the suppression of late relapse, although OS was not significantly different (16).…”