Germline DDX41 mutations are involved in familial myelodysplastic syndromes (MDSs) and acute myeloid leukemias (AMLs). We analyzed the prevalence and characteristics of DDX41-related myeloid ...malignancies in an unselected cohort of 1385 patients with MDS or AML. Using targeted next-generation sequencing, we identified 28 different germline DDX41 variants in 43 unrelated patients, which we classified as causal (n = 21) or unknown significance (n = 7) variants. We focused on the 33 patients having causal variants, representing 2.4% of our cohort. The median age was 69 years; most patients were men (79%). Only 9 patients (27%) had a family history of hematological malignancy, and 15 (46%) had a personal history of cytopenia years before MDS/AML diagnosis. Most patients had a normal karyotype (85%), and the most frequent somatic alteration was a second DDX41 mutation (79%). High-risk DDX41 MDS/AML patients treated with intensive chemotherapy (n = 9) or azacitidine (n = 11) had an overall response rate of 100% or 73%, respectively, with a median overall survival of 5.2 years. Our study highlights that germline DDX41 mutations are relatively common in adult MDS/AML, often without known family history, arguing for systematic screening. Salient features of DDX41-related myeloid malignancies include male preponderance, frequent preexisting cytopenia, additional somatic DDX41 mutation, and relatively good outcome.
•Germline DDX41 mutations are found in a significant proportion of sporadic MDS/AML patients.•Patients with DDX41-related MDS/AML have a relatively favorable outcome.
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Despite improvement in clinical management, allogeneic hematopoietic stem cell transplantation (HSCT) is still hampered by high morbidity and mortality rates, mainly due to graft versus host disease ...(GvHD). Recently, it has been demonstrated that the allogeneic immune response might be influenced by external factors such as tissues microenvironment or host microbiota. Here we used high throughput metabolomics to analyze two cohorts of genotypically HLA-identical related recipient and donor pairs. Metabolomic profiles markedly differ between recipients and donors. At the onset of acute GvHD, in addition to host-derived metabolites, we identify significant variation in microbiota-derived metabolites, especially in aryl hydrocarbon receptor (AhR) ligands, bile acids and plasmalogens. Altogether, our findings support that the allogeneic immune response during acute GvHD might be influenced by bile acids and by the decreased production of AhR ligands by microbiota that could limit indoleamine 2,3-dioxygenase induction and influence allogeneic T cell reactivity.
Background
The effects of eculizumab treatment in paroxysmal nocturnal hemoglobinuria (PNH) patients with or without high‐disease activity (HDA), defined by LDH ≥ 1.5 × ULN and history of major ...adverse vascular events (MAVEs; including thrombotic events TEs); anemia; and/or physician‐reported abdominal pain, dyspnea, dysphagia, erectile dysfunction, fatigue, and/or hemoglobinuria, in the International PNH Registry were evaluated.
Methods
Registry patients were stratified by baseline HDA and eculizumab‐treatment status. Longitudinal changes in laboratory and clinical PNH‐related endpoints were evaluated using linear mixed models (continuous variables) or Poisson regression (incidence rates).
Results
As of May 1, 2017, 3009 patients (HDA/eculizumab‐treated, n = 913; HDA/never‐treated, n = 651; no‐HDA/eculizumab‐treated, n = 173; no‐HDA/never‐treated, n = 1272) were analyzed. Higher proportions of eculizumab‐treated patients had HDA and history of MAVEs. In patients with and without HDA, respectively, eculizumab treatment resulted in reductions from baseline for (1) LDH ratio (mean SD: −5.3 4.0 and −2.3 3.8); (2) incidence rate ratio (IRR) for MAVEs (−80% and −70%); (3) IRR for TEs (−80% for both); and (4) units of red blood cell transfusions per year (from 6.8 to 2.8 and 3.6 to 2.5 units).
Conclusions
Eculizumab treatment in a real‐world setting improved outcomes, including substantial decreases in hemolysis, MAVE rates, TEs, and transfusions in PNH patients regardless of HDA.
ELANE neutropenia is associated with myelodysplasia and acute leukemia (MDS-AL), and severe infections. Because the MDS-AL risk has also been shown to be associated with exposure to GCSF, since 2005, ...in France, patients receiving high daily GCSF doses (>15 μg/kg/day) are eligible for HSCT, in addition to classic indications (MDS-AL or GCSF refractoriness). We analyzed the effect of this policy. Among 144 prospectively followed ELANE-neutropenia patients enrolled in the French Severe Congenital Neutropenia Registry, we defined two groups according to period: "before 2005" for those born before 2005 and followed until 31/12/2004 (1588 person-years); and "after 2005" comprised of those born after 2005 or born before 2005 but followed after 2005 until 31/03/2019 (1327 person-years). Sixteen of our cohort patients underwent HSCT (14 long-term survivors) and six developed MDS-ALs. Six leukemic transformations occurred in the before-2005 group and none after 2005 (respective frequencies 3.8 × 10
vs. 0; P < 0.01), while four HSCTs were done before 2005 and 12 since 2005 (respective HSCT rates increased 2.5 × 10
vs. 9 × 10
; P < 0.01). Our results support early HSCT for patients with ELANE mutations who received high GCSF doses, as it might lower the risk of leukemic transformation.
Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) ...with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.
•Next-generation sequencing broadens the spectrum of germ line mutations in a cohort of patients with likely-inherited BMF.•Salient clinical features and distinct natural histories are consistently found in SAMD9L and SAMD9, MECOM/EVI1, and ERCC6L2 disorders.
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At least 10% of patients with interstitial lung disease present monogenic lung fibrosis suspected on familial aggregation of pulmonary fibrosis, specific syndromes or early age of diagnosis. ...Approximately 25% of families have an identified mutation in genes mostly involved in telomere homeostasis, and more rarely in surfactant homeostasis.Beyond pathophysiological knowledge, detection of these mutations has practical consequence for patients. For instance, mutations involved in telomere homeostasis are associated with haematological complications after lung transplantation and may require adapted immunosuppression. Moreover, relatives may benefit from a clinical and genetic evaluation that should be specifically managed.The field of genetics of pulmonary fibrosis has made great progress in the last 10 years, raising specific problems that should be addressed by a specialised team.
Summary
Pure red cell aplasia (PRCA) following allogeneic haematopoietic stem cell transplantation (aHSCT) with major ABO incompatibility is responsible for transfusion dependent anaemia, impaired ...quality of life and iron overload. We conducted a retrospective study, over a 10‐year period, which included all consecutive patients who received a major ABO mismatched aHSCT, to assess the impact of specific treatment on PRCA. We did not observe any PRCA in the 57 aHSCT issued from cord blood. Among the remaining 631 patients, cumulative incidence of PRCA was 10·5% range 8·2–13.0. The median duration of resolved PRCA was 171 days IQR 116; 261. Pre‐transplant high isohaemagglutinins titre was associated with an increased risk of PRCA (P < 10−4). PRCA did not affect overall survival (P = 0·95). Twenty‐two patients (33·3%) received at least one specific treatment. The most commonly used treatments were rituximab (17 patients) and donor lymphocyte infusion (DLI; seven patients). Regarding PRCA resolution, we did not observe a significant difference between treated or untreated subjects (HR = 0·93, 95% confidence interval (CI) 0·48– 1·80; P = 0·82). Similar results were observed with erythropoietin treatment (22 patients, HR = 0·86 95% CI: 0·47–1·57 P = 0·62). Our data do not support the use of erythropoietin, rituximab or DLI for the treatment of PRCA.
Endothelial cell (EC) activation has been suspected of triggering a group of rare and dismal complications that can occur after allogeneic hematopoietic stem cell transplantation (HSCT). Capillary ...leak syndrome, engraftment syndrome, transplant-associated microangiopathy, diffuse alveolar hemorrhage, and idiopathic pneumonia syndrome are the main nosological entities. Post-HSCT endotheliitis can be triggered by chemotherapy, infections, and calcineurin inhibitors, but allogeneic reactivity is claimed to be the common denominator. Endothelial damages are thought to activate several deleterious pathways (proapoptotic, procoagulant, proinflammatory) and can lead to multiorgan failure; however, clinical manifestations of each syndrome overlap, and their relationship with graft-versus-host disease could be minimal. The lack of well-defined diagnostic criteria does not allow for a clear-cut comparison in the current literature. Therapeutic efforts have been made to intercept the pathogenic mechanisms leading to EC dysfunction, but remission rates and survival remain mostly unsatisfactory. In this article, we have reviewed the incidence, clinical features, and treatment approaches of EC activation syndromes, and we plead for the development of internationally accepted standard definitions.
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Carriers of germline telomerase‐related gene (TRG) mutations can show poor prognosis, with an increase in common hematological complications after lung transplantation (LT) for pulmonary fibrosis. ...The aim of this study was to describe the outcomes after LT in recipients carrying a germline TRG mutation and to identify the predictors of survival. In a multicenter cohort of LT patients, we retrospectively reviewed those carrying pathogenic TRG variations (n = 38; TERT, n = 23, TERC, n = 9, RTEL1, n = 6) between 2009 and 2018. The median age at LT was 54 years (interquartile range IQR 46–59); 68% were male and 71% had idiopathic pulmonary fibrosis. During the diagnosis of pulmonary fibrosis, 28 (74%) had a hematological disease, including eight with myelodysplasia. After a median follow‐up of 26 months (IQR 15–46), 38 patients received LT. The overall post‐LT median survival was 3.75 years (IQR 1.8‐NA). The risk of death after LT was increased for patients with myelodysplasia (HR 4.1 95% CI 1.5–11.5) or short telomere (HR 2.2 1.0–5.0) before LT. After LT, all patients had anemia, 66% had thrombocytopenia, and 39% had neutropenia. Chronic lung allograft dysfunction frequency was 29% at 4 years. The present findings support the use of LT in TRG mutation carriers without myelodysplasia. Hematological evaluation should be systematically performed before LT.
Among patients with telomerase‐related gene mutations who undergo lung transplantation for idiopathic pulmonary fibrosis, pre‐transplant myelodysolasia is associated with reduced post‐transplant survival.
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