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Erythropoietic protoporphyria (EPP) is a rare metabolic disease of the heme biosynthetic pathway where an enzymatic dysfunction results in protoporphyrin IX (PPIX) accumulation in erythroid cells. The porphyrins are photo-reactive and are responsible for severe photosensitivity in patients, thus drastically decreasing their quality of life. The liver eliminates PPIX and as such, the main and rare complication of EPP is progressive cholestatic liver disease, which can lead to liver failure. The management of this complication is challenging, as it often requires a combination of approaches to promote PPIX elimination and suppress the patient's erythropoiesis. Here we described a 3-year follow-up of an EPP patient, with three episodes of liver involvement, aggravated by the coexistence of a factor VII deficiency. It covers all the different types of intervention available for the management of liver disease, right through to successful allogeneic hematopoietic stem cell transplantation.

Objectives: To assess the clinical and healthcare resource burden among C5 inhibitor (C5i)-treated patients with paroxysmal nocturnal haemoglobinuria (PNH), using patient-reported data.Methods: This web-based, cross-sectional survey (01FEB2021–31MAR2021) of adults with PNH treated with eculizumab (France, Germany, UK) or ravulizumab (Germany) included: patient characteristics; treatment patterns/dosage; haematological outcomes (haemoglobin [Hb] levels, transfusions, thrombotic events, breakthrough haemolysis); and medical encounters. Treatment and Hb-level subgroup differences were assessed with statistical significance tests.Results: Among 71 patients, 98.6% were C5i-treated for ≥3 months. The majority (with reported Hb levels) had levels ≤12.0 g/dL (85.7%; n = 54/63). The mean Hb level was 10.2 g/dL (standard deviation [SD]: 2.0; median 10.0 g/dL). Treatment with above label-recommended doses was reported by 30.4% (eculizumab) and 5.3% (ravulizumab) of patients. Within the past 12 months among patients treated with C5i for ≥1 year: 24.1% had ≥1 transfusion; 3.2% had ≥1 thrombosis; and 28.6% had ≥1 breakthrough haemolysis. Among all patients, 26.8% and 31.0% reported emergency department/room [ER] and inpatient visits, respectively. Mean annual, per-patient all-cause medical encounters were: 0.5 (ER); 1.9 (inpatient); and overall outpatient visits ranged by setting from 2.0 to 6.4. Most encounters were PNH-related, with means of 0.4 (ER); 1.8 (inpatient); and 1.6–5.4 (outpatient). Primary haematological and medical encounter outcomes were similar between treatment as well as Hb-level subgroups, with almost no statistically significant differences.Conclusions: Despite at least 3 months of C5i treatment, high proportions of patients with PNH reported low haemoglobin levels and required transfusions and hospitalizations, which suggests remaining unmet needs.

Debates on the role and timing of allogeneic hemtopoietic stem cell transplantation (HSCT) in acute myelogenous leukemia (AML) have persisted for decades. Time to transplant introduces an immortal time and current treatment algorithm mainly relies on the European LeukemiaNet disease risk classification. Previous studies are also limited to age groups, remission status and other ill-defined parameters. We studied all patients at diagnosis irrespective of age and comorbidities to estimate the cumulative incidence and potential benefit or disadvantage of HSCT in a single center. As a time-dependent covariate, HSCT improved overall survival in intermediate- and poor-risk patients (hazard ratio =0.51; P=0.004). In goodrisk patients only eight were transplanted in first complete remission. Overall, the 4-year cumulative incidence of HSCT was only 21.9% but was higher (52.1%) for patients in the first age quartile (16-57 years old) and 26.4% in older patients (57-70 years old) (P

Germline GATA2 mutations predispose to myeloid malignancies resulting from the progressive acquisition of additional somatic mutations. Here we describe clinical and biological features of 78 GATA2-deficient patients. Hematopoietic stem and progenitor cell phenotypic characterization revealed an exhaustion of myeloid progenitors. Somatic mutations in STAG2, ASXL1 and SETBP1 genes along with cytogenetic abnormalities (monosomy 7, trisomy 8, der(1;7)) occurred frequently in patients with GATA2 germline mutations. Patients were classified into three hematopoietic spectra based on bone marrow cytomorphology. No somatic additional mutations were detected in patients with normal bone marrow (spectrum 0), whereas clonal hematopoiesis mediated by STAG2 mutations was frequent in those with a hypocellular and/or myelodysplastic bone marrow without excess blasts (spectrum 1). Finally, SETBP1, RAS pathway and RUNX1 mutations were predominantly associated with leukemic transformation stage (spectrum 2), highlighting their implications in the transformation process. Specific somatic alterations, potentially providing distinct selective advantages to affected cells, are therefore associated with the clinical/hematological evolution of GATA2 syndrome. Our study not only suggests that somatic genetic profiling will help clinicians in their management of patients, but will also clarify the mechanism of leukemogenesis in the context of germline GATA2 mutations.

Abstract Background Standardized and sensitive assays for Epstein Barr Virus (EBV) are needed to define universal cutoff for treatment initiation in allogeneic hematopoietic stem cells transplant recipients. In a context of accreditation and the availability of EBV international standard, we evaluated the Abbott RealTime EBV (RT) assay for EBV quantification in whole blood. Methods The RT assay was compared on 282 prospective clinical samples with the Artus EBV PCR Kit V1 assay (V1) and we analyzed the kinetics of EBV load in 11 patients receiving rituximab treatment. Results The estimated limit of detection was 88 IU/mL. The assay was linear (r2 = 0.9974) in the range of all samples tested (100 to 1,000,000 IU/mL). Intra-assay coefficients of variation (CV) ranged between 0.35 and 1.35%, and inter-assay CV between 3.40 and 4.5%. On samples above the limit of quantification, the two assays were strongly correlated. EBV RT values were on average 0.30 log10 IU/mL lower than those measured with the V1 assay. In patients treated with rituximab, the RT assay remained positive in 5 patients at the time it dropped below undetectable levels with the V1 assay. Conclusions In conclusion, the RT assay is a reliable assay for EBV load in whole blood. Its sensitivity will enable to estimate the kinetics of EBV load and the impact of treatments to control EBV reactivations.

Graft versus host disease (GvHD) still hinders allogeneic hematopoietic stem cell transplantation. Here, the authors use metabolomics to analyze two cohorts of paired transplant recipients and donors, identifying significant differences in both host- and microbiota-derived metabolites.

Abstract Background Genetic testing is proposed for suspected cases of monogenic pulmonary fibrosis, but clinicians and patients need specific information and recommendation about the related diagnosis and management issues. Because multidisciplinary discussion (MDD) has been shown to improve accuracy of interstitial lung disease (ILD) diagnosis, we evaluated the feasibility of a genetic MDD (geneMDD) dedicated to the indication for and interpretation of genetic testing. The geneMDD group met monthly and included pediatric and adult lung specialists with ILD expertise, molecular and clinical geneticists, and one radiologist. Hematologists, rheumatologists, dermatologists, hepatologists, and pathologists were also invited to attend. Results Since 2016, physicians from 34 different centers in 7 countries have participated in the geneMDD. The medical files of 95 patients (53 males) have been discussed. The median age of patients was 43 years [range 0–77], 10 were ≤ 15 years old, and 6 were deceased at the time of the discussion. Among 85 analyses available, the geneMDD considered the rare gene variants pathogenic for 61: 37 variants in telomere-related genes, 23 variants in surfactant-related genes and 1 variant in MARS. Genetic counseling was offered for relatives of these patients. The geneMDD therapeutic proposals were as follows: antifibrotic drugs (n = 25), steroids or immunomodulatory therapy (n = 18), organ transplantation (n = 21), watch and wait (n = 21), or best supportive care (n = 4). Conclusion Our experience shows that a dedicated geneMDD is feasible regardless of a patient’s age and provides a unique opportunity to adapt patient management and therapy in this very rare condition.

Abstract: 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.

Background: Ravulizumab, the only long-acting complement C5 inhibitor for adults with paroxysmal nocturnal hemoglobinuria (PNH), demonstrated non-inferiority to eculizumab after 26 weeks of treatment in complement inhibitor-naïve patients during a phase III randomized controlled trial. We present open-label extension results with up to 52 weeks of treatment. Methods: Patients assigned to ravulizumab every 8 weeks (q8w) or eculizumab every 2 weeks during the randomized primary evaluation period received ravulizumab q8w during the 26-week extension. Efficacy endpoints were lactate dehydrogenase (LDH) normalization, transfusion avoidance, breakthrough hemolysis (BTH), LDH levels, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and stabilized hemoglobin. Serum free C5 levels and safety were assessed. Outcomes as of the data cut-off (4 September 2018) were summarized using descriptive statistics. Results: Overall, 124 patients continued ravulizumab, and 119 switched from eculizumab to ravulizumab. During the extension, 43.5% and 40.3% of patients in the ravulizumab–ravulizumab and eculizumab–ravulizumab arms, respectively, achieved LDH normalization; 76.6% and 67.2% avoided transfusion. BTH decreased in the eculizumab–ravulizumab arm; no events were associated with free C5 ⩾0.5 μg/mL while receiving ravulizumab. Overall, 73.4% and 65.5% of patients in the ravulizumab–ravulizumab and eculizumab–ravulizumab arms, respectively, achieved stabilized hemoglobin. Similar proportions of patients achieved ⩾3-point improvement in FACIT-Fatigue at week 52 (ravulizumab–ravulizumab, 64.5%; eculizumab–ravulizumab, 57.1%). All patients maintained free C5

Significant morbidity and mortality have been associated with liver complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Causes and consequences of these hepato-biliary complications are various and might be life-threatening. A high misdiagnosis rate has been reported because of a weak correlation between clinical, laboratory and imaging data. Liver elastography, a liver stiffness measure, is able to assess liver fibrosis and portal hypertension in most liver diseases, but data after allo-HSCT are scarce. Our aim was to determine the interest of sequential liver stiffness measurements for the diagnosis of early hepatic complications after allo-HSCT. Over a two years period of time, 161 consecutive adult patients were included and 146 were analyzed. Ultrasonography and elastography measurements were performed before transplantation, at day+7 and day+14 by three different experienced radiologists unaware of patients'clinical status. Eighty-one (55%) patients had liver involvements within the first 100 days after allo-HSCT. Baseline elastography was not predictive for the occurrence of overall liver abnormalities. A significant increase in 2D real-time shearwave elastography (2D-SWE) was found in patients with sinusoidal obstruction syndrome (SOS). Fifteen patients (10%) fulfilled EBMT score criteria and twelve (8%) reached Baltimore criteria for SOS diagnosis, but only six (4%) had a confirmed SOS. 2D-SWE at day+14 allowed early detection of SOS (AUROC=0.84, p=0.004) and improved sensibility (75%), specificity (99%) and positive predictive value (60%) over the Seattle, Baltimore or EBMT scores. A 2D-SWE measurement above 8.1kPa at day+14 after allo-HSCT seems a promising, non-invasive, and reproducible tool for early and accurate diagnosis of SOS.

Abstract: Various pretransplant patient and disease characteristics are associated with treatment-related mortality (TRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, TRM cannot yet be satisfactorily predicted. We prospectively investigated the aggregate impact of pretransplant clinical variables (period, donor/recipient age, gender, cytomegalovirus status, disease risk, stem cell source, and HLA matching), comorbidity index scores (Hematopoietic Cell Transplantation Comorbidity Index), and biological markers (telomere length, ferritin, and C-reactive protein) on TRM in single-center patients receiving a first allo-HSCT. From 2006 to 2012, all variables were available for 178 patients. In multivariate analysis, only mismatched unrelated donor (hazard ratio [HR], 2.79; 95% confidence interval [CI], 1.19-6.58; P = .019) and shorter age-adjusted recipient telomere length (HR, 2.17; 95% CI, 1.03-4.57; P = .041) were independently associated with TRM. Pre–allo-HSCT age-adjusted telomere length thus appears to be a useful new predictor of TRM in the setting of HSCT.

BackgroundEculizumab has transformed management of paroxysmal nocturnal hemoglobinuria (PNH) since its approval. However, its biweekly dosing regimen remains a high treatment burden. Ravulizumab administered every 8 weeks demonstrated noninferiority to eculizumab in two phase 3 trials. In regions where two PNH treatment options are available, it is important to consider patient preference.ObjectiveThe aim of this study was to assess patient preference for ravulizumab or eculizumab.MethodsStudy 302s (ALXN1210-PNH-302s) enrolled PNH patients who participated in the extension period of phase 3 study ALXN1210-PNH-302. In the parent study, eculizumab-experienced adult PNH patients received ravulizumab or eculizumab during a 26-week primary evaluation period. All patients in the extension period received ravulizumab. In study 302s, patient treatment preference was evaluated using an 11-item PNH-specific Patient Preference Questionnaire (PNH-PPQ©). Of 98 patients, 95 completed PNH-PPQ© per protocol for analysis.ResultsOverall, 93% of patients preferred ravulizumab whereas 7% of patients either had no preference (6%) or preferred eculizumab (1%) (P < 0.001). For specific aspects of treatment, ravulizumab was preferred (in comparison to no preference or eculizumab) on infusion frequency (98% vs. 0% vs. 2%), ability to plan activities (98% vs. 0% vs. 2%), and overall quality of life (88% vs. 11% vs. 1%), among other aspects. Most participants selected frequency of infusions as the most important factor determining preference (43%), followed by overall quality of life (23%).ConclusionThis study shows that a substantial proportion of patients preferred ravulizumab over eculizumab and provides an important patient perspective on PNH treatment when there is more than one treatment option.

Aplastic anemia is a rare but potentially life-threatening disease that may affect older patients. Data regarding the treatment of aplastic anemia in this ageing population remains scarce. We conducted a retrospective nationwide multicenter study in France to examine current treatments for aplastic anemia patients over 60 years old. Our aims were to evaluate efficacy and tolerance, and to analyze predictive factors for response and survival. Over the course of a decade, 88 patients (median age 68.5 years) were identified in 19 centers, with a median follow up of 2.7 years; 21% had very severe and 36% severe aplastic anemia. We analyzed 184 treatment lines, mostly involving the standard combination of anti-thymocyte globulin and cyclosporine-A (33%), which was also the most frequent first-line treatment (50%). After first-line therapy, 32% of patients achieved a complete response, and 15% a partial response. Responses were significantly better in first line and in patients with good performance status, as well as in those that had followed an anti-thymocyte globulin and cyclosporine-A regimen (overall response rate of 70% after first-line treatment). All treatments were well tolerated by patients, including over the age of 70. Three-year survival was 74.7% (median 7.36 years). Age, Charlson comorbidity index and very severe aplastic anemia were independently associated with mortality. Age, per se, is not a limiting factor to aplastic anemia treatment with anti-thymocyte globulin and cyclosporine-A; this regimen should be used as a first-line treatment in elderly patients if they have a good performance status and low comorbidity index score.

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.

Few therapeutic options are available for patients with aplastic anemia who are ineligible for transplantation or refractory to immunosuppressive therapy. Eltrombopag was recently shown to produce trilineage responses in refractory patients. However, the effects of real-life use of this drug remain unknown. This retrospective study (2012–2016) was conducted by the French Reference Center for Aplastic Anemia on patients with relapsed/refractory aplastic anemia, and patients ineligible for antithymocyte globulin or transplantation, who received eltrombopag for at least 2 months. Forty-six patients with aplastic anemia were given eltrombopag without prior antithymocyte globulin treatment (n=11) or after antithymocyte globulin administration (n=35) in a relapsed/refractory setting. Eltrombopag (median daily dose 150 mg) was introduced 17 months (range, 8–50) after the diagnosis of aplastic anemia. At last followup, 49% were still receiving treatment, 9% had stopped due to a robust response, 2% due to toxicity and 40% due to eltrombopag failure. Before eltrombopag treatment, all patients received regular transfusions. The overall rates of red blood cell and platelet transfusion independence were 7%, 33%, 46% and 46% at 1, 3, 6 months and last follow-up. Responses were slower to develop in antithymocyte treatment-naïve patients. In patients achieving transfusion independence, hemoglobin concentration and platelet counts improved by 3 g/dL (interquartile range, 1.4–4.5) and 42×109/L (interquartile range, 11–100), respectively. Response in at least one lineage (according to National Institutes of Health criteria) was observed in 64% of antithymocyte treatment-naïve and 74% of relapsed/refractory patients, while trilineage improvement was observed in 27% and 34%, respectively. We found high rates of hematologic improvement and transfusion independence in refractory aplastic anemia patients but also in patients ineligible for antithymocyte globulin receiving first-line treatment. In conclusion, elderly patients unfit for antithymocyte globulin therapy may benefit from eltrombopag.

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.

We previously reported that bone marrow grafts from matched sibling donors resulted in best graft-versus-host disease-free, relapse-free survival at 1-year post allogeneic hematopoietic cell transplantation. However, pediatric patients comprised the majority of bone marrow graft recipients in that study. To better define this outcome in adults and pediatric patients at 1- and 2-years post- allogeneic hematopoietic cell transplantation, we pooled data from the University of Minnesota and the Hôpital Saint-Louis in Paris, France (n=1901). Graft-versus-host disease-free, relapse-free survival was defined as the absence of grade III–IV acute graft-versus-host disease, chronic graft-versus-host disease (requiring systemic therapy or extensive stage), relapse and death. In adults, bone marrow from matched sibling donors (n=123) had best graft-versus-host disease-free, relapse-free survival at 1- and 2-years, compared with peripheral blood stem cell from matched sibling donors (n=540) or other graft/donor types. In multivariate analysis, peripheral blood stem cells from matched sibling donors resulted in a 50% increased risk of events contributing to graft-versus-host disease-free, relapse-free survival at 1- and 2-years than bone marrow from matched sibling donors. With limited numbers of peripheral blood stem cell grafts in pediatric patients (n=12), graft-versus-host disease-free, relapse-free survival did not differ between bone marrow and peripheral blood stem cell graft from any donor. While not all patients have a matched sibling donor, graft-versus-host disease-free, relapse-free survival may be improved by the preferential use of bone marrow for adults with malignant diseases. Alternatively, novel graft-versus-host disease prophylaxis regimens are needed to substantially impact graft-versus-host disease-free, relapse-free survival with the use of peripheral blood stem cell.