Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

Germline ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition.

The genomics era has facilitated discovery of new genes predisposing to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ERG as a novel autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor critical for definitive hematopoiesis, stem cell function and platelet maintenance. ERG colocalizes with other transcription factors including RUNX1 and GATA2 on promoters/enhancers of genes orchestrating hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 thrombocytopenic individuals from one family and 14 additional ERG variants in unrelated individuals with BMF/HM including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germline ERG variants included cytopenias (thrombocytopenia, neutropenia, pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense, 1 truncating) including 3 missense population variants were functionally characterized. Thirteen potentially pathogenic ETS domain missense variants displayed loss-of-function characteristics disrupting transcriptional transactivation, DNA-binding and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture, and to promote acute erythroleukemia when transplanted into mice, concordant with these variants being loss-of-function. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germline ERG variants has clinical implications for patient/family diagnosis, counselling, surveillance, and treatment strategies including selection of bone marrow donors or cell/gene therapy.

Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia.

BACKGROUND: A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia. METHODS: In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months. RESULTS: Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome. CONCLUSIONS: The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.).

Rare germline complement factor H variants in patients with paroxysmal nocturnal hemoglobinuria.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) are susceptible to complement-mediated intravascular hemolysis and thrombosis. Factor H (FH) is the main regulator of the complement alternative pathway, which protects cells from unwanted complement-mediated damage. Although FH is not a glycosylphosphatidylinositol-linked molecule, it may play a role in PNH. We sought to determine if rare germline variants in complement factor H (CFH) affect the PNH course, screening 84 patients with PNH treated with eculizumab for rare variants in CFH, CFI, and C3 genes. We compared the allelic frequencies with populational data and a geographically-matched control group, looking for an association between presence of the variants and treatment response (transfusion independence by 6 months). Sixteen patients presented rare variants, 9 in CFH (10.7%). Germline CFH variants were more frequent among patients with PNH than among controls (P = .02) or public data (P < .001) and were more likely to be transfusion-dependent at 6 months after eculizumab initiation (P = .015). With a median follow-up of 5.8 years, 8 of 9 patients with the CFH variant received transfusions, and 2 developed thromboses. None of the patients with the CFH variant had severe aplastic anemia from eculizumab initiation until 6 months. We demonstrated for the first time that rare CFH variants are over-represented among patients with PNH and that germline genetic background may affect the response to eculizumab.

The clinical picture of ERCC6L2 disease: from bone marrow failure to acute leukemia.

Biallelic germ line excision repair cross-complementing 6 like 2 (ERCC6L2) variants strongly predispose to bone marrow failure (BMF) and myeloid malignancies, characterized by somatic TP53-mutated clones and erythroid predominance. We present a series of 52 subjects (35 families) with ERCC6L2 biallelic germ line variants collected retrospectively from 11 centers globally, with a follow-up of 1165 person-years. At initial investigations, 32 individuals were diagnosed with BMF and 15 with a hematological malignancy (HM). The subjects presented with 19 different variants of ERCC6L2, and we identified a founder mutation, c.1424delT, in Finnish patients. The median age of the subjects at baseline was 18 years (range, 2-65 years). Changes in the complete blood count were mild despite severe bone marrow (BM) hypoplasia and somatic TP53 mutations, with no significant difference between subjects with or without HMs. Signs of progressive disease included increasing TP53 variant allele frequency, dysplasia in megakaryocytes and/or erythroid lineage, and erythroid predominance in the BM morphology. The median age at the onset of HM was 37.0 years (95% CI, 31.5-42.5; range, 12-65 years). The overall survival (OS) at 3 years was 95% (95% CI, 85-100) and 19% (95% CI, 0-39) for patients with BMF and HM, respectively. Patients with myelodysplastic syndrome or acute myeloid leukemia with mutated TP53 undergoing hematopoietic stem cell transplantation had a poor outcome with a 3-year OS of 28% (95% CI, 0-61). Our results demonstrated the importance of early recognition and active surveillance in patients with biallelic germ line ERCC6L2 variants.

Long-term outcome after allogeneic stem cell transplantation for GATA2 deficiency: An analysis of 67 adults and children from France and Belgium.

Modalities and timing of haematopoietic stem cell transplant (HSCT) in patients with GATA2 deficiency are still subject to debate. On June 2022, 67 patients (median age 20.6 years) underwent a first allogeneic HSCT among 21 centres. Indications for HSCT were myelodysplastic syndrome (MDS) ≤5% blasts ± immunodeficiency (66%), MDS >5% blasts (15%), acute myeloid leukaemia (19%). Conditioning regimen was myeloablative in 85% and anti-thymocyte globulins were used in 67%. The cumulative incidence (CInc) of acute graft versus host disease (GvHD) grade II-IV and III-IV at day 100 were 42% and 13%, and CInc of chronic and extensive chronic GvHD at 2 years were 42% and 23%. CInc of relapses was 3% and 11% at 1 and 5 years. Overall survival (OS) at 1 and 5 years was 83% and 72% (median follow-up 5.6 years). The factors associated with worse OS in multivariable analysis were the year of HSCT, a history of excess blasts before transplant and peripheral blood stem cell (PBSC) grafts. Age at HSCT, non-myeloablative conditioning and PBSC grafts were associated with increased non-relapse mortality. In conclusion, bone marrow monitoring to identify clonal evolution and perform HSCT before the appearance of excess blast is mandatory.

Liver disease in germline mutations of telomere-related genes: Prevalence, clinical, radiological, pathological features, outcome, and risk factors.

BACKGROUND AND AIM: Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases. APPROACH AND RESULTS: Retrospective multicenter analysis of liver disease (transaminases > 30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n = 1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological, and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease in 48% and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and HCC occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score ≥ 3·25 and ≥1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group [80/396, (20%)], OR 12.9 (CI 95%: 7.8-21.3, p < 0.001). CONCLUSIONS: TRG mutations significantly increase the risk of developing liver disease. Although symptoms may be mild, they may be associated with severe disease. Porto-sinusoidal vascular disease and cirrhosis were the most frequent lesions, suggesting that the mechanism of action is multifactorial.

Clinical and immune features of human parvovirus B19 infection in allogeneic stem cell transplantation recipients: A retrospective monocentric study.

BACKGROUND: Human parvovirus B19 (B19V) infection is associated with pure red cell aplasia (PRCA) in immunocompromised patients; however, the spectrum of manifestations associated with B19V in allogeneic hematopoietic stem cell transplantation recipients (alloHSCT) has rarely been reported. METHODS: In this study, we aimed to report clinical and immune features of B19V infection after alloHSCT. We retrospectively collected and analyzed clinical and microbiological data of all transplanted patients with B19V DNAmia or tissue infection detected by polymerase chain reaction (PCR) in our center from 2010 to 2021. RESULTS: We report 35 cases of B19V infections in 33 patients. Median time from transplant to B19V first PCR positivity was 6.9 months (interquartile range (IQR) [1.6-18.9]). No preferential immune profile, type of transplantation or conditioning was identified. Hematological impairment was the most frequent sign, followed by rash and fever. Unconventional clinical forms were also detected, such as acute myelitis and myositis. For some cases, the direct relationship between symptoms and B19V infection was difficult to prove but was suggested by targeted tissue PCR positivity. When hematological impairment was not at the forefront, reticulocytopenia helped to diagnose B19V infections. Treatment was mainly based on high dose intravenous immunoglobulin. CONCLUSION: Although hematological impairment was the most frequent sign, B19V can affect multiple targets and lead to atypical manifestations. Because of its heterogeneous clinical presentation, B19V infection is likely under-diagnosed. Diagnosis of unusual B19V organ involvement needs combination of arguments which can include targeted tissue PCR.

Determinants of survival after lung transplantation in telomerase-related gene mutation carriers: A retrospective cohort.

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.

The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria.

Complement C5 inhibition is the standard of care (SoC) for patients with paroxysmal nocturnal hemoglobinuria (PNH) with significant clinical symptoms. Constant and complete suppression of the terminal complement pathway and the high serum concentration of C5 pose challenges to drug development that result in IV-only treatment options. Crovalimab, a sequential monoclonal antibody recycling technology antibody was engineered for extended self-administered subcutaneous dosing of small volumes in diseases amenable for C5 inhibition. A 3-part open-label adaptive phase 1/2 trial was conducted to assess safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy in healthy volunteers (part 1), as well as in complement blockade-naive (part 2) and C5 inhibitor-treated (part 3) PNH patients. Twenty-nine patients were included in part 2 (n = 10) and part 3 (n = 19). Crovalimab concentrations exceeded the prespecified 100-µg/mL level and resulted in complete and sustained terminal complement pathway inhibition in treatment-naive and C5 inhibitor-pretreated PNH patients. Hemolytic activity and free C5 levels were suppressed below clinically relevant thresholds (liposome assay <10 U/mL and <50 ng/mL, respectively). Safety was consistent with the known profile of C5 inhibition. As expected, formation of drug-target-drug complexes was observed in all 19 patients switching to crovalimab, manifesting as transient mild or moderate vasculitic skin reactions in 2 of 19 participants. Both events resolved under continued treatment with crovalimab. Subcutaneous crovalimab (680 mg; 4 mL), administered once every 4 weeks, provides complete and sustained terminal complement pathway inhibition in patients with PNH, warranting further clinical development (ClinicalTrials.gov identifier, NCT03157635).

Emerging drugs for the treatment of paroxysmal nocturnal hemoglobinuria.

INTRODUCTION: Eculizumab, the first anti-C5 monoclonal antibody approved for patients with paroxysmal nocturnal hemoglobinuria (PNH), has revolutionized the natural history of this disease, blocking intravascular hemolysis, reducing the risk of thromboembolic events, resulting in a significant improvement in survival and quality of life. However, the hematological response to eculizumab is extremely heterogeneous, with only one-third of PNH patients reaching normal hemoglobin levels. AREAS COVERED: This article reviews the current new drugs being investigated in phase II and III trials for adult PNH patients. Literature search was performed using Medline and Clinicaltrials.org databases. EXPERT OPINION: The new molecules have been classified according to the target of the complement system on which they act; we have novel terminal complement inhibitors, which target C5, and proximal complement inhibitors, which interfere with C3 or even further upstream (factor B and D). Ravulizumab is the first next-generation C5 inhibitor, approved by FDA and EMA, which reproduced the excellent results achieved with eculizumab, trying to improve the convenience of patients. However, unresolved issues remain, such as C3-mediated extravascular hemolysis, on which novel proximal complement inhibitors are showing their efficacy. Pegcetacoplan is the first C3-inihibitor approved by FDA. Long-term safety data for novel complement inhibitors are needed.

The burden of illness of patients with paroxysmal nocturnal haemoglobinuria receiving C5 inhibitors in France, Germany and the United Kingdom: Patient-reported insights on symptoms and quality of life.

OBJECTIVES: To assess the clinical, humanistic and economic burden of paroxysmal nocturnal haemoglobinuria (PNH) among C5 inhibitor (C5i)-treated patients with PNH. METHODS: This was a web-based, cross-sectional survey (01FEB2021-31MAR2021) of adults with PNH treated with eculizumab (France, Germany, United Kingdom) or ravulizumab (Germany). Self-reported outcomes included: patient characteristics; patient-reported symptoms; and standardised patient-reported outcomes (e.g. Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30]). RESULTS: Among 71 included patients, 98.6% were C5i-treated for ≥3 months (88.7% ≥12 months); among those with self-reported haemoglobin (Hb) levels (n = 63), most (85.7%) were anaemic (defined as ≤12.0 g/dL). Fatigue was the most common symptom at both diagnosis (73.2%) and survey time (63.4%); there were no statistically significant differences in symptom prevalence between treatment subgroups (eculizumab vs. ravulizumab). Total FACIT-Fatigue and EORTC QLQ-C30 scores were substantially lower than European general population references, but there were no statistically significant differences between treatment subgroups. Hb-level subgroups (<10.5 g/dL vs. ≥10.5 d/dL) followed similar trends for all measures, with few significant subgroup differences. CONCLUSIONS: Results suggest that there remains a considerable burden and unmet need among C5i-treated patients with PNH that requires improved therapies.

Treatment for pure red cell aplasia after major ABO-incompatible allogeneic stem cell transplantation: a multicentre study.

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.

Recurrent bacterial infections, but not fungal infections, characterise patients with ELANE-related neutropenia: a French Severe Chronic Neutropenia Registry study.

Among 143 patients with elastase, neutrophil-expressed (ELANE)-related neutropenia enrolled in the French Severe Chronic Neutropenia Registry, 94 were classified as having severe chronic neutropenia (SCN) and 49 with cyclic neutropenia (CyN). Their infectious episodes were classified as severe, mild or oral, and analysed according to their natural occurrence without granulocyte-colony stimulating factor (G-CSF), on G-CSF, after myelodysplasia/acute leukaemia or after haematopoietic stem-cell transplantation. During the disease's natural history period (without G-CSF; 1913 person-years), 302, 957 and 754 severe, mild and oral infectious events, respectively, occurred. Among severe infections, cellulitis (48%) and pneumonia (38%) were the most common. Only 38% of episodes were microbiologically documented. The most frequent pathogens were Staphylococcus aureus (37·4%), Escherichia coli (20%) and Pseudomonas aeruginosa (16%), while fungal infections accounted for 1%. Profound neutropenia (<200/mm3 ), high lymphocyte count (>3000/mm3 ) and neutropenia subtype were associated with high risk of infection. Only the p.Gly214Arg variant (5% of the patients) was associated with infections but not the overall genotype. The first year of life was associated with the highest infection risk throughout life. G-CSF therapy achieved lower ratios of serious or oral infectious event numbers per period but was less protective for patients requiring >10 µg/kg/day. Infections had permanent consequences in 33% of patients, most frequently edentulism.

Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study.

Ravulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. This phase 3, open-label study assessed the noninferiority of ravulizumab to eculizumab in complement inhibitor-naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Coprimary efficacy end points were proportion of patients remaining transfusion-free and LDH normalization. Secondary end points were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (Pinf < .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% [95% confidence interval (CI), -4.66, 18.14]), LDH normalization (53.6% vs 49.4%; odds ratio, 1.19 [0.80, 1.77]), percent reduction in LDH (-76.8% vs -76.0%; difference [95% CI], -0.83% [-5.21, 3.56]), change in FACIT-Fatigue score (7.07 vs 6.40; difference [95% CI], 0.67 [-1.21, 2.55]), breakthrough hemolysis (4.0% vs 10.7%; difference [95% CI], -6.7% [-14.21, 0.18]), and stabilized hemoglobin (68.0% vs 64.5%; difference [95% CI], 2.9 [-8.80, 14.64]). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02946463.

Germline DDX41 mutations define a significant entity within adult MDS/AML patients.

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.

Elastography improves accuracy of early hepato-biliary complications diagnosis after allogeneic stem cell transplantation.

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.

Letermovir for Secondary Prophylaxis of Cytomegalovirus Infection and Disease after Allogeneic Hematopoietic Cell Transplantation: Results from the French Compassionate Program.

Letermovir potently inhibits the cytomegalovirus (CMV)-terminase complex. Letermovir primary prophylaxis given for the first 3 months after allogeneic hematopoietic cell transplantation (HCT) has been shown to reduce clinically significant CMV infection and is well tolerated. Until now, only case reports or small retrospective series have been published on the use of letermovir for a secondary prophylaxis (SP) of CMV infection or diseases after HCT. Here we report the outcome of 80 consecutive CMV-seropositive adult patients included in the French compassionate program and who received letermovir as a SP after at least 1 CMV episode (infection or disease) since HCT. Letermovir was initiated at a median of 170 (49 to 1829) days after transplant and given orally for a median of 118 (26 to 396) days at the usual daily dose of 480 mg once daily and adjusted to 240 mg once daily when coadministered with cyclosporine. The donors were seronegative in 53% of the cases. Fifty patients had a current or previous graft-versus-host disease (GVHD) and 14 had experienced CMV disease since transplant. Four (5.5%) patients developed CMV breakthrough infections (n = 1) or diseases (n = 3) after the initiation of letermovir. In 3 of these 4 patients, further investigation of virologic resistance showed a CMV UL56 mutation C325Y or W, conferring the high-level letermovir resistance. One or more adverse reactions were declared by the local investigator in 15 (19%) patients. Only 2 patients stopped letermovir SP because of an adverse reaction (pruritus, 1; cytopenia, 1). In our experience, letermovir given as a SP may prevent a new CMV reactivation in a high-risk patient population and can be administered for several weeks, providing a bridge between the pre-emptive or therapeutic treatment of a CMV episode and CMV-specific immune reconstitution, giving time for tapering immunosuppressants. Prospective studies are required to confirm these results.

Effect of Ruxolitinib on Lung Function after Allogeneic Stem Cell Transplantation.

Ruxolitinib, a selective Janus kinase (JAK)1/2 inhibitor, has recently been proposed for steroid-refractory chronic graft-versus host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT), particularly in severe skin cGVHD. Lung function impairment is common in severe skin cGVHD through concomitant bronchiolitis obliterans syndrome (BOS) or restrictive lung disease (RLD) from skin sclerosis. To date, no treatment has shown a benefit on lung function in this context. We retrospectively assessed the effect of ruxolitinib on lung function in a cohort of 70 patients diagnosed with sclerotic-type skin cGVHD between March 2015 and April 2018. Among these patients, 36 received ruxolitinib. To handle confounding by indication bias, exposure groups were matched on the propensity score to receive ruxolitinib, incorporating age, myeloablative conditioning, total body irradiation, BOS, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and tobacco use at the time of cohort entry, as well as the time from transplantation. The 1:1 matching used a greedy-matching algorithm with replacement, with a caliper of 0.10. FVC and FEV1 trajectories during follow-up were compared in the matched samples, using linear mixed-effects models. The median duration of follow-up of the 46 matched patients was 58 months (interquartile range, 32 to 84 months). Ten patients had an RLD (6 exposed, 4 unexposed), and 13 patients were diagnosed with BOS (8 exposed, 5 unexposed). FEV1 decreased significantly over time independent of exposure to ruxolitinib (P < .0001). The FEV1 trajectory was similar in the exposed patients and the unexposed patients (P = .11). In conclusion, ruxolitinib administration did not demonstrate any improvement in the course of respiratory function in allogeneic HSCT recipients with sclerotic-type skin cGVHD.

Human-Derived α1-Antitrypsin is Still Efficacious in Heavily Pretreated Patients with Steroid-Resistant Gastrointestinal Graft-versus-Host Disease.

Almost one-half of patients developing graft-versus-host disease (GVHD) will not respond to standard first-line steroid treatment. Alpha-1 antitrypsin (AAT) is able to induce tolerance in preclinical models of GVHD. AAT alters the cytokine milieu, promotes a tolerogenic shift of dendritic cells, and skews effector T cells toward regulatory T cells. Gastrointestinal steroid-refractory (SR)-GVHD is a protein-losing enteropathy that might represent the optimal setting in which to use AAT. Here we analyze the outcomes of 16 patients treated with human-derived AAT in advanced-stage gut SR-GVHD, with two-thirds of the patients having failed at least 1 treatment for SR-GVHD. The overall response rate (ORR) was 44%, with a complete response (CR) rate of 27%. Gastrointestinal response was observed in 61% of patients. The median time to best response was 21 days (range, 6 to 26 days). At day 56 after AAT treatment, all CRs were maintained, and the ORR was 39%. The 1-year overall survival was 48% (95% confidence interval, 26% to 74%). Ancillary studies showed that AAT serum levels were in the normal range at the beginning of treatment, whereas fecal loss was elevated. AAT levels consistently rose after exogenous administration, but no correlation was found between serum levels and response. REG3α and IL-33 levels were associated with response while, in contrast to previous reports, regulatory T cells decreased during AAT treatment. This retrospective analysis supports a previous report of AAT as a promising agent in the management of gut SR-GVHD and should prompt its evaluation at an earlier stage.