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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 red-cell transfusions; 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 received no transfusion; none of the patients in the second trial received transfusions. 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.) [ABSTRACT FROM AUTHOR]

Background: In our previous study on erythropoiesis-stimulating agent (ESA) treatment in lower risk myelodysplastic syndromes from the European MDS (EUMDS) Registry, we showed that patients treated with ESAs had longer survival compared with patients who receive red blood cell transfusion (RBCT). In this study, with a longer follow up time and more patients included, we aimed to assess long-term effects on survival and health-related quality of life (HRQoL) of exposure to ESAs with or without RBCT in patients with lower risk myelodysplastic syndromes., Methods: The EUMDS Registry is a non-interventional, longitudinal, real-world registry prospectively enrolling newly diagnosed patients older than 18 years with lower risk (International Prognostic Scoring System low or intermediate-1) myelodysplastic syndromes from 16 European countries and Israel. The analysis was restricted to patients with haemoglobin concentrations less than 100 g/L enrolled between Jan 1, 2008, and July 1, 2019, with last censoring of data on Dec 31, 2021. Patient management was recorded every 6 months, including treatment, transfusions, and HRQoL. ESA treatment followed local guidelines. The patients were separated into four groups at each study visit: no ESA or RBCT, ESA only, ESA plus RBCT, and RBCT only. The data were analysed longitudinally over time according to ESA and RBCT status during each 6-month interval, using propensity score matching. The main outcomes were median overall survival and leukaemia-free survival, and HRQoL. This study is registered with ClinicalTrials.gov, NCT00600860, as is ongoing., Findings: 2448 patients (the ESA-unexposed group [n=1265] and ESA-exposed group [n=1183]) were diagnosed before July 1, 2019; 1520 (62·1%) were male and 928 (37·9%) were female. Median follow-up time was 3·9 years (IQR 1·6-6·5). After applying eligibility criteria and propensity matching, there were 426 patients in the ESA-unexposed group and 744 patients in the ESA-exposed group. Median overall survival in the ESA exposed group was 44·9 months (95% CI 40·2-50·5) compared with 34·8 months (28·6-39·2) in the ESA unexposed group; the absolute difference was 10·1 months (95% CI 2·2-18·0; hazard ratio [HR] 0·70 [95% CI 0·59-0·83]; p<0·0001). Patients without RBCT in the presence or absence of ESA exposure maintained significantly better HRQoL than those with RBCT, irrespective of ESA exposure (linear mixed effect model of EQ-5d-3L index score, RBCT coefficient -0·04 [95% CI -0·06 to 0·03], p<0·0001; linear mixed effect model of VAS, -4·57 [-6·02 to -3·13], p<0·0001)., Interpretation: ESA treatment in patients with lower risk myelodysplastic syndromes significantly improves overall survival when started before or early after the onset of regular transfusion therapy. Avoiding RBCT is associated with significantly better HRQoL., Funding: H2020 European Research Council, Novartis Pharmacy B V Oncology Europe, Amgen, BMS/Celgene International, Janssen Pharmaceutica, Takeda Pharmaceuticals International, and Gilead Sciences., Competing Interests: Declaration of interests RS reports honoraria from BMS for the MDS Right Horizon 2020 Project; financial support for meetings from Celgene/BMS, Lilly, Teva, AbbVie, and AHOP; advisory board participation for BMS and Otsuka; and is Servier President of Verein Senioren Krebshilfe. CvM and TdW work for the EUMDS Registry, which is supported by an educational grant from Novartis Pharmacy BV Oncology Europe, Amgen, BMS, Janssen Pharmaceutical, Takeda Pharmaceutical, Gilead Sciences, and a European commission H2020 Grant. AS is supported in part by the National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre (NIHR203331). HKGG, TB, AT, PF, DB, ArS, JC, SL, LM, UG, LS, MdA, DC, KAK, SCr, and EHL declare no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome-wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP-1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower-risk IPSS-M, this cluster displayed a significantly inferior overall survival ( p  < 0.0001). Our study showed that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention., Competing Interests: The authors declare no conflict of interest., (© 2025 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

ABP 959 is a biosimilar to the eculizumab reference product (RP), which is approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). This multicenter, randomized, double-blind, active-controlled, two-period crossover study randomized eculizumab RP-treated patients with PNH to one of two treatment sequences (ABP 959/eculizumab RP or eculizumab RP/ABP 959) to evaluate the clinical similarity of ABP 959 when compared with eculizumab RP. This study evaluated the efficacy of ABP 959 when compared with eculizumab RP based on control of intravascular hemolysis as measured by lactate dehydrogenase (LDH) and by the time-adjusted area under the effect curve of LDH. Secondary outcomes included safety, pharmacokinetics, and immunogenicity. Forty-two patients were randomized (20 in the ABP 959/eculizumab RP group and 22 in the eculizumab RP/ABP 959 group) across 25 centers. Similarity of efficacy was established by a ratio of geometric least squares means of LDH (ABP 959/eculizumab RP) of 1.0628, with a one-sided 97.5% upper CI of 1.1576 at week 27, and a geometric means ratio of time-adjusted area under the effect curve (ABP 959 vs. eculizumab RP) of LDH of 0.981, with a 90% CI of 0.9403-1.0239 from week 13 to 27, week 39 to 53, and week 65 to 79. All secondary efficacy endpoints were comparable between treatment groups. No new safety concerns were identified. The results of this study in patients with PNH, along with previously demonstrated similarity of analytical, nonclinical, and clinical pharmacokinetics and pharmacodynamics in healthy volunteers support a demonstration of no clinically meaningful differences between ABP 959 and eculizumab RP. Clinical Trial Registration: NCT03818607., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

The precise link between inflammation and pathogenesis of myelodysplastic syndrome (MDS) is yet to be fully established. We developed a novel method to measure ASC/NLRP3 protein specks which are specific for the NLRP3 inflammasome only. We combined this with cytokine profiling to characterise various inflammatory markers in a large cohort of patients with lower risk MDS in comparison to healthy controls and patients with defined autoinflammatory disorders (AIDs). The ASC/NLRP3 specks were significantly elevated in MDS patients compared to healthy controls (p < 0.001) and these levels were comparable to those found in patients with AIDs. The distribution of protein specks positive only for ASC was different to ASC/NLRP3 ones suggesting that other ASC-containing inflammasome complexes might be important in the pathogenesis of MDS. Patients with MDS-SLD had the lowest levels of interleukin (IL)-1β, tumour necrosis factor (TNF), IL-23, IL-33, interferon (IFN) γ and IFN-α2, compared to other diagnostic categories. We also found that inflammatory cytokine TNF was positively associated with MDS progression to a more aggressive form of disease and IL-6 and IL-1β with time to first red blood cell transfusion. Our study shows that there is value in analysing inflammatory biomarkers in MDS, but their diagnostic and prognostic utility is yet to be fully validated., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Abstract: Relapse after complete remission (CR) remains the main cause of mortality after allogeneic stem cell transplantation for hematological malignancies and, therefore, improved biomarkers for early prediction of relapse remains a critical goal toward development and assessment of preemptive relapse treatment. Because the significance of cancer stem cells as a source of relapses remains unclear, we investigated whether mutational screening for persistence of rare cancer stem cells would enhance measurable residual disease (MRD) and early relapse prediction after transplantation. In a retrospective study of patients who relapsed and patients who achieved continuous-CR with myelodysplastic syndromes and related myeloid malignancies, combined flow cytometric cell sorting and mutational screening for persistence of rare relapse-initiating stem cells was performed in the bone marrow at multiple CR time points after transplantation. In 25 CR samples from 15 patients that later relapsed, only 9 samples were MRD-positive in mononuclear cells (MNCs) whereas flowcytometric-sorted hematopoietic stem and progenitor cells (HSPCs) were MRD-positive in all samples, and always with a higher variant allele frequency than in MNCs (mean, 97-fold). MRD-positivity in HSPCs preceded MNCs in multiple sequential samples, in some cases preceding relapse by >2 years. In contrast, in 13 patients in long-term continuous-CR, HSPCs remained MRD-negative. Enhanced MRD sensitivity was also observed in total CD34+ cells, but HSPCs were always more clonally involved (mean, 8-fold). In conclusion, identification of relapse-initiating cancer stem cells and mutational MRD screening for their persistence consistently enhances MRD sensitivity and earlier prediction of relapse after allogeneic stem cell transplantation., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Patients with myelodysplastic syndromes (MDS) frequently experience a significant symptom burden, which reduces health-related quality of life (HRQoL). We aimed to identify determinants of low HRQoL in patients recently diagnosed with MDS, for guiding early intervention strategies. We evaluated longitudinal data in 2205 patients with MDS during their first year after diagnosis. Median values of EQ-5D 3-level (EQ-5D-3L) index (0.78) and visual analog scale (VAS) score (0.70) were used as thresholds for low HRQoL. In addition, the 5 dimensions of EQ-5D-3L were analyzed for impairments (any level vs "no problem" category). After multiple imputation of missing values, we used generalized estimating equations (GEE) to estimate odds ratios (OR) for univariable determinant screening (P < .15), and to subsequently derive multivariable models for low HRQoL with 95% confidence intervals (CI). Multivariable GEE analysis showed the following independent determinants (OR, 95% CI) for low EQ-5D index: increased age (60-75 years: 1.33, 1.01-1.75; >75: 1.84, 1.39-2.45), female sex (1.70, 1.43-2.03), high serum ferritin level (≥1000 vs ≤300 μg/L: 1.41, 1.06-1.87), comorbidity burden (per unit: 1.11, 1.02-1.20), and reduced Karnofsky performance status (KPS, per 10 units: 0.62, 0.58-0.67). For low VAS score, additional determinants were transfusion dependence (1.53, 1.03-2.29), low hemoglobin <10 g/dL (1.34, 1.12-1.61), and high body mass index (≥30 vs 23-29.9 kg/m2: 1.26, 1.02-1.57). Sex, KPS, comorbidity burden, hemoglobin count, and transfusion burden were determinants for all EQ-5D dimensions. Low HRQoL is determined by multiple factors, which should be considered in the management and shared decision making of patients with MDS. This trial was registered at www.clinicaltrials.gov as #NCT00600860., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Clinical decision-making for patients with myelodysplastic syndromes (MDS) is challenging, and both disease and treatment effects heavily impact health-related quality of life (HRQoL) of these patients. Therefore, disease-specific HRQoL measures can be critical to harness the patient voice in MDS research., Methods: We report a prospective international validation study of the Quality of Life in Myelodysplasia Scale (QUALMS) with a main focus on providing information on the psychometric characteristics of its three subscales: physical burden (QUALMS-P), emotional burden (QUALMS-E), and benefit finding (QUALMS-BF). The analysis is based on patients enrolled from three European countries and Israel, participating to the MDS-RIGHT Project. The scale structure and psychometric properties of the QUALMS were assessed., Results: Overall, 270 patients with a median age of 74 years were analyzed and the majority of them (60.3%) had a low MDS-Comorbidity Index score. Results of the confirmatory factor analysis supported the underlying scale structure of the QUALMS, which, in addition to a total score, includes three subscales: QUALMS-P, QUALMS-E, and the QUALMS-BF. The QUALMS-P exhibited the highest Cronbach's alpha coefficients. Discriminant validity analysis indicated good results with the QUALMS-P and QUALMS-E distinguishing between patients with different performance status, comorbidity, anemia, and transfusion dependency status. No floor and ceiling effects were observed. Responsiveness to change analysis supported the validity of the measure. Patients with a hemoglobin (Hb) level of <11 g/dL at study entry, who subsequently showed an improvement in their Hb levels, also reported a mean score change of 9 and 8 points (scales ranging between 0 and 100) in the expected direction of the QUALMS-E and QUALMS-P, respectively., Conclusions: Our study provides additional validation data on the QUALMS from the international MDS-RIGHT Project. The use of this disease-specific HRQoL measure may contribute to raise quality standards of patient-centered outcomes research in MDS., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Information on causes of death (CoDs) and the impact of myelodysplastic syndromes (MDS) on survival in patients with lower-risk MDS (LR-MDS) is limited. A better understanding of the relationship between disease characteristics, clinical interventions and CoDs may improve outcomes of patients with LR-MDS. We prospectively collected data on patients with LR-MDS in the European MDS registry from 2008 to 2019. Clinical, laboratory and CoDs data were obtained. To examine MDS-specific survival, relative survival (RS) was estimated using national life tables. Of 2396 evaluated subjects, 900 died (median overall survival [OS]: 4.7 years; median follow-up: 3.5 years). The most common CoDs were acute myeloid leukaemia/MDS (20.1%), infection (17.8%) and cardiovascular disease (CVD; 9.8%). Patients with isolated del(5q) and with red cell transfusion needed during the disease course, had a higher risk of fatal CVD. The 5-year OS was 47.3% and the 5-year RS was 59.6%, indicating that most patients died due to their underlying MDS. Older patients (aged >80 years) and the lowest-risk patients were more likely to die from competing causes. This study shows that MDS and its related complications play crucial role in the outcome of patients with LR-MDS., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: The complement component 5 (C5) inhibitor ravulizumab demonstrated non-inferiority to eculizumab following 26 weeks of treatment in complement inhibitor-naïve and complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH; studies 301 and 302, respectively). This study aims to describe the results of both studies from 27 weeks to 2 years., Methods: Patients (N = 441) continued to receive ravulizumab throughout the extension period. Efficacy endpoints included lactate dehydrogenase (LDH) normalization, transfusion avoidance and fatigue score (FACIT-F). Safety analyses were also performed., Results: From 27 weeks to 2 years, improvements in LDH levels were maintained in both study populations. Transfusion avoidance was maintained in 81.9% (study 301) and 85.6% (study 302) of patients, and FACIT-F scores remained stable. Ravulizumab was well tolerated, and the incidence of adverse events (AEs) were similar between patients of both studies. Incidence of serious AEs deemed related to ravulizumab treatment was low (<3%)., Conclusions: This study reports, to date, the longest period of follow-up in over 400 patients with PNH treated with ravulizumab (662 patient-years). Long-term, ravulizumab demonstrated durable efficacy and was well tolerated, highlighting the importance of C5 inhibitors as the mainstay of PNH treatment., (© 2022 Alexion, AstraZeneca Rare Disease. European Journal of Haematology published by John Wiley & Sons Ltd.)

We present a noninvasive Web-based app to help exclude or diagnose myelodysplastic syndrome (MDS), a bone marrow (BM) disorder with cytopenias and leukemic risk, diagnosed by BM examination. A sample of 502 MDS patients from the European MDS (EUMDS) registry (n > 2600) was combined with 502 controls (all BM proven). Gradient-boosted models (GBMs) were used to predict/exclude MDS using demographic, clinical, and laboratory variables. Area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were used to evaluate the models, and performance was validated using 100 times fivefold cross-validation. Model stability was assessed by repeating its fit using different randomly chosen groups of 502 EUMDS cases. AUC was 0.96 (95% confidence interval, 0.95-0.97). MDS is predicted/excluded accurately in 86% of patients with unexplained anemia. A GBM score (range, 0-1) of less than 0.68 (GBM < 0.68) resulted in a negative predictive value of 0.94, that is, MDS was excluded. GBM ≥ 0.82 provided a positive predictive value of 0.88, that is, MDS. The diagnosis of the remaining patients (0.68 ≤ GBM < 0.82) is indeterminate. The discriminating variables: age, sex, hemoglobin, white blood cells, platelets, mean corpuscular volume, neutrophils, monocytes, glucose, and creatinine. A Web-based app was developed; physicians could use it to exclude or predict MDS noninvasively in most patients without a BM examination. Future work will add peripheral blood cytogenetics/genetics, EUMDS-based prospective validation, and prognostication., (© 2021 by The American Society of Hematology.)

Purpose: To determine the safety of tipifarnib in combination with escalating doses of bortezomib and to determine the maximum tolerated dose in patients with untreated high-risk MDS and oligoblastic acute myeloid leukemia, who were not eligible for intensive therapy., Experimental Design: In a "3 + 3″ design, patients received fixed doses of tipifarnib 200 mg bid (days 1-21) and escalating doses of bortezomib (days 8, 15, 22) every 4 weeks in 4-6 cycles., Results: The combination was tolerated well by the 11 patients in this study without reaching the maximum tolerated dose. Myelosuppression was the most frequent side effect, but usually of short duration. Interestingly a complete response with or without complete count recovery was observed in three patients and three additional patients had stable disease. The median duration of overall survival was 449 days. Two patients were still alive at 4.0 and 4.3 years, including one patient in continuing CR., Conclusions: The combination of tipifarnib and bortezomib was tolerated well and appeared to have clinical activity in patients with high-risk MDS and AML with low counts of marrow blasts. Our results warrant further evaluation in a phase II study., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Ravulizumab every 8 weeks showed non-inferiority to eculizumab every 2 weeks in a 26-week, phase 3, randomized controlled trial in adults with paroxysmal nocturnal hemoglobinuria (PNH) who were clinically stable on eculizumab (NCT03056040). We report results from the first 26 weeks of the extension period in which patients continued ravulizumab (n = 96) or switched from eculizumab to ravulizumab (n = 95). At week 52, mean (SD) lactate dehydrogenase levels increased 8.8% (29%) with ravulizumab-ravulizumab and 5.8% (27%) with eculizumab-ravulizumab from primary evaluation period baseline. During the extension period, four patients (ravulizumab-ravulizumab, n = 3; eculizumab-ravulizumab, n = 1) experienced breakthrough hemolysis, but none associated with serum free C5 ≥ 0.5 μg/mL. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores remained stable through week 52. During the extension period, proportions of patients avoiding transfusion remained stable (ravulizumab-ravulizumab, 86.5%; eculizumab-ravulizumab, 83.2%); 81.2% and 81.1%, respectively, had stabilized hemoglobin. All patients maintained serum free C5 levels < 0.5 μg/mL. Adverse events were generally similar between groups, and rates were lower in the extension period. Adults with PNH on stable eculizumab therapy who received ravulizumab over 52 weeks experienced durable efficacy, with consistent efficacy in patients who received eculizumab during the primary evaluation period and then switched to ravulizumab. Ravulizumab was well tolerated., (© 2020 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell (HSC) disorder characterized by defective synthesis of the glycosylphosphatidylinositol (GPI) anchors as a result of somatic mutations in the X-linked PIGA gene. The disease is acquired. No constitutional PNH has been described. Here, we report familial PNH associated with unusual inflammatory symptoms. Genetic analysis revealed a germline heterozygous PIGB mutation on chromosome 15 without mutations in PIGA or any of the other genes involved in GPI biosynthesis. In vitro data confirmed that transfection of the mutant PIGB could not restore the surface expression of GPI-anchored proteins (APs) in PIGB-deficient Chinese hamster ovary cells. Homozygosity was caused by copy number-neutral loss of heterozygosity (CN-LOH) of the germline PIGB mutation, leading to deficient expression of GPI-APs in the affected blood cells of the index patient and her mother. The somatic event leading to homozygosity of the germline mutant PIGB gene involved a 70-kbp microdeletion of chromosome 15q containing the TM2D3 and TARSL2 genes, which was implicated in chromosome 15q mosaicism. Interestingly, we detected the deletion in both the patient and her mother. A sister of the mother, who carried the same germline PIGB mutation but without this microdeletion involving TM2D3 and TARSL2, did not have a PNH clone or CN-LOH. In conclusion, we describe PNH caused by CN-LOH of a germline heterozygous PIGB mutation in a patient and her mother and hypothesize that the 70-kbp microdeletion may have contributed to the PNH clone in both., (© 2020 by The American Society of Hematology.)

Complement C5 inhibitor eculizumab has a great impact on the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). However, this treatment success has a major drawback: a substantially increased susceptibility for life-threatening Neisseria meningitidis infections. Therefore, N meningitidis vaccination is strongly advised before initiating complement C5-blocking therapy. In this study, we show that the multicomponent N meningitidis serogroup B (4CMenB) vaccination of PNH patients treated with eculizumab results in a significant increase in anti-N meningitidis serogroup B (MenB) plasma immunoglobulin G (IgG) levels. Anti-MenB IgG was able to bind to the bacterial surface and initiate complement activation; however, inhibition of the membrane attack complex formation completely blocked whole blood-mediated killing of MenB. This would suggest that, despite 4CMenB vaccination, PNH patients taking C5 inhibitors are not sufficiently protected against MenB infection, which is in line with the fact that vaccinated PNH patients still experience meningococcal infections., (© 2020 by The American Society of Hematology.)

Iron overload due to red blood cell (RBC) transfusions is associated with morbidity and mortality in lower-risk myelodysplastic syndrome (MDS) patients. Many studies have suggested improved survival after iron chelation therapy (ICT), but valid data are limited. The aim of this study was to assess the effect of ICT on overall survival and hematologic improvement in lower-risk MDS patients in the European MDS registry. We compared chelated patients with a contemporary, non-chelated control group within the European MDS registry, that met the eligibility criteria for starting iron chelation. A Cox proportional hazards model was used to assess overall survival (OS), treating receipt of chelation as a time-varying variable. Additionally, chelated and non-chelated patients were compared using a propensity-score matched model. Of 2,200 patients, 224 received iron chelation. The hazard ratio and 95% confidence interval for OS for chelated patients, adjusted for age, sex, comorbidity, performance status, cumulative RBC transfusions, Revised-International Prognostic Scoring System (IPSS-R), and presence of ringed sideroblasts was 0.50 (0.34-0.74). The propensity-score analysis, matched for age, sex, country, RBC transfusion intensity, ferritin level, comorbidity, performance status, and IPSS-R, and, in addition, corrected for cumulative RBC transfusions and presence of ringed sideroblasts, demonstrated a significantly improved OS for chelated patients with a hazard ratio of 0.42 (0.27-0.63) compared to non-chelated patients. Up to 39% of chelated patients reached an erythroid response. In conclusion, our results suggest that iron chelation may improve OS and hematopoiesis in transfused lower-risk MDS patients. This trial was registered at clinicaltrials.gov identifier: 00600860., (Copyright© 2020 Ferrata Storti Foundation.)