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Peripheral venous access in children with sickle cell anaemia (SCA) requiring regular blood transfusions can become difficult over time. Previous reports have suggested the use of totally implantable venous access devices, Portacaths (PAC) in this patient group are associated with unacceptable high rates of complications. We present our experience in seven children with SCA over a 9-year period. Seven devices were placed for a total of 9754 PAC days during the study period. The median age at insertion was 6.3 years (range 3-15 years). The rate of PAC associated infection was 0.2 per 1000 PAC days. There were no episodes of thrombosis. The median length of time in situ during the study period was 3.7 years (range 1.3-7.5 years). Our experience highlights the safe and reliable use of PAC in children with SCA requiring regular blood transfusions when venous access has become a major problem. [ABSTRACT FROM AUTHOR]

Crovalimab, a novel C5 inhibitor, allows for low-volume, every-4- week, subcutaneous self-administration. COMMODORE 1 (NCT04432584) is a phase 3, global, randomized trial evaluating crovalimab versus eculizumab in C5 inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Adults with lactate dehydrogenase ≤1.5 × upper limit of normal and receiving approved eculizumab doses for ≥24 weeks were randomized 1:1 to receive crovalimab (weight-based tiered dosing) or continue eculizumab. The original primary study objective was efficacy; however, given the evolving treatment landscape, target recruitment was not met, and all efficacy endpoints became exploratory, with safety as the new primary objective. Exploratory efficacy endpoints included transfusion avoidance, hemolysis control, breakthrough hemolysis, hemoglobin stabilization, FACIT-Fatigue score, and patient preference (crovalimab vs. eculizumab). Eighty-nine patients were randomized (45 to crovalimab; 44 to eculizumab). During the 24-week primary treatment period, adverse events (AEs) occurred in 77% of patients receiving crovalimab and 67% receiving eculizumab. No AEs led to treatment withdrawal or death, and no meningococcal infections occurred. 16% of crovalimab-treated patients had transient immune complex reactions (also known as Type III hypersensitivity events), an expected risk when switching between C5 inhibitors that bind to different C5 epitopes; most were mild/moderate and all resolved without treatment modification. Crovalimab-treated patients had sustained terminal complement activity inhibition, maintained disease control, and 85% preferred crovalimab over eculizumab. Together with phase 3 COMMODORE 2 results in complement inhibitor-naive patients, these data support crovalimab's favorable benefit-risk profile. Crovalimab is a new C5 inhibitor for PNH that is potentially less burdensome than existing therapies for this lifelong disease., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease of uncontrolled terminal complement activation leading to intravascular hemolysis, thrombotic events and increased morbidity and mortality. This phase 3, open-label, single-arm, multicenter study evaluated ravulizumab treatment in eculizumab-naive or -experienced pediatric patients (aged <18 years) with PNH over a 26-week primary evaluation period (PEP) and 4-year extension period (EP). Patients included in the study received weight-based intravenous ravulizumab dosing. Primary end points were pharmacokinetic and pharmacodynamic parameters to confirm complement component 5 (C5) inhibition by ravulizumab; secondary end points assessed the efficacy (including percentage change in lactate dehydrogenase levels over time) and safety of ravulizumab. Thirteen patients, 5 (38.5%) eculizumab-naive and 8 (61.5%) eculizumab-experienced, were enrolled. Ravulizumab Ctrough levels were above the pharmacokinetic threshold of 175 μg/mL in the PEP and EP except in 1 patient. At the end of the study, pre- and post-infusion mean ± standard deviation serum ravulizumab concentrations were 610.50 ± 201.53 μg/mL and 518.29 ± 109.67 μg/mL for eculizumab-naive and eculizumab-experienced patients, respectively. After the first ravulizumab infusion, serum-free C5 concentrations were <0.5 μg/mL in both cohorts until the end of the study (0.061 ± 0.021 μg/mL and 0.061 ± 0.018 μg/mL for eculizumab-naive and eculizumab-experienced patients, respectively). Compared with baseline, ravulizumab improved and maintained efficacy outcomes in both groups. Ravulizumab had an acceptable safety profile with no new safety signals identified, and provided immediate, complete, and sustained terminal complement inhibition, translating to clinical benefit for pediatric patients with PNH. This trial was registered at www.ClinicalTrials.gov as #NCT03406507., (© 2024 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.)

Pegcetacoplan significantly improves outcomes for patients with paroxysmal nocturnal hemoglobinuria (PNH) experiencing extravascular hemolysis (EVH) on eculizumab, leading to approval in 2021/2022 (USA/Europe). We report the first collaborative real-world evidence on pegcetacoplan use in UK and France. A total of 48 patients were either currently receiving or previously received pegcetacoplan (2019-2023). A total of 12 patients had participated in the PEGASUS clinical trial, continuing treatment after trial completion. Five patients were on combination treatment of C5 inhibition and pegcetacoplan. Mean pegcetacoplan duration was 20.2 months. Indication for pegcetacoplan was EVH on C5 inhibitors (Eculizumab, n = 29, Ravulizumab n = 16, others n = 3) with 35/48 patients requiring blood transfusion within the previous 12 months. Mean hemoglobin and reticulocyte count at pegcetacoplan commencement and after 3 months: 91 g/L and 205 × 10 9 /L and 115.8 g/L and 107 × 10 9 /L, respectively, resulting in mean Hb change of 22.3 g/L. Mean LDH pre- and post-pegcetacoplan was unchanged. Six patients have stopped pegcetacoplan. A total of 32 breakthrough hemolysis (BTH) events occurred in 13/48 patients. A total of 14 events were within clinical trials (reported separately). Six patients experienced 18 acute BTH events outside clinical trials, 7/18 associated with complement activating conditions. Successful clinical management included daily pegcetacoplan subcutaneously for 3 days or single eculizumab doses; these events are manageable with prompt intervention. Pegcetacoplan is effective for patients with PNH experiencing EVH. In this large patient cohort, treatment was well tolerated with improved hemoglobin and reticulocytes and maintained LDH control. Although BTH occurs, this is manageable by acute dose modification, with the majority of patients being maintained on pegcetacoplan., (© 2024 Wiley Periodicals LLC.)

Abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder that occurs on a background of bone marrow failure (BMF). In PNH, chronic intravascular hemolysis causes an increase in morbidity and mortality, mainly because of thromboses. Over the last 20 years, treatment of PNH has focused on the complement protein C5 to prevent intravascular hemolysis using the monoclonal antibody eculizumab and more recently ravulizumab. In the United Kingdom, all patients are under review at 1 of 2 reference centers. We report on all 509 UK patients with PNH treated with eculizumab and/or ravulizumab between May 2002 and July 2022. The survival of patients with eculizumab and ravulizumab was significantly lower than that of age- and sex-matched controls (P = .001). Only 4 patients died of thromboses. The survival of patients with PNH (n = 389), when those requiring treatment for BMF (clonal evolution to myelodysplastic syndrome or acute leukemia or had progressive unresponsive aplastic anemia) were excluded, was not significantly different from that of age- and sex-matched controls (P = .12). There were 11 cases of meningococcal sepsis (0.35 events per 100 patient-years). Extravascular hemolysis was evident in patients who received treatment, with 26.7% of patients requiring transfusions in the most recent 12 months on therapy. Eculizumab and ravulizumab are safe and effective therapies that reduce mortality and morbidity in PNH, but further work is needed to reduce mortality in those with concomitant BMF., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

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.)., (Copyright © 2024 Massachusetts Medical Society.)

Androgens represent the historical therapeutic backbone of bone marrow failure (BMF) syndromes. However, their role has rarely been analyzed in a prospective setting, and systematic and long-term data regarding their usage, effectiveness and toxicity in both acquired and inherited BMF are currently unavailable. Here, taking advantage of a unique disease-specific international dataset, we retrospectively analyzed the largest cohort so far of BMF patients who received androgens before or in the absence of an allogeneic hematopoietic cell transplantation (HCT), re-evaluating their current use in these disorders. We identified 274 patients across 82 European Society for Blood and Marrow Transplantation (EBMT) affiliated centers: 193 with acquired (median age 32 years) and 81 with inherited (median age 8 years) BMF. With a median duration of androgen treatment of 5.6 and 20 months, respectively, complete and partial remission rates at 3 months were 6% and 29% in acquired and 8% and 29% in inherited disorders. Five-year overall survival and failure-free survival (FFS) were respectively 63% and 23% in acquired and 78% and 14% in inherited BMF. Androgen initiation after second-line treatments for acquired BMF, and after >12 months post diagnosis for inherited BMF were identified as factors associated with improved FFS in multivariable analysis. Androgen use was associated with a manageable incidence of organ-specific toxicity, and low rates of solid and hematologic malignancies. Sub-analysis of transplant-related outcomes after exposure to these compounds showed probabilities of survival and complications similar to other transplanted BMF cohorts. This study delivers a unique opportunity to track androgen use in BMF syndromes and represents the basis for general recommendations on this category of therapeutics on behalf of the Severe Aplastic Anemia Working Party of the EBMT.

Non-severe aplastic anemia is a rare bone marrow failure disorder characterized by variable degrees and combination of cytopenias, with limited data on management and outcome. We describe a large multicentric series of 259 patients, focusing on clinical and molecular features, treatment, evolution, and survival. The majority required treatment with cyclosporine (CyA) alone (N = 84) or in combination with anti-thymocyte globulin (ATG,44) or eltrombopag (20), eltrombopag alone (10), or others (25) including androgens. Similar outcomes were observed across different strategies, with a 6-month overall response rate of 73% for CyA, 74% for ATG plus CyA, 68% for CyA plus eltrombopag, 87% for eltrombopag, and 79% for others. Notably, 56 patients (39%), mainly receiving CyA plus eltrombopag, achieved a trilineage response (p = 0.02). Progression to myeloid neoplasms was limited (8%) and not related to mutational status. Hemolytic PNH developed in 10% of cases, being predicted by detection of small clones at diagnosis. Survival was negatively impacted by age, male gender, LDH, platelets/erythrocyte transfusion need, and somatic mutations by NGS, and positively by higher neutrophils at diagnosis, PNH clones, and trilineage response at 6 and 12 months. Multivariable analysis confirmed the detrimental role of age and the favorable association with PNH clone and trilineage response at 6 months., (© 2023. The Author(s).)

Background: Symptoms of anaemia due to clinically significant extravascular haemolysis can affect patients with paroxysmal nocturnal haemoglobinuria (PNH) treated with C5 inhibitors (ravulizumab or eculizumab). The aim of this study was to assess the efficacy and safety of danicopan (ALXN2040), an investigational, first-in-class, oral complement factor D inhibitor, as add-on therapy to ravulizumab or eculizumab in patients with PNH and clinically significant extravascular haemolysis., Methods: ALPHA is an ongoing, international, phase 3, randomised, double-blind, placebo-controlled trial evaluating danicopan as add-on therapy to ravulizumab or eculizumab. Eligible patients were adults (age ≥18 years) with PNH and clinically significant extravascular haemolysis (haemoglobin ≤9·5 g/dL; absolute reticulocyte count ≥120 × 10 9 /L) on ravulizumab or eculizumab for at least 6 months. Patients were randomly assigned (2:1) to danicopan or placebo added to ravulizumab or eculizumab for 12 weeks using an interactive response technology system. Randomisation was stratified based on transfusion history, haemoglobin, and patients enrolled from Japan. The initial oral danicopan dose was 150 mg three times a day; escalation to 200 mg three times a day was permitted based on clinical response. The infusion dose level of eculizumab (every 2 weeks) ranged from 900 mg to 1500 mg, and for ravulizumab (monthly or every 8 weeks) ranged from 3000 mg to 3600 mg. The primary endpoint was change in haemoglobin concentration from baseline to week 12. Here we present the protocol-prespecified interim analysis, planned when approximately 75% of participants were randomly assigned to treatment and completed or discontinued at 12 weeks. This trial is registered with ClinicalTrials.gov (NCT04469465)., Findings: Individuals were randomly assigned between Dec 16, 2020, and Aug 29, 2022. At data cutoff (June 28, 2022), 73 individuals were randomly assigned, received treatment, and were analysed for safety (danicopan, n=49; placebo, n=24). The protocol-prespecified interim efficacy analysis set included the first 63 participants (danicopan, n=42; placebo, n=21). At week 12, danicopan plus ravulizumab or eculizumab increased haemoglobin versus placebo plus ravulizumab or eculizumab (least squares mean [LSM] change from baseline: danicopan, 2·94 g/dL [95% CI 2·52 to 3·36]; placebo, 0·50 g/dL [-0·13 to 1·12]; LSM difference, 2·44 g/dL [1·69 to 3·20]; p<0·0001). Grade 3 adverse events in the danicopan group were increased alanine aminotransferase (two [4%] of 49 patients), leukopenia (one [2%]), neutropenia (two [4%]), cholecystitis (one [2%]), COVID-19 (one [2%]), increased aspartate aminotransferase (one [2%]), and increased blood pressure (one [2%]), and in the placebo group were anaemia (one [4%] of 24 patients), thrombocytopenia (one [4%]), and asthenia (one [4%]). The serious adverse events reported in the danicopan group were cholecystitis (one [2%] patient) and COVID-19 (one [2%]) and in the placebo group were anaemia and abdominal pain, both in one (4%) patient. There were no serious adverse events related to study drug or deaths reported in the study., Interpretation: These primary efficacy and safety results show that danicopan as add-on treatment to ravulizumab or eculizumab significantly improved haemoglobin concentrations at week 12 with no new safety concerns, suggesting an improved benefit-risk profile in patients with PNH and clinically significant extravascular haemolysis., Funding: Alexion, AstraZeneca Rare Disease., Competing Interests: Declaration of interests JWL has received honoraria from Alexion, AstraZeneca Rare Disease; and is a consultant to Alexion, AstraZeneca Rare Disease; AlloVir; Arrowhead; Kira; and Samsung. MG has received honoraria from Alexion, AstraZeneca Rare Disease and Sobi; has served as an advisory board member for Alexion, AstraZeneca Rare Disease; Amgen; Novartis; Biocryst; and Sobi; has served as a consultant for Biocryst and Regeneron Pharmaceuticals; and has received educational grant support from Apellis. JSK has received consulting fees from Alexion, AstraZeneca Rare Disease. CP has served as a consultant to Alexion, AstraZeneca Rare Disease; has served on board or advisory committees for Annexon Biosciences; Apellis; Alexion, AstraZeneca Rare Disease; Rigel; Sanofi; and Sobi; has served on a speakers bureau for Sobi; and has received research funding from Argenx; Alexion, AstraZeneca Rare Disease; Celgene; Oscotec; Rigel; Sanofi; and Incyte. JN has received grants from Alexion, AstraZeneca Rare Disease; is an advisory board member for Alexion, AstraZeneca Rare Disease; Chugai; and Roche; and has received honoraria from Alexion, AstraZeneca Rare Disease. CCI, DJ, PL, and GF are employees of Alexion, AstraZeneca Rare Disease. FSdF has received honoraria and research support (to Saint-Louis Hospital, Paris) from Alexion, AstraZeneca Rare Disease; Novartis; and Sobi. AR has received consulting fees and honoraria from Alexion, AstraZeneca Rare Disease; Roche; and Novartis; and research funding from Alexion, AstraZeneca Rare Disease and Roche. AGK has received honoraria from Alexion, AstraZeneca Rare Disease; Amgen; Celgene/BMS; Novartis; and Ra Pharma; is on the board of directors or is an advisory board member for Alexion, AstraZeneca Rare Disease; Amgen; Celgene/BMS; Novartis; Roche; and Ra Pharma; and has received consulting fees from Achillion; Agios Pharmaceuticals; Akari Therapeutics; Alexion, AstraZeneca Rare Disease; Biocryst; Celgene/BMS; Novo Nordisk; Janssen Pharmaceuticals; Roche; Samsung; and Novartis. LWLL declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In 2020, Beck et al 1 described a novel adult autoinflammatory syndrome entitled VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic), a newly-discovered disorder that connected previously unrelated inflammatory syndromes and a prototype for a new class of hematoinflammatory diseases. 2 Eighty-nine percent of published cases have documented skin involvement, but despite the high incidence and diagnostic accessibility of skin manifestations, there has been little focus on the dermatological features of VEXAS syndrome thus far. A PubMed search of all published case reports of VEXAS syndrome to date was performed, with inclusion of all cases confirmed by genetic sequencing, and this review summarizes the reported dermatological signs. There have already been 141 confirmed published cases since original publication, 126 of which had documented cutaneous signs. 1-34 A wide range of skin presentations are reported, including Sweet-like urticated and tender erythematous nodules, cartilaginous involvement with chondritis, cutaneous vasculitis, and periorbital angiodema. 1-34 Many patients had been diagnosed with Sweet syndrome, relapsing polychondritis, polyarteritis nodosa, or erythema nodosum. 1-34 Hallmarks of skin histopathology are a neutrophilic dermatosis with coexisting or exclusive leukocytoclastic vasculitis. 1 The new classification therefore helps link previously disparate inflammatory skin conditions into a unifying pathophysiological pathway., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by hemolysis and thrombosis and is associated with significant morbidity and mortality. Although complement inhibitors have significantly changed the outcomes in PNH patients, breakthrough hemolysis (BTH) may still occur as a response to stress factors such as pregnancy, surgery, and infections. Despite the well-described association between bacterial infections and hemolysis in PNH patients, little is known about the effect of respiratory viruses on triggering hemolytic episodes. This is the first study, to our knowledge, addressing this question. We retrospectively analyzed 34 patients with PNH disease between 2016 and 2018, who were on eculizumab treatment and who presented with respiratory symptoms and were subsequently tested for 10 respiratory viruses (influenza A, influenza B, parainfluenza, respiratory syncytial virus, adenovirus, rhinovirus, and human metapneumovirus). NTS+ patients had higher inflammatory markers, with the majority requiring antibiotics. Acute hemolysis, along with a significant drop in hemoglobin, was noted in the NTS+ group, with three of them requiring a top-up transfusion and two requiring an extra dose of eculizumab. Furthermore, the time from the last eculizumab dose was longer in the NTS+ patients who had BTH, than those who did not. Our data indicate that respiratory virus infections pose a significant risk for BTH in PNH patients on complement inhibitor treatment, underlining the need for regular screening and close monitoring of patients with respiratory symptoms. Furthermore, it implies a higher risk for patients who are not established on complement inhibitors, suggesting the necessity for greater vigilance in these patients.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare nonmalignant clonal hematological disorder that is characterized by a deficiency of the GPI-linked complement regulators on the membrane of hematopoietic cells, which renders them susceptible to complement-mediated damage. Intravascular hemolysis (IVH), increased tendency for thrombosis, and bone marrow failure constitutes hallmark features of the disease and are associated with high morbidity and mortality. The introduction of C5 inhibitors radically changed disease outcomes, offering a near-normal life expectancy to PNH patients. However, residual IVH and extravascular hemolysis (EVH) continue to occur during C5-inhibitor treatment, leaving a significant proportion of patients' anemic and some remaining transfusion dependent. Quality of life (QoL) has also been an issue with the regular intravenous (IV) administrations of the currently licensed C5 inhibitors. This has led to the exploration and development of novel agents, targeting different parts of the complement cascade, or having different formulations allowing for self-administration. Longer-acting and subcutaneous formulations of C5 inhibitors have shown equal safety and efficacy, whereas the development of proximal complement inhibitors is changing completely the therapeutic landscape of PNH, limiting both IVH and EVH and showing superior efficacy over C5 inhibitors, especially in improving haemoglobin. Combination treatments have also been tested with promising results. This review summarizes the current therapeutic options, gaps in anti-complement therapy and discusses emerging therapeutic approaches for PNH., (© 2023 Wiley Periodicals LLC.)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening, acquired disease in which blood cells lacking complement regulatory proteins are destroyed because of uncontrolled complement activity. Since 2007, terminal complement inhibitors have revolutionized the treatment of this disease. However, patients treated with these inhibitors can still experience anemia because of C3-mediated extravascular hemolysis and clinically relevant levels of breakthrough or residual intravascular hemolysis. Proximal complement inhibitors, which are only just beginning to emerge, have the potential to address this problem by targeting components of the pathway upstream of C5, thereby protecting patients against both intra- and extravascular hemolysis. In this review, we describe different biomarkers that can be used to monitor complement pathway blockade and discuss key laboratory assessments for evaluating treatment efficacy. We also consider how these assessments are affected by each class of inhibitor and highlight how evolving treatment goals may influence the relative importance of these assessments., Competing Interests: Declaration of Competing Interest AGK: Research support from Celgene / Bristol Myers Squibb and Novartis; and consultancy and speaker honoraria from Achillion, Akari, Alexion, Amgen, Apellis, AstraZeneca Rare Disease, BioCryst, Celgene, F. Hoffmann-La Roche, Novartis, Novo Nordisk, Pfizer, Ra Pharma, and Samsung. DJK: Research support from argenx, BioCryst, Immunovant, Principia, Rigel, Takeda (Bioverativ), and UCB; consultancy for Alexion (Syntimmune), Amgen, argenx, BioCryst, Bristol Myers Squibb, Caremark, Cellphire Therapeutics, Celularity, CRICO, Daiichi Sankyo, Immunovant, Incyte, Jiangsu Hengrui, Kyowa Kirin, Merck Sharp & Dohme, Momenta, Novartis, Pfizer, Platelet Biogenesis, Platelet Disorder Support Association, Rigel, Sanofi (Bioverativ), Sanofi (Genzyme), Sanofi (Principia), Sobi (Dova), Takeda, and UCB; and stock ownership with Rubius Therapeutics. MG: Speaker honoraria from Alexion and Sobi; consultancy for BioCryst, Regeneron, and Sobi; and advisory board for BioCryst, Novartis, and Sobi. ICW: Honoraria from Alexion. AR: Research support from Roche; travel support from AbbVie, Alexion, and Sobi; lecture honoraria from Alexion, Amgen, Novartis, Rigel, Roche, Sanofi, and Sobi; and consultancy for Alexion, Apellis, BioCryst, Bioverativ, Kira, Novartis, and Sanofi., (Copyright © 2023. Published by Elsevier Ltd.)

Myelodysplastic syndromes/myelodysplastic neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. Although the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS (HR-MDS) and their ability to fully capture the clinical benefits of novel investigational drugs or serve as valid surrogates for longer-term clinical end points (eg, overall survival). Further, issues related to the ambiguity and practicality of some criteria lead to variability in interpretation and interobserver inconsistency in reporting results from the same sets of data. Thus, we convened an international panel of 36 MDS experts and used an established modified Delphi process to develop consensus recommendations for updated response criteria that would be more reflective of patient-centered and clinically relevant outcomes in HR-MDS. Among others, the IWG 2023 criteria include changes in the hemoglobin threshold for complete remission (CR), the introduction of CR with limited count recovery and CR with partial hematologic recovery as provisional response criteria, the elimination of marrow CR, and specific recommendations for the standardization of time-to-event end points and the derivation and reporting of responses. The updated criteria should lead to a better correlation between patient-centered outcomes and clinical trial results in an era of multiple emerging new agents with novel mechanisms of action., (© 2023 by The American Society of Hematology.)

The implementation of whole genome sequencing and large somatic gene panels in haematological malignancies is identifying an increasing number of individuals with either potential or confirmed germline predisposition to haematological malignancy. There are currently no national or international best practice guidelines with respect to management of carriers of such variants or of their at-risk relatives. To address this gap, the UK Cancer Genetics Group (UKCGG), CanGene-CanVar and the NHS England Haematological Oncology Working Group held a workshop over two days on 28-29th April 2022, with the aim of establishing consensus guidelines on relevant clinical and laboratory pathways. The workshop focussed on the management of disease-causing germline variation in the following genes: DDX41, CEBPA, RUNX1, ANKRD26, ETV6, GATA2. Using a pre-workshop survey followed by structured discussion and in-meeting polling, we achieved consensus for UK best practice in several areas. In particular, high consensus was achieved on issues regarding standardised reporting, variant classification, multidisciplinary team working and patient support. The best practice recommendations from this meeting may be applicable to an expanding number of other genes in this setting., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Germ line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained ∼80% of known germ line predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n = 4461) compared with the general population of Japan (n = 20 238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years of age but rapidly increased to 49% by 90 years of age. Patients with myelodysplastic syndromes (MDS) along with a DDX41-mutation rapidly progressed to acute myeloid leukemia (AML), which was however, confined to those having truncating variants. Comutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and WT cases, in which none of the comutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multihit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System. Our findings establish that MDS with DDX41-mutation defines a unique subtype of MNs that is distinct from other MNs., (© 2023 by The American Society of Hematology.)

Objective: Blood supply shortages may create unnecessary burden, including treatment delay, worsened quality of life, or increased healthcare resource utilization in patients with myelodysplastic syndromes (MDS). This study examined physicians' experience with blood supply shortages in the MDS population. Additionally, physicians' perspectives on the factors that impact clinical, economic, and humanistic outcomes of patients with MDS were investigated., Methods: A total of 378 physicians primarily specializing in hematology/oncology across the UK, France, Germany, Italy, and Spain completed the survey ( n ≈  75 in each country). Physicians answered questions regarding adequacy of blood supply for patients with MDS who require red blood cell (RBC) transfusions and identified factors impacting the clinical, economic, and humanistic outcomes in the MDS population., Results: Over 65% of physicians reported that their patients with MDS requiring RBC transfusions encountered RBC transfusion delays due to blood supply shortage. Among physicians who reported delays, 13.8% of patients were impacted, ranging from 11.0% in Spain to 19.4% in Italy. On average, patients experienced a 4.2-day delay in receiving RBC transfusions due to blood supply shortages, and 16.7% of patients required additional healthcare provider visits. Eastern Cooperative Oncology Group performance status, threshold hemoglobin levels, and age were the top factors reported by more than two-thirds of physicians that impact outcomes of patients with MDS., Conclusion: Our findings support the need for new treatments in MDS that reduce transfusions and thus blood supply needs, and that would have a beneficial effect on clinical, humanistic, and economic outcomes.

Introduction: Complement C5 inhibitor eculizumab is the first approved treatment for paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder caused by uncontrolled terminal complement activation. Approximately 50% of patients with aplastic anemia (AA) have PNH cells. Limited data are available for patients with AA-PNH taking concomitant immunosuppressive therapy (IST) and eculizumab., Methods: Data from the International PNH Registry (NCT01374360) were used to evaluate the safety and effectiveness of eculizumab and IST in patients taking IST followed by concomitant eculizumab (IST + c-Ecu) or eculizumab followed by concomitant IST (Ecu + c-IST)., Results: As of January 1, 2018, 181 Registry-enrolled patients were included in the eculizumab effectiveness analyses (n = 138, IST + c-Ecu; n = 43, Ecu + c-IST); 87 additional patients received IST alone. Reductions from baseline with eculizumab were observed in the least squares mean lactate dehydrogenase ratio (IST + c-Ecu, -3.4; Ecu + c-IST, -3.5); thrombotic event incidence rates were similar between groups (IST + c-Ecu, 1.3; Ecu + c-IST, 0.7). Red blood cell transfusion rate ratios decreased from baseline for IST + c-Ecu (0.7) and increased for Ecu + c-IST (1.2); there were none for IST alone. Hematological parameters generally improved for IST + c-Ecu and IST alone, and changed minimally or worsened for Ecu + c-IST. Safety signals were generally consistent with those previously described for the respective therapies., Discussion/conclusion: Although some intergroup differences were seen, concomitant eculizumab and IST were safe and effective regardless of treatment sequence., (The Author(s). Published by S. Karger AG, Basel.)

Background: The current study investigated physicians' understanding of the impact of transfusion status (TS) on clinical and economic outcomes in patients with myelodysplastic syndromes (MDS)., Materials & Methods: 378 physicians primarily specializing in hematology/oncology across five European countries completed the survey. The survey asked physicians for their perspectives on the impact of TS on risk of death, risk of progression to acute myeloid leukemia (AML), chance of leukemia-free survival, and number of significant bleeding events, infection events, hospitalizations, and emergency room (ER) visits., Results: Physicians estimated that compared to transfusion-dependent (TD) patients, transfusion-independent (TI) patients had a 37.6% reduced risk of death, lower risk of progression to AML, and lower risk of non-leukemic death, for all MDS risk levels. TD patients who became TI after treatment were estimated to have 40.6% reduced risk of death and 34% reduced risk of progression to AML, compared to TD patients who remained TD., Conclusions: Compared with TD patients, physicians estimated that TI patients have fewer events of infection and significant bleeding, and experience fewer hospitalizations and ER visits per person per year. Overall, physicians reported better outcomes for TI patients. New treatment options for patients with MDS to reduce or eliminate transfusion burden are warranted., (© 2022 Bristol Myers Squibb. Cancer Reports published by Wiley Periodicals LLC.)

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.)

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled activation of the terminal complement pathway, leading to intravascular hemolysis (IVH) and a prothrombotic state. Treatment with terminal complement (C5) inhibitors, the current standard of care, suppresses IVH and reduces the risk of thrombosis and the associated morbidity and mortality. Opportunities exist to further improve care by alternative modes of administration and the reduction of clinically significant anemia and transfusion dependence caused by extravascular hemolysis in some patients., Areas Covered: This review describes the pathophysiology of PNH, provides an overview of the current standard of care, and discusses potential avenues for enhancing patient care, with a focus on the literature describing new and emerging treatments that target the alternative pathway. Emerging treatments include biosimilars and novel C5 inhibitors as well as agents with novel mechanisms of action that target the proximal complement pathways (C3 inhibitors, factor B inhibitors, and factor D inhibitors)., Expert Opinion: Alternative complement pathway inhibitors may offer further benefit as long as terminal complement is completely inhibited to reduce IVH and disease activity. This may lead to improvements in adherence and health-related quality of life for patients with PNH.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic hematologic disorder associated with inappropriate terminal complement activity on blood cells that can result in intravascular hemolysis (IVH), thromboembolic events (TEs), and organ damage. Untreated individuals with PNH have an increased risk of morbidity and mortality. Patients with PNH experiencing IVH often present with an elevated lactate dehydrogenase (LDH; ⩾ 1.5 × the upper limit of normal) level which is associated with a significantly higher risk of TEs, one of the leading causes of death in PNH. LDH is therefore used as a biomarker for IVH in PNH. The main objective of PNH treatment should therefore be prevention of morbidity and mortality due to terminal complement activation, with the aim of improving patient outcomes. Approval of the first terminal complement inhibitor, eculizumab, greatly changed the treatment landscape of PNH by giving patients an effective therapy and demonstrated the critical role of terminal complement and the possibility of modulating it therapeutically. The current mainstays of treatment for PNH are the terminal complement component 5 (C5) inhibitors, eculizumab and ravulizumab, which have shown efficacy in controlling terminal complement-mediated IVH, reducing TEs and organ damage, and improving health-related quality of life in patients with PNH since their approval by the United States Food and Drug Administration in 2007 and 2018, respectively. Moreover, the use of eculizumab has been shown to reduce mortality due to PNH. More recently, interest has arisen in developing additional complement inhibitors with different modes of administration and therapeutics targeting other components of the complement cascade. This review focuses on the pathophysiology of clinical complications in PNH and explores why sustained inhibition of terminal complement activity through the use of complement inhibitors is essential for the management of patients with this chronic and debilitating disease., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AK received consulting fees from Alexion, Celgene/BMS, Novartis, Ra Pharma, BioCryst, Amgen, Apellis, and Roche, and honoraria from Alexion, Celgene/BMS, Novartis, Ra Pharma, BioCryst, Amgen, Apellis, Roche, Takeda, and Jansen. AK received support for attending meetings and/or travel from Alexion, Ra Pharma, and Takeda, and has participated on a data safety monitoring board or advisory board for Alexion, Celgene/BMS, Novartis, Ra Pharma, BioCryst, Amgen, Apellis, and Roche. CJP has received honoraria and consulting fees from Alexion, Apellis/Sobi, Regeneron, and BioCryst Pharmaceuticals. CJP has participated on an outcomes adjudication committee for Amgen. HS received travel support, honoraria, and research support (all to University of Ulm) from Alexion, AstraZeneca Rare Disease, and honoraria (to University of Ulm) from Novartis, Roche, Apellis, and Sanofi. JN received honoraria from Alexion and Chugai, and served as an advisor to Apellis Pharmaceuticals, Alexion, Novartis, Chugai, F. Hoffmann-La Roche, and BioCryst Pharmaceuticals. RB received research funding and consultancy fees from Alexion and received honoraria from UpToDate, Indy Hematology Review, Alexion, ISTH Congress and American Society of Hematology., (© The Author(s), 2022.)

Importance: Large cohorts of patients with active cancers and COVID-19 infection are needed to provide evidence of the association of recent cancer treatment and cancer type with COVID-19 mortality., Objective: To evaluate whether systemic anticancer treatments (SACTs), tumor subtypes, patient demographic characteristics (age and sex), and comorbidities are associated with COVID-19 mortality., Design, Setting, and Participants: The UK Coronavirus Cancer Monitoring Project (UKCCMP) is a prospective cohort study conducted at 69 UK cancer hospitals among adult patients (≥18 years) with an active cancer and a clinical diagnosis of COVID-19. Patients registered from March 18 to August 1, 2020, were included in this analysis., Exposures: SACT, tumor subtype, patient demographic characteristics (eg, age, sex, body mass index, race and ethnicity, smoking history), and comorbidities were investigated., Main Outcomes and Measures: The primary end point was all-cause mortality within the primary hospitalization., Results: Overall, 2515 of 2786 patients registered during the study period were included; 1464 (58%) were men; and the median (IQR) age was 72 (62-80) years. The mortality rate was 38% (966 patients). The data suggest an association between higher mortality in patients with hematological malignant neoplasms irrespective of recent SACT, particularly in those with acute leukemias or myelodysplastic syndrome (OR, 2.16; 95% CI, 1.30-3.60) and myeloma or plasmacytoma (OR, 1.53; 95% CI, 1.04-2.26). Lung cancer was also significantly associated with higher COVID-19-related mortality (OR, 1.58; 95% CI, 1.11-2.25). No association between higher mortality and receiving chemotherapy in the 4 weeks before COVID-19 diagnosis was observed after correcting for the crucial confounders of age, sex, and comorbidities. An association between lower mortality and receiving immunotherapy in the 4 weeks before COVID-19 diagnosis was observed (immunotherapy vs no cancer therapy: OR, 0.52; 95% CI, 0.31-0.86)., Conclusions and Relevance: The findings of this study of patients with active cancer suggest that recent SACT is not associated with inferior outcomes from COVID-19 infection. This has relevance for the care of patients with cancer requiring treatment, particularly in countries experiencing an increase in COVID-19 case numbers. Important differences in outcomes among patients with hematological and lung cancers were observed.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterised by complement-mediated intravascular hemolysis (IVH) due to absence of complement regulators CD55 and CD59 on affected erythrocytes. Danicopan is a first-in-class oral proximal, complement alternative pathway factor D (FD) inhibitor. Therapeutic FD inhibition was designed to control IVH and prevent C3-mediated extravascular hemolysis (EVH). In this open-label, phase 2, dose-finding trial, 10 untreated hemolytic PNH patients received danicopan monotherapy (100-200 mg thrice daily). Endpoints included change in lactate dehydrogenase (LDH) at day 28 (primary) and day 84 and hemoglobin. Safety, pharmacokinetics/pharmacodynamics, and patient-reported outcomes were measured. Ten patients reached the primary endpoint; two later discontinued: one for a serious adverse event (elevated aspartate aminotransferase/alanine aminotransferase coincident with breakthrough hemolysis, resolving without sequelae) and one for personal reasons unrelated to safety. Eight patients completed treatment. IVH was inhibited, demonstrated by mean decreased LDH (5.7 times upper limit of normal [ULN] at baseline vs 1.8 times ULN [day 28] and 2.2 times ULN [day 84]; both p.

The complex pathophysiologic interplay between SARS-CoV-2 infection and complement activation is the subject of active investigation. It is clinically mirrored by the occurrence of exacerbations of complement mediated diseases during COVID-19 infection. These include complement-mediated hemolytic anemias such as paroxysmal nocturnal hemoglobinuria (PNH), autoimmune hemolytic anemia (AIHA), particularly cold agglutinin disease (CAD), and hemolytic uremic syndrome (HUS). All these conditions may benefit from complement inhibitors that are also under study for COVID-19 disease. Hemolytic exacerbations in these conditions may occur upon several triggers including infections and vaccines and may require transfusions, treatment with complement inhibitors and/or immunosuppressors (i.e., steroids and rituximab for AIHA), and result in thrombotic complications. In this manuscript we describe four patients (2 with PNH and 2 with CAD) who experienced hemolytic flares after either COVID-19 infection or SARS-Cov2 vaccine and provide a review of the most recent literature. We report that most episodes occurred within the first 10 days after COVID-19 infection/vaccination and suggest laboratory monitoring (Hb and LDH levels) in that period. Moreover, in our experience and in the literature, hemolytic exacerbations occurring during COVID-19 infection were more severe, required greater therapeutic intervention, and carried more complications including fatalities, as compared to those developing after SARS-CoV-2 vaccine, suggesting the importance of vaccinating this patient population. Patient education remains pivotal to promptly recognize signs/symptoms of hemolytic flares and to refer to medical attention. Treatment choice should be based on the severity of the hemolytic exacerbation as well as of that of COVID-19 infection. Therapies include transfusions, complement inhibitor initiation/additional dose in the case of PNH, steroids/rituximab in patients with CAD and warm type AIHA, plasma exchange, hemodialysis and complement inhibitor in the case of atypical HUS. Finally, anti-thrombotic prophylaxis should be always considered in these settings, provided safe platelet counts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fattizzo, Pasquale, Bellani, Barcellini and Kulasekararaj.)

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation and subsequent intravascular hemolysis (IVH). C5 inhibitors prevent membrane attack complex formation, but patients may experience extravascular hemolysis (EVH) and continue to require blood transfusions. Danicopan, an oral proximal complement inhibitor of alternative pathway factor D (FD), is designed to control IVH and EVH. In a phase 2 dose-finding trial, eculizumab-treated transfusion-dependent patients with PNH (n = 12) received danicopan, 100 to 200 mg thrice daily, in addition to their eculizumab regimen for 24 weeks. End points included hemoglobin (Hgb) change vs baseline at week 24 (primary), reduction in blood transfusions, and patient-reported outcomes. Safety, tolerability, and pharmacokinetics/pharmacodynamics were measured. Twelve patients received ≥1 danicopan dose; 1 patients discontinued from a serious adverse event deemed unlikely related to danicopan. Eleven patients completed the 24-week treatment period. Addition of danicopan resulted in a mean Hgb increase of 2.4 g/dL at week 24. In the 24 weeks prior to danicopan, 10 patients received 31 transfusions (50 units) compared with 1 transfusion (2 units) in 1 patient during the 24-week treatment period. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score increased by 11 points from baseline to week 24. The most common adverse events were headache, cough, and nasopharyngitis. Addition of danicopan, a first-in-class FD inhibitor, led to a meaningful improvement in Hgb and reduced transfusion requirements in patients with PNH who were transfusion-dependent on eculizumab. These benefits were associated with improvement of FACIT-Fatigue. This trial was registered at www.clinicaltrials.gov as #NCT03472885., (© 2021 by The American Society of Hematology.)

In this large single-centre study, we report high prevalence (25%) of, small (<10%) and very small (<1%), paroxysmal nocturnal hemoglobinuria (PNH) clones by high-sensitive cytometry among 3085 patients tested. Given PNH association with bone marrow failures, we analyzed 869 myelodysplastic syndromes (MDS) and 531 aplastic anemia (AA) within the cohort. PNH clones were more frequent and larger in AA vs. MDS (p = 0.04). PNH clone, irrespective of size, was a good predictor of response to immunosuppressive therapy (IST) and to stem cell transplant (HSCT) (in MDS: 84% if PNH+ vs. 44.7% if PNH-, p = 0.01 for IST, and 71% if PNH+ vs. 56.6% if PNH- for HSCT; in AA: 78 vs. 50% for IST, p < 0.0001, and 97 vs. 77%, p = 0.01 for HSCT). PNH positivity had a favorable impact on disease progression (0.6% vs. 4.9% IPSS-progression in MDS, p < 0.005; and 2.1 vs. 6.9% progression to MDS in AA, p = 0.01), leukemic evolution (6.8 vs. 12.7%, p = 0.01 in MDS), and overall survival [73% (95% CI 68-77) vs. 51% (48-54), p < 0.0001], with a relative HR for mortality of 2.37 (95% CI 1.8-3.1; p < 0.0001) in PNH negative cases, both in univariate and multivariable analysis. Our data suggest systematic PNH testing in AA/MDS, as it might allow better prediction/prognostication and consequent clinical/laboratory follow-up timing., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Myelodysplastic syndromes (MDS) are a group of malignant hematologic diseases characterized by ineffective hematopoiesis, which may lead to chronic anemia and transfusion dependency, with up to 30% of patients progressing to acute myeloid leukemia (AML). Studies suggest transfusion dependency may impact overall survival (OS); however, there is a lack of evidence concerning the association between transfusion status (TS) and OS in patients with MDS who become transfusion independent (TI) after treatment. In addition, the holistic impact of TS on other clinical, economic, and humanistic outcomes has not been well understood. We conducted a systematic literature review (SLR) to understand this impact. Ten studies were included and showed consistent decrease in OS in transfusion dependent (TD) compared with TI patients. These findings were confirmed by a meta-analysis (MA) reporting better OS prognosis for TI patients. A second SLR was conducted to understand the association between TS and other clinical, economic, and humanistic outcomes. Twenty-eight studies were included and showed better prognosis for other outcomes, including AML progression and leukemia-free survival for TI patients. Risk of AML progression and cumulative non-leukemic death assessed by the MA showed a trend toward worse prognosis and higher risk of AML progression for TD patients. Lower healthcare resource utilization, better quality of life, and reduced non-leukemic death for TI patients were observed. Studies not eligible for MA also showed better clinical, economic, and humanistic outcomes for TI patients. These findings contribute to understanding the association between transfusion dependence and OS among other outcomes in patients with MDS., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We document here that intensive care COVID-19 patients suffer a profound decline in hemoglobin levels but show an increase of circulating nucleated red cells, suggesting that SARS-CoV-2 infection either directly or indirectly induces stress erythropoiesis. We show that ACE2 expression peaks during erythropoiesis and renders erythroid progenitors vulnerable to infection by SARS-CoV-2. Early erythroid progenitors, defined as CD34 - CD117 + CD71 + CD235a - , show the highest levels of ACE2 and constitute the primary target cell to be infected during erythropoiesis. SARS-CoV-2 causes the expansion of colony formation by erythroid progenitors and can be detected in these cells after 2 weeks of the initial infection. Our findings constitute the first report of SARS-CoV-2 infectivity in erythroid progenitor cells and can contribute to understanding both the clinical symptoms of severe COVID-19 patients and how the virus can spread through the circulation to produce local inflammation in tissues, including the bone marrow., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)