Ferras Alashkar

Background: Sickle cell disease (SCD) is a rare inherited hemoglobinopathy associated with substantial morbidity and high healthcare needs. In Germany, population-based evidence on SCD epidemiology and real-world care patterns remains limited, despite increasing relevance in the context of migration and the introduction of nationwide newborn screening in 2021. Methods: We conducted a retrospective, non-interventional study using anonymized German statutory health insurance claims data from the InGef database (2015–2024). Patients with SCD were identified using ICD-10-GM codes D57.0, D57.1, D57.2, and D57.8 based on inpatient and confirmed outpatient diagnoses. Administrative prevalence was estimated using a carry-forward cohort approach, whereby SCD patients diagnosed in the current year and alive/observable in subsequent years were counted as prevalent. Administrative incidence was assessed in children aged < 6 years using the first recorded SCD diagnosis in claims data as the date of incidence. Analyses of patient characteristics, clinical outcomes, treatments and healthcare resource use (HCRU) were conducted cross-sectionally by calendar year, stratified by age group and sex. Results: Across 2015–2024, 1,019 individuals with SCD were identified. As might be expected using a carry forward cohort approach, annual prevalent counts increased from 225 (2015) to 864 (2024), and nationally extrapolated prevalence increased from 2.75 per 100,000 in 2015 to 10.50 per 100,000 in 2024. Median time to recorded diagnosis in children < 6 years decreased from 31 months (2015) to 11 months from 2021 onwards (2021–2024). In 2024, infections were the most frequently documented clinical outcome (34.5% [298/864]), followed by vaso‑occlusive crises (19.2% [166/864]) and mental health comorbidities (depression 19.1% [165/864]; anxiety 9.1% [79/864]). The proportions of patients with inpatient or outpatient visits, and with medication prescriptions (e.g. for antibiotics, antirheumatics, hydroxyurea), decreased over time. Conclusion: This claims-based analysis indicates increasing documented SCD prevalence in Germany. However, the extent to which prevalence increased due to a true increase in the general population, due to our carry-forward cohort approach, or due to other factors such as changes in coding practices or healthcare seeking behaviors, cannot be disentangled.We observed earlier recorded diagnosis timing in young children over time, alongside substantial age-dependent burden reflected in complications, mental health comorbidity, and healthcare utilization. Possible explanations for lower proportions of patients with inpatient/outpatient visits and medication prescriptions over time may include changes in disease awareness, patient management and/or healthcare seeking behaviours over time, and/or broader capture of patients with milder disease. Overall, our findings can inform healthcare planning and structured life-course–oriented SCD care pathways in Germany.

This retrospective, single‐center study aimed to characterize clonal dynamics of GPI‐deficient cells in patients with paroxysmal nocturnal hemoglobinuria (PNH) or PNH/aplastic anemia (AA) syndrome using multiparameter flow cytometry including FLAER. Among 108 patients diagnosed and treated at our center, 83 had longitudinal monitoring of GPI‐deficient neutrophils; 53 of these also had data on monocytes and lymphocytes. Median observation time was 29.4 months (range 1.1–162.7 months). Clone size in neutrophils showed a strong correlation with monocytes, but not with lymphocytes. Clonal persistence represented the most frequent individual pattern of clone evolution observed during follow‐up; clonal persistence was observed in 32/83 patients, while 24 patients exhibited clonal expansion (≥ 10%) and 13 showed regression. Expansion frequently involved all three lineages, suggesting ongoing biological mechanisms contributing to clonal selection. Regression was more likely in patients with small initial clones. In six patients undergoing allogeneic stem cell transplantation, complete eradication of PNH clones was achieved. Clonal dynamics were independent of eculizumab treatment; however, regression was observed in some patients treated with ATG and cyclosporine A. These findings support the need for longitudinal clone size monitoring, particularly in neutrophils and monocytes. Further studies are warranted to elucidate factors influencing clone expansion and remission. Trial Registration: 25‐12 634‐BO

Introduction: Aplastic anemia (AA) is a rare bone marrow failure syndrome with pancytopenia, mainly due to immune‐mediated stem cell destruction. First‐line therapy for acquired severe AA ≥ 50 years/non‐severe AA (NSAA) requiring treatment is immunosuppressive therapy with horse anti‐thymocyte globulin, cyclosporine A (CSA), and eltrombopag (EPAG). In pregnancy, cytopenia may worsen, while therapeutic options are limited. Results: We report the first case of a pregnant patient with NSAA/PNH receiving full‐dose EPAG (150 mg/d). Counts remained stable, delivery was uneventful, and the child was healthy. Postpartum, EPAG was discontinued, CSA tapered, and transfusion independence achieved. Conclusion: EPAG may represent a feasible option in selected pregnancies.

Cold agglutinin disease (CAD) is a low‐grade lymphoproliferative disorder accounting for 15%–30% of patients suffering from autoimmune hemolytic anemias. The clonal B cells produce autoantibodies primarily of the IgM‐κ class that cause agglutination of red blood cells (RBCs) at temperatures ≤ 37°C and activate the classical complement pathway with subsequent RBC destruction. Before the approval of the monoclonal antibody sutimlimab, treatment options were limited. Sutimlimab inhibits the classical complement pathway at C1s while sparing the lectin and alternative complement pathways. Efficacy, safety and tolerability of sutimlimab have been established in the multicenter CARDINAL and CADENZA trials. In the present investigation, 10 patients on sutimlimab were followed up to 96 weeks in the Managed Access Program (MAP) in Essen. Eight of these patients had previously participated in the multicenter trials and were restarted on sutimlimab after a median washout period of 12.6 weeks. In addition, two sutimlimab‐naive patients were included. Hemoglobin concentration increased in all patients (median hemoglobin concentration before therapy 9.8 vs. 12.5 g/dL at the end of the study). Bilirubin levels normalized already after 2 weeks in all patients. Reticulocyte count declined in nine, haptoglobin and hemopexin concentrations normalized in six and 10 patients, respectively. In conclusion, the present investigation with primary CAD patients in a single center demonstrates long‐term normalization of laboratory parameters, abrogation of specific clinical symptoms and absence of drug‐related side effects with sutimlimab.

Introduction: The marketing authorization for crizanlizumab (Adakveo^®), indicated for the prevention of recurrent vaso-occlusive crises (VOCs) in sickle cell patients (pts) aged ≥16, was revoked by the European Medicines Agency (EMA) as the STAND study did not demonstrate a significant difference between crizanlizumab and placebo in annualized rates of VOCs.Methods: This is a retrospective, monocentric analysis of adult pts with sickle cell disease (SCD) (age (median) 29 years, range 19-42, annual VOC rate 3, range 1-5, homozygous SCD (HbS/S) 50.0% (4/8)) receiving crizanlizumab as monotherapy at the University Hospital of Essen between Dec 2020 to May 2023 (observation time (median) 17.5 months, range 4.8-27.3). The results were compared to hydroxycarbamide (HC)-treated pts at maximum tolerated dose (MTD).Results: At 6, 9, and 12 months, mean VOC rate was 1.5 (range 0-3; N=6), 1.8 (range 0-3; N=5) and 4.0 (range 3-5; N=3), indicating a time-dependent increase in VOCs in crizanlizumab-treated pts (6-9 months: p=0.039; 6-12 months: p=0.008) (mean VOC rate in HC-treated pts: 6 months: 0.38, range 0-1 (N=8); 9 months: 0.50, range 0-2 (N=8); 12 months: 0.63, range 0-3 (N=8)). Serious adverse events were mandatory in 7 pts, resulting in 12 inpatient-admissions (acute chest syndrome (N=2), VOC-related pain crisis (N=9), infusion-related VOC (N=1)).Conclusion: These findings, together with the high economic burden of crizanlizumab in contrast to HC, do further support the revocation of crizanlizumab in Europe in our opinion. Physicians should consider the potential risks when making a therapeutic decision regarding the use of crizanlizumab outside of Europe.

Zusammenfassung: Die Sichelzellkrankheit (SCD) stellt eine seltene, aber äußerst komplexe, multisystemische Erkrankung dar, die eine umfassende interdisziplinäre und spezialisierte Versorgung und daher neue strukturelle Voraussetzungen erfordert. Neben der Versorgung dieser chronisch kranken Patienten stellt insbesondere der Transitionsprozess eine vulnerable Phase, mit maßgebendem Einfluss auf die weitere Behandlung, dar. Erschwerend kommt hinzu, dass fast ausschließlich Menschen mit Migrationshintergrund betroffen sind – mit häufigen Verständigungs- und Verständnisschwierigkeiten. Ein nationaler Leitfaden für einen standardisierten Prozess der Transition von Sichelzell-Patienten liegt bislang in Deutschland nicht vor. Im Rahmen eines strukturierten Konsensusprozesses entwickelte die „Transitionsinitiative Sichelzellkrankheit“ auf Basis der S3-Leitlinie zur Transition der DGfTM (Deutsche Gesellschaft für Transitionsmedizin e. V.) spezifische Empfehlungen für eine strukturierte Transition von SCD-Patienten. Diese sollen den vulnerablen Prozess bei dieser komplexen Erkrankung erleichtern, die adäquate Weiterbehandlung sichern und damit krankheitsspezifische akute und chronische Komplikationen, aber auch psychische, soziale, berufliche und gesellschaftliche Probleme verhindern. Neben der Verbesserung der Lebensqualität, der medizinischen Versorgung und des Überlebens ergeben sich daraus auch relevante gesundheitsökonomische Aspekte. Zur Unterstützung des Prozesses wurden Dokumente entwickelt (u. a. Fragebögen zur Transitionsbereitschaft, detaillierte Transitionsepikrise), die, wie auch zusätzliche allgemeine Informationen zur Transition bei SCD, unter https://www.sichelzellkrankheit.info/transition/ zu finden sind.

Objective: Describe the real‐world clinical profile of eculizumab‐treated patients by characterizing their short‐ and long‐term clinical and laboratory outcomes.Methods: This retrospective study used preexisting medical records of eculizumab‐treated patients with paroxysmal nocturnal hemoglobinuria (PNH) at the University Hospital Essen. Hematologic response, breakthrough hemolysis, transfusion dependence, and other outcomes were assessed.Results: Of 85 patients with PNH, 76 received eculizumab for ≥24 weeks (mean follow‐up: 5.59 years; total: 425 person‐years). At 24 weeks (n = 57 patients with data), 7% and 9% had complete and major hematologic response, respectively. Breakthrough hemolysis occurred in 8%, and 38% required a blood transfusion. Over long‐term follow‐up (25–264 weeks), 70%–82% of patients did not achieve complete or major hematologic response in any 24‐week period. Breakthrough symptoms, breakthrough hemolysis, and transfusion dependence occurred in 63%, 43%, and 63% of patients, respectively, at any point during follow‐up. The majority (79%–89%) of patients did not achieve normalized hemoglobin, with 76%–93% having elevated bilirubin or absolute reticulocyte count in any 24‐week window. Mean percentage reduction in lactate dehydrogenase (baseline to end of follow‐up) was 80.3% (95% CI, 64.0–96.6).Conclusions: A considerable proportion of patients with PNH receiving eculizumab did not achieve optimal clinical outcomes and had an ongoing disease burden.

Paravertebral extramedullary hematopoietic masses (EHMs) account for up to 15% of extramedullary pseudotumors in beta-thalassemia (BT) and are most likely related to compensatory hematopoiesis. In most cases, pseudotumors are incidentally detected, as the majority of patients are asymptomatic. Since June 2020, luspatercept is approved for the treatment of patients with BT who require regular red blood cell transfusions. Data addressing the safety and efficacy of luspatercept in patients with BT-associated EHMs are pending. To date (May 2022), paravertebral EHMs were observed in two asymptomatic patients out of currently 43 adult patients with BT registered at the Adult Hemoglobinopathy Outpatient Unit of the University Hospital Essen, Germany. In one of them, a paravertebral EHM was diagnosed more than 10 years prior to referral. Throughout observation time, treatment with luspatercept was associated with a clinically significant reduction in transfusion burden while allowing to maintain a baseline hemoglobin concentration of >= 10 g/dL aiming to suppress endogenous (ineffective) erythropoiesis associated with BT. Considering the rarity of paravertebral EHMs in BT, luspatercept might potentially represent a novel therapeutic option for these often-serious disease-associated complications. However, appropriate follow-up investigations are recommended to detect (early) treatment failures secondary to an undesired luspatercept-associated erythroid expansion.