Giovanna Cannas

Management of cerebral vasculopathy in sickle cell anemia (SCA) includes standard‐care, that is, chronic transfusion (CT) or hydroxyurea, and hematopoietic cell transplantation (HCT). DREPAGREFFE‐1 (December 2010/June 2013), a French multicenter trial, was the first prospective trial comparing standard‐care to match sibling donor (MSD)‐HCT in 67 (35F/32M) SCA children (5–15 year) on CT for abnormal time‐averaged mean maximum velocities (TAMMV ≥ 200 cm/s). Seven had a stroke history. We reported that MSD‐HCT reduced the highest TAMMVs at 1‐ and 3‐year ( p < 0.001) and improved quality of life (QoL) for physical and school functioning. In stroke‐free patients, the 3‐year stenosis score was lower ( p = 0.010). Nevertheless, no significant difference was observed for silent cerebral infarcts (SCI) and cognitive performance. This prompted us to initiate DREPAGREFFE‐2 to reevaluate the outcomes at 10 years (September 2022/August 2024) with the same 67 SCA children. No death or stroke occurred in either arm. No rejection or chronic‐GvHD arose in the MSD‐HCT group ( n = 32). In the standard‐care group ( n = 35), 16 were on hydroxyurea, and 16 on CT at Year 10, and 3 received haploidentical‐HCT. After MSD‐HCT, the QoL was better, even for social functioning, and the number of hospitalizations, hospitalized days ( p < 0.001), and crises ( p = 0.001) was lower than on standard‐care. In stroke‐free patients, stenosis ( p = 0.027) and SCI scores ( p = 0.041) decreased significantly more after MSD‐HCT than on standard‐care; working memory ( p = 0.016) and processing speed ( p = 0.011) improved significantly after MSD‐HCT, but worsened on standard‐care. These effects were not previously detected with shorter follow‐up. This supports earlier consideration of HCT for SCA children with MSD to preserve neurologic function and QoL for a more productive future.

1. Sickle cell disease (SCD) is an inherited autosomal recessive hemoglobinopathy marked by structurally abnormal hemoglobin S (HbS). It is thought to affect 3 to 6 million people in the world, mos...

Despite advances in the treatment of sickle cell disease (SCD), an inherited disorder leading to abnormal sickle hemoglobin (HbS) polymerization, patients continue to have a shorter life expectancy comparatively to the general population. Increase in the concentration of oxygenated HbS in red blood cells (RBCs) has been considered as a novel approach to inhibit HbS polymerization and reduce RBC sickling and their complications, raising interest for novel oxygen affinity modulators. This review summarizes the characteristics and primary results obtained with osivelotor, a novel oxygen affinity modulator, for the treatment of SCD. Osivelotor is presented with improved pharmacokinetic properties comparatively to voxelotor. It may enable higher hemoglobin (Hb) occupancy at lower doses potentially leading to significant improvements of clinical outcomes. The first clinical phase 2/3 trial with osivelotor reported increases of Hb levels and RBC counts, and decrease of RBC sickling. The treatment was apparently well tolerated. However, osivelotor shares the same mechanism of action as voxelotor, and therefore similar limitations regarding its efficacy for which the improvement in Hb level appears misleading. Several issues remain to be resolved before considering any drug approval.

Sickle cell disease (SCD) is a genetic disease of public health concern. Adult patients face various disease-related complications, which affect their quality of life (QoL). Few studies have examined relationships between these events and health-related (HR) QoL. We conducted a study of 240 adults with SCD seen in steady state at a routine clinic visit over one year. Two self-administered questionnaires were used to determine patients’ HRQoL: the sickle cell self-efficacy scale (SCSES) and the unspecific SF-36 scoring system evaluating physical and mental components. Factors impacting HRQoL were established using univariate and multivariate regression analyses. Participants had a median age of 28 years (Sex ratio male/female 0.61; 68% SS genotype). Most of them had experienced more than one SCD-related complication and more than one affected organ system. A good correlation was established between the SCD specific and the unspecific scoring systems. Using the SF-36 scoring system, energy/fatigue, general health and pain subscales showed the lowest median scores, while physical functioning had the highest median score. In univariate and multivariate analyses, hospitalization for SCD complications occurring during the last year preceding QoL evaluation was the main feature impacting HRQoL. Good compliance to hydroxyurea (HU) therapy was associated with higher SCSES and higher emotional role functioning scores. Our study confirms substantial impairment of HRQoL in adults with SCD. HRQoL was mainly influenced by the recent occurrence of severe SCD complications. Our study suggests that a more effective treatment through a better compliance to HU therapy would provide benefit in terms of QoL.

Introduction: Sickle cell disease (SCD) is one of the most common genetic diseases in the world, annually affecting approximately 310 000 births and causing >100 000 deaths. Vaso-occlusive crisis (VOC) is the most frequent complication of SCD, leading to bone pain, thoracic pain (acute chest syndrome) and/or abdominal spasms. It is the main cause of mortality in patients with SCD, reducing life expectancy. Hyperbaric oxygen therapy (HBOT) is a safe and well-established method of increasing tissue oxygen delivery immediately by up to 10-fold to 20-fold. In the context of VOC, HBOT has the potential to limit sickling. A previous pilot study of nine patients showed the safety and potential benefits of HBOT on VOC-induced pain. Our study aimed to assess the clinical safety and effectiveness of HBOT for treating VOC, its biological mechanisms of actions and its cost-effectiveness. Methods and analysis: This is a multicentric, triple-blinded, randomised controlled trial. Patients aged 8 years or above with a diagnosed major form of SCD, presenting at one of the participating centres’ emergency departments (EDs) with a VOC requiring level 3 analgesia (according to WHO definition), will be eligible. Exclusion criteria are pregnancy, mechanical ventilation, previous history of stroke or prior transcranial Doppler ultrasound anomaly, contraindication to HBOT and the need for above 2 L/min of oxygen. All patients will receive the usual care for VOCs, including hydration, analgesics, normobaric oxygen therapy and when medically indicated, antibiotic therapy and/or transfusions. Within 24 hours of their arrival in the ED (or longer in specific cases), and after obtaining informed consent, patients will be randomised into the HBOT intervention group (2.0 atmosphere absolute (ATA), 90 min, FIO ₂ =1) or the sham group (1.3 ATA, 90 min, FIO ₂ =0.21). After their first HBOT session, patients will return to their acute-care ward. Patients in both arms will undergo a second and third session within 24–36 hours of the first, unless their Visual Analogue Scale (VAS)-pain is ≤2 without use of level 3 analgesics. The difference in the pain-VAS before and after HBOT and other outcomes will be compared between the intervention and sham groups. Our composite primary outcome will be (1) the change in global VAS-pain 6 hours after initiation of HBOT; (2) the number of patients with a VAS-pain score >4 and/or a morphine dosage >1 mg/hour intravenous after the HBOT/sham session. Other outcomes to be reported are morphine usage, length of stay, biological parameters, satisfaction, complications and cost. Ethics and dissemination: Ethical approval CER Geneva 2019-01707 (last submission V.5.1, 06.15.2023). The results of the studies will be disseminated by several media, including publications in peer-reviewed international medical journals, and presentations at national and/or international conferences. Trial registration number: NCT04978116 .

In France, sickle cell disease newborn screening (SCD NBS) has been targeted to at-risk regions since 1984, but generalization to the whole population will be implemented from November 2024. Although tandem mass spectrometry (MS/MS) is already used for the NBS of several inherited metabolic diseases, its application for SCD NBS has not been widely adopted worldwide. The aim of this study was to evaluate a dedicated MS/MS kit (Targeted MS/MS Hemo, ZenTech, LaCAR Company, Liege, Belgium) for SCD NBS and to compare the results obtained with those from an NBS reference center using matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) and cation-exchange high-performance liquid chromatography (CE-HPLC, Variant NBS, Biorad Laboratories, Inc., Hercules, CA, USA) as confirmatory method. The MS/MS Hemo kit was used according to the manufacturer’s instructions and performed on a Waters Xevo TQ-D (Waters Corporation, USA). The software provided by the manufacturer was used for the calculation and analysis of peptide signal ratios. Among the 1333 samples, the results of 1324 samples were consistent with the HPLC and/or MALDI-TOF results (1263 FA, 50 FAS, 7 FAC, 1 FAO-Arab, and 3 FS). All the discordant results (one FAS on MS/MS vs. FA in CE-HPLC, one FA on MS/MS vs. FAS in CE-HPLC, seven FS on MS/MS vs. FAS in CE-HPLC) were corrected after modifying the peptide signal ratios thresholds, allowing the MS/MS Hemo kit to achieve near-100% sensitivity and specificity for SCD NBS. In conclusion, the MS/MS Hemo kit appears to be an effective method for SCD NBS, particularly for laboratories already equipped with MS/MS technology. However, these results should be confirmed in a larger cohort including a greater number of positive samples for SCD.

Sickle cell disease (SCD) is a severe monogenic hereditary hemoglobinopathy that is characterized by repeated clinical and biological manifestations able to generate stress erythopoiesis. A clonal hematopoiesis involving mainly variants of TP53, DNMT3A, ASXL1, and/or TET2 may be more prevalent in patients with SCD, suggesting that mutations in these genes may lead to an increased risk of leukemia. An increased prevalence of leukemia in patients with SCD has been confirmed by an increasing number of acute myeloid leukemia cases with myelodysplastic features reported in this patient population even in the absence of disease-modifying treatments. This leads to the hypothesis of a mechanism involving multifactorial causes through the pathophysiologic manifestations of SCD, in which cells are undergoing constant hematopoietic hyperplasia, inducing genomic damage and somatic mutations.

Acute chest syndrome (ACS) is a frequent complication of sickle cell disease (SCD). Because coronavirus disease 2019 (COVID‐19) increases mortality and morbidity in many diseases, we retrospectively analyzed the impact of SARS‐CoV‐2 infection on the incidence, the clinical presentation, and the prognosis of ACS in patients with SCD by comparing ACS episode before and during COVID‐19 pandemic.Ninety‐nine episodes of ACS were registered over 24 months before pandemic versus 81 episodes over 24 months during the pandemic period. The number of ACS episodes varies among children regarding the two period of time: 26 episodes (26%) for the pre‐pandemic period versus 11 episodes (13%) for the pandemic period (p = 0.03). Comparisons between adults and children showed a higher incidence of initial VOC (45% vs. 24%; p = 0.04) in adults, and a higher incidence of initial pneumonia (35% vs. 15%; p = 0.01) and documented infection (35% vs. 7%; p < 0.001) in children. One patient died during the pandemic period but without any relationship with ACS or COVID‐19. During this pandemic period, 13 episodes of ACS (16%) were found related to coronavirus infection. These ACS episodes did not show any significant differences in terms of outcome when compared to the other ACS episodes observed during this period.Overall, coronavirus infection did not demonstrate a negative impact on incidence, clinical presentation, and outcome of ACS in patients with SCD. Early management, chronic treatment with HU, and exchange transfusions could likely explain the low morbidity and mortality rates.

Population-based studies and case reports suggest that there may be an increased risk of acute leukemia associated with sickle cell disease (SCD). Following the description of a new case report, an extensive review of the literature identified 51 previously described cases. Most cases study showed myelodysplastic features confirmed, when available, by genetic markers such as chromosome 5 and/or chromosome 7 abnormalities and TP53 gene mutations. The increased risk of leukemogenesis is certainly multifactorial and related to the pathophysiologic mechanisms of the clinical manifestations of SCD. Chronic hemolysis and secondary hemochromatosis may cause increased chronic inflammation, resulting in persistent marrow stress, which could potentially compromise the genomic stability of the hematopoietic stem cells generating genomic damage and somatic mutations over the course of SCD and its treatment, resulting in a clone that led to acute myeloid leukemia.