Pubertal development of transfusion-dependent thalassemia patients in the era of oral chelation with deferasirox: results from the French registry.

Not available.

Hydroxyurea is associated with later onset of acute splenic sequestration crisis in sickle cell disease: Lessons from the European Sickle Cell Disease Cohort-Hydroxyurea (ESCORT-HU) study.

Acute splenic sequestration crisis (ASSC) is a potentially life-threatening complication of sickle cell disease (SCD), typically occurring in young patients under 5 years of age, with a median age at first episode of less than 2 years. Because a beneficial effect of hydroxyurea (HU) on spleen perfusion and splenic function has been suspected, we hypothesized that HU treatment might be associated with later onset of ASSC in patients with SCD. To investigate this hypothesis, we analyzed data from the ESCORT-HU study on a large cohort of patients with SCD receiving HU, enrolled between January 2009 and June 2017 with a follow-up of 7309 patient-years of observation. The median age at ASSC of the 14 patients who experienced a first episode of ASSC during the study period was 8.0 [IQR: 5.0-24.1] years. The median age at HU initiation was significantly lower in these 14 patients (4.8 [IQR: 3.3-18.7] years) compared to the 1664 patients without ASSC (19.9 [8.8-33.4] years, p = .0008). These findings suggest that ASSC may occur at an unusually late age in patients receiving HU, possibly reflecting longer preservation of spleen perfusion and function secondary to early initiation of HU. Further studies are needed to better characterize the effects of HU on spleen perfusion/function and on the occurrence of ASSC in patients with SCD (ClinicalTrials.gov identifier: NCT02516579; European registry ENCEPP/SDPP/10565).

A comprehensive view of pregnancy in patients with sickle cell disease in high-income countries: the need for robust data and further decline in morbidity and mortality.

Sickle cell disease is a major public health concern due to its prevalence and associated morbidities. In high-income countries, diagnosis and treatment advancements have extended patient's lives and enabled women to embrace motherhood. Although the provision of care in specialist centres has reduced maternal-fetal complication rates, the mortality rate among pregnant women with sickle cell disease remains disproportionately high. Complications arise from vaso-occlusive events, worsening organ damage, thrombotic risks, infections, and pregnancy-related issues, such as pre-eclampsia, premature birth, small-for-gestational-age, and pregnancy loss. Effective management during pregnancy includes preconception planning, genetic counselling, education, and collaborative care. There is no consensus on the overall approach to managing pregnant women with sickle cell disease; however, fostering a collaborative relationship between health-care professionals and researchers is crucial for advancing the understanding and management of this illness. The disparities in health-care outcomes associated with ethnicity and economic insecurity affect patients with sickle cell disease but have not been examined extensively. Hence, health-care personnel need sufficient training to address these issues alongside broader societal efforts to confront racism and discrimination. Comprehensive national and global action plans are required to address the multifaceted challenges of sickle cell disease.

A study of 28 pregnant women with sickle cell disease and COVID-19: elevated maternal and fetal morbidity rates.

Not available.

[Therapeutic approaches in sickle cell disease]. / Perspectives thérapeutiques dans la drépanocytose.

THERAPEUTIC APPROACHES IN SICKLE CELL DISEASE. Sickle cell disease, the most common genetic disease in France, is still burdened with morbidity and early mortality before the age of 50. When the first-line treatment, hydroxyurea, is insufficient or in the case of organic damage(s) (in particular cerebral vasculopathy), a therapeutic intensification must be considered. New molecules are now available, such as voxelotor and crizanlizumab, but only hematopoietic stem cell (HSC) transplantation can cure the disease. Allogeneic HSC transplantation during childhood with a sibling donor is the reference but it is now possible to perform this procedure in adults with a reduced pre-transplant conditioning. Gene therapy, which consists of an autograft of genetically modified HSCs, has obtained promising results but has not yet demonstrated a complete cure of the disease (protocols underway). The toxicity of myeloablative conditioning (used in pediatrics or for gene therapy), particularly the sterility induced, and the risk of graft-versushost disease (for allogeneic transplantation) are limiting factors of these treatments.

PERSPECTIVES THÉRAPEUTIQUES DANS LA DRÉPANOCYTOSE. La drépanocytose, maladie génétique la plus fréquente en France, reste grevée d'une morbidité et d'une mortalité précoce avant l'âge de 50 ans. Dans le cas où le traitement de première ligne, l'hydroxyurée, est insuffisant ou en cas d'atteinte(s) organique(s) (en particulier la vasculopathie cérébrale), une intensification thérapeutique doit être envisagée. De nouvelles molécules sont aujourd'hui disponibles comme le voxelotor et le crizanlizumab, mais seule la greffe de cellules souches hématopoïétiques (CSH) permet une guérison de la maladie. L'allogreffe de CSH pendant l'enfance avec un donneur compatible intrafamilial (géno-identique) est la référence, mais il est désormais possible de réaliser cette procédure chez les adultes avec un conditionnement prégreffe d'intensité réduite. La thérapie génique qui consiste en une autogreffe de CSH génétiquement modifiées a obtenu des résultats prometteurs mais n'a pas démontré à ce jour une guérison complète de la maladie (protocoles en cours). La toxicité des conditionnements dits myéloablatifs (utilisés en âge pédiatrique ou pour la thérapie génique), notamment la stérilité induite, le risque de réaction du greffon contre l'hôte (pour la greffe allogénique), sont des facteurs limitants de ces traitements.

Outcomes of Pregnancy in Sickle Cell Disease Patients: Results from the Prospective ESCORT-HU Cohort Study.

Sickle cell disease (SCD) refers to a group of inherited hemoglobin disorders in which sickle red blood cells display altered deformability, leading to a significant burden of acute and chronic complications, such as vaso-occlusive pain crises (VOCs). Hydroxyurea is a major therapeutic agent in adult and pediatric sickle cell patients. This treatment is an alternative to transfusion in some complications. Indeed, it increases hemoglobin F and has an action on the endothelial adhesion of red blood cells, leukocytes, and platelets. Although the safety profile of hydroxyurea (HU) in patients with sickle cell disease has been well established, the existing literature on HU exposure during pregnancy is limited and incomplete. Pregnancy in women with SCD has been identified as a high risk for the mother and fetus due to the increased incidence of maternal and non-fetal complications in various studies and reports. For women on hydroxyurea at the time of pregnancy, transfusion therapy should probably be initiated after pregnancy. In addition, there is still a significant lack of knowledge about the incidence of pregnancy, fetal and maternal outcomes, and management of pregnant women with SCD, making it difficult to advise women or clinicians on outcomes and best practices. Therefore, the objective of this study was to describe pregnancy outcomes (n = 128) reported in the noninterventional European Sickle Cell Disease COhoRT-HydroxyUrea (ES-CORT-HU) study. We believe that our results are important and relevant enough to be shared with the scientific community.

Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy.

X-linked chronic granulomatous disease (CGD) is associated with defective phagocytosis, life-threatening infections, and inflammatory complications. We performed a clinical trial of lentivirus-based gene therapy in four patients (NCT02757911). Two patients show stable engraftment and clinical benefits, whereas the other two have progressively lost gene-corrected cells. Single-cell transcriptomic analysis reveals a significantly lower frequency of hematopoietic stem cells (HSCs) in CGD patients, especially in the two patients with defective engraftment. These two present a profound change in HSC status, a high interferon score, and elevated myeloid progenitor frequency. We use elastic-net logistic regression to identify a set of 51 interferon genes and transcription factors that predict the failure of HSC engraftment. In one patient, an aberrant HSC state with elevated CEBPß expression drives HSC exhaustion, as demonstrated by low repopulation in a xenotransplantation model. Targeted treatments to protect HSCs, coupled to targeted gene expression screening, might improve clinical outcomes in CGD.

Adenine base editor-mediated correction of the common and severe IVS1-110 (G>A) ß-thalassemia mutation.

ß-Thalassemia (BT) is one of the most common genetic diseases worldwide and is caused by mutations affecting ß-globin production. The only curative treatment is allogenic hematopoietic stem/progenitor cells (HSPCs) transplantation, an approach limited by compatible donor availability and immunological complications. Therefore, transplantation of autologous, genetically-modified HSPCs is an attractive therapeutic option. However, current gene therapy strategies based on the use of lentiviral vectors are not equally effective in all patients and CRISPR/Cas9 nuclease-based strategies raise safety concerns. Thus, base editing strategies aiming to correct the genetic defect in patients' HSPCs could provide safe and effective treatment. Here, we developed a strategy to correct one of the most prevalent BT mutations (IVS1-110 [G>A]) using the SpRY-ABE8e base editor. RNA delivery of the base editing system was safe and led to ∼80% of gene correction in the HSPCs of patients with BT without causing dangerous double-strand DNA breaks. In HSPC-derived erythroid populations, this strategy was able to restore ß-globin production and correct inefficient erythropoiesis typically observed in BT both in vitro and in vivo. In conclusion, this proof-of-concept study paves the way for the development of a safe and effective autologous gene therapy approach for BT.

Safety of coronavirus disease 2019 vaccines in 213 adult patients with sickle cell disease.

Given the lack of information about safety of the COVID-19 vaccines for sickle cell disease (SCD) patients, we sought to determine whether COVID-19 vaccine was associated with subsequent hospital admission for vaso-occlusive events (VOEs). We included 402 patients with SCD, including 88 regularly transfused. As of July 31, 2021, 213 (53.0%) of them had received a least one dose of COVID vaccine (Pfizer 93.0%). We showed similar risk of hospital admission for a VOE among vaccinated patients (whether transfused or not) and among a control group of non-vaccinated patients matched for age, sex and genotype.

Case Report of Myelodysplastic Syndrome in a Sickle-Cell Disease Patient Treated with Hydroxyurea and Literature Review.

The safety profile of hydroxyurea (HU) in patients with sickle-cell disease (SCD) is relatively well known. However, despite the suspected association of HU with myeloid neoplasms in myeloproliferative neoplasms (MPN), and the publication of sporadic reports of myeloid malignancies in SCD patients treated with HU, the possible excess risk imparted by HU in this population having an increasing life expectancy has failed to be demonstrated. Herein, we report one case of myelodysplastic syndrome emanating from the results on safety and effectiveness of HU on the largest European cohort of 1903 HU-treated adults and children who were followed-up prospectively in an observational setting over 10 years, accounting for a total exposure of 7309.5 patient-years. A comparison of this single case with previously published similar cases did not allow us to draw any significant conclusions due to the paucity of these events.

Risks and Benefits of Prophylactic Transfusion before Cholecystectomy in Sickle Cell Disease.

Preoperative transfusion (PT) reduces acute postoperative vaso-occlusive events (VOE) in sickle cell disease (SCD), but exposes patients to alloimmunization, encouraging a recent trend towards transfusion sparing. The aim of this study was to investigate the benefit-risk ratio of PT before cholecystectomy on the occurrence of postoperative VOE. Adult SCD patients who underwent cholecystectomy between 2008 and 2019 in our center were included. Patients' characteristics, collected retrospectively, were compared according to PT. A total of 79 patients were included, 66% of whom received PT. Gallbladder histopathology found chronic cholecystitis (97%) and gallstones (66%). Transfused patients underwent more urgent surgeries and had experienced more painful vaso-occlusive crises (VOC) in the month before surgery (p = 0.05). Four (8.5%) post-transfusion alloimmunizations occurred, and two of them caused a delayed hemolytic transfusion reaction (DHTR) (4.3%). The occurrence of postoperative VOE was similar between the groups (19.2% vs. 29.6%, p = 0.45). Though not statistically significant, a history of hospitalized VOC within 6 months prior to surgery seemed to be associated to postoperative VOE among non-transfused patients (75% vs. 31.6%, p = 0.10). PT before cholecystectomy exposes to risks of alloimmunization and DHTR that could be avoided in some patients. Recent VOCs appear to be associated with a higher risk of postoperative VOE and prompt the preemptive transfusion of these patients.

Long-term outcomes of lentiviral gene therapy for the ß-hemoglobinopathies: the HGB-205 trial.

Sickle cell disease (SCD) and transfusion-dependent ß-thalassemia (TDT) are the most prevalent monogenic disorders worldwide. Trial HGB-205 ( NCT02151526 ) aimed at evaluating gene therapy by autologous CD34+ cells transduced ex vivo with lentiviral vector BB305 that encodes the anti-sickling ßA-T87Q-globin expressed in the erythroid lineage. HGB-205 is a phase 1/2, open-label, single-arm, non-randomized interventional study of 2-year duration at a single center, followed by observation in long-term follow-up studies LTF-303 ( NCT02633943 ) and LTF-307 ( NCT04628585 ) for TDT and SCD, respectively. Inclusion and exclusion criteria were similar to those for allogeneic transplantation but restricted to patients lacking geno-identical, histocompatible donors. Four patients with TDT and three patients with SCD, ages 13-21 years, were treated after busulfan myeloablation 4.6-7.9 years ago, with a median follow-up of 4.5 years. Key primary endpoints included mortality, engraftment, replication-competent lentivirus and clonal dominance. No adverse events related to the drug product were observed. Clinical remission and remediation of biological hallmarks of the disease have been sustained in two of the three patients with SCD, and frequency of transfusions was reduced in the third. The patients with TDT are all transfusion free with improvement of dyserythropoiesis and iron overload.

A new step in understanding stem cell mobilization in patients with Fanconi anemia: A bridge to gene therapy.

BACKGROUND: Fanconi anemia (FA) is an inherited disorder characterized clinically by congenital abnormalities, progressive bone marrow failure (BMF), and a predisposition to malignancy. Gene therapy (GT) of FA, via the infusion of gene-corrected peripheral blood (PB) autologous hematopoietic stem cells (HSCs), may constitute a cure for BMF. GT bypasses the donor restrictions and adverse events associated with allogenic HSC transplantation. However, adequate harvesting of PB-HSCs is a crucial determinant of successful engraftment in gene therapy. Harvesting the low numbers of HSCs in patients with FA is particularly challenging. STUDY DESIGN AND METHODS: This open-label phase I/II trial evaluates the feasibility and safety of co-administration of G-CSF and plerixafor in patients with FA for the mobilization and harvesting of peripheral HSCs, intending to use them in a gene therapy trial. Patients with mutations in the FANCA gene received two subcutaneous injections of G-CSF (6 µg/kg × 2/d from D1 to D8. Plerixafor (0.24 mg/kg/d) was administered 2 h before apheresis (from D5 onward). RESULTS: CD34+ cells were mobilized for four patients quickly but transiently after the plerixafor injection. One patient had a CD34+ cell count of over 100/µl; the mobilization peaked 2 h after the injection and lasted for more than 9 h. There were no short-term adverse events associated with the mobilization or harvesting procedures. CONCLUSION: Our data in patients with FA show that the mobilization of HSCs with G-CSF and plerixafor is safe and more efficient in younger individuals without BMF.