Ovarian tissue cryopreservation for fertility preservation before hematopoietic stem cell transplantation in patients with sickle cell disease: safety, ovarian function follow-up, and results of ovarian tissue transplantation.

PURPOSE: To describe the experience of performing ovarian tissue cryopreservation (OTC) before hematopoietic stem cell transplantation (HSCT), among girls/women with severe sickle cell disease (SCD)(SS or S/ß0-thalassemia) who are, besides the usual surgical risk, at risk of SCD-related complications during the fertility preservation procedure for improving their counseling and management. METHODS: This retrospective study included 75 patients (girls/women) with SCD who have had OTC before myeloablative conditioning regimen (MAC) for HSCT. Characteristics of patients and data on OTC, ovarian status follow-up, and results of ovarian tissue transplantation (OTT) were collected in medical records. RESULTS: At OTC, the median (IQR 25-75; range) age of the patients was 9.6 (6.9-14.1; 3.6-28.3) years, 56/75 were prepubertal, and no SCD or surgery-related complications occurred. The median follow-up post-HSCT was > 9 years. At the last follow-up, among prepubertal patients at HSCT, 26/56 were ≥ 15 years old and presented with a premature ovarian insufficiency (POI), except 2, including the patient who had received an OTT to induce puberty. Eight were 13-15 years old and presented for POI. The remaining 22 patients were under 13. Among the 19 patients who were menarche at HSCT, 2 died 6 months post-HSCT and we do not have ovarian function follow-up for the other 2 patients. All the remaining patients (n = 15) had POI. Five patients had OTT. All had a return of ovarian function. One patient gave birth to a healthy baby. CONCLUSION: OTC is a safe fertility preservation technique and could be offered before MAC independent of the patient's age.

[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.

Severity and burden of sickle cell disease in France: a nationwide real-world study.

The burden of sickle cell disease (SCD) in France has been difficult to apprehend due to the paucity of reliable nationwide epidemiological data. We aimed to describe the epidemiology of SCD and evaluate its burden and costs. Patients with SCD and most severely affected patients were identified between 2012 and 2018 from the French National Health Data System database (SNDS, Système national des données de santé). Outcomes of interest included rates of acute and chronic complications, healthcare resource utilization and associated costs, and were compared in subpopulations of patients before and after hematopoietic stem cell transplantation, initiating hydroxyurea or a chronic transfusion program. Between 2012 and 2018, 22,619 patients with SCD were identified, among which 4,270 patients were defined as most severely affected. Rates of vaso-occlusion episodes and acute chest syndrome were 86.29 (95% confidence interval [CI]: 85.75-86.83] and 12.90 (95% CI: 12.69-13.11) per 100 person years in the study population and 166.9 (95% CI: 165.4- 168.4) and 22.71 (95% CI: 22.16-23.27) per 100 person years in most severely affected patients. Median (Q1-Q3) annualized total costs were €5,073.63 (range, €1,633.74-14,000.94) and €13,295.67 (range, €5,754.67-26,385.23) in the study population and most severely affected patients. Median annualized costs were ten times lower after treatment intensification for hematopoietic stem cell transplantation (€29,011.75 vs. €2,465.98; P<0.001), they slightly decreased after hydroxyurea initiation (€13,057.79 vs. €12,752.44; P=0.003) and were five times higher after chronic transfusion program initiation (€4,643.11 vs. €22,715.85; P<0.001). SCD still places a significant demand on health resources, even after therapeutic intensification.

Incidence, kinetics, and risk factors for intra- and extracranial cerebral arteriopathies in a newborn sickle cell disease cohort early assessed by transcranial and cervical color Doppler ultrasound.

The risk of stroke in children with sickle cell disease (SCD) is detected by abnormal intracranial arterial time-averaged mean of maximum velocities (TAMVs ≥200 cm/s). Recently, extracranial internal carotid artery (eICA) arteriopathy has been reported, and a cross-sectional study showed that eICA-TAMVs ≥160 cm/s are significantly associated with eICA kinkings and stenosis. The cumulative incidence of and predictive risk factors for intracranial arteriopathy are well described in sickle cell anemia (SCA=SS/Sß0) but are lacking for SC/Sß+ children, as is the cumulative incidence of eICA arteriopathy. We report a prospective longitudinal cohort study including 493 children with SCD (398 SCA, 95 SC/Sß+), all assessed by transcranial and cervical color Doppler ultrasound. Cerebral MRI/MRA data were available in 375 children with SCD and neck MRA in 365 children. eICA kinkings were defined as eICA tortuosities on neck MRA, with an internal acute angle between the two adjacent segments <90°. The median follow-up was 10.6 years. The cumulative incidence of kinkings was significantly lower in SC/Sß+ children than in children with SCA, and no SC/Sß+ child developed intra- or extracranial stenotic arteriopathy. The 10-year KM estimate of cumulative incidence (95% CI) for eICA-TAMVs ≥160 cm/s revealed its development in the 2nd year of life in children with SCA, reaching a plateau of 17.4% (13.2-21.6%) by about 10 years of age, while the plateau for eICA stenosis was 12.3% (8.3-16.3%). eICA assessment identified 13.5% (9.3-17.7%) patients at risk of stroke who were not detected by transcranial color Doppler ultrasound. We also show, for the first time, that in addition to a congenital origin, eICA kinkings sin patients with SCD can develop progressively with aging as a function of eICA-TAMVs, themselves related to anemia severity. Ongoing hydroxyurea treatment was significantly associated with a lower risk of abnormal intracranial arteriopathy and eICA kinkings. After adjustment with hydroxyurea, baseline low hemoglobin, high reticulocyte, and WBC counts remained independent risk factors for intracranial arteriopathy, while low hemoglobin and SEN ß-haplotype number were independent risk factors for extracranial arteriopathy. The association between extracranial arteriopathy and SEN ß-haplotype number suggested a genetic link between the ethnic origin and incidence of eICA kinkings. This prospective cohort study shows the importance of systematically assessing the eICA and of recording biological parameters during the 2nd year of life before any intensive therapy to predict the risk of cerebral arteriopathy and treat patients with severe baseline anemia.

Evolution of Extracranial Internal Carotid Artery Disease in Children With Sickle Cell Anemia.

BACKGROUND: Cerebral arteriopathy in patients with sickle cell anemia mainly affects the intracranial anterior circulation. However, the extracranial internal carotid artery (eICA) can also be stenosed and responsible for ischemic lesions. In children with sickle cell anemia, we perform routine annual Doppler ultrasound assessment of the eICA and magnetic resonance imaging with 3-dimensional time-of-flight magnetic resonance angiography of the Willis circle and neck arteries in those with abnormal velocity. Our aim was to report the evolution of eICA stenoses from 2011 to the present as a function of therapy in a retrospective case-series study. We hypothesized that chronic transfusion (CTT) would be more effective than hydroxyurea and simple observation on the evolution of eICA stenosis. METHODS: Eligibility criteria were a history of eICA velocity ≥160 cm/s with a minimum Doppler and magnetic resonance imaging follow-up of 1 year. eICAs were graded for stenosis according to NASCET (The North American Symptomatic Carotid Endarterectomy Trial). Magnetic resonance imaging was investigated for ischemic lesions. Treatment with hydroxyurea and CTT were obtained from the chart review. RESULTS: Fifty-four patients were included. Eight patients had a stroke history. The median (range) follow-up was 4.7 years (1.1-9.2 years). On the first neck magnetic resonance angiography, stenosis was present in 48/54 (89%) patients. Kinking was found in 39/54 (72%) patients. On the last neck magnetic resonance angiography, the proportion of patients with eICA stenosis decreased to 39/54 (72%). ICA occlusion occurred in 5 patients despite CTT. Three patients had carotid webs without intracranial stenosis. The proportion of patients with improvement in stenosis score was 8% with no treatment intensification, 20% with hydroxyurea, and 48% with CTT (P=0.016). The mean (SD) change per year in stenosis score was 0.40 (0.60) without intensification, 0.20 (0.53) with hydroxyurea, and -0.18 (0.55) with CTT (P=0.006). Ischemic lesions were present initially in 46% of patients, and the incidence of progressive ischemic lesions was 2.5 events/100 patient-years. Cox regression analysis showed that the initial score for eICA stenosis was a significant predictive factor for the risk of new silent cerebral infarct events. CONCLUSIONS: Our study reinforces the need to assess cervical arteries for better prevention of cerebral ischemia and encourage initiation of CTT in sickle cell anemia children with eICA stenosis.

American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation.

BACKGROUND: Sickle cell disease (SCD) is a life-limiting inherited hemoglobinopathy that results in significant complications and affects quality of life. Hematopoietic stem cell transplantation (HSCT) is currently the only curative intervention for SCD; however, guidelines are needed to inform how to apply HSCT in clinical practice. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and health professionals in their decisions about HSCT for SCD. METHODS: The multidisciplinary guideline panel formed by ASH included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews (through 2019). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 8 recommendations to help patients and providers assess how individuals with SCD should consider the timing and type of HSCT. CONCLUSIONS: The evidence review yielded no randomized controlled clinical trials for HSCT in SCD; therefore, all recommendations are based on very low certainty in the evidence. Key recommendations include considering HSCT for those with neurologic injury or recurrent acute chest syndrome at an early age and to improve nonmyeloablative regimens. Future research should include the development of a robust SCD registry to serve as a comparator for HSCT studies.

HbF-promoting polymorphisms may specifically reduce the residual risk of cerebral vasculopathy in SCA children with alpha-thalassemia.

Sickle cell anemia (SCA) is a disease characterized by abnormal red blood cell rheology. Because of their effects on HbS polymerization and red blood cell deformability, alpha-thalassemia and the residual HbF level are known genetic modifiers of the disease. The aim of our study was to determine if the number of HbF quantitative trait loci (QTL) would also favor a specific sub-phenotype of SCA as it is the case for alpha-thalassemia. Our results confirmed that alpha-thalassemia protected from cerebral vasculopathy but increased the risk for frequent painful vaso-occlusive crises. We also showed that more HbF-QTL may provide an additional and specific protection against cerebral vasculopathy but only for children with alpha-thalassemia (-α/αα or -α/-α genotypes).

Improved stenosis outcome in stroke-free sickle cell anemia children after transplantation compared to chronic transfusion.

We report here the 3-year stenosis outcome in 60 stroke-free children with sickle cell anaemia (SCA) and an abnormal transcranial Doppler history, enrolled in the DREPAGREFFE trial, which compared stem cell transplantation (SCT) with standard-care (chronic transfusion for 1-year minimum). Twenty-eight patients with matched sibling donors were transplanted, while 32 remained on standard-care. Stenosis scores were calculated after performing cerebral/cervical 3D time-of-flight magnetic resonance angiography. Fourteen patients had stenosis at enrollment, but only five SCT versus 10 standard-care patients still had stenosis at 3 years. Stenosis scores remained stable on standard-care, but significantly improved after SCT (P = 0·006). No patient developed stenosis after SCT, while two on standard-care did, indicating better stenosis prevention and improved outcome after SCT.

What is the place of hematopoietic stem cell transplantation in the management of cerebral vasculopathy in children with sickle cell anemia?

Cerebral vasculopathy is the most severe complication affecting children with sickle cell anemia. Significant progress has been made in the management of sickle cell anemia cerebral vasculopathy, including early transcranial Doppler screening, chronic transfusion, andhydroxyurea. Nevertheless, for patients with a potential matched-sibling donor (MSD), stem cell transplantation (SCT) is now the treatment offering the best cerebral vasculopathy outcome. In the absence of MSD,alternative SCT should be recommended only in those with worsening cerebral vasculopathy despite standard treatments, and should be limited to related haplo-identical SCT undertaken in controlled studies.

Extensive multilineage analysis in patients with mixed chimerism after allogeneic transplantation for sickle cell disease: insight into hematopoiesis and engraftment thresholds for gene therapy.

Although studies of mixed chimerism following hematopoietic stem cell transplantation in patients with sickle cell disease (SCD) may provide insights into the engraftment needed to correct the disease and into immunological reconstitution, an extensive multilineage analysis is lacking. We analyzed chimerism simultaneously in peripheral erythroid and granulomonocytic precursors/progenitors, highly purified B and T lymphocytes, monocytes, granulocytes and red blood cells (RBC). Thirty-four patients with mixed chimerism and ≥12 months of follow-up were included. A selective advantage of donor RBC and their progenitors/precursors led to full chimerism in mature RBC (despite partial engraftment of other lineages), and resulted in the clinical control of the disease. Six patients with donor chimerism <50% had hemolysis (reticulocytosis) and higher HbS than their donor. Four of them had donor chimerism <30%, including a patient with AA donor (hemoglobin >10 g/dL) and three with AS donors (hemoglobin <10 g/dL). However, only one vaso-occlusive crisis occurred with 68.7% HbS. Except in the patients with the lowest chimerism, the donor engraftment was lower for T cells than for the other lineages. In a context of mixed chimerism after hematopoietic stem cell transplantation for SCD, myeloid (rather than T cell) engraftment was the key efficacy criterion. Results show that myeloid chimerism as low as 30% was sufficient to prevent a vaso-occlusive crisis in transplants from an AA donor but not constantly from an AS donor. However, the correction of hemolysis requires higher donor chimerism levels (i.e ≥50%) in both AA and AS recipients. In the future, this group of patients may need a different therapeutic approach.

Long-term event-free survival, chimerism and fertility outcomes in 234 patients with sickle-cell anemia younger than 30 years after myeloablative conditioning and matched-sibling transplantation in France.

Allogeneic stem cell transplantation remains the only curative treatment for sickle cell anemia (SCA), but the place of myeloablative conditioning in the procedure remains to be defined. The aim of the present study was to analyze long-term outcomes, including chimerism, SCA-related events and biological data (hemoglobin, reticulocytes, HbS%), and fertility in a French series of 234 SCA patients under 30 years of age who, from 1988 to 2012, received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning [busulfan, cyclophosphamide and rabbit antithymocyte globulin (ATG)]. Since the first report of the series (1988-2004), 151 new consecutive patients with SCA have been similarly transplanted. Considering death, non-engraftment or rejection (donor cells <5%) as events, the 5-year event-free survival was 97.9% (95% confidence interval: 95.5-100%), confirming, since the year 2000, an at least 95% chance of cure. In the overall cohort (n=234, median follow up 7.9 years), event-free survival was not associated with age, but chronic-graft-versus-host disease (cGvHD) was independently associated with recipient's age >15 years (hazard ratio=4.37; P=0.002) and lower (5-15 vs 20 mg/kg) ATG dose (hazard ratio=4.55; P=0.001). At one year, 44% of patients had mixed chimerism (5-95% donor cells), but those prepared with ATG had no graft rejection. No events related to SCA occurred in patients with mixed chimerism, even those with 15-20% donor cells, but hemolytic anemia stigmata were observed with donor cells <50%. Myeloablative transplantation with matched-sibling donor currently has a higher event-free survival (98%) in patients under 30 years of age than that reported for non-myeloablative conditioning (88%). Nevertheless, the risk of cGvHD in older patients and the need to preserve fertility might be indications for a non-myeloablative conditioning.

Evaluation of Outcomes and Quality of Care in Children with Sickle Cell Disease Diagnosed by Newborn Screening: A Real-World Nation-Wide Study in France.

This study's objective was to assess, on a national scale, residual risks of death, major disease-related events, and quality of care during the first five years in children diagnosed at birth with sickle cell disease (SCD). Data were retrospectively collected from medical files of all children with SCD born between 2006-2010 in France. Out of 1792 eligible subjects, 1620 patients (71.8% SS or S/beta°-thalassemia -SB°-) had available follow-up data, across 69 centers. Overall probability of survival by five years was 98.9%, with 12/18 deaths related to SCD. Probability of overt stroke by five years in SS/SB° patients was 1.1%, while transcranial Doppler (TCD) was performed in 81% before three years of age. A total of 26 patients had meningitis/septicemia (pneumococcal in eight cases). Prophylactic penicillin was started at a median age of 2.2 months and 87% of children had received appropriate conjugate pneumococcal vaccination at one year. By five years, the probability of survival without SCD-related events was 10.7% for SS/SB° patients. In contrast, hydroxyurea was prescribed in 13.7% and bone marrow transplant performed in nine patients only. In this study, residual risks of severe complications were low, probably resulting from a good national TCD, vaccination, and healthcare system coverage. Nonetheless, burden of disease remained high, stressing the need for disease-modifying or curative therapy.

Serum Immunoglobulin Levels in Children with Sickle Cell Disease: A Large Prospective Study.

Over the past 3 decades, the pediatric department of the university Intercommunal Créteil hospital, a referral center for sickle cell disease (SCD), has prospectively evaluated immunoglobulin (Ig) levels in a cohort of 888 children with SCD, including 731 with severe sickle genotypes (HbSS and HbSß0 thalassemia) and 157 with milder genotypes (HbSC and HbSß+ thalassemia). We found consistent sickle genotype differences in levels of IgG and IgA, with increased levels of IgA and IgG in the severe versus milder genotype, from early childhood to late adolescence. Additionally, our results revealed a low serum IgM level, irrespective of sickle genotype. Finally, we found that IgA and IgG levels were significantly increased after therapeutic intensification with hydroxyurea but were stabilized in children receiving a transfusion program. The mechanisms contributing to these changes in Ig levels are unclear as is their clinical significance. We believe they should be further investigated.

Why, Who, When, and How? Rationale for Considering Allogeneic Stem Cell Transplantation in Children with Sickle Cell Disease.

Considering the progress made in the management of sickle cell disease during the past 30 years, along with the excellent results obtained with hematopoietic stem cell transplantation (SCT), it is important to reexamine why, who, when and how to recommend allogeneic SCT in children with sickle cell disease. While sickle cell disease has a low risk of death in children and a high risk for morbidity during aging, SCT carries an early risk of death, graft-vs-host disease and infertility. Nevertheless, SCT offers at least 95% chance of cure with low risk of chronic graft-vs-host disease when a matched-sibling donor is available and the risks of infertility can be reduced by ovarian, sperm or testis cryopreservation. Thus, all available therapies such as hydroxyurea, transfusions and SCT should be presented to the parents, providers, and affected children and discussed with them from infancy. Furthermore, the use of these therapies should be adjusted to the severity of the disease and to local availabilities in order to choose the treatment offering the best benefit/risk ratio.

Effect of donor type and conditioning regimen intensity on allogeneic transplantation outcomes in patients with sickle cell disease: a retrospective multicentre, cohort study.

BACKGROUND: Donors other than matched siblings and low-intensity conditioning regimens are increasingly used in haematopoietic stem cell transplantation. We aimed to compare the relative risk of donor type and conditioning regimen intensity on the transplantation outcomes of in patients with sickle cell disease. METHODS: For this retrospective cohort study, we collected data from 90 US centres reported to the Center for International Blood and Marrow Transplant Research. Eligible patients were younger than 50 years, had genetically confirmed sickle cell disease (Hb SS) or sickle beta thalassemia (Hb Sß), and underwent allogeneic haematopoietic cell transplantation between Jan 15, 2008, and Dec 28, 2017. We considered transplants from donor-recipient pairs matched at the allele-level (HLA-A, HLA-B, HLA-C, and HLA-DRB1), including HLA-matched sibling donors, haploidentical related donors, matched unrelated donors, or mismatched unrelated donors. The main outcome was event-free survival. The effect of donor type, conditioning regimen intensity (myeloablative, non-myeloablative, and reduced-intensity regimens), age (≤12 or 13-49 years), sex, performance score, comorbidity index, recipient cytomegalovirus serostatus, graft type (bone marrow, peripheral blood, or umbilical cord blood), and transplantation period (2008-12 and 2013-17) on outcomes was studied using Cox regression models. FINDINGS: Of 996 patients with sickle cell disease and who underwent transplantation in 2008-17, 910 (91%) were included (558 [61%] patients had HLA-matched sibling donors, 137 [15%] haploidentical related donors, 111 [12%] matched unrelated donors, and 104 [11%] mismatched unrelated donors). The median follow-up was 36 months (IQR 18-60) after transplantation from HLA-matched siblings, 25 months (12-48) after transplantation from haploidentical related donors, 37 months (23-60) after transplantation from HLA-matched unrelated donors, and 47 months (24-72) after transplantation from mismatched unrelated donors. Event-free survival was worse in recipients aged 13 years or older than in those younger than 13 years (hazard ratio 1·74, 95% CI 1·24-2·45; p=0·0014) and in those who received a transplant from haploidentical related donors (5·30, 3·17-8·86; p<0·0001), matched unrelated donors (3·71, 2·39-5·75; p<0·0001), and mismatched unrelated donors (4·34, 2·58-7·32; p<0·0001) than in patients who received a transplant from matched siblings. There was no significant difference in event-free survival between recipients of transplants from non-sibling donors: haploidentical related donors (1·43, 0·81-2·50; p=0·21) or mismatched unrelated donors (1·17, 0·67-2·05; p=0·58) versus HLA-matched unrelated donors, or mismatched unrelated donors versus haploidentical related donors (1·22, 0·65-2·27; p=0·98). Event-free survival was also worse in patients conditioned with reduced-intensity regimens (1·97, 1·15-3·36; p=0·013) than in those conditioned with non-myeloablative regimens, but did not differ between those who received myeloablative compared with non-myeloablative regimens (1·57, 0·95-2·61; p=0·079). Interpretation Our data suggest that event-free survival is improved in patients with sickle cell disease who receive an allogenic transplantation at age 12 years or younger and those with an HLA-matched sibling donor. For patients without a matched sibling available for transplantation, our data do not favour one alternative donor type over another in this setting. FUNDING: National Institutes of Health and US Health Services Research Administration, Department of Health and Human Services.

Ovarian tissue cryopreservation for fertility preservation in 418 girls and adolescents up to 15 years of age facing highly gonadotoxic treatment. Twenty years of experience at a single center.

INTRODUCTION: The preservation of fertility is an integral part of care of children requiring gonadotoxic treatments for cancer or non-malignant diseases. In France, the cryopreservation of ovarian tissue has been considered and has been offered as a clinical treatment since its inception. The aim of this study is to review 20 years of activity in fertility preservation by ovarian tissue cryopreservation (OTC) for children and the feasibility of oocyte isolation and cryopreservation from the ovarian tissue at a single center. MATERIAL AND METHODS: Retrospective study including patients aged 15 years or younger who underwent OTC, combined for some with oocyte cryopreservation of isolated oocytes, before a highly gonadotoxic treatment for malignant or non-malignant disease was initiated. We describe the evolution of activities in our program for fertility preservation and patient characteristics at the time of OTC and follow up. RESULTS: From April 1998 to December 2018, 418 girls and adolescents younger than 15 years of age underwent OTC, representing 40.5% of all females who have had ovarian tissue cryopreserved at our center. In all, 313 patients had malignant diseases and 105 had benign conditions. Between November 2009 and July 2013, oocytes were isolated and also cryopreserved in 50 cases. The mean age of patients was 6.9 years (range 0.3-15). The most frequent diagnoses in this cohort included neuroblastoma, acute leukemia and hemoglobinopathies; neuroblastoma being the most common diagnosis in very young patients. During follow up, three patients requested the use of their cryopreserved ovarian tissue. All had undergone ovarian tissue transplantation, one for puberty induction and the two others for restoring fertility. So far, no pregnancies have been achieved. Eighty-four patients who had OTC died. CONCLUSIONS: Ovarian tissue cryopreservation is the only available technique for preserving fertility of girls. To our knowledge this is the largest series of girls and adolescents younger than 15 years so far reported on procedures of OTC before highly gonadotoxic treatment in a single center.

Hematopoietic stem cell transplantation in children with sickle cell anemia: The parents' experience.

Genoidentical HSCT is currently the only curative treatment for SCA, preventing further vascular complications in high-risk children. Studies on the psychological implications of HSCT for recipient, sibling donor, and the rest of the family have been limited in SCA. This study enrolled ten families and used semi-structured interviews to explore the parents' experience at three time points: first before transplantation, then 3 months later, and 1 year later. Three themes emerged from the results: (a) the presence of anxiety, experienced throughout the process, and alleviated by coping strategies (positive thinking, family support, praying); (b) the ability to remain parents to recipient and other family members, despite apprehension and feelings of helplessness, reinforced by the mobilization of important resources at the individual/family levels; (c) the ability to acknowledge the opportunity for their child to be cured of the disease, despite feelings of guilt toward families without a donor, or their own families back home. Overall, the parental experience with HSCT is complex, involving intra-psychic, familial, cultural, religious, and existential factors. Thus, it is important for medical teams to be cognizant of these issues in order to provide the best support to families during the HSCT process.