A 20-year overview of fertility preservation in boys: new insights gained through a comprehensive international survey.

STUDY QUESTION: Twenty years after the inception of the first fertility preservation programme for pre-pubertal boys, what are the current international practices with regard to cryopreservation of immature testicular tissue? SUMMARY ANSWER: Worldwide, testicular tissue has been cryopreserved from over 3000 boys under the age of 18 years for a variety of malignant and non-malignant indications; there is variability in practices related to eligibility, clinical assessment, storage, and funding. WHAT IS KNOWN ALREADY: For male patients receiving gonadotoxic treatment prior to puberty, testicular tissue cryopreservation may provide a method of fertility preservation. While this technique remains experimental, an increasing number of centres worldwide are cryopreserving immature testicular tissue and are approaching clinical application of methods to use this stored tissue to restore fertility. As such, standards for quality assurance and clinical care in preserving immature testicular tissue should be established. STUDY DESIGN SIZE DURATION: A detailed survey was sent to 17 centres within the recently established ORCHID-NET consortium, which offer testicular tissue cryopreservation to patients under the age of 18 years. The study encompassed 60 questions and remained open from 1 July to 1 November 2022. PARTICIPANTS/MATERIALS SETTING METHODS: Of the 17 invited centres, 16 completed the survey, with representation from Europe, Australia, and the USA. Collectively, these centres have cryopreserved testicular tissue from patients under the age of 18 years. Data are presented using descriptive analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Since the establishment of the first formal fertility preservation programme for pre-pubertal males in 2002, these 16 centres have cryopreserved tissue from 3118 patients under the age of 18 years, with both malignant (60.4%) and non-malignant (39.6%) diagnoses. All centres perform unilateral biopsies, while 6/16 sometimes perform bilateral biopsies. When cryopreserving tissue, 9/16 centres preserve fragments sized ≤5 mm3 with the remainder preserving fragments sized 6-20 mm3. Dimethylsulphoxide is commonly used as a cryoprotectant, with medium supplements varying across centres. There are variations in funding source, storage duration, and follow-up practice. Research, with consent, is conducted on stored tissue in 13/16 centres. LIMITATIONS REASONS FOR CAUTION: While this is a multi-national study, it will not encompass every centre worldwide that is cryopreserving testicular tissue from males under 18 years of age. As such, it is likely that the actual number of patients is even higher than we report. Whilst the study is likely to reflect global practice overall, it will not provide a complete picture of practices in every centre. WIDER IMPLICATIONS OF THE FINDINGS: Given the research advances, it is reasonable to suggest that cryopreserved immature testicular tissue will in the future be used clinically to restore fertility. The growing number of patients undergoing this procedure necessitates collaboration between centres to better harmonize clinical and research protocols evaluating tissue function and clinical outcomes in these patients. STUDY FUNDING/COMPETING INTERESTS: K.D. is supported by a CRUK grant (C157/A25193). R.T.M. is supported by an UK Research and Innovation (UKRI) Future Leaders Fellowship (MR/S017151/1). The MRC Centre for Reproductive Health at the University of Edinburgh is supported by MRC (MR/N022556/1). C.L.M. is funded by Kika86 and ZonMW TAS 116003002. A.M.M.v.P. is supported by ZonMW TAS 116003002. E.G. was supported by the Research Program of the Research Foundation-Flanders (G.0109.18N), Kom op tegen Kanker, the Strategic Research Program (VUB_SRP89), and the Scientific Fund Willy Gepts. J.-B.S. is supported by the Swedish Childhood Cancer Foundation (TJ2020-0026). The work of NORDFERTIL is supported by the Swedish Childhood Cancer Foundation (PR2019-0123; PR2022-0115), the Swedish Research Council (2018-03094; 2021-02107), and the Birgitta and Carl-Axel Rydbeck's Research Grant for Paediatric Research (2020-00348; 2021-00073; 2022-00317; 2023-00353). C.E is supported by the Health Department of the Basque Government (Grants 2019111068 and 2022111067) and Inocente Inocente Foundation (FII22/001). M.P.R. is funded by a Medical Research Council Centre for Reproductive Health Grant No: MR/N022556/1. A.F. and N.R. received support from a French national research grant PHRC No. 2008/071/HP obtained by the French Institute of Cancer and the French Healthcare Organization. K.E.O. is funded by the University of Pittsburgh Medical Center and the US National Institutes of Health HD100197. V.B-L is supported by the French National Institute of Cancer (Grant Seq21-026). Y.J. is supported by the Royal Children's Hospital Foundation and a Medical Research Future Fund MRFAR000308. E.G., N.N., S.S., C.L.M., A.M.M.v.P., C.E., R.T.M., K.D., M.P.R. are members of COST Action CA20119 (ANDRONET) supported by COST (European Cooperation in Science and Technology). The Danish Child Cancer Foundation is also thanked for financial support (C.Y.A.). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

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.

A 10-year experience in testicular tissue cryopreservation for boys under 18 years of age: What can be learned from 350 cases?

BACKGROUND: A growing number of centers worldwide are preserving testicular tissue (TT) of young boys at risk of fertility loss to preserve their fertility. Data in this regard are scarce and experience sharing is essential to the optimization of the process. OBJECTIVES: This report of our 10-year activity of pediatric fertility preservation (FP) has the objective to (1) improve knowledge regarding the feasibility, acceptability, safety, and potential usefulness of the procedure; (2) analyze the impact of chemotherapy on spermatogonia in the cryopreserved TT. MATERIALS AND METHODS: For this retrospective study of data prospectively recorded, we included all boys under 18 years of age referred to the FP consultation of our academic network between October 2009 and December 2019. Characteristics of patients and cryopreservation of testicular tissue (CTT) were extracted from the clinical database. Univariate and multivariate analyses were used to assess factors associated with the risk of absence of spermatogonia in the TT. RESULTS: Three hundred and sixty-nine patients (7.2 years; 0.5-17.0) were referred to the FP consultation for malignant (70%) or non-malignant (30%) disease, of whom 88% were candidates for CTT, after a previous chemotherapy exposure (78%). The rate of recorded immediate adverse events was 3.5%, with painful episodes dominating. Spermatogonia were detected in the majority of TTs: 91.1% of those exposed to chemotherapy and 92.3% of those not exposed (p = 0.962). In multivariate analysis, the risk of absence of spermatogonia was almost three-fold higher in boys > 10 years of age ([OR] 2.74, 95% CI 1.09-7.26, p = 0.035) and four-fold higher in boys exposed to alkylating agents prior to CTT ([OR] 4.09, 95% CI 1.32-17.94, p = 0.028). DISCUSSION/CONCLUSION: This large series of pediatric FP shows that this procedure is well accepted, feasible, and safe in the short term, strengthening its place in the clinical care pathway of young patients requiring a highly gonadotoxic treatment. Our results demonstrate that CTT post-chemotherapy does not impair the chance to preserve spermatogonia in the TT except when the treatment includes alkylating agents. More data on post-CTT follow-up are still required to ensure the long-term safety and usefulness of the procedure.

Factors associated with the collection of isolated immature oocytes during ovarian tissue cryopreservation.

PURPOSE: To identify patient characteristics associated with successful isolated immature oocyte retrieval (IsO) during ovarian tissue cryopreservation (OTC) and to determine whether they are predictive of the collection of larger numbers of oocytes. METHODS: We retrospectively analyzed all patients undergoing OTC with IsO for fertility preservation over three years of activity at a university hospital. Univariate and multivariate analyses were used to identify the patients with the highest and lowest chances of oocyte recovery, and those with the largest numbers of oocytes. We also analyzed the correlation of IsO with the number of ovarian fragments collected and histological parameters. RESULTS: We analyzed 257 consecutive patients undergoing these procedures, at a median age of 17.1 years [0.3-38.3 years]. Isolated oocytes were obtained from 47.1% of patients, and IsO was more likely in patients with ovulatory cycles (63.0% vs. 38.6%; P≤ .001), without chemotherapy before OTC (61.4% vs. 33.1; P< .001) and with non-malignant diseases other than Turner syndrome (77.5%). Oocyte collection failure rates were highest in patients with Turner syndrome (OR 25.0, 95% CI 3.99-157.0; P< .001) or undergoing chemotherapy with alkylating agents before OTC (OR 37.6, 95% CI 8.36-168.8; P< .001). Prepubescent status (P= .043) and large numbers of ovarian fragments (P< .001) were associated with the retrieval of larger numbers of oocytes. Oocyte recovery was correlated with the presence of follicles in the medulla, but not with follicular density. CONCLUSION: The chances of IsO differ between patients. Identifying patients with the highest chances of success facilitates appropriate resource allocation.

[Restatement. Cancer and fertility preservation]. / Mise au point. Cancer et préservation de la fertilité.

CANCER AND FERTILITY PRESERVATION. The integration of fertility preservation into the treatment pathway is a major issue for quality of life after cancer, particularly for very young children, adolescents and young adults. Responses must be adapted to age, gender and treatment. The recommendations of the French National Cancer Institute (INCa) aim to promote information on the risks of different treatments for fertility and on the possibilities of preserving fertility, in order to allow an informed choice, and to improve the quality of the medical service rendered in order to reduce inequalities in care. Referral to a center specialized in fertility preservation is sometimes recommended, so that a technique adapted to the patient's situation can be implemented before treatment begins.

CANCER ET PRÉSERVATION DE LA FERTILITÉ. L'intégration de la préservation de la fertilité dans le parcours de soins est un enjeu majeur pour la qualité de vie après cancer, en particulier pour les très jeunes enfants, les adolescents et les jeunes adultes. Les réponses doivent être adaptées à l'âge, au sexe et au traitement. Les recommandations de l'Institut national du cancer (INCa) visent à favoriser l'information sur les risques des différents traitements vis-à-vis de la fertilité et sur les possibilités de la préserver, pour permettre un choix éclairé, et d'améliorer la qualité du service médical rendu afin de réduire les inégalités de soins. L'orientation vers un centre spécialisé dans la préservation de la fertilité est parfois préconisée, afin qu'une technique adaptée à la situation du patient puisse être mise en oeuvre avant le début des traitements.

The uterine volume is dramatically decreased after hematopoietic stem cell transplantation during childhood regardless of the conditioning regimen.

OBJECTIVE: To study the impact of hematopoietic stem cell transplantation (HSCT) on the uterine volume of childhood acute leukemia (AL) survivor depending on age at HSCT and the type of myeloablative conditioning regimen. SETTING: Thirteen French University Teaching Hospitals. DESIGN: Prospective cohort study. PATIENT(S): Eighty-eight women who underwent HSCT during childhood or adolescence for AL compared to a control group. INTERVENTION(S): A multicentric prospective national study compared the uterine volume in a cohort of childhood AL survivor adult women treated with HSCT, matched 1:1 to control women. Pelvic magnetic resonance imaging scans included diffusion-weighted imaging sequences. Scans were centralized for a double-blinded reading by 2 radiologists. MAIN OUTCOME MEASURE(S): Uterine volume, uterine body-to-cervix ratio, and apparent diffusion coefficient. RESULT(S): The mean age at HSCT was 9.1 ± 0.3 years with a mean follow-up duration of 16.4 ± 0.5 years. The cohort of 88 HSCT survivor women was composed of 2 subgroups depending on the myeloablative conditioning regimen received: an alkylating agent-based regimen group (n = 34) and a total body irradiation (TBI)-based regimen group (n = 54). Among the 88 women, 77 were considered as having a "correct hormonal balance" with estrogens supplied by hormone replacement therapy (HRT) for premature ovarian insufficiency (POI) or because of a residual ovarian function. In the control group (n = 88), the mean uterine volume was 79.7 ± 3.3 mL. The uterine volume significantly decreased in all HSCT survivor women. After the alkylating agent-based regimen, the uterine volume was 45.3 ± 5.6 mL, corresponding to a significant volume reduction of 43.1% (28.8-57.4%) compared with that of the control group. After TBI, the uterine volume was 19.6 ± 1.9 mL, corresponding to a significant volume reduction of 75.3% (70.5%-80.2%) compared with that of the control group. After the alkylating agent-based regimen, the uterine volume dramatically decreased in women with POI without HRT compared with that in those with a correct hormonal balance (15.2 ± 2.6 vs. 49.3 ± 6 mL). In contrast, after TBI, the uterine volume was similar in all women, with no positive effect of hormonal impregnation on the uterine volume (16.3 ± 2.6 vs. 20.1 ± 2.2 mL, respectively). CONCLUSION(S): The uterine volume was diminished after HSCT, regardless of the conditioning regimen. The physiopathology needs to be further investigated: specific impact of a high dose of an alkylating agent; impact of hormone deprivation around puberty; poor compliance to HRT; or different myometrial impact of HRT compared with endogenous ovarian estrogens? CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov/NCT03583294 (enrollment of the first subject, November 11, 2017; enrollment of the last subject, June 25, 2021).

What should be done in terms of fertility preservation for patients with cancer? The French 2021 guidelines.

AIM: To provide practice guidelines about fertility preservation (FP) in oncology. METHODS: We selected 400 articles after a PubMed review of the literature (1987-2019). RECOMMENDATIONS: Any child, adolescent and adult of reproductive age should be informed about the risk of treatment gonadotoxicity. In women, systematically proposed FP counselling between 15 and 38 years of age in case of treatment including bifunctional alkylating agents, above 6 g/m2 cyclophosphamide equivalent dose (CED), and for radiation doses on the ovaries ≥3 Gy. For postmenarchal patients, oocyte cryopreservation after ovarian stimulation is the first-line FP technique. Ovarian tissue cryopreservation should be discussed as a first-line approach in case of treatment with a high gonadotoxic risk, when chemotherapy has already started and in urgent cases. Ovarian transposition is to be discussed prior to pelvic radiotherapy involving a high risk of premature ovarian failure. For prepubertal girls, ovarian tissue cryopreservation should be proposed in the case of treatment with a high gonadotoxic risk. In pubertal males, sperm cryopreservation must be systematically offered to any male who is to undergo cancer treatment, regardless of toxicity. Testicular tissue cryopreservation must be proposed in males unable to cryopreserve sperm who are to undergo a treatment with intermediate or severe risk of gonadotoxicity. In prepubertal boys, testicular tissue preservation is: - recommended for chemotherapy with a CED ≥7500 mg/m2 or radiotherapy ≥3 Gy on both testicles. - proposed for chemotherapy with a CED ≥5.000 mg/m2 or radiotherapy ≥2 Gy. If several possible strategies, the ultimate choice is made by the patient.

Sexual and Emotional Health after Allogeneic Hematopoietic Cell Transplantation: A Comprehensive Review and Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC).

A person's sexual and emotional life is greatly impacted after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This topic is not addressed very much by patients and caregivers. Physical, endocrine and genital chronic graft versus host disease (cGVHD)-related disorders are multiple and intertwined with psychological disorders. The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) has issued recommendations for a better gynecological monitoring of female recipients after allo-HCT. A patient booklet was also offered to patients in the form of questions and answers to facilitate discussions between patients and caregivers and to improve the management of sexual and emotional life after transplant.

Impact of the COVID-19 pandemic on fertility preservation activities in France: A survey by the Groupe de Recherche et d'Etude sur la Conservation Ovarienne et Testiculaire (GRECOT; group for research and studies on ovarian and testicular preservation).

BACKGROUND: To study the repercussions of the COVID-19 pandemic for fertility preservation activities in France. BASIC PROCEDURES: A questionnaire was sent to all the fertility preservation centres, requesting, for fertility preservation techniques (gamete and gonadal tissue preservation), the number of patients managed before, during and after the lockdown, and the number of patients who were not able to have access to these techniques and thus suffered definitive losses of fertility, during the lockdown period in spring 2020. MAIN FINDINGS: Fertility preservation activities in France did not cease entirely during the lockdown, but a 42.6% decrease in activity was observed. After lockdown, the levels of sperm, testicular and ovarian tissue cryopreservation returned to pre-lockdown levels (95.2%). The restoration of activity was partial only for oocyte freezing, which reached a level 56.8% that before lockdown. In total, 45 patients (8.35%) lost all chance of fertility preservation during the lockdown period. PRINCIPAL CONCLUSIONS: In France, fertility preservation activities were significantly affected by the lockdown in spring 2020 linked to the COVID-19 pandemic.

Minimal residual disease detection by multicolor flow cytometry in cryopreserved ovarian tissue from leukemia patients.

BACKGROUND: Cryopreservation of ovarian tissue is a fertility-preservation option for women before gonadotoxic treatments. However, cryopreserved ovarian tissue transplantation must be performed with caution in women with malignancies that may metastasize to the ovaries. For this purpose, detecting minimal residual disease (MRD) in the ovarian cortex using sensitive methods is a crucial step. We developed an automated ovarian tissue dissociation method to obtain ovarian cell suspensions. RESULTS: We assessed MRD by multicolor flow cytometry (MFC) in cryopreserved ovarian cortex of 15 leukemia patients: 6 with B-cell acute lymphoblastic leukemia (B-ALL), 2 with T-cell acute lymphoblastic leukemia (T-ALL) and 7 with acute myeloid leukemia (AML). Ovarian MRD was positive in 5 of the 15 leukemia patients (one T-ALL and 4 AML). No B-ALL patient was positive by MFC. Quantitative reverse-transcribed polymerase chain reaction was performed when a molecular marker was available, and confirmed the MFC results for 3 patients tested. Xenografts into immunodeficient mice were also performed with ovarian cortical tissue from 10 leukemia patients, with no evidence of leukemic cells after the 6-month grafting period. CONCLUSIONS: In conclusion, this is the first study using MFC to detect MRD in ovarian cortical tissue from acute leukemia patients. MFC has been accepted in clinical practice for its ease of use, the large number of parameters available simultaneously, and high throughput analysis. We demonstrate here that MFC is a reliable method to detect MRD in cryopreserved ovarian tissue, with a view to controlling the oncological risk before ovarian tissue transplantation in leukemia 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.

Semen Cryopreservation in Adolescents and Young Adults with Hematologic Diseases: from Bed to Benchside.

Purpose: Infertility in adolescents and young adult (AYA) survivors of malignant disease remains a major long-term adverse effect, but semen collection for fertility preservation in fertility centers is not always feasible and makes AYAs uncomfortable. We evaluated the feasibility of collecting sperm samples on the ward versus in fertility centers. Methods: Consecutive hospitalized AYA-aged male patients in the Hematology AYA unit (Saint-Louis Hospital, France) between August 2010 and June 2016 with hematological disease and indication of semen collection (n = 95) were included in this retrospective study. Semen quality was analyzed according to World Health Organization guidelines and was compared according to semen collection place: on the ward (n = 46) or in fertility center (n = 49). Results: The median age was median age 19.1 years (range: 13.7-33.3; interquartile range: 17.1-22.8) and 85 patients successfully collected semen. Sperm collection failure was ∼11% and was comparable between the two modalities as were main sperm quality characteristics (semen volume, sperm concentration, total sperm count, progressive motility and vitality, sperm morphology, and multiple anomalies index). Oligospermia was significantly higher in the samples obtained in fertility center (47.7%) than on the ward (26.8%), p = 0.047. Average frozen straws were comparable, 12.2 ± 6.4 on the ward versus 11.9 ± 6.3 in fertility center. Conclusion: Semen collection on the ward is feasible and would be particularly interesting for AYA male patients without altering semen quality characteristics.

Fertility Preservation: How to Preserve Ovarian Function in Children, Adolescents and Adults.

Chemotherapy, pelvic radiotherapy and ovarian surgery have known gonadotoxic effects that can lead to endocrine dysfunction, cessation of ovarian endocrine activity and early depletion of the ovarian reserve, causing a risk for future fertility problems, even in children. Important determinants of this risk are the patient's age and ovarian reserve, type of treatment and dose. When the risk of premature ovarian insufficiency is high, fertility preservation strategies must be offered to the patient. Furthermore, fertility preservation may sometimes be needed in conditions other than cancer, such as in non-malignant diseases or in patients seeking fertility preservation for personal reasons. Oocyte and/or embryo vitrification and ovarian tissue cryopreservation are the two methods currently endorsed by the American Society for Reproductive Medicine, yielding encouraging results in terms of pregnancy and live birth rates. The choice of one technique above the other depends mostly on the age and pubertal status of the patient, and personal and medical circumstances. This review focuses on the available fertility preservation techniques, their appropriateness according to patient age and their efficacy in terms of pregnancy and live birth rates.

Transplantation of cryopreserved ovarian tissue in a series of 285 women: a review of five leading European centers.

The feasibility of freezing and thawing ovarian tissue is nowadays widely documented. However, ovarian tissue transplantation (OTT) is happening at a much slower pace, and clinical experience is somewhat limited. In this review, five European centers present their collective experience of transplanting ovarian tissue in 285 women. The focus is on surgical techniques and OTT outcomes, reproductive outcomes, the impact of chemotherapy before ovarian tissue cryopreservation (OTC), the risk of relapse, and endocrine resumption and longevity of transplanted tissue. The risk of relapse due to reimplantation of ovarian tissue appears to be very low according to current data. Recovery of endocrine function is seen in almost all women undergoing transplantation of ovarian tissue, and about one in four gives birth to a healthy child. The efficacy of in vitro fertilization in these patients is not very high, however, and needs to be substantially improved. Radiation to the pelvis, especially with relatively high doses, appears to considerably decrease the likelihood of a successful pregnancy and may be contraindicated. Our results demonstrate that chemotherapy before OTC does not impair the chances of success, depending, of course, on the total dose and type of chemotherapy administered. At this early stage of development of OTT for restoration of fertility, the results are encouraging and demonstrate clear potential. However, the method is far from being fully developed and requires continued research efforts to optimize our approach.

Sexuality- and Fertility-Related Issues in Women after Allogeneic Hematopoietic Stem Cell Transplantation.

Sexual dysfunction and fertility related issues appear as major post-allogeneic hematopoietic stem cell transplantation (HSCT) late effects in young women, with a heavy impact on quality of life. The objective of the present study was to evaluate the impact of disease and treatments on sexual quality of life, ovarian function, and family planning initiatives in the context of allogeneic HSCT. Between January 2014 and January 2016, adult female patients who underwent HSCT before age 35 and had been followed for more than 2 years in our center were offered participation in the study through a self-reported survey and/or ovarian function assessment if age <40 at inclusion. A total of 63 patients were included, with a median age of 23.4 years at transplantation and 30.9 years at inclusion. Twenty-nine patients (46%) underwent HSCT for acute leukemia and 16 (25%) underwent HSCT for aplastic anemia (AA). The conditioning regimen was myeloablative conditioning (MAC) in 37 patients (59%) and reduced-intensity conditioning (RIC) in 26 (41%). Fifty-eight patients completed the survey, and 34 were evaluated for ovarian function. Symptoms of hypoestrogenism were reported by 86% of the patients and changes in sexual life were reported by 76%, due mainly to low sex drive, negative impact of infertility problems, physical sequelae, and loss of self-confidence. Premature ovarian failure (POF) occurred in 74% of patients and was significantly associated with conditioning regimen (MAC versus RIC; P = .001) and baseline disease (bone marrow failure versus acute leukemia versus others; P < .001). However, one-half of the patients developed a POF despite the use of a RIC regimen. For 27 patients (47%), disease and treatments modified their desire for pregnancy, due mainly to fear of relapse and of disease transmission to offspring. Thirteen pregnancies were reported (21%), of which 8 were spontaneous and 5 were obtained through assisted reproductive technologies, mainly oocyte donation. With a median post-transplantation follow-up of 12.2 years, the 10-year cumulative incidence of first pregnancy was 16.6% (95% CI, 8.8-30.0). Among 20 patients (32%) who engaged in a family planning initiative, 13 (65%) succeeded in having children: 11 got pregnant and 2 adopted. Sixteen patients benefited from fertility preservation techniques consisting of ovarian tissue cryopreservation, and a single autologous ovarian tissue transplantation had been performed at the time of this report. This study shows a strong impact of disease and treatments on sexual quality of life, ovarian function, and family planning initiatives in the context of HSCT. It demonstrates the need to improve clinicians' awareness of sexual health- and fertility-related issues after HSCT. The difficulty of predicting ovarian function and fertility issues after RIC supports wide indications of pretransplantation fertility preservation. Evaluation of the use of cryopreserved ovarian tissues is warranted.

Can Some Anticancer Treatments Preserve the Ovarian Reserve?

BACKGROUND: Preventing premature ovarian failure (POF) is a major challenge in oncology. With conventional regimens, cytotoxicity-associated POF involves primordial follicles (PF) pool depletion by apoptosis or overactivation mechanisms, notably mediated by the ABL/TAp63 and PI3K/Akt/mTOR pathways. New anticancer treatments have been designed to target pathways implicated in tumor growth. Although concerns regarding fertility arise with these targeted therapies, we hypothesized that targeted therapies may exert off-tumor effects on PF that might delay POF. We provide an overview of evidence concerning these off-tumor effects on PF. Limitations and future potential implications of these findings are discussed. DESIGN: PubMed was searched by combining Boolean operators with the following keywords: fertility, ovarian, follicle, anti-tumoral, cancer, targeted, cytotoxic, and chemotherapy. RESULTS: Cisplatin-related PF apoptosis via the ABL/TAp63 pathway was targeted with a tyrosine kinase inhibitor, imatinib, in mice, but effects were recently challenged by findings on human ovarian xenografts in mice. In cyclophosphamide-treated mice, PI3K/Akt/mTOR pathway inhibition with mTOR inhibitors and AS101 preserved the PF pool. Proteasome and GSK3 inhibitors were evaluated for direct and indirect follicle DNA damage prevention. Surprisingly, evidence for cytotoxic drug association with PF pool preservation was found. We also describe selected non-anticancer molecules that may minimize gonadotoxicity. CONCLUSION: Not all anticancer treatments are associated with POF, particularly since the advent of targeted therapies. The feasibility of associating a protective drug targeting PF exhaustion mechanisms with cytotoxic treatments should be evaluated, as a way of decreasing the need for conventional fertility preservation techniques. Further evaluations are required for transfer into clinical practice. IMPLICATIONS FOR PRACTICE: Anticancer therapies are associated with infertility in 10%-70% of patients, which is the result of primordial follicles pool depletion. Alone or associated with gonadotoxic treatments, some targeted therapies may exert favorable off-targets effects on the primordial follicle pool by slowing down their exhaustion. Current evidence of these effects relies on murine models or human in vitro models. Evaluation of these protective strategies in humans is challenging; however, if these results are confirmed with clinical and biological data, it not only could be a new approach to female fertility preservation but also would change standard fertility strategies.

[Sexual and emotional life after allogeneic hematopoietic stem cell transplant: Guidelines and patient booklet from the Francophone Society of Bone marrow Transplant and Cellular therapy (SFGM-TC)]. / Vie sexuelle et affective après allogreffe de cellules souches hématopoïétiques : recommandations et livret patient de la SFGM-TC (Société francophone de greffe de moelle et de thérapie cellulaire).

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organises annual workshops in an attempt to harmonise clinical practices among different francophone transplantation centres. The SFGM-TC harmonisation workshops aim at establishing practical guidelines, on the one hand, from data from the literature and international recommendations and, on the other hand, by consensus in the absence of formally proven data. The sexual and emotional life of allogeneic hematopoietic stem cells transplanted (HSCT) patients is often very impacted and remains a subject relatively little addressed by patients and caregivers. This article is an update from a previous workshop and is accompanied by a patient booklet, which will be included in the post allograft follow-up workbook published by the SFGM-TC. The purpose of these two documents is to facilitate discussions between patients and caregivers on the subject and to present proposals for follow-up and tools to better manage the sexual and emotional life of allotransplanted patients.

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.