Pregnancy and pregnancy outcomes after hematopoietic stem cell transplantation in childhood: a cross-sectional survey of the EBMT Pediatric Diseases Working Party.

STUDY QUESTION: What are the characteristics of patients with conceptions transplanted in childhood and adolescence? SUMMARY ANSWER: Insemination and conception after hematopoietic stem cell transplantation (HCT) in childhood or adolescence was possible, even after myeloablative conditioning regimes, although some patients required reproductive medicine support. WHAT IS KNOWN ALREADY: Preparative regimens of HCT are highly gonadotoxic, which leads to gonadal failure and pubertal development disorders. There are few population-based studies assessing the risk of future infertility in children after HCT. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective study to investigate natural or assisted conceptions and their outcomes in patients <18 years old before their first transplantation who received HCT between 1995 and 2016 and were in the European Society for Blood and Marrow Transplantation (EBMT) registry. Adoptions were excluded from the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Detailed information concerning pregnancy occurrences and outcomes were obtained by a separate questionnaire. Quantitative variables were presented as medians with their interquartile range (IQR) or range, and categorical variables were presented as frequencies and percentages. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 62 988 pediatric patients received a first HCT in EBMT centers between 1995 and 2016. Pregnancy was reported in 406 patients in the database. The median age at transplantation was 15.7 (range: 0.7-18) years, and the median age at declared conception was 25.0 (range: 16.3-38.8) years. Details concerning the first pregnancy and pregnancy outcome were obtained from 99 patients (24%) from the returned questionnaires. The median age at delivery or pregnancy interruption of the females was 23.0 (IQR: 20.8-27) years, with a median time after transplant of 10.7 (IQR: 6.6-15.4) years. Compared with the mean age of healthy women at their first child's birth (29 years old), the transplanted women delivered 5 years earlier (mean: 24.3 years). In terms of conception modality, 13/25 (52%) females conditioned with total body irradiation (TBI) and 50/52 (96%) of those conditioned without TBI conceived naturally. All seven male patients who had been conditioned with TBI achieved fatherhood but required assisted fertilization or used their cryopreserved sperm. In the females, 63/70 (90%) of all conceptions resulted in a live birth, 49/63 (84.5%) were at term and 43/46 (93%) had normal birthweight. Cesarean delivery was performed in 9/61 (15%) especially in women who had received a myeloablative regimen. LIMITATIONS, REASONS FOR CAUTION: In the EBMT pediatric dataset, the age at last follow-up or death was <17 years for 75% of the patients, therefore a longer follow-up for all patients would be necessary to calculate the cumulative incidence of conception for patients transplanted during childhood and allow all patients to realize their reproductive willingness/potential. WIDER IMPLICATIONS OF THE FINDINGS: Reproductive health surveillance and fertility preservation counseling are important in younger transplanted patients. Our results showed that there is a window of opportunity to conceive naturally or with reproductive medicine support. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the 'Stiftung für krebskranke Kinder Regio Basiliensis', Basel, Switzerland. All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

High dose chemotherapy and autologous hematopoietic cell transplantation for Wilms tumor: a study of the European Society for Blood and Marrow Transplantation.

Survival for subgroups of patients with Wilms tumor (WT), such as those who suffer from relapse, is disappointing. Some patients' treatment plans include high-dose chemotherapy (HDT) with autologous hematopoietic cell transplantation (aHCT), although proof for its benefit is lacking. To increase the level of evidence regarding children with WT receiving aHCT as consolidation of first or second remission (after first relapse), we extracted relevant data from the European Blood and Marrow Transplantation Registry concerning 69 patients. Different HDT regimens were administered, mostly either melphalan-containing (n = 34) or thiotepa-containing (n = 14). For the whole population, 5-year overall survival (OS) and event-free survival (EFS) probabilities were 0.67 (±0.06) and 0.63 (±0.06), respectively (median observation time 7.8 years); for children transplanted in first remission, OS and EFS were 0.69 (±0.09) and 0.72 (±0.08). In univariate analysis, male gender and relapse in multiple sites were associated with lower OS probabilities. The use of a given pretransplant regimen (i.e. melphalan alone versus regimens with multiple drugs) did not seem to influence EFS/OS probability after aHCT, but significantly influenced platelet engraftment (more delayed with thiotepa). We here provide further data to improve the basis for future evidence-based clinical decision-making when using HDT and aHCT in relapsed/refractory WT.

Fertility preservation issues in pediatric hematopoietic stem cell transplantation: practical approaches from the consensus of the Pediatric Diseases Working Party of the EBMT and the International BFM Study Group.

Fertility preservation is an urgent challenge in the transplant setting. A panel of transplanters and fertility specialists within the Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation (EBMT) and the International BFM Study Group provides specific guidelines. Patients and families should be informed of possible gender- and age-specific cryopreservation strategies that should be tailored according to the underlying disease, clinical condition and previous exposure to chemotherapy. Semen collection should be routinely offered to all postpubertal boys at the diagnosis of any disease requiring therapy that could potentially impair fertility. Testicular tissue collection might be offered to postpubertal boys; nevertheless, its use has been unsuccessful to date. Oocyte collection after hormonal hyperstimulation should be offered to postpubertal girls facing gonadotoxic therapies that could be delayed for the 2 weeks required for the procedure. Ovarian tissue collection could be offered to pre-/post-pubertal girls. Pregnancies have been reported after postpubertal ovarian tissue reimplantation; however, to date, no pregnancy has been reported after the reimplantation of prepubertal ovarian tissue or in vitro maturation of pre-/post-pubertal ovarian tissue. Possible future advances in reproductive medicine could change this scenario. Health authorities should prioritize fertility preservation projects in pediatric transplantation to improve patient care and quality of life.

State-of-the-art fertility preservation in children and adolescents undergoing haematopoietic stem cell transplantation: a report on the expert meeting of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) in Baden, Austria, 29-30 September 2015.

Nowadays, allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a well-established treatment procedure and often the only cure for many patients with malignant and non-malignant diseases. Decrease in short-term complications has substantially contributed to increased survival. Therefore long-term sequelae are reaching the focus of patient care. One of the most important risks of stem cell transplant survivors is infertility. As well as in the field of allo-HSCT also the field of reproductive medicine has achieved substantial advances to offer potential options for fertility preservation in both boys and girls. Access to these procedures as well as their financing differs significantly throughout Europe. As all European children and adolescents should have the same possibility, the Paediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation organised an expert meeting in September 2015. This manuscript describes the recommendations for the diagnosis and pre-emptive procedures that should be offered to all children and adolescents in Europe who have to undergo an allo-HSCT.

Fertility preservation practices in pediatric and adolescent cancer patients undergoing HSCT in Europe: a population-based survey.

Chemotherapy and irradiation can affect the gonads, leading to impairment of pubertal development and/or infertility. Fertility preservation (FP) is therefore a crucial endeavor in hematopoietic stem cell transplantation (HSCT) because of the severe impact of infertility on the quality of life of long-term survivors. Despite the existence of different international guidelines, FP counseling and procedures are not routinely implemented as part of patient care. We present herein a survey conducted by the Pediatric Working Party of the European Society for Blood and Marrow Transplantation (EBMT), which aims to analyze and compare different FP practices for children and adolescents across EBMT centers in 2013. A total of 177 pediatric centers reporting to the EBMT were contacted; of this number, 38 centers (21%) located in 16 different countries responded. These centers reported 834 patients receiving HSCT in 2013 (73% prepubertal), corresponding to 22% of all children (n=3789) undergoing HSCT in EBMT reporting centers. Overall, 39% of the reported patients received counseling and 29% received an FP procedure. The increased need for FP programs, extended education for patient-care teams, and more personal resources and funding emerged from this survey as pivotal factors necessary to support and implement such programs.

Incidence and severity of crucial late effects after allogeneic HSCT for malignancy under the age of 3 years: TBI is what really matters.

Younger children are considered to be more vulnerable to late effects (LE), which prompted us to study LE in patients after haematopoietic stem cell transplantation (HSCT) for a haematological malignancy before the age of 3. In this multicentre EBMT study, cumulative incidence (CI) and severity of endocrine LE, central nervous system complications and secondary malignancies at 5, 10, 15 and 20 years of follow-up were assessed. Risk factors (RF) like gender, diagnosis, age at and year of HSCT, TBI- or chemo-conditioning and GVHD were analysed. CI of any LE was 0.30, 0.52, 0.66 and 0.72 at 5, 10, 15 and 20 years after HSCT, respectively. In 25% of the patients, LE were severe at a median follow-up of 10.4 years. In multivariate analysis, only TBI was a RF for having any LE and for thyroid dysfunction and growth disturbance. Female gender was a RF for delayed pubertal development. Some more insight could be gained by descriptive analysis regarding the role of TBI and GVHD on the severity of LE. Although only five selected LE have been studied and median follow-up is relatively short, the incidence and severity of these LE are considerable but not different from what has been found in older children and TBI is the main RF.