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.

Association between oral and fecal microbiome dysbiosis and treatment complications in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation.

The oral and gastrointestinal mucosae represent the main targets of the toxic effect of chemo and/or radiotherapy administered during the conditioning regimen before hematopoietic stem cell transplant (HSCT). These harmful consequences and the immunological complications that may occur after the transplant (such as Graft versus Host Disease, GvHD) are responsible for the clinical symptoms associated with mucositis during the aplasia phase, like pain, nausea, vomiting, and diarrhea. These toxicities could play a critical role in the oral and gastrointestinal microbiomes during the post-transplant phase, and the degree of microbial dysbiosis and dysregulation among different bacterial species could also be crucial in intestinal mucosa homeostasis, altering the host's innate and adaptive immune responses and favoring abnormal immune responses responsible for the occurrence of GvHD. This prospective pediatric study aims to analyze longitudinally oral and gut microbiomes in 17 pediatric patients who received allogeneic HSCT for malignant and non-malignant diseases. The oral mucositis was mainly associated with an increased relative abundance of Fusobacteria, and Prevotella species, while Streptococcus descendants showed a negative correlation. The fecal microbiome of subjects affected by cutaneous acute GvHD (aGvHD) correlated with Proteobacteria. Oral mucosal microbiota undergoes changes after HSCT, Fusobacteria, and Prevotella represent bacterial species associated with mucositis and they could be the target for future therapeutic approaches, while fecal microbiome in patients with acute GvHD (aGvHD) revealed an increase of different class of Proteobacteria (Alphaproteobacteria and Deltaproteobacteria) and a negative correlation with the class of Gammaproteobacteria.

Allogeneic stem cell transplantation for patients with advanced rhabdomyosarcoma: a retrospective assessment.

BACKGROUND: Allogeneic haematopoietic stem cell transplantation (allo-SCT) may provide donor cytotoxic T cell-/NK cell-mediated disease control in patients with rhabdomyosarcoma (RMS). However, little is known about the prevalence of graft-vs-RMS effects and only a few case experiences have been reported. METHODS: We evaluated allo-SCT outcomes of 30 European Group for Blood and Marrow Transplantation (EBMT)-registered patients with advanced RMS regarding toxicity, progression-free survival (PFS) and overall survival (OS) after allo-SCT. Twenty patients were conditioned with reduced intensity and ten with high-dose chemotherapy. Twenty-three patients were transplanted with HLA-matched and seven with HLA-mismatched grafts. Three patients additionally received donor lymphocyte infusions (DLIs). Median follow-up was 9 months. RESULTS: Three-year OS was 20% (s.e.±8%) with a median survival time of 12 months. Cumulative risk of progression was 67% (s.e.±10%) and 11% (s.e.±6%) for death of complications. Thirteen patients developed acute graft-vs-host disease (GvHD) and five developed chronic GvHD. Eighteen patients died of disease and four of complications. Eight patients survived in complete remission (CR) (median: 44 months). No patients with residual disease before allo-SCT were converted to CR. CONCLUSION: The use of allo-SCT in patients with advanced RMS is currently experimental. In a subset of patients, it may constitute a valuable approach for consolidating CR, but this needs to be validated in prospective trials.

Hepatitis B reactivation in allogeneic hemopoietic stem cell transplantation setting: a pediatric experience.

Reactivation of HBV is a well known complication in patients undergoing HSCT. Lamivudine treatment appears to prevent hepatitis B virus reactivation and to decrease the mortality in at risk HSCT patients. We describe HBV reactivation occurred in three allogeneic HSCT pediatric patients coming from Eastern Europe, one of whom was successfully treated with lamivudine. Our experience confirms that HBV-DNA may persist as intra-hepatic infection or in extra-hepatic sites and that HBV reactivation may appear during immunodepression. Careful and complete screening for HBV markers is mandatory before HSCT, especially in children coming from countries at risk for HBV. Furthermore, a treatment with lamivudine could also represent an efficacious prophylaxis in pediatric patients to avoid HBV reactivation and to decrease the development of severe hepatic disease.

SCT for Wilms' tumour.

Thanks to advances in treatment, approximately 85-90% of patients suffering from Wilms' tumour are now cured. However, success rate after relapse is significantly lower, ranging from 25 to 45%. Several different re-induction approaches, more or less intensive according to first-line therapy and characteristics of relapse, have been proposed. A number of adverse prognostic factors related to a bad outcome after relapse have been identified and are used as inclusion criteria for entering in a programme including high-dose chemotherapy (HCT). HCT followed by autologous haematopoietic stem cell rescue has been used in small numbers of patients worldwide and promising results have been reported. Information from the European Group for Blood and Marrow Transplantation Database regarding more than 300 transplants have been gathered. In addition, literature data on rescue therapy and HCT will be discussed, such as recent treatment proposals currently under discussion within European and US cooperative groups.

Early complications following haematopoietic SCT in children.

Early complications can be defined as those occurring within 100 days after transplant. Both epithelial and endothelial damage represent the pathogenetic basis for the onset of the most frequent complications. Clinical features related to endothelial damage depend on the involved district or on the grade and type of general distribution. Veno-occlusive disease (VOD) most often occurs within the first 20 days of haematopoietic SCT (HSCT) and is characterized by the obstruction of small intrahepatic venules and is caused by an initial injury of the sinusoid endothelial cells. The incidence in children ranges between 27 and 40%, and symptoms include hepatomegaly, portal hypertension and ascites. Early intervention with defibrotide (DF) proved to be effective for the treatment; however, overall mortality ranges between 20 and 50%. Thrombotic microangiopathy (TAM) incidence is 4-13%. It is often associated with the use of CYA or tacrolimus, and symptoms include haemolytic anaemia, thrombocytopenia and renal and/or central nervous system impairment. Treatment includes plasmapheresis and supportive care. The promising role of DF needs to be confirmed. The onset of engraftment syndrome may occur 1 or 2 days before the neutrophil count in peripheral blood increases. Clinical symptoms include fever not related to infection, respiratory involvement with pulmonary infiltrates or hypoxia and skin rash. Treatment consists of steroid administration for a few days. Haemorrhagic cystitis (HC) may occur early or later following transplant. Early-onset HC is related to mucosal damage caused by the catabolites of chemotherapy drugs, and late-onset HC is mostly caused by viral infections. The incidence ranges between 1 and 25%. Clinical symptoms include haematuria and dysuria without infections. Treatment includes hyperhydration and platelet support. In case of vescical clots, bladder irrigation is indicated. In advanced cases, hyperbaric oxygen administration or surgery may be useful. The use of cidofovir for BK virus-related HC seems encouraging, but further studies are needed to confirm its real efficacy.

Non-endocrine late complications in children after allogeneic haematopoietic SCT.

Non-endocrine events represent a heterogeneous group of complications occurring in children who survive long term after haematopoietic SCT. This review highlights the late sequel in a growing child. The preparative regimen itself with high-dose chemotherapy and/or radiotherapy (TBI) or the treatment given before the transplant procedure may cause organ damage with permanent sequel. Immune reconstitution and chronic GvHD have crucial role in occurrence of clinical abnormalities and late severe infections. Autoimmune syndromes may occur after use of novel transplant modalities (cord blood transplantation, reduced intensity conditioning regimen and haploidentical T-cell-depleted SCTs). Exposure to chemo- and/or radiotherapy increases the risk of second malignant neoplasms. Surveillance strategy focusing on each potential complication risk at continuous follow-up will allow vigilant post transplant care. Each paediatrician must be well versed in appropriate monitoring of these complications. Guidelines and recommendations are provided for serious problems occurring at follow-up, which must rapidly be identified so that appropriate intervention can be initiated. To achieve cure at a lowest possible price in terms of suffering and cost expenditures for health care is an extended frontier of paediatric haematopoietic SCT and biggest challenge for a paediatrician.

Endocrinological late complications after hematopoietic SCT in children.

The main challenge for a pediatric hemato-oncologist today is to obtain a cure for the sick child with the minimum of treatment-related complications. Children on their way to achieving adulthood face many risks after hematopoietic SCT (HSCT). Continuous follow-up includes assessment of organ function, focus on vaccinations and screening for secondary malignancies. Updated treatment protocols are already adjusted according to the knowledge obtained on late effects, and the potential risks for complications are well balanced with expected benefits hopefully resulting in decreased potential risk for organ damage but still maintaining an unchanged or improved survival rate. Recent developments on pre-HSCT regimens, such as the introduction of new anticancer regimens and immunosuppressive agents will hopefully contribute to minimize the frequency and the severity of late complications. Knowledge about increased risk for long-term complications due to cancer therapy and pre-HSCT preparative regimens should encourage each caring physician to stick to follow-up protocols and treatment guidelines not only to improve the survival rate of transplanted children but also to improve their quality of life. To achieve adulthood by maintaining cognitive ability and psychosocial skills is the highest goal for an individual to become a competent member of a society. This review of late endocrine complications after HSCT focuses on growth, pubertal development, thyroid disorders and glucose metabolism in long-term survivors.

Prevention and treatment of acute GvHD.

GvHD remains a source of significant morbidity and mortality in the setting of allogeneic haematopoietic SCT. Improving outcomes in stem cell transplant recipients requires additional therapeutic modalities for GvHD, especially for patients who fail to respond to initial therapy with steroids. Moreover, while the absence of acute GvHD (aGvHD) is associated with a higher risk of relapse of the underlying malignant disease, severe aGvHD usually induces the occurrence of life-threatening complications such as severe infections. This article summarizes the current state of aGvHD prophylaxis and treatment.

Bacteremias in children receiving hemopoietic SCT.

The incidence of bacteremia following hemopoietic SCT (HSCT) changes over time from the procedure. The first 30 days have the highest incidence, both in autologous and allogeneic HSCT recipients. In the following periods, bacteremia is a frequent complication in allogeneic HSCT, especially from alternative donors. Gram-positive cocci represent the most frequent cause of single-agent bacteremia. Knowledge of epidemiology (incidence and etiology) of bacteremias following HSCT is pivotal for planning management strategies (prevention, diagnosis and therapy) that must be distinct in the different post-transplant period.

Incidence of bacteremias and invasive mycoses in children undergoing allogeneic hematopoietic stem cell transplantation: a single center experience.

We performed a retrospective single center study to define the epidemiology of bacteremias or invasive mycoses in pediatric allogeneic hematopoietic SCT (HSCT) from matched related donors (MRD) or alternative donors (AD). During 119 213 days of follow-up, 156 infections were observed: 130 bacteremias (27 in MRD-HSCT and 103 in AD-HSCT recipients) and 26 invasive mycoses (8 in MRD-HSCT and 18 in AD-HSCT recipients). Overall, the risk of bacteremia was fivefold that of invasive mycosis (P<0.001). AD-HSCT recipients had a higher percentage of infections (89 vs 27%; P<0.001), a higher rate/100 days of immunosuppression (infection rate (IR): 0.21 vs 0.06; P<0.001) and a higher proportion of repeated infections (44 vs 9%; P=0.001). In AD-HSCT, the relative risk of bacteremia was 2.87 in the pre-engraftment period, 5.84 in the early post-engraftment period and 6.46 in the late post-engraftment period (P<0.001) compared to MRD-HSCT. Only after 1 year did the epidemiology become similar. The epidemiology of invasive mycoses did not differ significantly between the two types of transplant.

Rare viral infections in children receiving hemopoietic stem cell transplant.

Viral infections are a rare complication in autologous hemopoietic stem cell transplant (HSCT) recipients but represent a frequent cause of disease after allogeneic HSCT. In the last years, there has been an increase in the number of viral diseases observed in these patients. This fact may be at least partially due to an improvement in diagnostic facilities, but the increasing number of transplant procedures and the more severe immunosuppression may also have played an important role.

Invasive mycoses in children receiving hemopoietic SCT.

Invasive mycoses represent a rare but severe complication following hemopoietic SCT (HSCT) in children. Their incidence is related to the type of donor, being higher after allogeneic transplant, especially from alternative donors. Moreover, the incidence of invasive mycoses varies in the different post transplant phases. Neutropenia, lymphopenia, GvHD, high-dose steroids or other immunosuppressive drugs represent well-known risk factors. The clinical features of invasive mycoses after HSCT in children are similar to those observed in adults, and the diagnostic tools, including Aspergillus galactomannan antigen detection, are feasible also in pediatrics. Mortality due to invasive mycoses after HSCT in children is high.

Anti-varicella-zoster vaccination in contacts of children receiving antineoplastic chemotherapy: a prospective pilot study.

Varicella may be a severe infection in children with malignancy. Varicella vaccination is either not recommended for immunocompromised children or it requires temporary discontinuation of immunosuppression. We prospectively evaluated the feasibility of a varicella vaccination programme of household contacts of varicella-negative children receiving antineoplastic chemotherapy. From April 2004 to April 2005, 207 children were evaluated; in 49 (24 percent) the attending physicians collected no history about previous varicella and performed no serological evaluation before any transfusion. Among the 158 patients with complete history and/or a screening test, 51 (32 percent) were negative, with a total of 110 household contacts eligible for the study. Of these, 13 (12 percent) subjects resulted negative for varicella. In three of them vaccination was not performed due to parental refusal. This study demonstrates the difficulties in implementing a varicella vaccination programme targeting negative household contacts of immunocompromised children. The attitude of paediatric oncologists and parental refusal currently represent the main challenges against the complete success of this strategy in countries where VZV vaccination is not inserted in the general vaccination programme.

'Real-life' report on the management of chronic GvHD in the Gruppo Italiano Trapianto Midollo Osseo (GITMO).

Several guidelines have been published about management of chronic GvHD (cGvHD), but the clinical practice still remains demanding. The Gruppo Italiano Trapianto di Midollo Osseo (GITMO) has planned a prospective observational study on cGvHD, supported by a dedicated software, including the updated recommendations. In view of this study, two surveys have been conducted, focusing the management of cGvHD and ancillary therapy in cGvHD, to address the current 'real life' situation. The two surveys were sent to all 57 GITMO centers, performing allografting in Italy; the response rate was 57% and 66% of the interviewed centers, respectively. The first survey showed a great disparity especially regarding steroid-refractory cGvHD, although extracorporeal photo-apheresis resulted as the most indicated treatment in this setting. Another challenging issue was the strategy for tapering steroid: our survey showed a great variance, and this disagreement could be a real bias in evaluating outcomes in prospective studies. As for the second survey, the results suggest that the ancillary treatments are not standardized in many centers. All responding centers reported a strong need to standardize management of cGvHD and to participate in prospective trials. Before starting observational and/or interventional studies, a detailed knowledge of current practice should be encouraged.

Impact of cumulative anthracycline dose, preparative regimen and chronic graft-versus-host disease on pulmonary and cardiac function in children 5 years after allogeneic hematopoietic stem cell transplantation: a prospective evaluation on behalf of the EBMT Pediatric Diseases and Late Effects Working Parties.

This prospective study focused on risk factors and clinical outcome of pulmonary and cardiac late effects after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We prospectively evaluated 162 children by pulmonary function tests (PFTs) and cardiac shortening fraction (SF) before allo-HSCT and yearly up to the 5th year of follow-up. The 5-year cumulative incidence of lung and cardiac impairment was 35 (hazard rate=0.03) and 26% (hazard rate=0.06), respectively. Patients presenting abnormal PFTs and SF at last follow-up were 19 and 13%, respectively, with a median Lansky performance status of 90% (70-100). Chronic graft-versus-host disease (c-GVHD) was the major risk factor for reduced lung function in univariate (P=0.02) and multivariate analysis (P=0.02). Total body irradiation (TBI) alone and TBI together with pre-transplant anthracycline administration were significant risk factors for reduced cardiac function in univariate analysis, only (P=0.04 and 0.004, respectively). In conclusion, our prospective study demonstrates an asymptomatic post-allo-HSCT deterioration of pulmonary and cardiac function in some long-term survivors, who had been transplanted in childhood, and thus emphasizes the need for lifelong cardiopulmonary monitoring and the development of new strategies both to reduce pre-transplant cardiotoxic regimens and to treat more efficiently c-GVHD.

Nebulized liposomal amphotericin B and combined systemic antifungal therapy for the treatment of severe pulmonary aspergillosis after allogeneic hematopoietic stem cell transplant for a fatal mitochondrial disorder.

Nebulized liposomal amphotericin B (20-15 mg twice daily by nebulizer) was combined with high dose intravenous liposomal amphotericin B (10 mg/kg/day) and high dose caspofungin (100 mg/m(2)) for the treatment of severe, recurrent pulmonary aspergillosis following allogeneic hematopoietic stem cell transplantation from alternative donor in a patient with mitochondrial disease (Pearson's syndrome). This combined treatment was administered for 8 days. Nebulized liposomal amphotericin B was well tolerated. Since severe transplant complications developed, nebulized administration was withdrawn and intravenous doses of liposomal amphotericin B and caspofungin were tapered to usual schedules. Pulmonary aspergillosis responded well to 45 days of combined intravenous antifungal therapies which were maintained for 2 years with secondary prophylaxis, because of persistent immunosuppressive treatment.

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.

Frameshift suppression by thyA mutants of Escherichia coli K-12.

We have extended our previous study on the suppression of frameshift mutants by Escherichia coli thyA mutants by assaying suppression of 15 rIIB frameshift mutants of bacteriophage T4 on one of our suppressing thyA mutant strains. The majority of insertion mutants were suppressible, whereas none of the deletion mutants tested was suppressible. Frameshift suppression could be inhibited by adding thymidine to the assay medium, but was not affected by the presence of a restrictive rpsL mutation in the host strain. We suggest that the frameshift suppression event occurs at a nonsense codon generated by the frameshift mutation.