Efficacy of haematopoietic stem cell boost as a rescue for poor graft function after haematopoietic stem cell transplantation: A multicentre retrospective study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC).

Haematopoietic stem cell reinjection may be a curative option for poor graft function after haematopoietic stem cell transplantation; however, literature supporting its use remains limited. We conducted a multicentre retrospective study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy, including 55 patients. We demonstrated response rates of nearly 40% and two-year survival of more than 60% in the context of an otherwise deadly complication and we observed that the timing of injection and the degree of cytopenia are strongly associated with outcomes. This study shows the feasibility of the procedure informing on its epidemiology, outcomes and prognostic factors, setting the stage for future guidelines.

Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation.

Acute Graft versus Host Disease (aGvHD) grades 2-4 occurs in 15-60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2-4 in 60 pediatric patients. The cumulative incidence of aGvHD 2-4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2-4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3-191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2-4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06-3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.

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.

Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation.

The advances in hematopoietic cell transplantation (HCT) over the last decade have led to a transplant-related mortality below 15%. Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication of HCT that belongs to a group of diseases increasingly identified as transplant-related, systemic endothelial diseases. In most cases, SOS/VOD resolves within weeks; however, severe SOS/VOD results in multi-organ dysfunction/failure with a mortality rate >80%. A timely diagnosis of SOS/VOD is of critical importance, given the availability of therapeutic options with favorable tolerability. Current diagnostic criteria are used for adults and children. However, over the last decade it has become clear that SOS/VOD is significantly different between the age groups in terms of incidence, genetic predisposition, clinical presentation, prevention, treatment and outcome. Improved understanding of SOS/VOD and the availability of effective treatment questions the use of the Baltimore and Seattle criteria for diagnosing SOS/VOD in children. The aim of this position paper is to propose new diagnostic and severity criteria for SOS/VOD in children on behalf of the European Society for Blood and Marrow Transplantation.

[French recommendations on control measures to reduce the infectious risk in immunocompromised patients]. / Quelles mesures pour maîtriser le risque infectieux chez les patients immunodéprimés ? Recommandations formalisées d'experts.

The increase use of immunosuppressive treatments in patients with solid cancer and/or inflammatory diseases requires revisiting our practices for the prevention of infectious risk in the care setting. A review of the literature by a multidisciplinary working group at the beginning of 2014 wished to answer the following 4 questions to improve healthcare immunocompromised patients: (I) How can we define immunocompromised patients with high, intermediate and low infectious risk, (II) which air treatment should be recommended for this specific population? (III) What additional precautions should be recommended for immunocompromised patients at risk for infection? (IV) Which global environmental control should be recommended? Based on data from the literature and using the GRADE method, we propose 15 recommendations that could help to reduce the risk of infection in these exposed populations.

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.

Scleral lenses for severe chronic GvHD-related keratoconjunctivitis sicca: a retrospective study by the SFGM-TC.

Chronic GvHD-related keratoconjunctivitis sicca (cGvHD-related KCS) can significantly alter the quality of life of patients after allogeneic hematopoietic stem cell transplantation. The aim of this work was to assess the efficacy and tolerability of scleral lenses to treat severe cGvHD-related KCS. In this retrospective, multicenter study, we included 60 consecutive patients diagnosed with cGvHD-related KCS and fitted with scleral lenses. Patients were evaluated at baseline and at 2 months with the following tests: the Ocular Surface Disease Index (OSDI) to assess quality of life, the Oxford score to grade corneal damage and the logarithm of minimal angle of resolution (Log MAR) scale to determine visual acuity. We observed improvement in quality of life in 58 patients (97%). All parameters improved at 2 months. We observed significant differences at 2 months compared with baseline for the mean OSDI (86 versus 30, respectively, P<0.001), the mean Oxford score (3.2 versus 1.3, respectively, P<0.001) as well as visual acuity (Log MAR of 0.33 versus 0.10, respectively, P<0.001). Treatment with scleral lenses was discontinued in only 5 patients (8%) with a median follow-up of 20.5 months (range: 2-125 months). Scleral lenses were very efficient and well tolerated in patients with severe cGvHD-related KCS.

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.

Outcome after failure of allogeneic hematopoietic stem cell transplantation in children with acute leukemia: a study by the société Francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in the case of post-transplantation relapse. We aimed to compare treatment strategies in 334 consecutive children with acute leukemia relapse or progression after SCT in a recent 10-year period. Data could be analyzed in 288 patients (157 ALL, 123 AML and 8 biphenotypic AL) with a median age of 8.16 years at transplantation. The median delay from first SCT to relapse or progression was 182 days. The treatment consisted of chemotherapy alone (n=108), chemotherapy followed by second SCT (n=70), supportive/palliative care (n=67), combination of chemotherapy and donor lymphocyte infusion (DLI; n=30), or isolated reinfusion of donor lymphocytes (DLI; n=13). The median OS duration after relapse was 164 days and differed according to therapy: DLI after chemotherapy=385 days, second allograft=391 days, chemotherapy=174 days, DLI alone=140 days, palliative care=43 days. A second SCT or a combination of chemotherapy and DLI yielded similar outcome (hazard ratio (HR)=0.85, P=0.53) unlike chemotherapy alone (HR=1.43 P=0.04), palliative care (HR=4.24, P<0.0001) or isolated DLI (HR=1,94, P<0.04). Despite limitations in this retrospective setting, strategies including immunointervention appear superior to other approaches, mostly in AML.

Cytogenetics and outcome of allogeneic transplantation in first remission of acute myeloid leukemia: the French pediatric experience.

We analyzed the impact of cytogenetics on 193 children enrolled in two successive French trials (LAME89/91 and ELAM02), who received hematopoietic stem cell transplantation during CR1. Detailed karyotype was available for 66/74 (89%) in LAME89/91 and 118/119 (99%) in ELAM02. Several karyotype and transplant characteristics differed according to therapeutic protocol: unfavorable karyotypes were more frequent in ELAM02 (36% vs 18%), pretransplant chemotherapy included high-dose cytarabine in ELAM02 and not in LAME89/91, IV replaced oral busulfan in the conditioning regimen, methotrexate was removed from post-transplant immunosuppression, and matched unrelated donor and cord blood transplantation were introduced. Five-year overall survival (OS) was 78.2% in LAME89 and 81.4% in ELAM02. OS was significantly lower for the unfavorable cytogenetic risk group in LAME89/91 when compared with intermediate and favorable groups (50% vs 90.6 and 86.4%, P=0.001). This difference was no longer apparent in ELAM02 (80.9% vs 71.3% and 5/5, respectively). Survival improvement for children with unfavorable karyotype was statistically significant (P=0.026) and was due to decrease in relapse risk. Five-year transplantation-related mortality was 6.75% in LAME89/91. In ELAM02, it was 3.2% for patients with a sibling donor and 10.9% with an unrelated donor or cord blood. We conclude that the outcome of children with unfavorable karyotype transplanted in CR1 has improved.

Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation.

Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life threatening complication that can develop after hematopoietic cell transplantation. Although SOS/VOD progressively resolves within a few weeks in most patients, the most severe forms result in multi-organ dysfunction and are associated with a high mortality rate (>80%). Therefore, careful attention must be paid to allow an early detection of SOS/VOD, particularly as drugs have now proven to be effective and licensed for its treatment. Unfortunately, current criteria lack sensitivity and specificity, making early identification and severity assessment of SOS/VOD difficult. The aim of this work is to propose a new definition for diagnosis, and a severity-grading system for SOS/VOD in adult patients, on behalf of the European Society for Blood and Marrow Transplantation.

Metabolic syndrome in adults who received hematopoietic stem cell transplantation for acute childhood leukemia: an LEA study.

We evaluated prospectively the incidence and risk factors of the metabolic syndrome (MS) and its components in 170 adult patients (mean age at evaluation: 24.8±5.4 years) who received an hematopoietic stem cell transplantation for childhood ALL, n=119, or AML, n=51. TBI was carried out in 124 cases; a busulfan-based conditioning was done in 30 patients. Twenty-nine patients developed a MS (17.1%, 95% confidence intervals: 11.7-23.6). The cumulative incidence was 13.4% at 25 years of age and 35.5% at 35 years of age. A higher body mass index (BMI) before transplantation and a growth hormone deficiency were associated with increased MS risk (P=0.002 and 0.01, respectively). MS risk was similar for patients who received TBI or busulfan-based conditioning. The TBI use increased the hyperglycemia risk (odds ratio (OR): 4.7, P=0.02). Women were at the risk of developing increased waist circumference (OR: 7.18, P=0.003) and low levels of high-density lipoprotein cholesterol (OR: 2.72, P=0.007). The steroid dose was not a risk factor. The MS occurs frequently among transplanted survivors of childhood leukemia. Its incidence increases with age. Both intrinsic (BMI, gender) and extrinsic factors (TBI, alkylating agents) contribute to its etiopathogenesis.

Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes.

Allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential to cure patients with an inherited bone marrow failure syndrome (IBMFS). However, the procedure involves the risk of treatment-related mortality and may be associated with significant early and late morbidity. For these reasons, the benefits should be carefully weighed against the risks. IBMFS are rare, whereas case reports and small series in the literature illustrate highly heterogeneous practices in terms of indications for HSCT, timing, stem cell source and conditioning regimens. A consensus meeting was therefore held in Vienna in September 2012 on behalf of the European Group for Blood and Marrow Transplantation to discuss HSCT in the setting of IBMFS. This report summarizes the recommendations from this expert panel, including indications for HSCT, timing, stem cell source and conditioning regimen.