Search

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.

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.

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

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., FM was supported by educational grants from the 'Association for Training, Education and Research in Hematology, Immunology and Transplantation' (ATERHIT, Nantes, France)

More chronic GvHD and non-relapse mortality after peripheral blood stem cell compared with bone marrow in hematopoietic transplantation for paediatric acute lymphoblastic leukemia: a retrospective study on behalf of the EBMT Paediatric Diseases Working Party

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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.

Sinusoidal obstruction syndrome or veno-occlusive disease (SOS/VOD) is a potentially life-threatening complication of hematopoietic SCT (HSCT). This review aims to highlight, on behalf of the European Society for Blood and Marrow Transplantation, the current knowledge on SOS/VOD pathophysiology, risk factors, diagnosis and treatments. Our perspectives on SOS/VOD are (i) to accurately identify its risk factors; (ii) to define new criteria for its diagnosis; (iii) to search for SOS/VOD biomarkers and (iv) to propose prospective studies evaluating SOS/ VOD prevention and treatment in adults and children.

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.

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.

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.Bone Marrow Transplantation advance online publication, 23 January 2017; doi:10.1038/bmt.2016.363.

Human CMV infection is a frequent complication after HSC in children with remarkable morbidity and mortality. Antiviral drugs are relatively efficient but have numerous side effects. They are used as prophylactic, pre-emptive or therapeutic medicines. It is still a matter of debate which option is the best strategy. No uniform procedure has emerged regarding these three options, and new immunologic tools have raised more questions for physicians. To assess the current practice in the management of CMV infection, we sent a questionnaire to the EBMT centers performing hematopoietic SCT (HSCT) in children. Fifty-six out of 196 responded to the questionnaire (28.5%). Quantitative PCR was the most common monitoring tool (44/56). Only 4/56 centers use the pp65 antigenemia alone. All centers used pre-emptive strategy (56/56). 21/56 centers also used prophylactic measures, 13/21 after analysis of donor/receptor serologic status. Ganciclovir was the most common first-line agent for CMV disease (55/56). The most common dose and duration for induction treatment were 5 mg/kg bid (47/55) for 14 days (20/55). There is no uniform procedure for researching resistance strain, antiviral second-line therapy or cell therapy. A harmonization process should enable sound prospective trials to improve prevention, control and cure of CMV disease in children and adolescents. © 2014 Macmillan Publishers Limited.

Resume L’allogreffe de cellules souches hematopoietiques a beaucoup evolue depuis ses origines, multipliant les sources cellulaires utilisables (moelle, cellules souches peripheriques, sang placentaire), les donneurs mobilisables (intrafamiliaux, non apparentes, totalement ou partiellement compatibles) et les modalites therapeutiques entourant la greffe (immunosuppresseurs, manipulations du greffon, soins de support), ouvrant la voie a un ensemble vaste de therapies cellulaires. Les pathologies pour lesquelles une greffe est indiquee sont de plus en plus nombreuses : hemopathies malignes, hemopathies benignes severes telles que les aplasies medullaires congenitales ou acquises, les hemoglobinopathies ou encore les deficits immunitaires severes et certaines maladies de surcharge. Cet article se propose d’offrir un tour d’horizon complet de cette technique pour l’enfant en 2012.

Dyskeratosis congenita is a rare inherited bone marrow failure characterized by excessively short telomeres in highly proliferative tissues. These abnormalities are due to disturbance of the telomere maintenance machinery. The clinical presentation is characterized by skin pigmentation, nail dystrophy, and mucosal leukoplakia. All these mucocutaneous features are rare in childhood: they usually appear between 5 and 10 years of age. In young children, the initial presentation can associate bone marrow failure and neurological or ocular problems: Hoyeraal-Hreidarsson and Revesz syndromes, respectively. Clinical progression of the disease can lead to aplastic anemia (86% of all patients) and to pulmonary or hepatic complications. These patients also have an increased risk of cancer. Diagnosis is often suspected on bone marrow failure with no clinical or biological abnormalities compatible with Fanconi anemia diagnosis. The telomere length study can be helpful for diagnosis in case of aplastic anemia in children before studying gene mutations. Until now, 6 genes (DKC1, TERT, TERC, NOLA2, NOLA3, TINF2) have been identified in dyskeratosis congenita. Transmission of the disease can be autosomal recessive, autosomal dominant, or X-linked. In half of the cases, the genetic abnormality is unknown. Treatment of DC has to be adapted to each patient, from symptomatic or androgenic treatment to hematopoietic stem cell transplantation.

Shortened apheresis-based extra-corporeal photochemotherapy for acute refractory GVHD in children: a prospective study

Fanconi anemia (FA) is a rare genetic disease, transmitted in an autosomal recessive mode. The clinical phenotype is very broad and heterogeneous, related to the wide range of genes involved in this pathology. The classical triad of short height, physical abnormalities, and bone marrow failure is suggestive. The main physical abnormalities found involve the limbs, spinal column, skin, kidneys and urinary tract, and the ORL zone. Recent progress in molecular biology has identified 15 genes whose mutation causes FA chromosomal instability. FA is diagnosed by cytogenetic examination, then specified by molecular analysis. As FA patients may present multiorgan abnormalities and a high risk for neoplasia development, their medical follow-up has to be multidisciplinary and prolonged throughout life. The main challenges of the follow-up are patient information and education. Bone marrow failure, appearing during the first decade, requires close hematological monitoring and for severe cases requires hematopoietic stem cell transplantation, major and specific care with frequent serious complications and high mortality, but this is the only curative treatment in FA. Extrahematological care consists in screening for organ abnormalities and defects as well as monitoring precancerous lesions and tumors.

In this report, we address the issue of allogeneic stem cell transplantation in children with congenital neutropenia. Constitutional disorders with neutropenia are exceptional. Treatment and prevention of severe infections are a major concern in the management of chronic neutropenia. These disorders, especially Kostmann's disease and Shwachman-Bodian-Diamond syndrome, are associated with an increased risk of leukemia. The role of allogeneic stem cell transplantation in these patients is still unclear. In an effort to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual series of workshops which brought together practitioners from all member centers and took place in September 2013 in Lille.

International audience; 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

Unrelated cord blood transplantation for childhood acute myelogenous leukemia: The influence of cytogenetic risk group stratification

From 1989 to 1998, 341 children were included in the French multicentric LAME (Leucémie Aiguë Myéloblastique Enfant) trials. A total of 309 children were registered in the LAME 89/91 protocol. This intensive regimen included an induction phase (mitoxantrone plus cytarabine), two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase and amsacrine; 276 (90%) achieved a CR. The 5-year overall survival (OS) and event-free survival (EFS) were 60+/-4 and 48+/-4%, respectively. From 1997, timed-sequencing of the LAME SP induction chemotherapy led to an unacceptable frequency of consolidation delay; future improvements are unlikely to come from further increases in intensity. The role of allogenic bone-marrow transplantation from an HLA-identical sibling in CR1 was examined. The disease-free survival (DFS) was 52+/-4% for non-allografted patients and 57+/-7% for allografted patients (P=NS); a better OS for allografted patients was shown and could be related either to allo-BMT early in CR1 or to a second allo-BMT in CR2. For the complete responders after consolidation therapy, the 5-year OS was significantly better in patients randomized for no maintenance therapy (MT-) than in patients randomized for MT (77.6+/-8 vs 59+/-8%; P=0.05), while the 5-year DFS was not significantly different. Exposure to low-dose MT might contribute to clinical drug resistance and treatment failure in relapsing patients.

As a result of major progresses in anti-cancer treatment, many children with malignancy have to be admitted to an intensive care unit. Therefore it has become a necessity for paediatric oncologists and haematologists and paediatric intensive care physicians to work together. What are the current tools to guide their discussion and decision? There are few useful published studies about the outcome of oncology paediatric patients admitted to intensive care unit. Due to the very specificity of paediatric oncology it is difficult to extrapolate from the available adult studies. Legislative texts specify the limits of the debate but feed it little. Philosophers concentrate on the risk of therapeutic doggedness and the right to dye with dignity. The oncology paediatric patients may be sent to an intensive care unit at different steps of their diseases: at the time of diagnosis, during the curative treatment, or after treatment failure. For each step, there is a need for a wide debate between oncologists, intensivists, nurses, psychologists, and the child's family in order to define the most consensual decisions. The development of validated prognostic scores for this particular population will be very helpful for the decision making. As frequently as possible the decision should be anticipated before the transfer of the child to the intensive care unit.

International audience

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a treatment option for relapsed anaplastic large cell lymphoma (ALCL) in children, but reports on its efficacy in this disease are still limited. We analyzed data concerning 34 patients under 18 years of age prospectively registered in the French SFGM-TC database, who had undergone an allo-SCT for the treatment of ALK+ ALCL between 1993 and 2011. At transplant, 28 patients (82.4%) were in CR, whereas 6 exhibited detectable disease. Conditioning regimens were mostly myelo-ablative (n=31). With a median follow-up of 6 years, 5-year overall and event-free survival rates were 70% (SE=8%) and 58% (SE=9%), respectively. The 5-year cumulative incidence of relapse and treatment-related mortality was 18% (SE=7%) and 24% (SE=8%), respectively. Six patients had relapsed (median time, 141 days (35-235)). A durable CR had been obtained in 4/6 patients after injection of donor lymphocytes (n=1) or vinblastine-corticosteroid therapy (n=3). Ten patients had died, eight due to transplant toxicity and two due to progressive disease. Allo-SCT is an efficient treatment for pediatric patients with high-risk relapsed ALK+ ALCL. However, the overall morbidity of allo-SCT raises questions about its place, given the efficacy of targeted agents currently under development in this disease.

Exact data on prognosis of children receiving invasive mechanical ventilation (IMV) after allogeneic hematopoietic SCT (HSCT) is lacking. We therefore started a prospective registry in four European university HSCT centers (Leiden, Paris, Prague and Utrecht) and their pediatric intensive care units (PICUs). The registry started in January 2009. In January 2013, the four centers together had treated a total of 83 admissions with IMV. The case fatality rate in these patients was 52%. Mortality 6 months after PICU discharge was 45%. There were significant differences between centers in the proportion of children who received IMV after HSCT (6-23%, P

Fanconi anemia (FA) is a rare autosomal recessive disease characterized by congenital abnormalities, cancer predisposition and progressive BM failure. FA patients present spontaneous and induced chromosome breakage. Hematopoietic SCT (HSCT) represents the unique therapeutic option to restore normal hematopoiesis when marrow failure or clonal hematopoietic abnormality occurs. Conventional myeloablative conditioning regimen, especially including a high dose of irradiation, appeared strongly toxic for FA patients. Then, reduced-intensity conditioning regimens were developed successfully for those patients. However, TRM still remained higher than for other HSCT indications. The development of fludarabine containing a non-myeloablative conditioning regimen appears to be a major progress. Long-term follow-up is absolutely necessary.

Resume Le syndrome d'activation macrophagique est rapporte dans differentes situations infectieuses (EBV, CMV, tuberculose…) mais il l'a rarement ete au cours de l'infection a VIH chez l'adulte et jamais chez l'enfant. Observations. — Un syndrome d'activation macrophagique a ete observe chez une enfant de 9 ans dont l'infection a VIH s'est compliquee d'une infection a EBV; le traitement par corticotherapie et chimiotherapie antimitotique a echoue et l'enfant est decedee peu de temps apres. Il en a ete de meme chez une fillette de 3 ans ayant une infection a Aspergillus fumigatus dont le traitement par amphotericine B a permis une rapide amelioration et chez un enfant de 8 ans et demi presentant une infection par un pneumocoque multiresistant, chez qui l'antibiotherapie adaptee a conduit a la remission de l'hemophagocytose. Discussion. — L'association VIH-syndrome d'activation macrophagique ne semble pas exceptionnelle du fait de l'association pathologie infectieuse et deficit immunitaire lie a l'infection a VIH. Ce tableau requiert un diagnostic et un traitement etiologique. A defaut, la therapeutique pourrait comporter des corticoides associes ou non a une chimiotherapie. Conclusion. — Le diagnostic de syndrome d'activation macrophagique doit etre rapidement porte car l'evolution peut etre letale.

To address the prognostic value of minimal residual disease (MRD) before unrelated cord blood transplantation (UCBT) in children with acute lymphoblastic leukemia (ALL), we analyzed 170 ALL children transplanted in complete remission (CR) after myeloablative conditioning regimen. In all, 72 (43%) were in first CR (CR1), 77 (45%) in second CR (CR2) and 21 (12%) in third CR (CR3). The median interval from MRD quantification to UCBT was 18 days. All patients received single-unit UCBT. Median follow-up was 4 years. Cumulative incidence (CI) of day-60 neutrophil engraftment was 85%. CI of 4 years relapse was 30%, incidence being lower in patients with negative MRD before UCBT (hazard ratio (HR)=0.4, P=0.01) and for those transplanted in CR1 and CR2 (HR=0.3, P=0.002). Probability of 4 years leukemia-free survival (LFS) was 44%, (56, 44 and 14% for patients transplanted in CR1, CR2 and CR3, respectively (P=0.0001)). Patients with negative MRD before UCBT had better LFS after UCBT compared with those with positive MRD (54% vs 29%; HR=2, P=0.003). MRD assessment before UCBT for children with ALL in remission allows identifying patients at higher risk of relapse after transplantation. Approaches that may decrease relapse incidence in children given UCBT with positive MRD should be investigated to improve final outcomes.

Allogeneic hematopoietic SCT (HSCT) has been used as treatment for single patients with autoimmune diseases (AD). To summarise currently available information, we analyzed all patients who underwent allogeneic HSCT for AD and who reported to the European Group for Blood and Marrow Transplantation (EBMT) database. Thirty-five patients receiving 38 allogeneic transplantations for various hematological and non-hematological AD were identified. Four patients had had an allogeneic HSCT for a conventional hematological indication in the past. Fifty-five per cent of the transplantation procedures led to a complete clinical response of the refractory AD and 23% to at least a partial response. The median duration of response at the last follow-up was 70.7 (15.2-130) months. Three patients relapsed at a median of 12.3 months after HSCT. Treatment-related mortality at 2 years was 22.1% (95% CI: 7.3-36.9%). Two deaths were caused by progression of AD. The probability of survival at 2 years was 70%. No single factor predicting the outcome could be identified. The retrospective nature of this study and the heterogeneous, partly incomplete data are its limitations. However, allogeneic HSCT can induce remission in patients suffering from refractory AD. These data provide the basis for carefully conducted prospective trials.

Successful anti-CD20 antibody treatment of pemphigus foliaceus after unrelated cord blood transplantation