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Terminal complement blockade by humanised monoclonal antibody eculizumab has been used to treat transplantation-associated thrombotic microangiopathy (TA-TMA) in recent years. This retrospective international study conducted by the Paediatric Diseases (PDWP) and Inborn Error Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT) describes outcome and response of 82 paediatric patients from 29 centres who developed TA-TMA and were treated with eculizumab between January 2014 and May 2019. The median time from hematopoietic stem cell transplantation (HSCT) to TA-TMA manifestation was 92 days (range: 7-606) and from TA-TMA diagnosis to the start of eculizumab treatment 6 days (range: 0-135). Most patients received eculizumab weekly (72%, n = 55) with a standard weight (kg)-based dose (78%, n = 64). Six months from beginning of eculizumab therapy, the cumulative incidence of TA-TMA resolution was 36.6% (95% CI: 26.2-47) and the overall survival (OS) was 47.1% (95% CI: 35.9-57.5). All 43 patients with unresolved TA-TMA died. The cause of death was HSCT-related in 41 patients. This study also documents poor outcome of patients without aGvHD and their frequent concomitant viral infections. Considering recent publications, intensified eculizumab dosing and complement monitoring could potentially improve upon outcomes observed in this study.

In hemoglobinopathy-prone regions, like the Middle East, thalassemia is the most prevalent noncommunicable life-threatening disorder of children and is highly curable by hematopoietic stem cell transplantation (HSCT). Moreover, transplantation is very cost-effective, and HSCT programs can be established directly in middle-income countries (MICs) at a reduced cost while maintaining quality standards and outcomes consistent with international ones. The aim of the present study was to review and verify the efficacy of the applied methodology through the analysis of 47 consecutive matched-related HSCTs in children with thalassemia. In 2016, the first HSCT unit for adults and children with both malignant and nonmalignant diseases was developed in Iraqi Kurdistan, thanks to a capacity building project funded by the Italian Agency for Development Cooperation. Data on clinical activity were obtained from a cohort of patients treated in the newly established HSCT unit. Primary endpoints were overall survival (OS) and thalassemia-free survival (TFS). Startup of the HSCT unit was completed over a 3-year period. Assessing and meeting minimum requirements were crucial for the startup; moreover, a team of international health care professionals (HCPs), all experts in the field of HSCT, conducted the education and training phase, involving all the clinical and nonclinical professionals in the program. At a median follow-up of 2.6 years, the 3-year TFS and OS were 82.8% (SE, 5.5%) and 87.1% (SE, 4.9%), respectively. TFS and graft-versus-host-disease-free composite survival was 80.6% (SE, 5.8%). At present, the HSCT service is completely autonomous, and more than 250 transplants have been done in both adults and children. The minimal essential requirements for an HSCT startup may be affordable in many MICs. Our results for thalassemia are comparable with international data. A twinning program with an international group of experts and a capacity-building approach is crucial for the success of the program, a strategy that allows for rapid development of HSCT units.

Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. Clinical data surrounding cGVHD therapies in younger children are limited and critically needed. Primary endpoints were to determine the recommended pediatric equivalent dose (RPED) and assess pharmacokinetics (PK) and safety. Secondary endpoints included overall response rate (ORR; comprising complete response and partial response) according to the 2014 National Institutes of Health criteria at 24 weeks, overall survival, and duration of response (DOR). Here we present the primary results from the open-label, multicenter, international phase 1/2 iMAGINE study (PCYC-1146-IM), which evaluated the PK, safety, and efficacy of ibrutinib in patients age ≥1 to22 years with treatment-naive (TN) or relapsed/refractory (R/R) moderate/severe cGVHD. Patients age12 years received once-daily ibrutinib starting at 120 mg/m

Osteonecrosis (ON) is a well-known sequela of paediatric acute lymphoblastic leukaemia (ALL) treatment. Incidence differs substantially among studies and the clinical significance of radiological findings is not fully established. We analysed 256 consecutive patients with ALL treated in our Institution between October 2010 and December 2016. Within the cohort, 41 developed ON, with a mean 5-year cumulative incidence of 18.5 (standard error, SE, 5.7)% overall. The mean (SE) 5-year cumulative incidence of ON was 12.7 (2.1)% after censoring upon stem cell transplantation (SCT) and/or relapse. Patients aged >= 10 years and patients allocated to the high-risk stratum had a 10-fold and fivefold higher risk of ON respectively. The risk of ON was more than double in relapsed patients, whereas no significant impact of gender, immunophenotype and SCT was demonstrated. Multiple lesions (median four joints involved per patient) were detected by magnetic resonance imaging in all but one patient, with the knee being the most affected joint. Lesions affecting convex joint surfaces experienced the worst evolution, whereas most lesions on diaphyses and concave surfaces remained radiologically stable or disappeared during follow-up. ON has a high prevalence in paediatric ALL, presenting with multiple lesions. Lesions involving convex surfaces were at higher risk of radiological deterioration.

Publisher Copyright: © 2020, The Author(s). Severe blood disorders and cancer are the leading cause of death and disability from noncommunicable diseases in the global pediatric population and a major financial burden. The most frequent of these conditions, namely sickle cell disease and severe thalassemia, are highly curable by blood or bone marrow transplantation (BMT) which can restore a normal health-related quality of life and be cost-effective. This position paper summarizes critical issues in extending global access to BMT based on ground experience in the start-up of several BMT units in middle-income countries (MICs) across South-East Asia and the Middle East where close to 700 allogeneic BMTs have been performed over a 10-year period. Basic requirements in terms of support systems, equipment, and consumables are summarized keeping in mind WHO’s model essential lists and recommendations. BMT unit setup and maintenance costs are summarized as well as those per transplant. Low-risk BMT is feasible and safe in MICs with outcomes comparable to high-income countries but at a fraction of the cost. This report might be of assistance to health care institutions in MICs interested in developing hematopoietic stem cell transplantation services and strengthening context appropriate tertiary care and higher medical education.

Isavuconazole is a new azole approved for adults with invasive aspergillosis and mucormycosis, with a favorable hepatic tolerability reported in Phase III trials. Here, we report on a case of drug-induced liver failure related to isavuconazole in a pediatric patient treated for invasive aspergillosis after bone marrow transplant.

Objective Adenovirus (AdV) infections are potentially life‐threatening for allogeneic hematopoietic stem cell transplant (allo‐HCT) recipients. The AdVance study aimed to evaluate the incidence, management, and outcomes of AdV infections in European allo‐HCT recipients. Methods As part of the study, physician surveys were conducted to determine current AdV screening and treatment practices at their center. Results All of the 28 respondents who treat pediatric patients reported routine AdV screening practices, with 93% screening all allo‐HCT recipients and others screening those with transplant‐related risk factors. Nearly all centers take a pre‐emptive approach to AdV treatment in both high‐ (89%) and low‐risk patients (75%). Among the 14 respondents who treat adult patients, 5 (36%) reported routine screening practices and few (21%) screen all allo‐HCT recipients unless risk factors are present. In adults, pre‐emptive AdV treatment is uncommon and quantitative AdV thresholds are rare. Typical treatment for all patients with symptomatic AdV infection is off‐label intravenous cidofovir. Conclusions Our findings confirm that screening for AdV is more common in pediatric patients. Antiviral treatment is employed in both pediatric and adult patients, although adults are generally treated when AdV disease is diagnosed. The approach to AdV screening and treatment is risk‐based and consistent with clinical guidelines.

The start-up of new HSCT centers in low-middle income countries (LMIC) has received little attention, due to a lack of local resources and expertise,1 despite a high frequency of malignant and non-malignant conditions, such as thalassemia and sickle cell disease, requiring transplantation. As a result, many patients are forced to go abroad when a transplant is needed, with major problems for their families and the governments.

We describe the entire process leading to the start-up of a hematopoietic stem cell transplantation center at the Hiwa Cancer Hospital, in the city of Sulaymaniyah, Kurdistan Iraqi Region. This capacity building project was funded by the Italian Development Cooperation Agency and implemented with the support of the volunteer work of Italian professionals, either physicians, nurses, biologists and technicians. The intervention started in April 2016, was based exclusively on training and coaching on site, that represent a significant innovative approach, and led to a first autologous transplant in June 2016 and to the first allogeneic transplant in October. At the time of reporting, 9 months from the initiation of the project, 18 patients have been transplanted, 15 with an autologous and 3 with an allogeneic graft. The center at the HCH represents the first transplantation center in Kurdistan and the second in wide Iraq. We conclude that international development cooperation may play an important role also in the field of high-technology medicine, and contribute to improved local centers capabilities through country to country scientific exchanges. The methodology to realize this project is innovative, since HSCT experts are brought as volunteers to the center(s) to be started, while traditionally it is the opposite, i.e. the local professionals to be trained are brought to the specialized center(s).

Introduction: Blood or marrow transplantation (BMT) programs are largely insufficient to meet the growing need in MICs. Where BMT is not available families, charities or governments often seek for alternative programs, usually to send children abroad for BMT; this policy is associated with many drawbacks, including costs, and difficulties to manage transplant related complications after the patient return home. Evaluation of feasibility and sustainability plays a crucial role in the success of all cooperative projects but especially of high specialization ones. Materials and methods: In 2016 the first HSCTU inclusive of a pediatric section was developed in Iraqi Kurdistan at Hiwa Cancer Hospital of Sulaymaniah, thanks to a cooperative project funded by the Italian Agency for Development Cooperation and to the availability of professionals from specialized centers to train local personnel. After verifying with an appropriate grid that essential requirements were in place, a capacity building project was started. An intensive educational course was carried on initially and then, using a training on the job approach, all specific skills were set-up and/or implemented. A complete protocol handbook was created with involvement of the local staff; a staggered approach to the disease was chosen, starting from low risk diseases and moving later to high risk ones. After 3 years project the center is now completely autonomous; up to now they have been performed 158 transplants (autologous and allogeneic, both in adult and children) with results comparable with those of high-income countries (HICs). In a cohort of 26 pediatric patients with thalassemia the event free survival (EFS) is over 90% with a median follow up of 492 days. Next to this experience, in 2018 a new project has been activated in Paraguay, following a specific request from the pediatric hospital Ninos de Acosta Nu in Asuncion. The similar methodology has been applied. After documenting the feasibility, a 3 years project has been set-up, with an initial intensive educational course, followed by training on the job by experts in the field and also limited training of the local staff abroad. A six months continuously oversight by experienced nurses and periodically by expert physicians has been planned along with the continuous support through on line contacts; focused training in Europe on minimal residual disease, chimerism, apheresis and HLA typing has been scheduled. The first allogeneic transplant from matched sibling donor is planned in autumn 2019. Discussion: Based on our experience new centers should start with patients highly curable, low-risk matched sibling transplants, well-established context-appropriate protocols with minimal toxicity, proven high success rates and contained costs. If socio-economical context of the country and needs of the population allow to move to oncological patients, a staggered approach is suggested: from matched sibling donor transplant to mismatched ones. Minimal essential requirements for a pediatric BMT start-up activity may be affordable in many MICs, if health authorities and/or local charities/foundations are committed. This shall include good quality blood products (leuco-reduced or irradiated); drugs for conditioning regimens (busulphan, tiothepa, fludarabine, cyclophosphamide, melphalan), GVHD prophylaxis and treatment (methotrexate, thymoglobuline, cyclosporine, mycophenolate mofetil), infections control (broad spectrum antibiotics, one anti-mold drug, ganciclovir) and essential laboratory tests (at least cyclosporin levels and citomegalovirus copies count). Conclusion: The strategy described above requires the availability of expert BMT physicians and nurses willing to rotate periodically in MICs Units for training on the job and supervision. This model is replicable in different contexts, allows a fast development of BMT units in MICs, and in our opinion compares favorably with that of offering training to multiple professionals in specialized centers. Figure Disclosures No relevant conflicts of interest to declare.

Central precocious puberty (CPP), the onset of sexual development before age 8 in girls, reflects early activation of the hypothalamic-pituitary-gonadal axis and currently is treated with a gonadotropin-releasing hormone analog (GnRHa). One of the goals of such treatment is to slow bone maturation and thereby increase final adult height. Some patients, however, grow at a less than optimal rate and become short-statured as a result. This open-label study was carried out in 20 girls with CPP who experienced marked growth deceleration (height velocity below the 25th centile for age) during GnRHa treatment. All of them continued to receive 3.75 mg Leuprorelina intramuscularly at monthly intervals. Ten girls (group 1) also received, by mouth, 0.06 mg/kg daily of the androgen oxandrolone (Ox). The remaining 10 girls (group 2) continued to receive only the GnRHa. The groups were matched for chronologic age, bone age, the duration of GnRH analog treatment (averaging 5 years), and the degree of growth deceleration. In both groups, plasma concentrations of luteinizing hormone and follicle-stimulating hormone remained suppressed, rising to appropriate levels within 18 months of the time that GnRHa treatment stopped. Menarche occurred an average of 16 and 18 months after treatment stopped in groups 1 and 2, respectively. Bone age progressed regularly in both groups. When GnRHa treatment began, predicted adult height (PAH) in patients in group 1 did not differ significantly from that recorded at the time Ox was added. At the end of combined treatment, PAH was significantly higher than at the time of diagnosis and at the start of GnRHa therapy. Final height significantly exceeded target height in patients in group 1, was similar to the PAH at the end of treatment, and was significantly higher than when GnRHa treatment began. In patients in group 2, PAH at the start of treatment did not differ significantly from that at the time GnRHA therapy ended. Their final height was similar to the PAH at both the beginning of treatment and its end. Target height was not reached and it significantly exceeded final height. The gap between pretreatment PAH and final height in patients in group 1 differed significantly from that in patients in group 2 (7.8 vs -3.8 cm). The same was the case for the difference between final height and target height (4.6 vs -4.2 cm). No adverse effects were noted in either treatment group. Treatment did not alter circulating levels of insulin-like growth factor I. Adding oxandrolone to GnRHa treatment in girls with idiopathic CPP whose growth has markedly decelerated improves final height without causing significant side effects. In the present study, combined treatment permitted the girls to reach a final height greater than the target height. This was not the case for girls who continued to receive only GnRHa whose final height was lower than target height.

Catheter-related bacteremias carry high mortality rates in hematological patients. When a multidrug-resistant microorganism is involved, the catheter should ideally be removed; however, this approach is not always possible. Tigecycline lock therapy was used in two pediatric oncohematological patients with intravascular catheter-related infection due to KPC-producing Klebsiella pneumoniae . The catheter was salvaged in both cases, and the patients were later discharged. Our experience suggests the usefulness of this approach in treating this type of infection.

We tested the possibility to prepare a hyperproteic and hyperenergetic supplementary food for malnutrition rehabilitation in children starting from available ingredients in popular markets in Sierra Leone. Twelve residents in Paediatrics from University of Parma, Italy, prepared in a hospital near the capital Freetown with modest technology a mixture of peanut flour, palm oil, milk powder, sugar and vitamins to which they gave the name of "Parma pap". Three hundred and thirty-two malnourished children (mean age 14±6.3 months) who were receiving Feeding Program Supplementations (FPS), were enrolled in the study: 177 participants received randomly FSP portions only (Group 1), and 159 participants were treated with FSP regimen plus a supplement of "Parma pap" (Group 2). Outcomes of the study were computed as WHZ-score increment (Δ value) by subtracting the discharge WHZ-score from the admission WHZ-score. The best Δ-WHZ-scores (gt;+4) were recorded among participants of Group 2 (64%) rather than in Group 1 (21%; p=0.040). The children receiving FSP portions plus "Parma pap" recovered faster (5.54 week on average) than those treated with FSP regimen only (8.16 on average). The percentage of children who did not recover was higher in Group 1 (25.3%) than in Group 2 (; 13%; p=0.05). A slight positive correlation has been found between WHZ-scores at admission and at the end of the study (r=0.19; p=0.045). During the experience in Sierra Leone we have had the chance to give "Parma pap" to twenty one malnourished children admitted to Xaverian Mission in Makeni, northern Sierra Leone, not taking other supplementary food. Sixteen of these children recovered in 4.9 week on average and five in 6 to 8 weeks. Mean Δ-WHZ-scores ranged between + 1 and + 5. The data from the present study suggest that "Parma pap" could be an effective additional food to FPS regimen in malnutrition recovering. Further researches are needed on the contrary to prove if "Parma pap" could be defined as a veritable ready to use therapeutic food, although this characteristic seems already to result from the experience in Makeni Mission.

Leishmaniasis is a parasitic disease that is transmitted through a bite of some species of sandflies. It is caused by obliged intra-cellular protozoa of the genus Leishmania and is responsible for a broad spectrum of clinical syndromes: cutaneous leishmaniasis (CL), visceral leishmaniasis (VL) and mucocutaneous leishmaniasis (ML). The visceral disease (classically known as "kala azar") is the most aggressive form and if undervalued is fatal. Here we describe the first case of visceral leishmaniasis in the Tharaka District reported in literature.

Kawasaki disease is an acute febrile disease of unknown etiology, characterized by systemic vascular inflammation involving the small and medium sized arteries, with a predilection for the coronary arteries. It represents the leading cause of acquired heart diseases in children in developed countries. Diagnosis, difficult because of the clinical characteristics of the disease with typical signs and symptoms appearing sequentially and not simultaneously, may be even more complicated in case of unusual presentation, leading to delay in recognition, particularly in infant in whom a higher incidence of coronary arteries aneurysms has been reported. A high index of suspicion of Kawasaki disease must be maintained in case of prolonged fever in these patients. Timely appropriate treatment is essential to avoid severe sequels. We report the case of a 2 months old male infant with persistent febrile episode, transferred to us from another institution, who presented on echocardiography giant aneurysms on both coronary arteries.