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Aims: To evaluate cardiopulmonary exercise tolerance in a large cohort of apparently healthy paediatric cancer survivors in order to determine their participation in sporting activities.Methods: A total of 84 young (<21 years) asymptomatic childhood cancer survivors, who had been exposed to anthracyclines (mean dose 212 mg/m[2]) and/or chest irradiation (median dose 2000 cGy), with normal left ventricular systolic function at rest (fractional shortening >29%), and 79 healthy controls were studied. Exercise testing was performed on a treadmill ergometer. Gas exchange analysis and derived variables were measured on a breath-by-breath basis. Pulmonary functional evaluation was performed before exercise. Echocardiographic evaluation at rest was performed within one month before the exercise test.Results: There were no differences in exercise responses between patients and controls. In boys <13 years, mean VO[2] max was slightly but significantly lower than in controls. This finding was thought to be a result of decreased physical fitness as all the other exercise parameters were similar to those in the controls.Conclusions: Results show that apparently healthy survivors of paediatric cancer can take part in dynamic sporting activities if they exhibit a normal response to cardiopulmonary exercise testing, while those that exhibit a reduced VO[2] max should be re-evaluated after an aerobic training programme, and should undergo tailored dynamic physical activity if the VO[2] max does not normalise. [ABSTRACT FROM AUTHOR]

Malignant autosomal recessive (AR) osteopetrosis represents an absolute indication for bone marrow transplantation (BMT). Over the last 15 years, almost 100 BMTs for osteopetrosis have been reported. The median age at transplant of most patients is 4 months. Very few cases of mild AR osteopetrosis have been described. Here, we report the good outcome of two cases of mild AR osteopetrosis with a follow-up of 5 and 6 years, respectively, after an HLA-identical sibling transplant undergone at 5 and 12 years of age, respectively. At the time of BMT, severe visual impairment was present in both children. Bone biopsy demonstrated hypermineralization with virtual obliteration of the medullary spaces, rare microfoci of hematopoiesis and marked deficiency in osteoclastic activity. Successful engraftment was complicated by hypercalcemia, controlled by a combination of bisphosphonate, phosphate infusions, vigorous hydration and calcitonin. Following BMT, radiological and histological findings showed extensive bone resorption with marked augmentation of the osteoclasts in normalized marrow. No improvement was observed in visual acuity, despite complete remodeling of skeletal abnormalities. We conclude that allogeneic BMT is the only chance of curing mild AR osteopetrosis. Bone Marrow Transplantation (2000) 26, 219–224. [ABSTRACT FROM AUTHOR]

Caspofungin, in association with other antifungal drugs, was administered as rescue therapy in two cases of documented and one case of possible invasive fungal infection in children with acute leukaemia or undergoing allogeneic bone marrow transplant. The combined therapy was well-tolerated and seemed to be effective in all three patients. A combination antifungal therapy including caspofungin could represent an effective therapy for children with invasive mycoses refractory to single-agent antifungal therapy. [ABSTRACT FROM AUTHOR]

Abstract: In REACH4, a phase 1/2, open-label, single-arm, multicenter study, the pharmacokinetics (PK), efficacy, and safety of ruxolitinib were evaluated in treatment-naïve and steroid-refractory pediatric patients with grade 2 to 4 acute graft-versus-host disease (aGVHD; n = 45). Ruxolitinib dosing was based on age and targeted the exposure in adults receiving 10 mg twice daily; group 1 (aged ≥12 to <18 years) received 10 mg twice daily and preliminary starting doses for groups 2 (aged ≥6 to <12 years) and 3 (aged ≥2 to <6 years) were 5 mg twice daily and 4 mg/m2 twice daily, respectively. The phase 1 primary objective was to assess ruxolitinib PK parameters and define an age-appropriate recommended phase 2 dose (RP2D) for patients aged <12 years. The phase 2 primary objective was to measure the activity of ruxolitinib as assessed by overall response rate (ORR) at day 28; the key secondary objective was to assess the durable ORR at day 56. Ruxolitinib exposure was comparable across age groups; starting doses were confirmed as the RP2D. The median duration of ruxolitinib exposure was 3.8 months (range, 0.3-11.2). ORR in all patients was 84.4% (90% confidence interval [CI], 72.8-92.5) at day 28, with a durable ORR at day 56 of 66.7% (90% CI, 53.4-78.2); high response rates were observed across age groups and in both treatment-naïve and steroid-refractory subgroups. Adverse events were consistent with those expected in patients with aGVHD (anemia, decreased neutrophil and leukocyte count) treated with ruxolitinib. In pediatric patients with aGVHD, ruxolitinib showed clinically meaningful efficacy with no new safety signals. This trial was registered at www.clinicaltrials.gov as #NCT03491215., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: CMV reactivation represents a frequent complication after HSCT. The aim of this study was to describe the incidence of CMV reactivation in a pediatric HSCT cohort and analyze the potential impact of recipient/donor-related or transplant-related factors on this complication. Furthermore, we analyzed the management of CMV reactivation in order to purpose criteria for pre-emptive therapy., Methods: Allogeneic HSCTs, performed at IRCCS Istituto Gaslini between 2012 and 2022, were included in this analysis. CMV-DNAemia was regularly monitored. Risk stratification was based on donor/recipient serological status and additional potential risk factors were considered: haploidentical transplant; any HSCT subsequent to the first; acute and chronic GvHD; steroids; and other immunosuppressive therapies. We described also the approach for pre-emptive therapy during the period 2012-2019., Results: A total of 214 allogeneic HSCTs were performed in 189 patients. In total, 100 (46.7%) HSCTs were complicated by at least one reactivation. CMV reactivation was significantly associated with high serological risk and steroid treatment. Pre-emptive therapy was administered in 59/69 (85.5%) HSCTs during 2012-2019. In the presence of predefined risk conditions, therapy was started at a median viremia of 2050 copies/mL. No difference was observed in OS between patients with CMV reactivation versus patients who did not present this complication., Conclusions: These results suggest the potential effectiveness of the approach used in providing pre-emptive therapy based on viral load monitoring and individualized risk factors.

Background: Epstein-Barr virus (EBV) reactivation represents a frequent condition after allogeneic hematopoietic stem cell transplantation (allo-HCT) and can cause the development of a severe complication: post-transplant lymphoproliferative disease (PTLD). This retrospective study aims at investigating the incidence of EBV reactivations and analyzing the potential impact of recipient/donor-related transplant-related factors in pediatric patients. The secondary objective was to study the consequences of the approach used at our center regarding the initiation of pre-emptive therapy., Methods: This study used a retrospective evaluation of patients aged ≤25 years who received an allo-HCT at IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Giannina Gaslini, between 2012 and 2022, with follow-up censored in July 2023. Criteria to start rituximab were as follows: a viral load ≥20,000 copies/10 5 PBMCs or ≥10,000/10 5 PBMCs associated with a rise in the proportion of CD 20+ lymphocytes., Results: Overall, 214 allo-HCTs were performed in 189 patients. A total of 127 (59.3%) procedures were complicated by at least one EBV reactivation, but in only one rituximab was administered. All other reactivations were characterized by viremia below reference ranges and no increase in CD20+ lymphocytes, without clinical consequences. Risk factors for EBV reactivation identified were associated with delayed immune reconstitution., Conclusion: These results could suggest the effectiveness of the approach used in providing pre-emptive therapy. The strategy adopted differs from that highlighted by other studies and allowed the reduction of the number of children who received rituximab. It has proven effective considering the low incidence rate of PTLD and reduces the risk of rituximab-related adverse events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ferrando, Bagnasco, Pierri, Pestarino, Dell’Orso, Giardino, Di Marco, Santaniello, Castagnola and Faraci.)

Abstract: Up to 70% of patients with Wiskott-Aldrich syndrome (WAS) develop autoimmune and inflammatory manifestations. Dysregulation of interleukin 1 (IL-1) may be involved in their pathogenesis, yet there is little evidence on treatment with anti-IL-1 agents in these patients. We conducted a multicenter retrospective analysis of 9 patients with WAS treated with anti-IL-1 agents (anakinra or canakinumab). All patients had prominent inflammatory manifestations, including systemic, cutaneous, articular, and intestinal symptoms; 3 patients presented with a severe systemic inflammatory syndrome since the first months of life. Corticosteroid therapy was associated with partial or no response, whereas treatment with anakinra or canakinumab resulted in prompt, often dramatic, responses in all patients, allowing bridging to gene therapy (4 patients) or hematopoietic stem cell transplantation (HSCT; 5 patients). Treatment was overall well tolerated. Low donor myeloid chimerism developed in 4 patients after HSCT and was associated with the appearance or the recurrence of inflammatory manifestations. A second HSCT was performed in 2 patients, achieving full-donor chimerism and resolution of inflammatory manifestation, whereas the other 2 patients were treated with prolonged therapy with anti-IL-1 agents. Our experience demonstrates that some inflammatory manifestations of WAS are dependent on IL-1 and respond well to its pharmacologic blockade., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Acute central nervous system (CNS) complications are common and well described among pediatric patients undergoing haematopoietic cell transplantation (HCT). However, their long-term outcomes are not known. The aim of this study is to describe the incidence, characteristics, and risk factors of long-term epilepsy in pediatric patients with acute CNS complications of HCT., Methods: This retrospective study included pediatric patients who developed acute CNS complications from autologous or allogeneic HCT between 2000 and 2022. Clinical, therapeutic and prognostic data including long-term outcomes were analyzed. A diagnosis of epilepsy was provided if unprovoked seizures occurred during follow-up., Results: Ninety-four patients (63 males, 31 females, median age 10 years, range 1-21 years) were included. The most common acute CNS complications were posterior reversible encephalopathy syndrome (n = 43, 46 %) and infections (n = 15, 16 %). Sixty-five patients (69 %) had acute symptomatic seizures, with 14 (16 %) having one or more episodes of status epilepticus (SE). Nine patients (9.6 %) were diagnosed with long-term focal epilepsy during the follow-up (5-year cumulative incidence from the acute complication, 13.3 %). Acute symptomatic SE during neurological complications of HCT was associated with an increased risk of long-term epilepsy (OR=14, 95 % CI 2.87-68.97)., Conclusions: A higher occurrence of epilepsy has been observed in our cohort compared to the general population. Acute symptomatic SE during HCT was associated with a higher risk of long-term epilepsy. Pediatric patients with CNS complications during HCT could benefit from specific neurological follow-up. Further studies are needed to characterize mechanisms of epileptogenesis in pediatric patients undergoing HCT., Competing Interests: Declaration of competing interest The Authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative option for Fanconi anemia (FA)-associated bone marrow failure (BMF)/aplastic anemia (AA) and acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS). We performed a retrospective multicenter study on 813 children with FA undergoing first HSCT between 2010 and 2018. Median duration of follow-up was 3.7 years. Median age at transplant was 8.8 years (IQR, 6.5-18.1). Five-year overall survival (OS), event-free survival (EFS), and graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) were 83% (95% confidence interval [CI], 80-86), 78% (95% CI, 75-81), and 70% (95% CI, 67-74), respectively. OS was comparable between matched family donor (MFD; n = 441, 88%) and matched unrelated donor (MUD; n = 162, 86%) and was superior to that of mismatched family donor (MMFD) or mismatched unrelated donor (MMUD; n = 144, 72%) and haploidentical donor (HID; n = 66, 70%; P < .001). In multivariable analysis, a transplant indication of AML/MDS (vs AA/BMF), use of MMFD/MMUD and HID (vs MFD), and fludarabine-cyclophosphamide (FluCy) plus other conditioning (vs FluCy) independently predicted inferior OS, whereas alemtuzumab vs antithymocyte globulin was associated with better OS. Age ≥10 years was associated with worse EFS and GRFS. Cumulative incidences (CINs) of primary and secondary graft failure were 2% and 3% respectively. CINs of grade 3 to 4 acute GVHD and chronic GVHD were 12% and 8% respectively. The 5-year CIN of secondary malignancy was 2%. These data suggest that HSCT should be offered to patients with FA with AA/BMF at a younger age in the presence of a well-matched donor., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Congenital amegakaryocytic thrombocytopenia is a rare, inherited bone marrow failure syndrome. Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is currently the only curative treatment. In this retrospective study, we analysed 66 patients with allo-HSCT, reported in the European Society for Blood and Marrow Transplantation (EBMT) registry. Bone marrow (BM) was the most widely used stem cell source (n = 40; 61%) followed by peripheral blood (PB) (n = 18; 27%), and unrelated umbilical cord blood (UCB) (n = 8; 12%). Most frequently was a HLA-matched graft from related (n = 26; 39%) and unrelated (n = 15; 23%) donors after a myeloablative busulfan-based conditioning regimen. GvHD prophylaxis was mostly cyclosporine and methotrexate (53%). The 6-year cumulative incidence of graft-failure and second transplant were 25% and 17%, respectively. The 6-year disease-free survival (DFS) and overall survival (OS) were 66.9% and 85.6%, respectively. The 6-year transplant-related mortality (TRM) was 8.0%. In conclusion, most patients with CAMT benefit from allo-HSCT, but with many graft failures., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The optimal management of hemorrhagic cystitis (HC) in hematopoietic stem cell transplantation (HCT) is debated, both for early onset HC (EOHC) secondary to chemotherapy toxicity and BK Polyomavirus (BKPyV)-related HC, due to the lack of controlled trials, particularly referred to pediatric setting. Actually, clinical practice is mainly based on guidelines of the European Conference on Infections in Leukemia, 6 th edition, which considers both adult and pediatric populations but concludes that, despite much progress in understanding the pathogenesis, epidemiology, and risk factors, this complication still represents a disabling unmet clinical need with limited prophylactic and therapeutic options. Additionally, the Guidelines of the American Society of Clinical Oncology define the management of chemotherapeutic toxicity independently from the patients' population. A panel of experts belonging to the Hematopoietic Cell Transplant and Infectious Disease Working Group (WG) of Associazione Italiana di Emato-Oncologia Pediatrica (AIEOP) developed a consensus to define the best practices in prevention, diagnosis, and management of HC in pediatric HCT setting., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Abstract: HLA-mismatched transplants with either in vitro depletion of CD3+ T-cell receptor (TCR)αβ/CD19 (TCRαβ) cells or in vivo T-cell depletion using posttransplant cyclophosphamide (PTCY) have been increasingly used for patients with inborn errors of immunity (IEIs). We performed a retrospective multicenter study via the EBMT registry on 306 children with IEIs undergoing their first transplant between 2010 and 2019 from an HLA-mismatched donor using TCRαβ (n = 167) or PTCY (n = 139). The median age for hematopoietic stem cell transplantation (HSCT) was 1.2 years (range, 0.03-19.6 years). The 3-year overall survival (OS) was 78% (95% confidence interval (CI), 71-84) after TCRαβ and 66% (57-74) after PTCY (P = .013). Pre-HSCT morbidity score (hazard ratio [HR], 2.27; 1.07-4.80, P = .032) and non-busulfan/treosulfan conditioning (HR, 3.12; 1.98-4.92, P < .001) were the only independent predictors of unfavorable OS. The 3-year event-free survival (EFS) was 58% (50%-66%) after TCRαβ and 57% (48%-66%) after PTCY (P = .804). The cumulative incidence of severe acute graft-versus-host disease (GvHD) was higher after PTCY (15%, 9%-21%) than TCRαβ (6%, 2%-9%, P = .007), with no difference in chronic GvHD (PTCY, 11%, 6%-17%; TCRαβ, 7%, 3%-11%, P = .173). The 3-year GvHD-free EFS was 53% (44%-61%) after TCRαβ and 41% (32%-50%) after PTCY (P = .080). PTCY had significantly higher rates of veno-occlusive disease (14.4% vs TCRαβ 4.9%, P = .009), acute kidney injury (12.7% vs 4.6%, P = .032), and pulmonary complications (38.2% vs 24.1%, P = .017). Adenoviremia (18.3% vs PTCY 8.0%, P = .015), primary graft failure (10% vs 5%, P = .048), and second HSCT (17.4% vs 7.9%, P = .023) were significantly higher in TCRαβ. In conclusion, this study demonstrates that both approaches are suitable options in patients with IEIs, although they are characterized by different advantages and outcomes., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

In children with acute myeloid leukemia (AML) who lack a human leukocyte antigen (HLA) identical sibling, the donor can be replaced with an HLA-matched unrelated donor (MUD) or a haploidentical donor (haplo). We compared outcomes of patients <18 years with AML in first and second complete remission (CR1 and CR2) undergoing a hematopoietic stem cell transplantation (HCT) either with a MUD with anti-thymocyte globulin (ATG) (N=420) or a haplo HCT with post-transplant cyclophosphamide (PT-CY) (N=96) after a myeloablative conditioning regimen (MAC) between 2011 and 2021, reported to the European Society for Blood and Marrow Transplantation. A matched pair analysis was performed to adjust for differences among groups. The final analysis was performed on 253 MUD and 95 haplo-HCT. In the matched cohort, median age at HCT was 11.2 and 10 years and median year of HCT was 2017 and 2018, in MUD and haplo-HCT recipients, respectively. The risk of grade III-IV acute graft-versus-host disease (aGVHD) was significantly higher in the haplo group (hazard ratio [HR]=2.33, 95% confidence interval [CI]: 1.18-4.58; P=0.01). No significant differences were found in 2 years overall survival (OS; 78.4% vs. 71.5%; HR=1.39, 95% CI: 0.84-2.31; P=0.19), leukemia-free survival (LFS; 72.7% vs. 69.5%; HR=1.22, 95% CI: 0.76-1.95; P=0.41), CI of relapse (RI; 19.3% vs. 19.5%; HR=1.14, 95% CI: 0.62-2.08; P=0.68) non-relapse-mortality (NRM; 8% vs. 11%; HR=1.39, 95% CI: 0.66-2.93; P=0.39) and graft-versus-host free relapse-free survival (GRFS; 60.7% vs. 54.5%, HR=1.38, 95% CI: 0.95-2.02; P=0.09) after MUD and haplo-HCT respectively. Our study suggests that haplo-HCT with PT-CY is a suitable option to transplant children with AML lacking a matched related donor.

This prospective multicentre trial evaluated the safety and the efficacy of a thiotepa/melphalan-based reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) in children and adolescents with chronic myeloid leukaemia (CML) in chronic phase (CP). Thirty-two patients were transplanted from matched siblings or matched unrelated donors. In 22 patients, HSCT was performed due to insufficient molecular response or loss of response to first- or second-generation tyrosine kinase inhibitor (TKI), with pretransplant BCR::ABL1 transcripts ranging between 0.001% and 33%. The protocol included a BCR::ABL1-guided intervention with TKI retreatment in the first year and donor lymphocyte infusions (DLI) in the second-year post-transplant. All patients engrafted. The 1-year transplant-related mortality was 3% (confidence interval [CI]: 0%-6%). After a median follow-up of 6.3 years, 5-year overall survival and event-free survival are 97% (CI: 93%-100%) and 91% (CI: 79%-100%) respectively. The current 5-year leukaemia-free survival with BCR::ABL1 <0.01% is 97% (CI: 88%-100%) and the current TKI- and DLI-free survival is 95% (CI: 85%-100%). The incidence of chronic graft-versus-host disease (GvHD) was 32%, being severe in four patients (13%). At last follow-up, 31 patients are GvHD-free and have stopped immunosuppression. RIC HSCT following pretreatment with TKI is feasible and effective in children and adolescents with CP-CML with an excellent disease-free and TKI-free survival., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Haploidentical stem cell transplantation (haplo-SCT) represents the main alternative for children with inherited bone marrow failure syndrome (I-BMF) lacking a matched donor. This retrospective study, conducted on behalf of the EBMT SAAWP and PDWP, aims to report the current outcomes of haplo-SCT in I-BMFs, comparing the different in vivo and ex vivo T-cell depletion approaches. One hundred and sixty-two I-BMF patients who underwent haplo-SCT (median age 7.4 years) have been registered. Fanconi Anemia was the most represented diagnosis (70.1%). Based on different T-cell depletion (TCD) approaches, four categories were identified: (1) TCRαβ + /CD19 + -depletion (43.8%); (2) T-repleted with post-transplant Cyclophosphamide (PTCy, 34.0%); (3) In-vivo T-depletion with ATG/alemtuzumab (14.8%); (4) CD34 + positive selection (7.4%). The cumulative incidences (CI) of neutrophil and platelet engraftment were 84% and 76% respectively, while that of primary and secondary graft failure was 10% and 8% respectively. The 100-day CI of acute GvHD grade III-IV(95% CI) was 13%, while the 24-month CI of extensive chronic GvHD was 4%. After a median follow-up of 43.4 months, the 2-year overall survival(OS) and GvHD/Rejection-free Survival (GRFS) probabilities are 67% and 53%, respectively. The TCR CD3 + αβ + /CD19 + depletion group showed a significantly lower incidence of both acute and chronic GvHD and higher OS (79%; p0.013) and GRFS (71%; p < .001), while no significant differences in outcomes have been observed by different diagnosis and conditioning regimens. This large retrospective study supports the safety and feasibility of haplo-SCT in I-BMF patients. TCRαβ + /CD19 + depletion offers higher chances of patients' survival, with a significantly lower risk of severe a- and c-GvHD in I-BMFs compared to other platforms., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Despite aggressive multimodal treatment, the outcomes of pediatric patients with high-risk (HR) neuroblastoma (NB) remain poor. The rationale for allogeneic hematopoietic stem cell transplantation (allo-HCT) to treat NB was based on the possible graft-versus-tumor effect; however, toxicity limits its efficacy. We sought to prospectively assess the feasibility and efficacy of allo-HCT using a reduced-intensity conditioning regimen in pediatric patients with HR NB in a multicenter phase II trial. Primary endpoints were the rate of neutrophil and platelet engraftment, 5-year transplantation-related mortality (TRM), and disease-free survival (DFS). Secondary endpoint measures included the incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD. Fifty-one patients were enrolled in the study. The 5-year cumulative incidence (CuI) of TRM was 29.4 ± 6.4%, and that of DFS was 11.8 ± 4.5%. Patients undergoing allo-HCT within 1 year of diagnosis or with bone marrow as their stem cell source had a higher DFS probability. The CuI of neutrophil engraftment, platelet engraftment, and grade II-IV aGVHD was 97.9 ± 2.1%, 93.8 ± 3.5%, and 47.1 ± 7.0%, respectively. The development of new therapeutic strategies could further improve disease control., (Copyright © 2024. Published by Elsevier Inc.)

Hematopoietic cell transplantation (HCT) remains the sole available curative treatment for Fanconi anemia (FA), with particularly favorable outcomes reported after matched sibling donor (MSD) HCT. This study aimed to describe outcomes, with a special focus on late complications, of FA patients who underwent umbilical cord blood transplantation (UCBT). In this retrospective analysis of allogeneic UCBT for FA performed between 1988 and 2021 in European Society for Blood and Marrow Transplantation (EBMT)-affiliated centers, a total of 205 FA patients underwent UCBT (55 related and 150 unrelated) across 77 transplant centers. Indications for UCBT were bone marrow failure in 190 patients and acute leukemia/myelodysplasia in 15 patients. The median age at transplantation was 9 years (range, 1.2 to 43 years), with only 20 patients aged >18 years. Among the donor-recipient pairs, 56% (n = 116) had a 0 to 1/6 HLA mismatch. Limited-field radiotherapy was administered to 28% (n = 58) and 78% (n = 160) received a fludarabine (Flu)-based conditioning regimen. Serotherapy consisted of antithymocyte globulin (n = 159; 78%) or alemtuzumab (n = 12; 6%). The median follow-up was 10 years for related UCBT and 7 years for unrelated UCBT. Excellent outcomes were observed in the setting of related UCBT, including a 60-day cumulative incidence (CuI) of neutrophil recovery of 98.1% (95% confidence interval [CI], 93.9% to 100%), a 100-day CuI of grade II-IV acute graft-versus-host disease (GVHD) of 17.3% (95% CI, 9.5% to 31.6%), and a 5-year CuI of chronic GVHD (cGVHD) of 22.7% (95% CI, 13.3% to 38.7%; 13% extensive). Five-year overall survival (OS) was 88%. In multivariate analysis, none of the factors included in the model predicted a better OS. In unrelated UCBT, the 60-day CuI of neutrophil recovery was 78.7% (95% CI, 71.9% to 86.3%), the 100-day CuI of grade II-IV aGVHD was 31.4% (95% CI, 24.6% to 40.2%), and the 5-year CuI of cGVHD was 24.3% (95% CI, 17.8% to 32.2%; 12% extensive). Five-year OS was 44%. In multivariate analysis, negative recipient cytomegalovirus serology, Flu-based conditioning, age <9 years at UCBT, and 0 to 1/6 HLA mismatch were associated with improved OS. A total of 106 patients, including 5 with acute leukemia/myelodysplasia, survived for >2 years after UCBT. Nine of these patients developed subsequent neoplasms (SNs), including 1 donor-derived acute myelogenous leukemia and 8 solid tumors, at a median of 9.7 years (range, 2.3 to 21.8 years) post-UCBT (1 related and 8 unrelated UCBT). In a subset of 49 patients with available data, late nonmalignant complications affecting various organ systems were observed at a median of 8.7 years (range, 2.7 to 28.8 years) post-UCBT. UCB is a valid source of stem cells for transplantation in patients with FA, with the best results observed after related UCBT. After unrelated UCBT, improved survival was observed in patients who underwent transplantation at a younger age, with Flu-based conditioning, and with better HLA parity. The incidence of organ-specific complications and SNs was relatively low. The incidence of SNs, mostly squamous cell carcinoma, increases with time. Rigorous follow-up and lifelong screening are crucial in survivors of UCBT for FA., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Poor-risk (PR) cytogenetic/molecular abnormalities generally direct pediatric patients with acute myeloid leukemia (AML) to allogeneic hematopoietic stem cell transplant (HSCT). We assessed the predictive value of cytogenetic risk classification at diagnosis with respect to post-HSCT outcomes in pediatric patients. Patients younger than 18 years at the time of their first allogeneic HSCT for AML in CR1 between 2005 and 2022 who were reported to the European Society for Blood and Marrow Transplantation registry were subgrouped into four categories. Of the 845 pediatric patients included in this study, 36% had an 11q23 abnormality, 24% had monosomy 7/del7q or monosomy 5/del5q, 24% had a complex or monosomal karyotype, and 16% had other PR cytogenetic abnormalities. In a multivariable model, 11q23 (hazard ratio [HR] = 0.66, P = 0.03) and other PR cytogenetic abnormalities (HR = 0.55, P = 0.02) were associated with significantly better overall survival when compared with monosomy 7/del7q or monosomy 5/del5q. Patients with other PR cytogenetic abnormalities had a lower risk of disease relapse after HSCT (HR = 0.49, P = 0.01) and, hence, better leukemia-free survival (HR = 0.55, P = 0.01). Therefore, we conclude that PR cytogenetic abnormalities at diagnosis predict overall survival after HSCT for AML in pediatric patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Patients undergoing hematopoietic stem cell transplantation (HSCT) for hematologic malignancies during childhood have an increased risk of developing long-term sequelae that are in part attributable to the conditioning regimen. The present study aimed to assess the occurrence of long-term toxicities in a population of children who underwent HSCT for hematologic malignancies using either treosulfan or busulfan in the conditioning regimen. The cumulative incidences of growth impairment, altered gonadal function, altered thyroid function, cataracts, secondary malignant neoplasia, and altered pulmonary function were evaluated retrospectively by univariable and multivariable analyses in a population of 521 pediatric patients with acute leukemias or myelodysplastic syndromes treated in 20 Italian transplant centers affiliated with the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP). The median duration of follow-up for the entire study population was 7.1 years (range, 1 to 16 years). Overall, a larger proportion of patients given busulfan developed long-term toxicities compared to patients treated with treosulfan (34% versus 20%; P = .01). In univariable analysis, gonadal toxicity developed in 10% of patients who received treosulfan (95% confidence interval [CI], 3% to 15%), compared with 38% (95% CI, 24% to 39%) of busulfan-treated patients (P = .02), and this finding was confirmed by multivariable analysis (relative risk, .51; 95% CI, .34 to .76; P = .0009). We did not find any statistically significant associations between the occurrence of other long-term toxicities and the use of either busulfan or treosulfan. This study provides evidence that the use of treosulfan is correlated with a reduced incidence of gonadal toxicity in children undergoing HSCT for hematologic malignancies., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

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., (© 2024. The Author(s).)

Background: Infections are the main reason for mortality during acute leukaemia treatment and invasive aspergillosis (IA) is a major concern. Allogeneic stem cell transplantation (alloSCT) is a standard therapy and often is the only live-saving procedure in leukaemia patients. The profound immunodeficiency occurring after alloSCT led to high IA-associated mortality in the past. Therefore, patients with IA were historically considered transplant-ineligible. Recently, there has been improvement of anti-fungal management including novel anti-fungal agents. As a result, more leukaemia patients with IA are undergoing alloSCT. Outcome has not been prospectively assessed., Methods: We performed a prospective study in acute leukaemia patients undergoing alloSCT to analyse the impact of a prior history of probable or proven IA (pre-SCT IA). The primary endpoint was 1-year non-relapse mortality (NRM). Relapse free survival and overall survival were analysed as secondary endpoints., Findings: 1439 patients were included between 2016 and 2021. The incidence of probable or proven pre-SCT IA was 6.0% (n = 87). The cumulative incidence of 1-year NRM was 17.3% (95% CI 10.2-26.0) and 11.2% (9.6-13.0) for patients with and without pre-SCT IA. In multivariate analyses the hazard ratio (HR) for 1-year NRM was 2.1 (1.2-3.6; p = 0.009) for patients with pre-SCT IA. One-year relapse-free survival was inferior in patients with pre-SCT IA (59.4% [48.3-68.9] vs. 70.4 [67.9-72.8]; multivariate HR 1.5 [1.1-2.1]; p = 0.02). Consequently, 1-year overall survival was lower in patients with pre-SCT IA: (68.8% [57.8-77.4] vs. 79.0% [76.7-81.1]; multivariate HR 1.7 [1.1-2.5]; p = 0.01)., Interpretation: Pre-SCT IA remains to be significantly associated with impaired alloSCT outcome. On the other hand, more than two thirds of patients with pre-SCT IA were alive at one year after alloSCT. IA is not anymore an absolute contraindication for alloSCT because the majority of patients with IA who undergo alloSCT benefit from this procedure., Funding: There was no external funding source for this study., Competing Interests: R.dlC. Has received honoraria from Pfizer and MSD; J.S. reports personal fees from Gilead, outside the submitted work. EDK reports grants from Gilead sciences, personal fees from Pfizer, outside the submitted work. L.Y. reports grants and personal fees from Janssen, personal fees from Abbvie, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Beigene, personal fees and non-financial support from Kite/Gilead, personal fees and non-financial support from Pfizer, outside the submitted work; S.M reports other from Celgene/BMS, other from Novartis, other from Kite/Gilead, other from Pfizer, other from Miltenyi, other from Mendes, other from SWECARNET, other from Scientify Research, outside the submitted work; J.M. reports personal fees and non-financial support from Gilead Sciences, personal fees and non-financial support from Mundipharma, personal fees and non-financial support from F2G, personal fees and non-financial support from Takeda, personal fees and non-financial support from Basilea, outside the submitted work; M.M. reports grants and personal fees from Gilead, personal fees from Mundipharma, personal fees from Pfizer, from null, outside the submitted work; H.P. reports non-financial support from Neovii, during the conduct of the study; OP has no COIs directly related to this work. HP reports non-financial support from Neovii during the conduct of the study; OP has received honoraria or travel support from Gilead, Jazz, MSD, Neovii, Novartis, Pfizer and Therakos. He has received research support from Incyte and Priothera. He is member of advisory boards to Equillium Bio, Jazz, Gilead, Novartis, MSD, Omeros, Orca Bio, Priothera, Sanofi, Shionogi and SOBI. T.Z. reports personal fees from AbbVie, personal fees from Orgenesis Inc, personal fees from BioSight Ltd, personal fees from Cellect Biotechnology, personal fees from Janssen, personal fees from Novartis, personal fees from Gilead Sciences, outside the submitted work. The remaining authors declare no conflict of interests., (© 2023 The Authors.)

Up-front allogeneic haematopoietic stem cell transplantation (allo-HSCT) after a reduced intensity conditioning regimen is the standard treatment in children with acquired severe aplastic anaemia (aSAA) and inherited bone marrow failure syndromes (iBMFs) in the presence of a healthy matched related donor (MRD). The paper by Alsultan et al. report the safety and efficacy of MRD HSCT conditioned with low-dose cyclophosphamide, fludarabine and thymoglobulin in both aSAA and non-Fanconi iBMFs, strengthening the concept of the pivotal role of immunosuppressive approach in allo-HSCT for specific subgroups of non-malignant diseases requiring a reduced risk of toxicities, offering the opportunity to discuss the essential points for achieving patients' long-term survival after MRD HSCT in BMF. Commentary on: Alsultan et al. Human leucocyte antigen-matched related haematopoietic stem cell transplantation using low-dose cyclophosphamide, fludarabine and thymoglobulin in children with severe aplastic anaemia. Br J Haematol 2023;203:255-263., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Personalization of busulfan (Bu) exposure via therapeutic drug monitoring (TDM) is recommended for patients treated with high-dose conditioning regimens. Several laboratories' developed methods are available in the literature with a lack of standardization. The aim of this study is to develop a new standardized LC-MS/MS method and validate it according to the international ICH M10 (EMA) guidelines. Our method is based on rapid protein precipitation from 50 µL plasma followed by separation on a reversed-phase C-18 UHPLC column after the addition of deuterated internal standard and has been tested on real samples from pediatric patients treated with myeloablative conditioning regimens, including Bu, before autologous or allogeneic hematopoietic stem cell transplantation (HSCT). The validated LC-MS/MS method is linear over wide concentration ranges (125-2000 ng/mL), accurate, and reproducible in the absence of matrix effects, allowing for the specific and rapid quantification of Bu and allowing next-dose recommendations to be made in a timely fashion to answer clinicians' needs. Given the lack of data on the stability of Bu in real clinical samples, stability was assessed both on quality controls and on real samples to set up a robust protocol in real-life conditions. This novel LC-MS/MS method is suitable for application to the TDM-guided personalization of conditioning treatments with high-dose busulfan in pediatric patients undergoing HSCT.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents an effective treatment for a variety of inborn errors of immunity (IEI). We report the experience of children affected by IEI who received allo-HSCT over a period of 32 years at IRCCS Istituto Giannina Gaslini, Genoa, Italy. HSCTs were performed in 67 children with IEI. Kaplan-Meier estimates of overall survival (OS) rate at 5 years in the whole group of patients was 83.4% after a median follow-up of 4 years. Median age at transplant was 2.5 years. Eight allo-HSCTs were complicated by either primary or secondary graft failure (GF), the overall incidence of this complication being 10.9%. Incidence of grade 3-4 acute GvHD (aGvHD) was 18.7%, significantly lower in the haploidentical transplant cohort ( p = 0.005). Year of transplant (≤2006 vs . >2006) was the main factor influencing the outcome. In fact, a significant improvement in 5-year OS was demonstrated (92.5% >2006 vs . 65% ≤2006, p = 0.049). Frequency of severe aGvHD was significantly reduced in recent years (≤2006 61.5%, vs . >2006 20%, p = 0.027). A significant progress has been the introduction of the TCR αβ/CD19-depleted haploidentical platform, which was associated with the absence of severe aGvHD. However, it was associated with 23.5% incidence of GF. All but one patient experiencing GF in the this specific cohort were successfully retransplanted. In summary, allo-HSCT is confirmed to be an effective treatment for children with IEI, even in the absence of an HLA-matched donor., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dell’Orso, Bagnasco, Giardino, Pierri, Ferrando, Di Martino, Micalizzi, Guardo, Volpi, Sabatini, Miano, Gattorno, Dufour and Faraci.)

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., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

In children affected by malignancies and/or who received hematopoietic stem cell transplantation (HSCT), acute kidney injury (AKI) may occur causing a high mortality rate, despite the implementation of renal replacement therapy (RRT). We performed a nationwide, multicenter, retrospective, observational cohort study including consecutive patients between January 2010 and December 2019. One hundred and fourteen episodes of AKI requiring RRT coming from nine different Italian centers were included. The overall mortality rate was 61.4%. At the 3-month follow-up, the mortality rate was 47.4%. The mortality rate was higher in transplanted patients than those receiving chemotherapy. In particular, HSCT ( p  = 0.048) and invasive mechanical ventilation ( p  = 0.040) were significantly associated with death at three months after the end of dialysis in the multivariate analysis. Pediatric patients affected by malignancies complicated by AKI requiring RRT have a high mortality. The main factors associated to death are respiratory failure and having received HSCT.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT., (© 2022 by The American Society of Hematology.)

Mutations in the ARPC1B isoform component of human actin-related protein 2/3 complex have been recently associated with an inborn error of immunity characterized by combined immunodeficiency, allergies, autoinflammation, and platelet abnormalities. Currently, indications on the management of this novel disease and information on its outcome are lacking. We report the first case series of 7 children with a homozygous mutation in ARPC1B gene who underwent allogeneic-HSCT (allo-HSCT). All patients presented an early clinical onset, characterized by recurrent infections, failure to thrive and gastrointestinal bleeding episodes complicated with neonatal hemorrhagic enteritis in 3 cases, and macrophage activating syndrome in 2. Allo-HSCT was performed at the median age of 1.83 years after a myeloablative conditioning regimen in all cases. Engraftment occurred in all patients with full donor chimerism in 6 out of 7. The clinical course after engraftment was uneventful in 3 out of 7 children; 2 patients developed a grade 1-2 acute graft-versus-host disease (GvHD), and 1 patient a grade 1 chronic-GvHD. JC virus-related progressive multifocal leukoencephalopathy was diagnosed in one patient 13 months after haploidentical-HSCT and successfully managed with donor-derived viral-specific T-cell infusion. Only one patient had a fatal outcome 3 months after HSCT because of sepsis, after veno-occlusive disease, and transplant-associated microangiopathy. At a median follow-up of 19 months (range 3-110), 6 out of 7 patients are alive and disease-free. The severity of the clinical phenotype at diagnosis and the high survival rate, with limited transplant-related morbidity, strongly support the indication to allo-HSCT for patients with this diagnosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Mevalonate kinase deficiency (MKD) is a rare autoinflammatory syndrome. Several reports have described allogeneic hematopoietic stem cell transplantation in severely affected patients, sometimes with promising results. In view of the scarcity of data, this study aims to analyse the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) to give a more complete overview of this treatment., Methods: This multicentre retrospective study on behalf of the European Society for Blood and Marrow Transplantation aimed to include all MKD patients who had undergone allogeneic HSCT. All centres related to EMBT and centres that have reported cases of allogeneic HSCT in the literature were contacted via the EBMT data office., Results: We analyzed 9 patients (5 male). Treosulfan based conditioning was the most frequently used conditioning regimen. Engraftment occurred in all but one patient. Source of stem cells was cord blood (n = 2), peripheral blood stem cells (n = 4) and bone marrow (n = 5). Two patients needed a second transplantation due to an incomplete response or primary graft failure. Seven patients went into complete remission after stem cell transplantation. At final follow-up these patients reported no symptoms of MKD. Four patients suffered from grade II-IV acute graft-versus-host disease (GvHD). During follow-up two patients died due to transplantation related complications., Conclusion: In conclusion, allogeneic stem cell transplantation represents an effective treatment for the most severely affected MKD patients. However, treatment-related morbidity and mortality are significant. Transplantation may be justified in patients with a severe disease course on conservative therapy., (© 2022. The Author(s).)

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a valuable alternative for children with nonmalignant disease and ex vivo negative selection of TCR-αβ + cells is an emerging graft manipulation option that carries several potential advantages in terms of reduced risk of graft-versus-host disease (GvHD) and improved immune reconstitution. We report all consecutive patients with a diagnosis of nonmalignant disease who received a TCR-αβ + and CD19 + depleted haplo-HSCT at "IRCCS Istituto Giannina Gaslini" from 2013 to 2019; the conditioning regimen was myeloablative or non-myeloablative, depending on underlying disease; all patients received antithymocyte globulin and rituximab. No post-transplantation GvHD prophylaxis was given in presence of a TCR-αβ + cell dose in the graft lower than the threshold of 1 × 10 5 /kg of the recipient's weight. Among 20 HSCTs, engraftment occurred in 17 (85%) after a median of 14 and 12 days from graft infusion for neutrophils and platelets, respectively. Primary graft failure was diagnosed in 3 (15%) patients, and 2 (10%) experienced secondary rejection; all of these patients underwent a second HSCT. The cumulative incidence of a-GvHD and c-GvHD was 15% (2 = grade 1, 1 = grade 4) at 90 days and 5% (1 = grade 1) at 7 months, respectively. Cytomegalovirus reactivation requiring pre-emptive treatment was observed in 9 patients (45%). One patient developed a JC virus-related progressive multifocal leukoencephalopathy, successfully managed with donor-derived virus-specific T-cell infusions. A complete immunological recovery was reached in most patients within 6 months. After a median follow-up of 4 years, 18 patients are alive, with a cumulative survival probability of 90%. Haplo-HSCT after ex vivo TCR-αβ + /CD19 + negative selection may be considered a good option for children with nonmalignant diseases because it ensures a high engraftment rate with an acceptable risk of graft failure, very low incidence of significant GvHD, and good immune reconstitution with low frequency of severe virus-related disease. However, the control of viral infection/reactivation should be kept high to promptly provide pre-emptive treatments and approaches of antiviral adoptive immunotherapy., Competing Interests: Conflict of interest statement There are no conflicts of interest to report. Authorship statement: SG contributed to data collection, material preparation, analysis of results, and wrote the manuscript. SG, MF, and EL contributed equally to the study conception and to the patient's management. FB performed all statistical analyses. MR and MF contributed to donor selection and management. MP and FS managed the graft manipulation. MM, FP, GD, BC and MR contributed to data collection and to the clinical management of patients. All authors contributed to the manuscript revision and approved its final version., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: Primary immune regulatory disorders encompass a range of clinical conditions caused by different defects of immune regulatory mechanisms, including systemic autoinflammatory diseases (AIDs). Allogeneic hematopoietic stem cell transplantation may be a therapeutic option for AIDs, particularly if response to conventional treatments is lacking., Areas Covered: HSCT has been reported as a possible therapeutic option in several AID subgroups, namely, inflammasomopathies, immuno-proteinopathies,actinopathies, relopathies, interferonopathies, and Adenosine Deaminase 2 deficiency. Here, an extensive review of the literature summarizes the available data on HSCT outcome in AIDs., Expert Opinion: HSCT in AIDs is mainly indicated in case of ineffectiveness of conventional therapies and/or co-existence of immunodeficiency in conditions characterized by a primary involvement of the hematopoietic compartment. An effective control of the inflammatory process before HSCT reduces the risk of alloreactivity. HLA identical family donor represents the first choice, but in most cases it is essential to exclude a possible carrier status. If a suitable HLA identical family donor is not available, a haploidentical donor with platform with T-depletion could offer some benefit lowering the risk of GvHD. Treosulfan-based conditioning regimens could be recommended to reduce toxicity and prevent rejection. Target chimerism may differ based on the primary disease's pathogenic mechanism.

Introduction: Autoimmune disease (AD) may occur after allogeneic hematopoietic stem cell transplantation (HSCT). The autoimmune mechanism seems to be related to an imbalance of the immune regulation effect of T-regulatory lymphocytes on autoreactive T-lymphocytes., Areas Covered: ADs include hematological ADs (HADs) and nonhematologic ADs (NHADs) involving organs such as thyroid, peripheral and central nervous system, skin, liver, connective tissue, gastrointestinal tract, and kidney. To identify the risk factors for ADs, to report their clinical characteristics, and to discuss new approaches represent the areas covered in this review., Expert Opinion: Some risk factors for HAD and NHAD are common and include nonmalignant diseases, young age, cord blood as a stem cell source, conditioning regimens without total body irradiation, alemtuzumab, antithymocyte globulin, T-cell-depleted transplant, some viral infection, mixed chimerism, and chronic Graft versus Host Disease. In NHADs, the detection of autoantibodies is more frequent and the transfer of autoimmunity from the donor to the recipient represents the pathogenetic mechanism responsible for these complications. New therapeutic approaches such as bortezomib, daratumumab, sirolimus, eculizumab, and eltrombopag appear to be promising in terms of better efficacy and reduced toxicity compared to traditional therapies. New horizons based on personalized therapies will allow us to improve the prognosis of AD.

Vaccines represent the best tool to prevent the severity course and fatal consequences of the pandemic by the new Coronavirus 2019 infection (SARS-CoV-2). Considering the limited data on vaccination of pediatric oncohematological patients, we developed a Consensus document to support the Italian pediatric hematological oncological (AIEOP) centers in a scientifically correct communication with families and patients and to promote vaccination. The topics of the Consensus were: SARS-CoV-2 infection and disease (COVID-19) in the pediatric subjects; COVID-19 vaccines (type, schedule); who and when to vaccinate; contraindications and risk of serious adverse events; rare adverse events; third dose and vaccination after COVID-19; and other general prevention measures. Using the Delphi methodology for Consensus, 21 statements and their corresponding rationale were elaborated and discussed with the representatives of 31 centers, followed by voting. A high grade of Consensus was obtained on topics such as the potential risk of severe COVID-19 outcome in pediatric oncohematological patients, the need for vaccination as a preventative measure, the type, schedule and booster dose of vaccine, the eligibility of the patients for vaccination, and the timing, definition, and management of contraindications and serious adverse events, and other general prevention measures. All 21 of the statements were approved. This consensus document highlights that children and adolescents affected by hematological and oncological diseases are a fragile category. Vaccination plays an important role to prevent COVID-19, to permit the regular administration of chemotherapy or other treatments, to perform control visits and hospital admissions, and to prevent treatment delays.

The objectives of this study were to describe clinical, histological, and endoscopic findings in children undergoing gastrointestinal (GI) endoscopy for symptoms of digestive acute graft-versus-host disease (a-GvHD), to evaluate the rate of steroid-resistant GvHD and transplant-related mortality, and to describe the feasibility and safety of the endoscopic procedure., Methods: This was a retrospective study conducted, at the IRCSS Istituto G. Gaslini in Genova, Italy, in 26 children undergoing upper or lower GI endoscopy after allogeneic hematopoietic stem cell transplantation between 2000 and 2017., Results: Histology confirmed a diagnosis of a-GvHD in 73% of patients; it was frequently associated with steroid-resistant a-GvHD ( P = 0.001) and with an increased transplant-related mortality. Additionally, one patient developed duodenal hematoma after endoscopy for a high-grade GI a-GvHD., Conclusions: In our experience, the endoscopic approach in the diagnosis of GI a-GvHD in children was feasible and safe. Furthermore, the histological diagnosis of GI a-GvHD was associated with an increased risk of steroid-resistant GvHD and with high transplant-related mortality., Competing Interests: The authors report no funding and conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: Drug resistant epilepsy has rarely been reported following posterior reversible encephalopathy syndrome (PRES), with few cases of mesial temporal sclerosis (MTS). The aim of this study was to report clinical and neuroimaging features of MTS subsequent to PRES in hemato-oncologic/stem cell transplanted children., Materials and Methods: Among 70 children treated in 2 pediatric hemato-oncologic Italian centers between 1994 and 2018 and presenting an episode of PRES, we retrospectively identified and analyzed a subgroup of patients who developed epilepsy and MTS., Results: Nine of 70 patients (12.8%) developed post-PRES persistent seizures with magnetic resonance imaging evidence of MTS. One patient died few months after MTS diagnosis, because of hematologic complications; the remaining 8 patients showed unprovoked seizures over time leading to the diagnosis of epilepsy, focal in all and drug resistant in 4. At PRES diagnosis, all patients with further evidence of epilepsy and MTS suffered of convulsive seizures, evolving into status epilepticus in 3. In 3 patients a borderline cognitive level or intellectual disability were diagnosed after the onset of epilepsy, and 2 had behavioral problems impacting their quality of life., Conclusions: MTS and long-term focal epilepsy, along with potential cognitive and behavioral disorders, are not uncommon in older pediatric patients following PRES., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)