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Primary hemophagocytic lymphohistiocytosis (pHLH) is a severe, life-threatening hyperinflammatory syndrome caused by defects in genes of the granule-dependent cytotoxic pathway. Here we investigated the clinical presentation and outcome in a large cohort of 143 patients with pHLH diagnosed in the last 15 years and enrolled in the Italian registry. The median age at diagnosis was 12 months (interquartile range, 2-81), and 92 patients (64%) fulfilled the HLH-2004 criteria. Of 111 patients who received first-line combined therapy (HLH-94, HLH-2004, Euro-HIT protocols), 65 (59%) achieved complete response and 21 (19%) partial response. Thereafter, 33 patients (30%) reactivated, and 92 (64%) received hematopoietic stem cell transplantation, 78 of whom (85%) survived and were alive at a median follow-up from diagnosis of 67 months. Thirty-six patients (25%) died before hematopoietic stem cell transplantation and 14 (10%) after. Overall, 93 patients (65%) were alive after a median follow-up of 30 months. Unadjusted predictors of non-response were age <6 months and high ferritin and bilirubin levels, while predictors of pre-transplant and overall mortality were high ferritin and bilirubin levels. At multivariable analysis, high levels of ferritin predicted non-response, while high levels of bilirubin predicted pre-transplant and overall mortality. Despite recent advances in therapeutic management, pHLH remains a life-threatening condition with significant early mortality. Liver dysfunction is the main predictor of poor prognosis.

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.)

Post-transplantation lymphoproliferative disorder (PTLD) is a severe complication of haematopoietic stem cell transplantation (HSCT), occurring in a setting of immune suppression and dysregulation. The disease is in most cases driven by the reactivation of the Epstein-Barr virus (EBV), which induces B cell proliferation through different pathomechanisms. Beyond EBV, many factors, variably dependent on HSCT-related immunosuppression, contribute to the disease development. PTLDs share several features with primary lymphomas, though clinical manifestations may be different, frequently depending on extranodal involvement. According to the WHO classification, histologic examination is required for diagnosis, allowing also to distinguish among PTLD subtypes. However, in cases of severe and abrupt presentation, a diagnosis based on a combination of imaging studies and EBV-load determination is accepted. Therapies include prophylactic and pre-emptive interventions, aimed at eradicating EBV proliferation before symptoms onset, and targeted treatments. Among them, rituximab has emerged as first-line option, possibly combined with a reduction of immunosuppression, while EBV-specific cytotoxic T lymphocytes are effective and safe alternatives. Though prognosis remains poor, survival has markedly improved following the adoption of the aforementioned treatments. The validation of innovative, combined approaches is the future challenge.

Patients given allogeneic hematopoietic stem cell transplantation (alloHSCT) present an increased incidence of long-term toxicities that can be attributed to the preparative regimen. We retrospectively analyzed in a population of 670 children receiving allo-HSCT for acute leukemia the occurrence of different late effects in function of the choice made between total body irradiation (TBI) and busulfan, as part of the preparative regimen. In univariable analysis, we found that patients treated with TBI developed cataract in 24% of the cases compared with 4% in patients treated with BU (p = 0.0001) and that the incidence of secondary malignant neoplasia (SMN) was higher in patients treated with TBI (18%) as compared with those prepared to the allograft with a Bu-based regimen (0%) (p = 0.019). Conditioning regimen did not show a statistically significant correlation with the occurrence of all the other investigated late effects. In multivariable analysis, TBI remained associated with the occurrence of cataracts (Relative Risk: 0.33 p = 0.012) and secondary malignancies (Relative Risk 3.96 × 10e-6 p < 0.001); however, other variables, as GvHD and disease type, were also correlated with these long-term sequels, indicating that in our study population the preparative regimen is not the only factor influencing the incidence of these complications.

Relapse of acute lymphoblastic leukemia (ALL) may occur in extramedullary sites, mainly central nervous system (CNS) and testis. Optimal post-remissional treatment for isolated extramedullary relapse (IEMR) is still controversial. We collected data of children treated with hematopoietic stem cell transplantation (HSCT) for ALL IEMR from 1990 to 2015 in Italy. Among 281 patients, 167 had a relapse confined to CNS, 73 to testis, 14 to mediastinum, and 27 to other organs. Ninety-seven patients underwent autologous HSCT, 79 received allogeneic HSCT from a matched family donor, 75 from a matched unrelated donor, and 30 from an HLA-haploidentical donor. The 10-year overall survival was 56% and was not influenced by gender, ALL blast immune-phenotype, age, site of relapse, duration of first remission, and type of HSCT. In multivariable analysis, the only prognostic factors were disease status at HSCT and year of transplantation. Patients transplanted in third or subsequent complete remission (CR) had a risk of death 2.3 times greater than those in CR2. Children treated after 2000 had half the risk of death than those treated before that year. Our results suggest that both autologous and allogeneic HSCT may be considered for the treatment of pediatric ALL IEMR after the achievement of CR2.

Traditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating children with acute leukemia (AL) in need of an allograft. Recently, HLA-haploidentical HSCT after αβ T-cell/B-cell depletion (αβhaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 matched UD (MUD), 118 mismatched UD (MMUD), and 98 αβhaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and αβhaplo-HSCT groups. In MUD vs MMUD-HSCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute graft-versus-host disease (GVHD) was 35% vs 44% and 6% vs 18%, respectively, compared with 16% and 0% in αβhaplo-HSCT recipients ( P < .001). Children treated with αβhaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GVHD ( P < .01). Eight (6%) MUD, 32 (28%) MMUD, and 9 (9%) αβhaplo-HSCT patients died of transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55%, and 62%, respectively. In the 3 groups, chronic GVHD-free/relapse-free (GRFS) probability of survival was 61%, 34%, and 58%, respectively ( P < .001). When compared with patients given MMUD-HSCT, αβhaplo-HSCT recipients had a lower cumulative incidence of nonrelapse mortality and a better GRFS ( P < .001). These data indicate that αβhaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available., (© 2018 by The American Society of Hematology.)

Background: Although rabbit anti-T-lymphocyte globulin (ATLG) is largely used for the prevention of immune-mediated complications in patients given allogeneic haemopoietic stem-cell transplantation (HSCT) from an unrelated donor, the optimum dose of this drug in children is still undefined. We aimed to test whether a higher dose of ATLG was superior to a lower dose for prevention of grade II-IV acute graft-versus-host disease (GVHD)., Methods: We conducted a multicentre, randomised, open-label, phase 3 trial in seven Italian centres comparing two different doses of ATLG (30 mg/kg vs 15 mg/kg, given intravenously over 3 days, from day -4 to -2) in children (aged 0-18 years) with haematological malignancies transplanted from an unrelated donor, selected using high-resolution typing for HLA-class I/II loci. All patients received a myeloablative regimen and cyclosporine-A plus short-term methotrexate as post-transplantation GVHD prophylaxis. Patients were randomly assigned (1:1) to either of the two groups and were stratified by the degree of HLA-compatibility with their donor, the source of haemopoietic stem cells used (bone marrow vs peripheral blood stem cells), and the disease risk category. The randomisation was open label; all investigators were aware of the treatment allocation. The primary endpoint of the study was 100-day cumulative incidence of grade II-IV acute GVHD. Statistical analyses were done according to the per-protocol principle. Other outcomes included cumulative incidence of chronic GVHD, non-relapse mortality, disease recurrence, and probability of overall survival and event-free survival. This study was registered with ClinicalTrials.gov, number NCT00934557., Findings: Between Jan 15, 2008, and Sept 25, 2012, 89 patients were randomly assigned to the 30 mg/kg ATLG group and 91 to the 15 mg/kg ATLG group; 84 patients in the 30 mg/kg ATLG group and 88 in the 15 mg/kg ATLG group were included in the analysis. The median follow-up for the whole study population was 3·4 years (IQR 1·7-5·1). The 100-day cumulative incidence of grade II-IV acute GVHD was 36% (95% CI 28-48) in the 15 mg/kg ATLG group and 29% (20-40) in the 30 mg/kg ATLG group (hazard ratio [HR] 0·74, 95% CI 0·44-1·25; p=0·26). The cumulative incidence of non-relapse mortality was 9% (5-18) in the 15 mg/kg ATLG group and 19% (12-30) in the 30 mg/kg ATLG group (HR 2·08, 0·89-4·96; p=0·092). Cumulative incidence of disease recurrence was 15% (12-24): 14% (8-23) in the 15 mg/kg ATLG group versus 20% (13-31) in the 30 mg/kg ATLG group (HR 1·54, 0·74-3·21; p=0·25). The 5-year overall survival probability was 70% (62-77) for the whole study population: 78% (69-87) in the 15 mg/kg ATLG group versus 62% (50-73) in the 30 mg/kg ATLG group (HR 1·80, 1·01-3·20; p=0·045). The 5-year event-free survival was 77% for children in the 15 mg/kg ATLG group versus 61% in the 30 mg/kg ATLG group (HR 1·87, 1·07-3·28; p=0·028)., Interpretation: Children with haematological malignancies transplanted from unrelated donors selected through high-resolution HLA-typing benefit from the use of a 15 mg/kg ATLG dose in comparison with a 30 mg/kg ATLG dose. ATLG at 15 mg/kg should thus be regarded as the standard serotherapy regimen for unrelated donor allogeneic HSCT in this patient population. Future randomised studies will continue to aim to optimise patient outcome and strategies to prevent acute GVHD occurrence., Funding: Fresenius/Neovii Biotech., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative option for patients with Diamond Blackfan anaemia (DBA). We report the transplantation outcome of 30 Italian DBA patients referred to the Italian Association of Paediatric Haematology and Oncology Registry between 1990 and 2012. This is one of the largest national registry cohorts of transplanted DBA patients. Most patients (83%) were allografted after 2000. A matched sibling donor was employed in 16 patients (53%), the remaining 14 patients (47%) were transplanted from matched unrelated donors. Twenty-eight of the 30 patients engrafted. One patient died at day +6 due to veno-occlusive disease without achieving neutrophil recovery and another patient remained transfusion-dependent despite the presence of a full donor chimerism. The 5-year overall survival and transplant-related mortality was 74·4% and 25·6%, respectively. Patients younger than 10 years as well as those transplanted after 2000 showed a significantly higher overall survival and a significantly lower risk of transplant-related mortality. No difference between donor type was observed. Our data suggest that allogeneic HSCT from a related or unrelated donor was a reasonable alternative to transfusion therapy in young and well chelated DBA patients., (© 2014 John Wiley & Sons Ltd.)

Children with high-risk acute lymphoblastic leukemia in first complete remission can benefit from allogeneic hematopoietic stem cell transplantation. We analyzed the outcome of 211 children with high-risk acute lymphoblastic leukemia in first complete remission who were given an allogeneic transplant between 1990 and 2008; the outcome of patients who, despite having an indication for transplantation and a suitable donor, did not receive the allograft for different reasons in the same time period was not analyzed. Sixty-nine patients (33%) were transplanted between 1990 and 1999, 58 (27%) between 2000 and 2005, and 84 (40%) between 2005 and 2008. A matched family donor was employed in 138 patients (65%) and an unrelated donor in 73 (35%). The 10-year probabilities of overall and disease-free survival were 63.4% and 61%, respectively. The 10-year cumulative incidences of transplantation-related mortality and relapse were 15% and 24%, respectively. After 1999, no differences in either disease-free survival or transplant-related mortality were observed in patients transplanted from unrelated or matched family donors. In multivariate analysis, grade IV acute graft-versus-host disease was an independent factor associated with worse disease-free survival. By contrast, grade I acute graft-versus-host disease and age at diagnosis between 1 and 9 years were favorable prognostic variables. Our study, not intended to evaluate whether transplantation is superior to chemotherapy for children with acute lymphoblastic leukemia in first complete remission and high-risk features, shows that the allograft cured more than 60% of these patients; in the most recent period, the outcome of recipients of grafts from matched family and unrelated donors was comparable.

Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) still represents a major challenge. We report the experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP) with allogeneic hematopoietic stem cell transplantation (HSCT) in children with Ph+ ALL from 1990 to 2008. Sixty-nine patients received HSCT from either a related (37, 54%) or an unrelated (32, 46%) donor. Twenty-five patients (36%) underwent transplantation before 2000 and 44 (64%) after 2000. Twenty-three patients (33%) received Imatinib mesylate treatment before HSCT and seven (10%) after HSCT. After a median follow-up of 56 months, the overall survival (OS) probability was 51% (95% confidence interval [CI], 38-63), the leukemia-free survival (LFS) was 47% (95% CI, 34-59), transplantation-related mortality (TRM) was 17% (95% CI, 10-30), and relapse incidence (RI) was 36% (95% CI, 26-50). Transplantation in first complete remission, female gender, and lower WBC count at diagnosis were associated with a better LFS in both univariate and multivariate analyses. Patients with p210 transcript had a trend for a worse prognosis compared with those who had the p190 transcript. Our series confirms the role of HSCT in the eradication of Ph+ ALL. Early HSCT is recommended once morphologic remission is obtained., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Immune reconstitution after allogeneic stem cell transplantation protects against opportunistic infections and disease relapse. Identifying the most protective lymphocyte subset would have implications of adoptive immunotherapy. We followed up a case series of 34 allogeneic transplantations for pediatric leukemias, aplastic anemias, or solid tumors. Regardless of baseline hematologic disorder, the speed of reconstitution of cytotoxic CD8 T lymphocytes and the achieving of the 10th percentile of normal CD4 T lymphocytes (but not B lymphocytes or natural killer cells) conditioned overall survival. The source of hematopoietic stem cells (peripheral blood vs bone marrow) and the occurrence of graft-versus-host disease (either acute or chronic) did not impact on immune reconstitution. Larger case series are needed to confirm the pivotal role of cytotoxic CD8 T lymphocytes in overall survival.

Acute lymphoblastic leukemia (ALL) in second complete remission is one of the most common indications for allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients. We compared the outcome after HCST of adolescents, aged 14 to 18 years, with that of children (ie, patients < 14 years of age). Enrolled in the study were 395 patients given the allograft between January 1990 and December 2007; both children (334) and adolescents (61) were transplanted in the same pediatric institutions. All patients received a myeloablative regimen that included total body irradiation in the majority of them. The donor was an HLA-identical sibling for 199 patients and an unrelated volunteer in the remaining 196 patients. Children and adolescents had a comparable cumulative incidence of transplantation-related mortality, disease recurrence, and of both acute and chronic graft-versus-host disease. The 10-year probability of overall survival and event-free survival for the whole cohort of patients were 57% (95% confidence interval, 52%-62%) and 54% (95% confidence interval, 49%-59%), respectively, with no difference between children and adolescents. This study documents that adolescents with ALL in second complete remission given HSCT in pediatric centers have an outcome that does not differ from that of patients younger than 14 years of age.

We carried out a randomized, multicenter study comparing the inception of cyclosporine- A (CsA) on day -7 to conventional CsA (on day -1) to evaluate the influence of this modification on graft-versus-host disease (GVHD), treatment-related mortality (TRM), relapse rate (RR), and event-free survival (EFS) in children with hematologic malignancies given unrelated donor (UD) hematopoietic stem cell transplantation (HSCT). Between 1997 and 2002, 152 children transplanted for acute leukemia (102), myelodysplastic syndromes (23), chronic myelogenous leukemia (20), and non-Hodgkin lymphoma (7) were enrolled in the study and randomized to receive either early CsA (group 1, N = 72) or conventional CsA (group 2, N = 80), after stratification according to HLA compatibility and disease phase. The cumulative incidence of both grade II-IV and grade II-IV acute GVHD (aGVHD), as well as of chronic GVHD (cGVHD), did not differ between the 2 groups. No significant differences were observed also with regard to TRM and RR. The 8-year Kaplan-Meier estimates of EFS were 56% in group 1, and 46% in group 2 (P = NS). In the Cox model, advanced disease phase, male recipient, older donor, and occurrence of grade III-IV aGVHD predicted inferior overall EFS. These data indicate that early inception of CsA does not improve posttransplantation outcome of children with hematologic malignancies given UD-HSCT.

This report assessed the results of allogeneic stem cell transplantation (allo-SCT) in 26 patients with Shwachman-Diamond disease (SDS) and severe bone marrow abnormalities. The conditioning regimen was based on busulphan (54%), total body irradiation (23%), fludarabine (15%) or other chemotherapy combinations (8%). Standard prevention of graft versus host disease (GVHD) with cyclosporin +/- methotrexate was adopted in 54% of the patients whilst in vivo or in vitro T-cell depletion was used in 17 and four patients respectively. Neutrophil and platelet engraftment were achieved in 21 (81%) and 17 (65%) of 26 patients after a median time of 18 days and 29 days respectively. The incidence of grade III and IV acute GVHD was 24% and of chronic GVHD 29%. Nine patients died after a median time of 70 d, post-SCT. After a median follow-up of 1.1 years, the transplant-related mortality was 35.5% (95% CI 17-54) whilst the overall survival was 64.5% (95% CI 45.7-83.2). Allo-SCT was found to be successful in more than half of SDS patients with severe bone marrow dysfunction. Further improvements would be anticipated by a better definition of the optimum time in the course of disease to transplant and by the adoption of less toxic conditioning regimens.

Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). However, only a few studies specifically focused on children, and little information is available on the antileukemic effect of cGVHD and its impact on disease-free survival (DFS) in children. We retrospectively analyzed 696 children given allogeneic HSCT for malignant (n = 450) or nonmalignant (n = 246) diseases. The donor was an HLA-identical sibling in 461 cases and an alternative donor in 235. Bone marrow was the stem cell source in 647 cases, peripheral blood in 17, and cord blood (CB) in 32. cGVHD developed in 173 children (25%) at a median of 116 days after HSCT. Three-year cGVHD probability was 27%. In multivariate analysis, variables predicting cGVHD were donor and recipient age, grade II to IV acute GVHD, female donor for male recipient, diagnosis of malignancy, and use of total body irradiation; CB transplants had a very low risk of cGVHD (RR = 0.07, P =.0001). cGVHD occurrence increased transplant-related mortality (P <.05). Nevertheless, in hematologic malignancies, patients with cGVHD had a reduced relapse probability compared with children without cGVHD (16% +/- 3% versus 39% +/- 3%, P =.0001) and a better DFS (68% +/- 4% versus 54% +/- 3%, P =.01). The antileukemic effect of cGVHD was observed mainly in patients with acute lymphoblastic leukemia (ALL). This study provides novel data on cGVHD in childhood. Use of CB stem cells and preparative regimens without radiotherapy may prevent its development. In patients affected by ALL, cGVHD was associated with a strong graft-versus-leukemia effect, improving DFS.

STAT3 gain-of-function (GOF) mutations can be responsible for an incomplete phenotype mainly characterized by hematological autoimmunity, even in the absence of other organ autoimmunity, growth impairment, or severe infections. We hereby report a case with an incomplete form of STAT3 GOF intensified by a concomitant hereditary hematological disease, which misleads the diagnosis. The patient presented with lymphadenopathy, splenomegaly, hypogammaglobulinemia, and severe autoimmune hemolytic anemia (AIHA) with critical complications, including stroke. A Primary Immune Regulatory Disorders (PIRD) was suspected, and molecular analysis revealed a de novo STAT3 gain-of-function mutation. The response to multiple immune suppressive treatments was ineffective, and further investigations revealed a spectrin deficiency. Ultimately, hematopoietic stem cell transplantation from a matched unrelated donor was able to cure the patient. Our case shows an atypical presentation of STAT3 GOF associated with hereditary spherocytosis, and how achievement of a good long-term outcome depends on a strict clinical and laboratory monitoring, as well as on prompt therapeutic intervention. [ABSTRACT FROM AUTHOR]

In the last decades, the therapeutic potential of hematopoietic stem cell transplantation (HSCT) has acquired a primary role in the management of a broad spectrum of diseases including cancer, hematologic conditions, immune system dysregulations, and inborn errors of metabolism. The different types of HSCT, autologous and allogeneic, include risks of severe complications including acute and chronic graft-versus-host disease (GvHD) complications, hepatic veno-occlusive disease, lung injury, and infections. Despite being a dangerous procedure, it improved patient survival. Hence, its use was extended to treat autoimmune diseases, metabolic disorders, malignant infantile disorders, and hereditary skeletal dysplasia. HSCT is performed to restore or treat various congenital conditions in which immunologic functions are compromised, for instance, by chemo- and radiotherapy, and involves the administration of hematopoietic stem cells (HSCs) in patients with depleted or dysfunctional bone marrow (BM). Since HSCs biology is tightly regulated by oxidative stress (OS), the control of reactive oxygen species (ROS) levels is important to maintain their self-renewal capacity. In quiescent HSCs, low ROS levels are essential for stemness maintenance; however, physiological ROS levels promote HSC proliferation and differentiation. High ROS levels are mainly involved in short-term repopulation, whereas low ROS levels are associated with long-term repopulating ability. In this review, we aim summarize the current state of knowledge about the role of β3-adrenoreceptors (β3-ARs) in regulating HSCs redox homeostasis. β3-ARs play a major role in regulating stromal cell differentiation, and the antagonist SR59230A promotes differentiation of different progenitor cells in hematopoietic tumors, suggesting that β3-ARs agonism and antagonism could be exploited for clinical benefit. [ABSTRACT FROM AUTHOR]

Abstract CD25 deficiency is a very rare autosomal recessive disorder that shows a clinical phenotype highly overlapping IPEX syndrome with an increased susceptibility to viral, bacterial, and fungal infections. It is due to mutations in the IL2Rα gene that codes for the α subunit of the IL2 receptor complex. Here we report the characterization of a novel IL2Rα gene mutation leading to a severe protein conformational alteration that abrogates its cell surface expression in a child presenting with early-onset IPEX-like disorder. Cytofluorimetric analysis revealed the total absence of CD25 cell surface expression and addressed IL2Rα molecular investigation. The early clinical and molecular diagnosis of CD25 deficiency in this patient promptly led to hematopoietic stem cell transplantation (HSCT), allowing complete resolution of the symptoms and definitive cure of the disease. Highlights • Novel homozygous missense IL2Rα gene mutation. • Cytofluorimetric analysis as diagnostic tool of CD25 deficiency. • Homology Modeling as method to confirm IL2Rα mutated protein instability. [ABSTRACT FROM AUTHOR]

We report on 109 patients with hemophagocytic lymphohistiocytosis (HLH) undergoing 126 procedures of allogeneic hematopoietic stem cell transplantation (HSCT) between 2000 and 2014 in centers associated with the Italian Pediatric Hematology Oncology Association. Genetic diagnosis was FHL2 (32%), FHL3 (33%), or other defined disorders known to cause HLH (15%); in the remaining patients no genetic abnormality was found. Donor for first transplant was an HLA-matched sibling for 25 patients (23%), an unrelated donor for 73 (67%), and an HLA-partially matched family donor for 11 children (10%). Conditioning regimen was busulfan-based for 61 patients (56%), treosulfan-based for 21 (20%), and fludarabine-based for 26 children (24%). The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 71% and 60%, respectively. Twenty-six patients (24%) died due to transplant-related causes, whereas 14 (13%) and 10 (9%) patients experienced graft rejection and/or relapse, respectively. Twelve of 14 children given a second HSCT after graft failure/relapse are alive and disease-free. Use of HLA-partially matched family donors was associated with higher risk of graft failure and thus with lower EFS (but not with lower OS) in multivariable analysis. Active disease at transplantation did not significantly affect prognosis. These data confirm that HSCT can cure most HLH patients, active disease not precluding successful transplantation. Because in HLH patients HLA-haploidentical HSCT performed through CD34 + cell positive selection was found to be associated with poor sustained engraftment of donor cells, innovative approaches able to guarantee a more robust engraftment are warranted in patients given this type of allograft. [ABSTRACT FROM AUTHOR]