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Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for bone marrow failure or hematopoietic malignant diseases for Fanconi anemia (FA) patients. Although results have improved over the last decades, reaching more than 90% survival when a human leukocyte antigen (HLA)-identical donor is available, alternative HCT donors are still less reported. We compared HCT outcomes using HLA-mismatched unrelated donors (MMUD; n = 123) or haplo-identical donors (HDs), either using only in vivo T cell depletion (n = 33) or T cells depleted in vivo with some type of graft manipulation ex vivo (n = 59) performed for FA between 2000 and 2018. Overall survival (OS) by 24 months was 62% (53-71%) for MMUD, versus 80% (66-95%) for HDs with only in vivo T cell depletion and 60% (47-73%) for HDs with in vivo and ex vivo T cell depletion (p = .22). Event-free survival (EFS) was better for HD-transplanted FA patients with only in vivo T cell depletion 86% (73-99%) than for those transplanted from a MMUD 58% (48-68%) or those with graft manipulation 56% (42-69%) (p = .046). Grade II-IV acute graft-versus-host disease (GVHD) was 41% (MMUD) versus 40% (HDs with no graft manipulation) versus 17% (HDs with T cell depleted graft), (p = .005). No differences were found for the other transplant related outcomes. These data suggest that HDs might be considered as an alternative option for FA patients with better EFS using unmanipulated grafts., (© 2021 Wiley Periodicals LLC.)

Unrelated allogeneic transplantation for severe aplastic anemia is a treatment option after immunosuppressive treatment failure in the absence of a matched sibling donor. Age, delay between disease diagnosis and transplantation, and HLA matching are the key factors in transplantation decisions, but their combined impact on patient outcomes remains unclear. Using the French Society of Bone Marrow Transplantation and Cell Therapies registry, we analyzed all consecutive patients (n=139) who underwent a first allogeneic transplantation for idiopathic severe aplastic anemia from an unrelated donor between 2000 and 2012. In an adjusted multivariate model, age over 30 years (Hazard Ratio=2.39; P=0.011), time from diagnosis to transplantation over 12 months (Hazard Ratio=2.18; P=0.027) and the use of a 9/10 mismatched unrelated donor (Hazard Ratio=2.14; P=0.036) were independent risk factors that significantly worsened overall survival. Accordingly, we built a predictive score using these three parameters, considering patients at low (zero or one risk factors, n=94) or high (two or three risk factors, n=45) risk. High-risk patients had significantly shorter survival (Hazard Ratio=3.04; P<0.001). The score was then confirmed on an independent cohort from the European Group for Blood and Marrow Transplantation database of 296 patients, with shorter survival in patients with at least 2 risk factors (Hazard Ratio=2.13; P=0.005) In conclusion, a simple score using age, transplantation timing and HLA matching would appear useful to help physicians in the daily care of patients with severe aplastic anemia., (Copyright© Ferrata Storti Foundation.)

Umbilical cord blood (UCB) from an human leucocyte antigen (HLA)-identical sibling can be used for transplantation of patients with malignant and non-malignant diseases. However, the low cellular content of most UCB units represents a limitation to this approach. An option to increase cell dose is to harvest bone marrow (BM) cells from the same donor and infuse them along with the UCB. We studied 156 children who received such a combined graft between 1992 and 2011. Median age was 7 years and 78% of patients (n = 122) were transplanted for non-malignant diseases, mainly haemoglobinopathies. Acute leukaemia (n = 26) was the most frequent malignant diagnosis. Most patients (91%) received myeloablative conditioning. Median donor age was 1·7 years, median infused nucleated cell dose was 24·4 × 10(7) /kg and median follow-up was 41 months. Sixty-days neutrophil recovery occurred in 96% of patients at a median of 17 d. The probabilities of grade-II-IV acute and chronic graft-versus-host disease (GVHD) were 19% and 10%, respectively. Four-year overall survival was 90% (68% malignant; 97% non-malignant diseases) with 3% probability of death. In conclusion, combined UCB and BM transplantation from an HLA-identical sibling donor is an effective treatment for children with malignant and non-malignant disorders with high overall survival and low incidence of GVHD., (© 2014 John Wiley & Sons Ltd.)

Objective: To compare uterine and ovarian volumes and uterine artery (UA) Doppler blood flow among women who were treated with antineoplastic regimens when pediatric aged versus healthy controls., Design: Case-control study., Setting: Tertiary obstetric and gynecologic center., Patient(s): One hundred twenty-seven women who were treated for childhood cancer with bone marrow transplantation (BMT) and∖or chemotherapy and total body irradiation (TBI) and 64 age-matched healthy controls., Intervention(s): Ultrasonographic and clinical evaluations., Main Outcome Measure(s): Uterine and ovarian volume, detection of follicles, and UA pulsatility index (PI)., Result(s): Median uterus and ovarian volumes were reduced by 64% (95% CI, 56.6-70.6) and 83.6% (95% CI, 79.6-86.7), respectively, among cases compared with controls. Median UA PI among cases was increased by 30.3% (95% CI, 19.6-40.8) compared with controls. Ovarian follicles were identified in 24 (18.9%) of 127 cases and 25 (39%) of 64 controls. Uterine volume was reduced after TBI (percent reduction 81.9%; 95% CI, 71.8-87.8) or busulfan (percentage reduction 67.4%; 95% CI, 58.5-75.6) compared with those who had not received a conditioning regimen (percentage reduction 24.4%; 95% CI, 7.6-38.2). The only factors independently associated with reduced uterine and ovarian volumes compared with controls were TBI, busulfan, and BMT. The worst effect on UA PI resulted from BMT and a diagnosis of hematologic disease., Conclusion(s): Bone marrow transplantation as main treatment and TBI and busulfan as conditioning regimens had the worst effect on uterine and ovarian sizes compared with controls. These data should be considered in counseling families on preserving future fertility in children undergoing BMT., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Delayed hematopoietic recovery is the main factor precluding a wider use of cord blood (CB) transplants. We hypothesized that this delayed engraftment might not be related to an insufficient number of stem cells in the graft, but to an intrinsic difficulty of these cells to undergo differentiation. To test our hypothesis, 2 groups of children were compared; 12 received a CB transplant and 12 an adult bone marrow (BM) transplant. We studied neutrophil and platelet recovery and, at a median time of approximately 1 year after transplantation, the frequency of colony-forming cells (CFCs) and long-term culture initiating cells (LTC-ICs) in the BM of the 2 groups. Recipients of BM transplants received 1-log more cells and had significantly faster neutrophil and platelet recovery. Conversely, the frequency of committed and early progenitors was significantly higher in the BM of children given CB cells compared with BM transplant recipients (median count of CFC/2 x 10(4) BM mononuclear cells, 20 versus 11, P =.007; median count of LTC-IC/10(6) BM mononuclear cells, 8.2 versus 0.2 P =.001). CB, but not adult BM stem cells, can better restore the host hematopoietic progenitor cell reservoir; the delayed engraftment after CB transplantation may reflect the difficulty of CB progenitors to reprogram themselves toward differentiation.

Background and Objectives: Unrelated donor bone marrow transplant (UD-BMT) has become an attractive, alternative source of hematopoietic cells for patients lacking a matched sibling. The aim of this paper is to report on 520 patients below 19 years of age undergoing UD BMT in 31 Italian centers between September 1989 and December 2001, and to focus on the results achieved in the 423 patients grafted before December 2000., Designs and Methods: In 1989 the Italian Bone Marrow Transplant Group (GITMO) and the Italian Association for Pediatric Hematology and Oncology (AIEOP) established the Italian Bone Marrow Donor Registry (IBMDR) to facilitate donor search and marrow procurement for patients lacking an HLA identical sibling. By the end of December 2001, 296,720 HLA-A, B typed volunteer donors had been cumulatively registered and 3,411 searches had been activated for Italian patients. At least one HLA-A, B, DRB1 matched donor was found for 54% of the patients and 520 UD BMTs were performed in patients below 19 years of age before December 2001. Since 1999 more than 90% of the patients < or = 14 years old, and more than 50% of the patients 15-18 years old undergoing UD BMT have been treated in AIEOP institutions. In 50% of the cases donors were found in the IBMDR, and in 50% they were found in 14 other Registries. The average time from search activation to transplant was 6 months for diseases other than chronic myeloid leukemia (CML), while for CML it was 8.7 months., Results: Actuarial 100-day transplant-related mortality (TRM) was 32% in patients grafted between 1989 and 1997, and 21% for patients grafted after 1998 (p = 0.003). Twenty-eight per cent of the patients developed grade III or IV acute graft-versus-host disease (GvHD), and 20% developed extensive chronic GvHD. The rate of disease-free survival at three years was 37% for patients with acute lymphoblastic leukemia, 38% for acute myeloid leukemia or myelodysplastic syndrome patients, 59% for patients with inborn errors, and 51% for patients with CML., Interpretation and Conclusions: We conclude that the IBMDR has benefited a substantial number of patients lacking a matched sibling and has facilitated the recruitment of UDs into the international donor pool. Results show a positive trend after 1998, mainly due to a decrease in transplant-related-mortality.

BACKGROUND. The human bone marrow (BM) niche contains a population of mesenchymal stromal cells (MSCs) that provide physical support and regulate hematopoietic stem cell (HSC) homeostasis. [beta]-Thalassemia (BT) is a hereditary disorder characterized by altered hemoglobin beta-chain synthesis amenable to allogeneic HSC transplantation and HSC gene therapy. Iron overload (IO) is a common complication in BT patients affecting several organs. However, data on the BM stromal compartment are scarce. METHODS. MSCs were isolated and characterized from BM aspirates of healthy donors (HDs) and BT patients. The state of IO was assessed and correlated with the presence of primitive MSCs in vitro and in vivo. Hematopoietic supportive capacity of MSCs was evaluated by transwell migration assay and 2D coculture of MSCs with human CD3[4.sup.+] HSCs. In vivo, the ability of MSCs to facilitate HSC engraftment was tested in a xenogenic transplant model, whereas the capacity to sustain human hematopoiesis was evaluated in humanized ossicle models. RESULTS. We report that, despite iron chelation, BT BM contains high levels of iron and ferritin, indicative of iron accumulation in the BM niche. We found a pauperization of the most primitive MSC pool caused by increased ROS production in vitro which impaired MSC stemness properties. We confirmed a reduced frequency of primitive MSCs in vivo in BT patients. We also discovered a weakened antioxidative response and diminished expression of BM niche-associated genes in BT-MSCs. This caused a functional impairment in MSC hematopoietic supportive capacity in vitro and in cotransplantation models. In addition, BT-MSCs failed to form a proper BM niche in humanized ossicle models. CONCLUSION. Our results suggest an impairment in the mesenchymal compartment of BT BM niche and highlight the need for novel strategies to target the niche to reduce IO and oxidative stress before transplantation. FUNDING. This work was supported by the SR-TIGET Core grant from Fondazione Telethon and by Ricerca Corrente., Introduction [beta]-Thalassemia (BT) is one of the most common inherited monogenic disorders in the world, with an overall carrier rate of 1.5% of the world population, and 60,000 BT symptomatic [...]

The outcomes of adult patients transplanted for Fanconi anaemia ( FA) have not been well described. We retrospectively analysed 199 adult patients with FA transplanted between 1991 and 2014. Patients were a median of 16 years of age when diagnosed with FA, and underwent transplantation at a median age of 23 years. Time between diagnosis and transplant was shortest (median 2 years) in those patients who had a human leucocyte antigen identical sibling donor. Fifty four percent of patients had bone marrow ( BM) failure at transplantation and 46% had clonal disease (34% myelodysplasia, 12% acute leukaemia). BM was the main stem cell source, the conditioning regimen included cyclophosphamide in 96% of cases and fludarabine in 64%. Engraftment occurred in 82% (95% confidence interval [ CI] 76-87%), acute graft-versus-host disease (Gv HD) grade II- IV in 22% (95% CI 16-28%) and the incidence of chronic Gv HD at 96 months was 26% (95% CI 20-33). Non-relapse mortality at 96 months was 56% with an overall survival of 34%, which improved with more recent transplants. Median follow-up was 58 months. Patients transplanted after 2000 had improved survival (84% at 36 months), using BM from an identical sibling and fludarabine in the conditioning regimen. Factors associated with improved outcome in multivariate analysis were use of fludarabine and an identical sibling or matched non-sibling donor. Main causes of death were infection (37%), Gv HD (24%) and organ failure (12%). The presence of clonal disease at transplant did not significant impact on survival. Secondary malignancies were reported in 15 of 131 evaluable patients. [ABSTRACT FROM AUTHOR]

The safety and efficacy of a preparation with treosulfan/thiotepa/fludarabine were explored in 20 thalassaemia patients given allogeneic marrow transplantation. Seventeen patients were transplanted from unrelated donors after receiving anti-thymocyte globulin. The regimen was well tolerated. Two patients experienced secondary graft failure; one died of acute graft-versus-host disease. Cumulative incidence (95% confidence interval, CI) of transplantation-related mortality and graft failure was 5% (95% CI, 0–34%) and 11% (95% CI, 3–43%), respectively. Two-year probability of survival and thalassaemia-free survival was 95% (95% CI, 85–100%) and 85% (95% CI, 66–100%), respectively. This regimen might find elective application in patients at high risk of developing life-threatening complications. [ABSTRACT FROM AUTHOR]

Autologous transplantation of lymphocyte-depleted peripheral blood stem cells (PBSC) has been proposed for treatment of patients with severe autoimmune disease. However, several patients have been reported to achieve only transient remissions. We report on a child with thalassaemia intermedia and immune-mediated haemolytic anaemia, given an autologous lymphocyte-depleted PBSC transplant, who relapsed 7 weeks after transplant. A complete remission, lasting 18 months to date, was obtained with allogeneic bone marrow transplantation (BMT) from an HLA-matched unrelated donor. This experience indicates that, in selected cases, allogeneic BMT may be the treatment of choice for life-threatening autoimmune disease. A graft-versus-autoimmunity effect may favour the eradication of the recipient autoaggressive lymphocytes. [ABSTRACT FROM AUTHOR]

Highlights • In our cohort the incidence of SOS/VOD was 2%, and by applying the new pediatric EBMT criteria, all SOS/VOD were severe. • Age at HSCT < 2 years, Bu, female gender, and HLH increased the risk of SOS/VOD. • The OS at 1 year was lower in patients with SOS/VOD. • The NRM at 1 and 5 years was higher in patients with SOS/VOD. Abstract Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a potentially life-threatening complication that may develop after hematopoietic stem cell transplantation (HSCT). The aims of this retrospective multicenter study were to evaluate the incidence of SOS/VOD in a large cohort of children transplanted in centers across Italy by applying the new European Society for Blood and Marrow Transplantation (EBMT) criteria and to analyze the risk factors underlying this complication. We retrospectively reviewed data of pediatric HSCTs performed in 13 AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica)-affiliated centers between January 2000 and April 2016. The new pediatric EBMT criteria were retrospectively applied for diagnoses of SOS/VOD and severity grading. Among 5072 transplants considered at risk for SOS/VOD during the study period, 103 children (2%) developed SOS/VOD, and the grade was severe or very severe in all patients. The median time of SOS/VOD occurrence was 17 days after HSCT (range, 1 to 104). Sixty-nine patients (67%) were treated with defibrotide for a median time of 16 days (range, 4 to 104). In multivariable analysis age < 2 years, use of busulfan during the conditioning regimen, female gender, and hemophagocytic lymphohistiocytosis were risk factors statistically associated with the development of SOS/VOD. The overall mortality directly related to SOS/VOD was 15.5%. Overall survival at 1 year was worse in patients with SOS/VOD (P =.0033), and this difference disappeared 5 years after HSCT. Nonrelapse mortality was significantly higher 1 and 5 years after transplantation in patients who developed SOS/VOD (P <.001). Based on the application of new EBMT criteria, the overall incidence of SOS/VOD recorded in this large Italian pediatric retrospective study was 2%. Nonrelapse mortality was significantly higher in patients who developed SOS/VOD. Identifying the risk factors associated with SOS/VOD can lead to more effective early treatment strategies of this potentially fatal HSCT complication in childhood. [ABSTRACT FROM AUTHOR]

Bone marrow ABO incompatible transplantations require graft manipulation prior to infusion to avoid potentially lethal side effects. We analyzed the influence of pre-manipulation factors (temperature at arrival, transit time, time of storage at 4 °C until processing and total time from collection to red blood cell depletion) on the graft quality of 21 red blood cell depletion procedures in ABO incompatible pediatric transplants. Bone marrow collections were processed using the Spectra Optia ® (Terumo BCT) automated device. Temperature at arrival ranged between 4 °C and 6 °C, median transit time was 9.75 h (range 0.33–28), median time of storage at 4°–6 °C until processing was 1.8 h (range 0.41–18.41) and median time from collection to RBC depletion was 21 h (range1–39.4). Median percentage of red blood cell depletion was 97.7 (range 95.4–98.5), median mononuclear cells recovery was 92.2% (range 40–121.2), median CD34+ cell recovery was 93% (range 69.9–161.2), median cell viability was 97.7% (range 94–99.3) and median volume reduction was 83.9% (range 82–92 ). Graft quality was not significantly different between BM units median age. Our preliminary data show that when all good manifacturing practices are respected the post-manipulation graft quality is excellent also for those units processed after 24 h. [ABSTRACT FROM AUTHOR]