Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease after Autologous or Allogeneic Hematopoietic Stem Cell Transplantation in Children: a retrospective study of the Italian Hematology-Oncology Association-Hematopoietic Stem Cell Transplantation Group.

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.

Long-term survival of beta thalassemia major patients treated with hematopoietic stem cell transplantation compared with survival with conventional treatment.

Allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia remains a challenge. We reported a single-centre case-control study of a large cohort of 516 children and adult patients treated with HSCT or blood transfusion support and iron chelation therapy; 258 patients (median age 12, range 1-45) underwent sibling (67%) or unrelated (33%) HSCT; 97 patients were adults (age ≥ 16 years). The median follow-up after HSCT was 11 years (range 1-30). The conditioning regimen was busulfan (80.6%) or treosulfan-based (19.4%). A cohort of 258 age-sex matched conventionally treated (CT) patients was randomly selected. In transplanted patients the 30-year overall survival (OS) and thalassemia-free survival (TFS) were 82.6 ± 2.7% and 77.8 ± 2.9%, compared to the OS of 85.3 ± 2.7% in CT patients (P = NS); The incidence of grade II-IV acute and chronic graft versus host disease (GvHD) was 23.6% and 12.9% respectively. The probability of rejection was 6.9%. Transplant-related mortality (TRM) (13.8%) was similar to the probability of dying of cardiovascular events in CT patients (12.2%). High-risk Pesaro score (class 3) was associated with lower OS (OR = 1.99, 95% C.I.=1.31-3.03) and TFS (OR = 1.54, 95% C.I.=1.12-2.12). In adult patients, the 23-years OS and TFS after HSCT were 70 ± 5% and 67.3 ± 5%, compared to 71.2 ± 5% of OS in CT (P = NS). Finally, treosulfan was associated with lower risk of acute GvHD (P = .004; OR = 0.28, 95% C.I.=0.12-0.67). In conclusion, the 30-year survival rate of ex-thalassemia patients after HSCT was similar to that expected in CT thalassemia patients, with the vast majority of HSCT survivors cured from thalassemia.

Health-Related Quality-of-Life Profile of Pediatric Patients with ß Thalassemia after Hematopoietic Stem Cell Transplantation.

Matched hematopoietic stem cell transplantation (HSCT) is a feasible and curative treatment in pediatric patients with beta thalassemia major (ß-TM). However, little data are available regarding patients and their parents' health-related quality of life (HRQoL) after the procedure. As such, we investigated the HRQoL of pediatric patients with ß-TM after HSCT compared to that of patients treated with blood transfusions and iron chelation. The health-related quality of life of 43 ß-TM pediatric patients and 43 parents were evaluated using the Pediatric Quality of Life Inventory (PedsQL). A total of 25 patients underwent HSCT: 15 from a sibling and 10 from an HLA-matched donor. The median follow-up time from HSCT was 5 years (range 1-13 years). The mean ages at the survey were 10.1 years (range 5-15) and 9.6 years (range 5-15) for transfused and transplanted patients, respectively. A significant reduction in HRQoL was reported in the group of transfused patients compared with that of patients transplanted in the following PedsQL domains: children's and parents' physical functions, Δ = -15.4, p = 0.009 and Δ = -11.3, p = 0.002, respectively; children's and parents' emotional functioning, Δ = -15.2, p = 0.026 and Δ = -15.2, p = 0.045, respectively; child's and parents' school functioning, Δ = -25, p = 0.005 and Δ = -22.5, p = 0.011, respectively; total child and parents scores, Δ = -14.5, p = 0.004 and Δ = -13.2, p = 0.005, respectively. The results of a multivariable analysis showed that the HSCT procedure was significantly associated with a higher total child PedsQL score (adjusted mean difference = 15.3, p = 0.001) and a higher total parent PedsQL score (adjusted mean difference = 14.1, p = 0.006). We found no significant difference in the HRQoL measured after sibling or unrelated human leukocyte antigen (HLA)-matched HSCT. Finally, a significant positive correlation across all the PedsQL domains was found between the scores reported by the children and those reported by their parents. In conclusion, our study shows that HSCT in pediatric patients with ß-TM is associated with a good overall HRQoL profile. This information further supports physicians when counseling patients and their parents before the HSCT procedure.

Platelet-lysate-expanded mesenchymal stromal cells as a salvage therapy for severe resistant graft-versus-host disease in a pediatric population.

Despite advances in graft-versus-host-disease (GVHD) treatment, it is estimated that overall survival (OS) at 2 years for hematopoietic cell transplantation (HCT) recipients who experience steroid-resistant GVHD is 10%. Among recent therapeutic approaches for GVHD treatment, mesenchymal stromal cells (MSCs) hold a key position. We describe a multicenter experience of 11 pediatric patients diagnosed with acute or chronic GVHD (aGVHD, cGVHD) treated for compassionate use with GMP-grade unrelated HLA-disparate donors' bone marrow-derived MSCs, expanded in platelet-lysate (PL)-containing medium. Eleven patients (aged 4-15 years) received intravenous (i.v.) MSCs for aGVHD or cGVHD, which was resistant to multiple lines of immunosuppression. The median dose was 1.2 x 10(6)/kg (range: 0.7-3.7 x 10(6)/kg). No acute side effects were observed, and no late side effects were reported at a median follow-up of 8 months (range: 4-18 months). Overall response was obtained in 71.4% of patients, with complete response in 23.8% of cases. None of our patients presented GVHD progression upon MSC administration, but 4 patients presented GVHD recurrence 2 to 5 months after infusion. Two patients developed chronic limited GVHD. This study underlines the safety of PL-expanded MSC use in children. MSC efficacy seems to be greater in aGVHD than in cGVHD, even after failure of multiple lines of immunosuppression.

No influence of chromosome Y haplogroup variation in acute graft-versus-host disease in sardinia.

The donor-recipient sex-related mismatch has been reported as a risk factor for acute graft-versus-host disease (GVHD). However, the results obtained in previous studies appear to be contradictory. Here we evaluate the impact of donor-recipient sex-related mismatch in a series of 204 Sardinian individuals (92.1% of them affected by Beta- Thalassemia major) who underwent bone marrow transplantation (BMT) from human leukocyte antigen (HLA) identical siblings. In all, 78 of these patients had acute GVHD (aGVHD). We found that also in this homogenous group of patients from a homogenous population, the donor-female/recipient-male pair provided an increased risk for aGVHD when compared with a reference donor-male/recipient-male pair (POR=2.3, P=0.042). This data could be consistent with a role of variation in the male-specific portion of the Y chromosome in aGVHD. To assess this, we compared the distribution of the main Y-chromosome haplogroups in 28 male patients, who had aGVHD and underwent BMT from HLA-identical sisters, and 366 ethnically-matched controls. No significant differences were observed. These findings do not support the presence of Y chromosome founder variants contributing significantly to aGVHD in the Sardinian population.

Fetal HLA typing in beta thalassaemia: implications for haemopoietic stem-cell transplantation.

Stem-cell transplantation can cure beta thalassaemia. We aimed to assess whether fetal HLA typing done early in the pregnancy of couples who were at risk of beta thalassaemia could provide an alternative to pregnancy termination if the prospect of a bone-marrow transplantation from a family member was available. In our clinic in Sardinia, we did fetal HLA typing for 49 couples at risk of having a baby with beta thalassaemia. Two affected children were born and successfully received a transplantation from a family donor. Five non-affected fetuses were HLA compatible with an affected sibling and their cord blood was harvested for a future transplantation.

Reassessing the approach to informed consent: the case of unrelated hematopoietic stem cell transplantation in adult thalassemia patients.

INTRODUCTION: The informed consent process is the legal embodiment of the fundamental right of the individual to make decisions affecting his or her health., and the patient's permission is a crucial form of respect of freedom and dignity, it becomes extremely important to enhance the patient's understanding and recall of the information given by the physician. This statement acquires additional weight when the medical treatment proposed can potentially be detrimental or even fatal. This is the case of thalassemia patients pertaining to class 3 of the Pesaro classification where Allogenic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative treatment. Unfortunately, this kind of intervention is burdened by an elevated transplantation-related mortality risk (TRM: all deaths considered related to transplantation), equal to 30% according to published reports. In thalassemia, the role of the patient in the informed consent process leading up to HSCT has not been fully investigated. This study investigated the hypothesis that information provided by physicians in the medical scenario of HSCT is not fully understood by patients and that misunderstanding and communication biases may affect the clinical decision-making process. METHODS: A questionnaire was either mailed or given personally to 25 patients. A second questionnaire was administered to the 12 physicians attending the patients enrolled in this study. Descriptive statistics were used to evaluate the communication factors. RESULTS: The results pointed out the difference between the risks communicated by physicians and the risks perceived by patients. Besides the study highlighted the mortality risk considered to be acceptable by patients and that considered to be acceptable by physicians. CONCLUSIONS: Several solutions have been suggested to reduce the gap between communicated and perceived data. A multi-disciplinary approach may possibly help to attenuate some aspects of communication bias. Several tools have also been proposed to fill or to attenuate the gap between communicated and perceived data. But the most important tool is the ability of the physician to comprehend the right place of conscious consent in the relationship with the patient.

Graft rejection after unrelated donor hematopoietic stem cell transplantation for thalassemia is associated with nonpermissive HLA-DPB1 disparity in host-versus-graft direction.

The success of allogeneic hematopoietic stem cell transplantation (HSCT) from matched unrelated donors (UDs) for beta-thalassemia may be hampered by the occurrence of graft rejection. Here, we show that the rate of this complication can be reduced by selecting 5-loci HLA-matched donors without nonpermissive mismatches at HLA-DPB1, defined according to an algorithm previously described and based on principles of central T-cell tolerance. Seventy-two consecutive patients and their UDs, prospectively selected for matching at the allelic level for HLA-A, -B, -C, -DRB, and -DQB1 loci, were enrolled in the analysis. These pairs were either DPB1 matched/permissively mismatched (n = 45, control group) or had at least one nonpermissive DPB1 mismatch in the host-versus-graft (HvG; n = 17) or in the graft-versus-host (GvH; n = 10) direction. In multivariate analysis, the risk of rejection was significantly increased in the group with HvG disparity (RR = 7.42; 95% CI = 1.29-42.68; P = .02) as compared to the control group. A lower, statistically significant, probability of thalassemia-free survival was found in patients belonging to the HvG group as compared to controls (RR = 5.15; 95% CI = 1.58-16.82; P = .01). These data suggest that in patients with thalassemia, the incidence of graft failure after HSCT may be reduced by appropriate selection of UDs, with such selection taking into account the functional rules of immunogenetics.