Stem Cell Transplantation In Children Research Articles

Accelerated Progression of Diabetic Retinopathy in a Patient with Acquired Lipodystrophy Following Hematopoietic Stem Cell Transplantation.

To report a case of bilateral proliferative diabetic retinopathy and lipemia retinalis in a patient with acquired lipodystrophy. A retrospective case report. A 23-year-old woman with a diagnosis of acquired lipodystrophy was referred for ophthalmic evaluation. She had been diagnosed with acute lymphocytic leukemia at the age of 3 years and undergone hematopoietic stem cell transplantation. Best-corrected visual acuity was 20/20 in both eyes; however, funduscopy revealed bilateral diabetic retinopathy and lipemia retinalis, neither of which was apparent 2 years earlier. She had a glycated hemoglobin level of 9.6% and a triglyceride level of 7,394 mg/dL with creamy appearance of serum. Fluorescein angiography showed bilateral neovascularization. Accelerated progression of diabetic retinopathy in the present case appeared to be associated with the onset of lipemia retinalis. We encourage continued ophthalmologic monitoring of patients who underwent hematopoietic stem cell transplantation in childhood for possible accelerated course of diabetic retinopathy.

αβ+ /CD19+ -depleted haploidentical stem cell transplantation for children with acute leukemia: Is there a protective effect of increased γδ+ T-cell content in the graft?

Haploidentical hematopoietic stem cell transplantation (HSCT) with depletion of αβ+ T cells and CD19+ B cells has emerged as a viable alternative to traditional donors for treating acute leukemia in children. As the use of this innovative approach continues to grow and more experience is gained, it is essential to identify and comprehend the key factors that contribute to successful transplantation and improved outcomes. We conducted a retrospective analysis of single-center data from 27 children with acute lymphoblastic leukemia and 11 children with acute myeloid leukemia who underwent haploidentical HSCT with depletion of αβ+ T cells and CD19+ B cells between the years 2013 and 2020. Engraftment was successful in 34 out of 38 patients (90%). The 5-year overall survival and event-free survival rates were 51% and 42%, respectively. There were no cases of grade III-IV acute graft-versus-host disease, and only two patients developed chronic graft-versus-host disease. Patients with a higher content of γδ+ T cells in the graft demonstrated a longer event-free survival. αβ+ /CD19+ -depleted haploidentical hematopoietic stem cell transplantation can offer long-term remission for children with acute leukemia with minimal graft-versus-host disease.

Natural killer cell reconstitution after hematopoietic stem-cell transplantation in children.

After hematopoietic stem cell transplantation (HSCT), natural killer (NK) cells reconstitution is the main barrier against viral infections. To determine that the knowledge on the kinetics of NK cell reconstitution after HSCT contributes to transplant efficient monitoring, which increases the possibility of its success. Twenty-one patients undergoing HSCT were included, as well as a control group of clinically healthy individuals. At different time points after transplantation (range of 21 to 670 days), CD3- CD16+ CD56+ NK cells were quantified by flow cytometry in peripheral blood samples. NK cell recovery occurs at three to six months and 10 to 12 months post-transplantation; their number was significantly lower (in comparison with the control group) in the rest of the monitoring time. The first period of NK cell recovery occurs between three and six months after transplantation. Reconstitution is transient and the number of NK cells varies in the first years.

Adenoviral Penton and Hexon Proteins Are Equivalent Immunogenic Targets of Virus-Specific T Cells after Hematopoietic Stem Cell Transplantation in Children

Human adenovirus (HAdV) infection is a serious complication that can lead to significant morbidity and mortality, especially in immunocompromised pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Control and elimination of HAdV requires the presence of the respective antiviral T cells, and adoptive transfer of virus-specific T cells has become an important new treatment option for patients refractory to antiviral treatment. Although the adenoviral capsid protein hexon is known to be a major immunodominant T cell target across HAdV species, up to 30% of HAdV-seropositive donors show no T cell responses to the overlapping peptide pool spanning the entire protein. Our group recently verified the capsid protein penton as a second immunodominant target in HAdV infection. Here we aimed to investigate the prevalence of both penton-specific and hexon-specific HAdV T cells and their impact in virus control after HSCT. We analyzed the prevalence and characteristics of HAdV-specific T cells in 33 consecutive pediatric patients with HAdV reactivation following allogeneic HSCT and correlated them with viral load analysis. Our study demonstrates that penton is an important immunodominant target antigen of HAdV reactivation/ infection after HSCT in most patients. We demonstrate that in the majority of patients, both penton- and hexon-specific T cells appear at similar time intervals after transplantation. Despite the prevalence for either hexon-specific or penton-specific T cells in individual patients, we were unable to attribute the predominance to specific HLA types or HAdV serotypes. The occurrence of HAdV-specific T cells was closely linked to viral control, arguing for immune monitoring strategies to tailor antiviral treatment and adoptive T cell therapy.

Third-Party and Patient-Specific Donor-Derived Virus-Specific T Cells Demonstrate Similar Efficacy and Safety for Management of Viral Infections after Hematopoietic Stem Cell Transplantation in Children and Young Adults

Infections with double-stranded DNA viruses are a common complication after hematopoietic stem cell transplantation (HSCT) and cause significant morbidity and mortality in the post-transplantation period. Both donor-derived (DD) and third-party (TP) virus-specific T cells (VSTs) have shown efficacy and safety in viral management following HSCT in children and young adults. Owing to a greater degree of HLA matching between the recipient and stem cell donor, DD VSTs potentially persist longer in circulation compared to TP VSTs, because they are collected from a well-matched donor. However, TP VSTs are more easily accessible, particularly for smaller transplantation centers that do not have VST manufacturing capabilities, and more economical than creating a customized product for each transplant recipient. We conducted the present study to compare clinical efficacy and safety outcomes for DD VSTs and TP VSTs in a large cohort of pediatric and young adult HSCT recipients and to determine whether DD VSTs are associated with improved outcomes owing to potentially longer persistence in the recipient's circulation. This retrospective cohort study included 145 patients who received VSTs at Cincinnati Children's Hospital Medical Center (CCHMC) between 2017 and 2021 for the treatment of adenovirus, BK virus, cytomegalovirus, and/or Epstein-Barr virus. Viruses were detected using quantitative polymerase chain reaction. Patients received VSTs on a DD (NCT02048332) or TP (NCT02532452) protocol, and VST products for both protocols were manufactured in an identical fashion. The primary study outcome was clinical response to VSTs, evaluated 4 weeks after VST administration, defined as decrease in viral load to under the inclusion thresholds, or resolution of symptoms of invasive viral infection, without the need for additional conventional antiviral medication following VST administration. Secondary outcomes included graft-versus-host-disease, transplant-associated thrombotic microangiopathy, renal function, hospital length of stay, and overall survival at 30 days and 100 days after VST administration and 1 year after HSCT. Statistical analysis was performed using the Fisher exact test or chi-square test. An unpaired t test was used to compare continuous variables. The study group comprised 77 patients in the DD cohort and 68 patients in the TP cohort. Eighteen patients in the TP cohort underwent HSCT at CCHMC, and the other 50 underwent HSCT at other institutions and presented to CCHMC solely for VST administration. There was no statistically significant difference in clinical response rates between DD and TP cohorts (65.6% versus 62.7%; odds ratio [OR], 1.162; 95% confidence interval [CI], .619 to 2.164; P=.747). There were no significant differences in secondary outcomes between the 2 cohorts. The percentage of patients requiring multiple infusions for a clinical response did not differ significantly between the DD and TP cohorts (38.2% versus 32.5%; OR, .780; 95% CI, .345 to 1.805; P=.666). We found no significant difference in clinical response rate between DD VSTs and TP VSTs and a similar safety profile. Our data suggest that TP VSTs may be sufficient to control viral infection until immune reconstitution occurs despite the potential for more rapid VST clearance compared to DD VSTs. The lack of significant differences between DD VSTs and TP VSTs is an important finding, indicating that it is not necessary for every transplant center to manufacture customized DD VSTs, and that TP VSTs are a satisfactory substitute.

Low-dose decitabine for refractory thrombocytopenia following allogeneic hematopoietic stem cell transplantation in children: A pilot study

Refractory thrombocytopenia is a critical complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is not sensitive to conventional treatment and often leads to lower overall survival and disease-free survival. Previous studies have showed the efficacy and safety of low-dose decitabine for adults' refractory prolonged isolated thrombocytopenia in hematologic malignancy after allo-HSCT. However, clinical data on pediatric patients or non-hematologic malignancies are lacking. Herein, we evaluated the safety and efficacy of low-dose decitabine in nine children with persistent thrombocytopenia after HSCT. Patients received decitabine at 3.5mg/m2, 5mg/m2 or 10mg/m2 respectively for three to five consecutive days according to underlying diseases and hyperplastic state of bone marrow. Six patients reached sustained platelets count more than 100×109/L, two patients achieved platelet transfusion independence. The total response rate was 88.8% (8/9). One patient died from severe infection because of persistent agranulocytosis longer than 3weeks. In conclusion, the present study supports the safety and efficacy of low-dose decitabine for treatment of refractory thrombocytopenia after allogeneic HSCT in children.

Missing observations in regression: a conditional approach.

This note presents an alternative to multiple imputation and other approaches to regression analysis in the presence of missing covariate data. Our recommendation, based on factorial and fractional factorial arrangements, is more faithful to ancillarity considerations of regression analysis and involves assessing the sensitivity of inference on each regression parameter to missingness in each of the explanatory variables. The ideas are illustrated on a medical example concerned with the success of hematopoietic stem cell transplantation in children, and on a sociological example concerned with socio-economic inequalities in educational attainment.

345 - Prophylactic Tocilizumab Decreases Incidence of Acute Graft-Versus-Host Disease Following Alpha/Beta T-Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation in Children and Young Adults

345 - Prophylactic Tocilizumab Decreases Incidence of Acute Graft-Versus-Host Disease Following Alpha/Beta T-Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation in Children and Young Adults

Relapse after allogeneic haematopoietic stem cell transplantation in children with acute lymphoblastic leukemia

Relapse after allogeneic haematopoietic stem cell transplantation in children with acute lymphoblastic leukemia

Excellent outcomes in haematopoietic stem cell transplantation for children with inborn error of immunity – Experience from tertiary referral centre in India

Excellent outcomes in haematopoietic stem cell transplantation for children with inborn error of immunity – Experience from tertiary referral centre in India

Low dose post-transplant cyclophosphamide as GVHD prophylaxis for matched unrelated donor allogeneic hematopoietic stem cell transplants in children

Low dose post-transplant cyclophosphamide as GVHD prophylaxis for matched unrelated donor allogeneic hematopoietic stem cell transplants in children

Inotuzumab as a bridge to hematopoietic stem cell transplant in children with relapse/refractory acute lymphoblastic leukemia

Inotuzumab as a bridge to hematopoietic stem cell transplant in children with relapse/refractory acute lymphoblastic leukemia

Hematopoietic stem cell transplantation in children –Early experience from a newly established center in India

Hematopoietic stem cell transplantation in children –Early experience from a newly established center in India

Comprehensive and long-term outcomes of enzyme replacement therapy followed by stem cell transplantation in children with Gaucher disease type 1 and 3.

Gaucher disease (GD) is a lysosomal storage disorder, characterized by hepatosplenomegaly, pancytopenia, bone diseases, with or without neurological symptoms. Plasma glucosylsphingosine (lyso-Gb1), a highly sensitive and specific biomarker for GD, has been used for diagnosis and monitoring the response to treatment. Enzyme replacement therapy (ERT) is an effective treatment for the non-neurologic symptoms of GD. Neuronopathic GD (type 2 and 3) accounts for 60%-70% of the Asian affected population. We explored combination therapy of ERT followed by hematopoietic stem cell transplantation (HSCT) and its long-term outcomes in patients with GD type 3 (GD3). Four patients with GD3 and one with GD type 1 (GD1) underwent HSCT. The types of donor were one matched-related, one matched-unrelated, and three haploidentical. The age at disease onset was 6-18months and the age at HSCT was 3.8-15years in the patients with GD3. The latest age at follow-up was 8-22years, with a post-HSCT duration of 3-14years. All patients had successful HSCT. Chronic graft-versus-host disease occurred in one patient. The enzyme activities were normalized at 2weeks post HSCT. Lyso-Gb1 concentrations became lower than the pathological value. All of the patients are still alive and physically independent. Most of them (4/5) returned to school. None of the patients with GD3 had seizures or additional neurological symptoms after HSCT, but showed varying degrees of cognitive impairment. ERT followed by HSCT could be considered as an alternative treatment for patients with GD3 who have a high risk of fatal neurological progression.

Antithymocyte Globulin Plus Post-Transplant Cyclophosphamide Combination as an Effective Strategy for Graft-versus-Host Disease Prevention in Haploidentical Peripheral Blood Stem Cell Transplantation for Children with High-Risk Malignancies.

Haploidentical hematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has emerged as a valid alternative transplant strategy for patients lacking a suitable HLA-matched related donor. The high risk of severe GVHD remains the major clinical challenge in this setting. The addition of antithymocyte globulin (ATG) in PTCy-based regimens for GVHD reduction in haploidentical hematopoietic stem cell transplantation is rational and was reported in adult series. However, its feasibility is unknown in pediatric patients. Here, we firstly describe our experience of 15 consecutive children with high-risk malignancies receiving haploidentical peripheral blood stem cell transplantation using ATG plus PTCy for GVHD prophylaxis. Only three patients developed grade 1-2 acute GVHD, limited to skin. No grade 3-4 acute GVHD and chronic GVHD were observed. Viral reactivations were frequently seen but manageable. Six patients relapsed, as the main cause of death in our series. None died from events related to GVHD. Our data suggest that ATG plus PTCy is an effective strategy for GVHD prevention in haploidentical peripheral blood stem cell transplantation and is feasible in children with high-risk malignancies.

HLA-Haploidentical Stem Cell Transplantation in Children with Inherited Bone Marrow Failure Syndromes: A Retrospective Analysis on Behalf of EBMT Severe Aplastic Anemia Working Party

INTRODUCTION: HLA-haploidentical stem cell transplantation (HAPLO) has been widely used in the last years in children with an indication to receive an allogeneic hematopoietic stem cell transplantation (allo-HSCT) and lacking a matched donor. The introduction of new, more selective techniques of graft manipulation and in vivo T-cell depletion have improved the outcome of HAPLO in several diseases. Allo-HSCT represents the only well-established cure for the hematological manifestations of inherited bone marrow failure syndromes (I-BMFs), featuring complex molecular pathophysiology resulting in ineffective hematopoiesis and increased risk of progression to myelodysplastic syndrome and acute leukemia. However, data on HAPLO in these diseases are limited. This retrospective study aims to report the current outcomes of HAPLO in the EBMT network in patients with I-BMFs, comparing the different approaches introduced over the years. PATIENTS AND METHODS The study was conducted on behalf of the Severe Aplastic Anemia Working Party of the EBMT. Data were collected from patients who underwent HAPLOs of I-BMFs and registered in the EBMT ProMISe database between 1990-2020 with a diagnosi. Clinical and biological information about the disease and details on transplant procedures and outcomes were collected through a specific case report form distributed to participating EBMT centers. RESULTS Data was collected from 162 patients (53.1% males) affected by I-BMFs undergoing HAPLO in 56 centers. The median age at HAPLO was 7.4 years (IQR 4.9-10.9). Table 1 summarizes the diagnoses and main HSCT details. Most HAPLOs were performed in 2015 (n=125, 77.2%). Based on different T-cell depletion (TCD) approaches, 4 categories were identified: 1) TCRCD3+ or ab+/CD19+depletion performed in 71 transplants (43.8%); 2) T-repleted with post-transplant Cyclophosphamide (PTCy) in 55 (34.0%); 3) in vivo T-depletion approach in 24 (14.8%; 20 ATG, 4 anti-CD52); and 4) CD34+ positive selection in 12 (7.4%). Neutrophil and platelet engraftment occurred on day + 14 (95% CI 13-15), and +18 (95% CI 16-21) respectively. Primary graft rejection was diagnosed in 14 children (10% [5-14%]), while 11 experienced secondary graft failure (8% [3-12%]). The 100-day cumulative incidence of grade II-IV and III-IV acute GvHD (95% CI) was 29 % (22-36) and 13% (8-19), while the 24-month cumulative incidence of chronic GvHD was 11% (6-16%) and that for the extensive form was 4% (1-7%). After a median follow-up of 43.4 months (IQR 32.9- 51), the 2-year overall survival (OS) and GvHD/Rejection-free Survival (GRFS) probability are 67% (60-74%) and 53% (45-61%) respectively (Figure 1). The main causes of death were infections (40.4%), GvHD (28.8 %), other HSCT-related events (28.85 %), and relapse of acute leukemia in 1 patient with malignant transformation (1.9 %). When we analyzed the outcome by the modality of TCD, the TCR CD3+ab+/CD19+ depletion group showed the best OS (79%) and GRFS (71%) that were significantly higher (p 0.013 and p <0.001, respectively) than those observed in the other groups. (Figure 1). The TCR CD3+ab+/CD19+ depletion group also was associated with a lower incidence of acute (15%, vs 46 % PT-Cy, vs 9% CD34+ positive, vs 41% in-vivo TCD; p 0.001) and chronic GvHD (9%, vs 19% PT-Cy, vs 0% CD34+ positive selection vs 0 % in-vivo TCD; p < 0.041). No differences in outcome were observed based on the underlying diagnosis. CONCLUSION This is the largest retrospective study on HAPLO in I-BMFs comparing the main TCD approaches and the long median follow-up of almost 4 years contributes to the reliability of the data reported. The satisfactory outcome supports HAPLO HSCT as a safe and effective alternative for patients lacking a full-matched donor. The most widely adopted approaches are TCR CD3+ab+/CD19+ depletion and PT-Cy. PT-Cy is largely used because of its easy accessibility, but for the time being, the TCR CD3+ab+/CD19+ depletion platform offers the highest OS and GRFS and the lower incidence of both acute and chronic GvHD in I-BMFs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pleuroparenchymal fibroelastosis after hematopoietic stem cell transplantation in children: a propensity score-matched analysis.

To investigate the incidence, risk factors, and clinical outcomes of pleuroparenchymal fibroelastosis (PPFE) in pediatric hematopoietic stem cell transplantation (HSCT) recipients. This single-center, retrospective, case-control study included 738 consecutive patients who underwent chest CT more than 3 months after HSCT. We identified patients who fulfilled the diagnostic criteria for PPFE and assessed their clinical characteristics and radiologic findings. Propensity score-matched analysis was performed using four covariates (age, sex, HSCT type, and primary disease). The risk factors and clinical outcomes of PPFE were analyzed using the Fine and Gray regression model and stratified log-rank test in the matched groups. PPFE was identified in 4% (31/738, 8.3 ± 3.1 years, 15 males) of the pediatric HSCT recipients with a median time of 2.7 years after HSCT, and it occurred following allogeneic (5%, 15/317), autologous (4%, 15/379), or both (2%, 1/42). Matching yielded 30 and 130 cases in the PPFE and control groups, respectively. The PPFE group showed more frequent late-onset noninfectious pulmonary complications (LONIPCs) and pneumonia more than 3 months after HSCT (p < 0.05). Multivariable analysis showed a significantly higher risk of PPFE in HSCT recipients who had pneumonia more than 3 months after HSCT (hazard ratio = 10.78 [95% confidence interval: 4.29, 27.13], p < 0.001). The PPFE group showed higher mortality (73%, 22/30) and poorer median overall survival (6.8 years [95% confidence interval: 4.1, 9.5]) than the control group (p < 0.001). PPFE represents a severe type of LONIPC after HSCT. HSCT recipients with pneumonia after HSCT may have an increased risk of PPFE. • The incidence of pleuroparenchymal fibroelastosis is not negligible (4%), and it can occur after either allogeneic or autologous hematopoietic stem cell transplantation. • Pleuroparenchymal fibroelastosis after hematopoietic stem cell transplantation showed poor outcome with a high mortality rate of 73% and median overall survival of 6.8 years. • After hematopoietic stem cell transplantation, pneumonia may increase the risk of pleuroparenchymal fibroelastosis development in children. • Lung biopsy should not be indicated in patients with pleuroparenchymal fibroelastosis findings on chest CT as it can cause refractory pneumothorax without helping the diagnosis.

High-Dose Busulfan-Fludarabine Conditioning and Low Alveolar Volume as Predictors of Pulmonary Complications after Allogeneic Peripheral Blood Stem Cell Transplantation in Children

This study was conducted to investigate risk factors and predictors of infectious and noninfectious pulmonary complications (PCs) after allogeneic hematopoietic stem cell transplantation in children. We conducted a retrospective analysis of the post-transplantation PCs of 240 patients who underwent allogeneic peripheral blood stem cell transplantation (allo-PBSCT) between 2009 and 2018. Transplantation-related variables, pretransplantation baseline spirometry, body plethysmography, and CO diffusing capacity were analyzed for association with the development of infectious PCs (IPCs) and noninfectious PCs (NIPCs). Compared with the control group, the PC group had statistically significantly lower overall survival (50.6% versus 77.8%; P < .001), higher disease-related mortality (26.6% versus 54.4%; P < .001), and higher nonrelapse mortality (31.6% versus 5.9%; P < .001). A greater number of patients received pretransplantation conditioning with high-dose busulfan (520 mg/m2; Bu 520) and fludarabine (160 mg/m2; Flu 160) in both the IPC and NIPC groups. In the multivariate Cox hazard regression analysis, Bu 520 significantly increased the risk of NIPCs (hazard ratio [HR], 1.99; 95% confidence interval [CI], 1.13 to 3.49; P=.016), and Flu 160 was a predictor of IPCs (HR, 1.99; 95% CI, 1.13 to 3.49; P=.016). The Bu 520+Flu 160 regimen was associated with a statistically significant increase in the risk of NIPC (HR, 1.92; 95% CI, 1.09 to 3.37; P=.023). In a multivariate analysis using pretransplantation baseline lung function, alveolar volume (VA) grades 3 and 4 and lung function score (LFS) VA categories III and IV were associated with increased risk for both IPCs and NIPCs. Our data identify receipt of the high-dose Bu-Flu conditioning regimen as an independent risk factor for NIPCs after allo-PBSCT. Impaired CO diffusing capacity before transplantation, especially VA reduction, contributes to the risk of post-transplantation pulmonary complications, and pretransplantation risk can be estimated by grading the degree of insufficiency of VA and LFS VA.

Hematopoetic stem cell transplantation in children

Hematopoetic stem cell transplantation in children

Hematopoietic stem cell Transplantation in Children with very Early Onset Inflammatory Bowel Disease Secondary to Monogenic Disorders of immune-dysregulation.

Background: Very early-onset inflammatory bowel disease (VEOIBD) is defined as IBD in children under six years of age. We present outcome data of hematopoietic stem cell transplantation (HSCT) in the above children. Patients and methods: We performed a retrospective study in children under six years of age who underwent HSCT for VEOIBD with an identified monogenic disorder from December 2012 to December 2020. Results: Of the 25 children included, the underlying diagnosis was IL10R deficiency (n = 4), Wiskott-Aldrich syndrome (n = 4), Leukocyte adhesion defect (n = 4), Hyper IgM syndrome (n = 3), Chronic granulomatous disease (n = 2), and one each with XIAP deficiency, severe congenital neutropenia, Omenn syndrome, Hyper IgE syndrome, Griscelli syndrome, MHC Class II deficiency, LRBA deficiency, and IPEX syndrome. Donors included a matched family donor in 10(40%); a matched unrelated donor in 8 (32%), haploidentical in 7 (28%) (T depleted 16%, T replete with post-transplant cyclophosphamide12%). Conditioning was myeloablative in 84% ofHSCTs. We documented engraftment in 22 (88%) children, primary graft failure in 2 children (8%), mixed chimerism in 6 (24%) children with mortality in 4/6 children. Children with a sustained chimerism of > 95% did not have recurrence of any features of IBD. Overall survival was 64%, with a median follow-up of 55 months. Mixed chimerism was associated with a significantly increased risk of mortality (p-value = 0.001). Conclusions: VEOIBD caused by monogenic disorders can be offered HSCT. Early recognition, optimal supportive care, and complete chimerism are essential components to achieving survival.