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Differential analysis of immune reconstitution after allogeneic hematopoietic stem cell transplantation in children with Wiskott-Aldrich syndrome and chronic granulomatous disease
Zhou, Y., Zhang, L., Meng, Y., Lei, X., Jia, L., Guan, X., Yu, J., Dou, Y.
Frontiers in immunology. 2023;14:1202772
Abstract
OBJECTIVE To investigate similarities and differences in immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). METHOD We retrospectively analyzed the lymphocyte subpopulations and the serum level of various immune-related protein or peptide on Days 15, 30, 100, 180 and 360 post-transplantation in 70 children with WAS and 48 children with CGD who underwent allo-HSCT at the Transplantation Center of the Department of Hematology-Oncology, Children's Hospital of Chongqing Medical University from January 2007 to December 2020, and we analyzed the differences in the immune reconstitution process between the two groups. RESULTS ① The WAS group had higher lymphocyte subpopulation counts than the CGD group. ② Among children aged 1-3 years who underwent transplantation, the WAS group had higher lymphocyte subpopulation counts than the CGD group. ③ Further comparisons were performed between children with non-umbilical cord blood transplantation (non-UCBT) and children with umbilical cord blood transplantation (UCBT) in the WAS group. On Day 15 and 30 post-transplantation, the non-UCBT group had higher B-cell counts than the UCBT group. On the remaining time points post-transplantation, the UCBT group had higher lymphocyte subpopulation counts than the non-UCBT group. ④ Comparisons were performed between children with non-UCBT in the WAS group and in the CGD group, the lymphocyte subpopulation counts were higher in the WAS group compared to the CGD group. ⑤ On Day 100 post-transplantation, the CGD group had higher C3 levels than the WAS group. On Day 360 post-transplantation, the CGD group had higher IgA and C4 levels than the WAS group. CONCLUSION ① The rate of immunity recovery was faster in children within the WAS group compared to those children within the CGD group, which may be attributed to the difference of percentage undergoing UCBT and primary diseases. ② In the WAS group, the non-UCBT group had higher B-cell counts than the UCBT group at Day 15 and 30 post-transplantation, however, the UCBT group had higher B-cell counts than the non-UCBT group at Day 100 and 180 post-transplantation, suggesting that cord blood has strong B-cell reconstitution potentiality after transplantation.
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Early response markers predict survival after etoposide-based therapy of hemophagocytic lymphohistiocytosis
Verkamp, B., Zoref-Lorenz, A., Francisco, B., Kieser, P., Mack, J., Blackledge, T., Brik Simon, D., Yacobovich, J., Jordan, M. B.
Blood advances. 2023;7(23):7258-7269
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that is most commonly treated with etoposide and dexamethasone. This standard of care therapy has improved survival, but ∼15% of patients still die in the first months after diagnosis, and poor responses prompting salvage therapy are frequent. Thus, identifying patients at risk promptly is likely to improve outcomes. We conducted a multi-institutional, retrospective study of pediatric and young adults treated per HLH-94 or HLH-2004 from 2010 to 2019 to identify patients at risk for early mortality. Biweekly data during the first 100 days of treatment were analyzed using receiver operating curves to define optimal prognostic indicators and their thresholds. The primary end point was survival to bone marrow transplant (BMT) or ∼1 year if no BMT was pursued. Eighty-nine patients met the study inclusion criteria. Pre-BMT mortality was 13% (n = 12), and overall mortality was 27% (n = 24). Laboratory markers measured on day 7 of therapy more efficiently predicted outcomes than did either pretreatment or later assessments. The most potent day 7 unfavorable marker was improvement in soluble CD25 (sCD25) of less than 25% from pretherapy levels. Absolute sCD25 level, platelet count, absolute lymphocyte count, and blood urea nitrogen were also discriminatory markers (area under the curve ≥ 0.7). The presence of ≥3 of these unfavorable markers was strongly associated with pre-BMT mortality (accuracy, 0.93). Thus, serial monitoring of sCD25 and assessment of other early (day 7) response markers optimally predicts prognosis with etoposide-based therapy and may indicate the need for earlier use of alternative, response-adapted therapeutic strategies for HLH.
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Optimizing diagnostic methods and stem cell transplantation outcomes in pediatric bone marrow failure: a 50-year single center experience
Vissers, L., van der Burg, M., Lankester, A., Smiers, F., Mohseny, A.
European journal of pediatrics. 2023
Abstract
Peripheral blood cytopenia, a frequent presenting symptom in pediatric patients, can be caused by bone marrow failure (BMF). Timely identification of patients with non-reversible BMF is of crucial importance to reduce the risks of invasive infections and bleeding complications. Most pediatric patients with severe persistent cytopenia, independent of the underlying cause, are offered allogeneic hematopoietic stem cell transplantation (HSCT) as curative therapy. Here we report on our management guidelines and HSCT outcomes of pediatric BMF patients to pinpoint improvements and future challenges. We formulated recommendations based on this 50 years' experience, which were implemented at our center in 2017. By analysis of the HSCT cohort of 2017-2023, the 5-year outcome data is presented and compared to historical outcome data. In addition, outcomes of patients transplanted for identified inherited bone marrow failure syndromes (IBMFS) are compared to severe aplastic anemia (SAA) outcomes to underline the often multiorgan disease in IBMFS with implications for long-term survival. Survival of pediatric patients with irreversible BMF has improved tremendously. SAA patients transplanted after 2017 had a superior 5-year overall (OS) and event-free survival (EFS) of 97% and 85% compared to 68% and 59% in the cohort transplanted before 2017 (p = 0.0011 and p = 0.017). A similar trend was seen for BMF, with an OS and EFS of 89% for those transplanted after 2017 compared to 62% and 59% (p > 0.05). This improvement is mainly related to better survival in the first months after HSCT. The long-term survival after HSCT is lower in IBMFS patients as compared to SAA patients due to secondary malignancies and multiorgan toxicity. Conclusion: Unbiased protocolized in-depth diagnostic strategies are crucial to increase the frequency of identifiable causes within the heterogeneous group of pediatric BMF. A comprehensive approach to identify the cause of BMF can prevent treatment delay and be useful to tailor treatment and follow-up protocols. What is Known: • Irreversible BMF in pediatric patients can be caused by a wide spectrum of underlying diseases including (pre)malignant disease, IBMFS and AA. Identifying the exact underlying cause of BMF is crucial for tailored therapy, however often challenging and time-consuming. • Frontline allogeneic HSCT is offered to most pediatric patients with severe BMF as curative treatment. What is New: • Protocolized unbiased diagnostics, short time to treatment (< 3 months) and maximal supportive care until curative treatment can prevent complications with a negative effect on survival such as infection and bleeding. • Personalized follow-up protocols for IBMFS patients are essential to prevent a second decline in survival due to long-term treatment toxicity and extra-hematological disease complications.
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Autoimmune Cytopenias Post Hematopoietic Stem Cell Transplantation in Pediatric Patients With Osteopetrosis and Other Nonmalignant Diseases
Even-Or, E., Schejter, Y. D., NaserEddin, A., Zaidman, I., Shadur, B., Stepensky, P.
Frontiers in immunology. 2022;13:879994
Abstract
Autoimmune cytopenia (AIC) is a rare complication post hematopoietic stem cell transplantation (HSCT), with a higher incidence in nonmalignant diseases. The etiology of post-HSCT AIC is poorly understood, and in many cases, the cytopenia is prolonged and refractory to treatment. Diagnosis of post-HSCT AIC may be challenging, and there is no consensus for a standard of care. In this retrospective study, we summarize our experience over the past five years with post-HSCT AIC in pediatric patients with osteopetrosis and other nonmalignant diseases. All pediatric patients who underwent HSCT for nonmalignant diseases at Hadassah Medical Center over the past five years were screened for post-HSCT AIC, and data were collected from the patient's medical records. From January 2017 through December 2021, 140 pediatric patients underwent HSCT for osteopetrosis (n=40), and a variety of other nonmalignant diseases. Thirteen patients (9.3%) presented with post-HSCT AIC. Of these, 7 had osteopetrosis (17.5%), and 6 had other underlying nonmalignant diseases. Factors associated with developing AIC included unrelated or non-sibling family donors (n=10), mixed chimerism (n=6), and chronic GvHD (n=5). Treatment modalities included steroids, IVIG, rituximab, bortezomib, daratumumab, eltrombopag, plasmapheresis, and repeated HSCT. Response to treatment was variable; Seven patients (54%) recovered completely, and three patients (23%) recovered partially, still suffering from mild-moderate thrombocytopenia. Three patients died (23%), two following progressive lung disease and one from sepsis and multi-organ failure after a 3(rd) HSCT. In our experience, post-HSCT AICs in pediatric patients with nonmalignant diseases may pose a challenging post-transplant complication with a variable presentation and a wide spectrum of severity. A relatively high prevalence is seen in patients with osteopetrosis, possibly due to difficult engraftment and high rates of mixed chimerism. There is a dire need for novel treatment modalities for better management of the more severe and refractory cases.
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Stem cell transplantation for pediatric patients with adrenoleukodystrophy: A nationwide retrospective analysis in Japan
Kato, K., Yabe, H., Shimozawa, N., Adachi, S., Kurokawa, M., Hashii, Y., Sato, A., Yoshida, N., Kaga, M., Onodera, O., et al
Pediatric transplantation. 2022;26(1):e14125
Abstract
BACKGROUND Adrenoleukodystrophy (ALD) is an X-linked recessive disorder and 30-40% of patients develop progressive cerebral neurodegeneration. For symptomatic ALD patients, allogeneic stem cell transplantation (SCT) is considered the standard treatment modality to stabilize or prevent the progression of neurological symptoms. METHODS We retrospectively analyzed the transplant outcomes of 99 pediatric patients with cerebral ALD in Japan. The conditioning regimens included Regimen A: fludarabine/melphalan/low-dose total body irradiation (TBI) with brain sparing (n = 39), Regimen B; busulfan/cyclophosphamide ± others (n = 23), Regimen C: melphalan/total lymphoid irradiation/thoracoabdominal irradiation ± anti-T lymphocyte globulin ± fludarabine (n = 27), and Regimen D: others (n = 10). RESULTS The 5-year overall survival (OS) and event-free survival (EFS) of all patients were 90.0% and 72.9%, respectively. The 5-year OS was 100.0% for Regimen A, 91.1% for Regimen B, 84.4% for Regimen C, and 67.5% for Regimen D (p = 0.028). The 5-year EFS was 78.3% for Regimen A, 78.0% for Regimen B, 70.4% for Regimen C, and 48.0% for Regimen D (p = 0.304). The OS marginally improved after 2007 compared with before 2006 (95.3% vs. 85.2%, p = 0.066), due to the improvement of cord blood transplantation (CBT) outcomes after 2007 compared with before 2006 (96.6% vs. 68.4%, p = 0.005). On magnetic resonance imaging of the brain, a reduced Loes score after SCT was only observed in one of the 15 bone marrow transplantation (BMT) patients, but in 5 of the 15 CBT patients (p = 0.173). CONCLUSIONS Our study revealed that a reduced conditioning regimen with fludarabine/melphalan/low-dose TBI provides better outcomes, and the results of CBT significantly improved after 2007.
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Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT
Schuetz, C., Gerke, J., Ege, M. J., Walter, J. E., Kusters, M., Worth, A. J. J., Kanakry, J. A., Dimitrova, D., Wolska-Kusnierz, B., Chen, K., et al
Blood. 2022
Abstract
Patients with hypomorphic mutations in RAG1 and RAG2 genes present as either Omenn syndrome or atypical combined immunodeficiency (CID) with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% autoimmunity and 18% granulomas pre-transplant. These complications were frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3 - 42.9 years) from matched unrelated donors, matched sibling or matched family donors or mismatched donors (MMFD) in 48%, 22% and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5 and 67.5% (median follow-up 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft and transplant from a MMFD were predictive of worse outcome, while organ damage and T-cell depletion remained significant in multivariable analysis (HR=6.01, HR=8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences (CI) of acute and chronic GvHD were 35% and 22% respectively. CI of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T-cells was faster and more robust in patients transplanted before 3.5 years and without organ damage. These findings support the indication for early transplantation.
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Variables Affecting Outcomes After Allogeneic Hematopoietic Stem Cell Transplant for Cerebral Adrenoleukodystrophy
Chiesa, R., Boelens, J. J., Duncan, C. N., Kuehl, J. S., Sevin, C., Kapoor, N., Prasad, V. K., Lindemans, C. A., Jones, S. A., Amartino, H. M., et al
Blood advances. 2021
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in early cerebral adrenoleukodystrophy (CALD) can stabilize neurologic function and improve survival but has associated risks including transplant related mortality (TRM), graft failure, and graft-versus-host disease (GVHD). An observational study of 59 patients with median age at allo-HSCT of 8 years addressed impact of donor source, donor match, conditioning regimen, and cerebral disease stage on first allo-HSCT outcomes. Efficacy analyses included 53 patients stratified by disease category: advanced disease (AD; n=16) with Loes score >9 or neurological function score (NFS) >1 and two early disease (ED) cohorts (ED1 [Loes =4 and NFS =1; n=24] and ED2 [Loes >4-9 and NFS =1; n=13]). Survival free of major functional disabilities and without second allo-HSCT at 4 years was significantly higher in the ED (66%) versus AD (41%) cohort (p=0.015) and comparable between ED1 and ED2 cohorts (p=0.991). The stabilization of neurologic function post-transplant was greater in the ED versus AD cohort, with a median change from baseline at 24 months post-allo-HSCT in NFS and Loes score, respectively, of 0 and 0.5 in ED1 (n=13), 0.5 and 0 in ED2 (n=6), and 2.5 and 3.0 (n=4) in AD cohort. TRM was lower in the ED (7%) compared with AD (22%) cohort, however the difference was not significant (p=0.094). Transplant-related safety outcomes were also impacted by transplant-related characteristics: graft failure incidence was significantly higher with unrelated umbilical cord grafts versus matched related donors (MRD) (p=0.039), and acute GVHD and graft failure incidences varied by conditioning regimen. The study is registered to https://clinicaltrials.gov as NCT02204904.
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Long-term effect of hematopoietic cell transplantation on systemic inflammation in patients with mucopolysaccharidoses
van den Broek, B. T. A., Lindemans, C. A., Boelens, J. J., Delemarre, E. M., Drylewicz, J., Verhoeven-Duif, N., van Hasselt, P. M., Nierkens, S.
Blood advances. 2021;5(16):3092-3101
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Abstract
Mucopolysaccharidoses (MPS) are devastating inherited diseases treated with hematopoietic cell transplantation (HCT). However, disease progression, especially skeletal, still occurs in all patients. Secondary inflammation has been hypothesized to be a cause. To investigate whether systemic inflammation is present in untreated patients and to evaluate the effect of HCT on systemic inflammation, dried blood spots (n = 66) of patients with MPS (n = 33) treated with HCT between 2003 and 2019 were included. Time points consisted of pre-HCT and, for patients with MPS type I (MPS I), also at 1, 3, and 10 years of follow-up. Ninety-two markers of the OLINK inflammation panel were measured and compared with those of age-matched control subjects (n = 31) by using principal component analysis and Wilcoxon rank sum tests with correction. Median age at transplantation was 1.3 years (range, 0.2-4.8 years), and median time of pre-HCT sample to transplantation was 0.1 year. Normal leukocyte enzyme activity levels were achieved in 93% of patients post-HCT. Pretransplant samples showed clear separation of patients and control subjects. Markers that differentiated pre-HCT between control subjects and patients were mainly pro-inflammatory (50%) or related to bone homeostasis and extracellular matrix degradation (33%). After 10 years' follow-up, only 5 markers (receptor activator of nuclear factor kappa-? ligand, osteoprotegerin, axis inhibition protein 1 [AXIN1], stem cell factor, and Fms-related tyrosine kinase 3 ligand) remained significantly increased, with a large fold change difference between patients with MPS I and control subjects. In conclusion, systemic inflammation is present in untreated MPS patients and is reduced upon treatment with HCT. Markers related to bone homeostasis remain elevated up to 10 years after HCT and possibly reflect the ongoing skeletal disease, making them potential biomarkers for the evaluation of new therapies.
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Neurocognitive benchmarks following transplant for emerging cerebral adrenoleukodystrophy
Pierpont, E. I., Nascene, D. R., Shanley, R., Kenney-Jung, D. L., Ziegler, R. S., Miller, W. P., Gupta, A. O., Lund, T. C., Orchard, P. J., Eisengart, J. B.
Neurology. 2020
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Abstract
OBJECTIVE To quantify benchmark treatment outcomes that may be enabled by newborn screening surveillance for X-linked adrenoleukodystrophy (ALD), we report neurocognitive, neuropsychiatric, and MRI change for boys who underwent hematopoietic stem cell transplant (HSCT) at initial stages of demyelination, prior to neurocognitive signs of disease. METHODS Retrospective chart review identified 36 patients whose cerebral ALD was detected and treated early, with lesion severity less than 5 on the ALD-specific MRI scoring system. Median age at transplant was 7.3 years (range, 4.0-16.1). Progression of radiologic disease on MRI in the 2 years following HSCT was examined relative to the severity of the initial lesion for 33 patients, and longitudinal neurocognitive and neuropsychiatric outcomes were studied for 30 patients. RESULTS Patients whose pretransplant lesion extended beyond the splenium of the corpus callosum and adjacent periventricular white matter (MRI severity score >2) demonstrated lower posttransplant neurocognitive scores, more neuropsychiatric symptoms, and more disease progression on MRI than patients with a less severe lesion. Changes from baseline neurocognitive functioning were greater at 2 years posttransplant as compared to 1 year. There was greater variance and risk of lesion progression as pretransplant MRI severity increased. CONCLUSION To realize the full benefits of newborn screening, clinicians must detect very small demyelinating lesions during surveillance and intervene quickly. Novel interventions that reduce risks inherent in allogeneic transplantation are needed. Trial endpoints should include direct neurocognitive assessment and extend at least 2 years posttreatment to provide the greatest sensitivity to detect neurocognitive morbidity.
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Comparison of Optic Canal Diameter in Children With Malignant Infantile Osteopetrosis and Normal Children and the Effects of Hematopoietic Stem Cell Transplantation on the Optic Canal Diameter
Cao, W., Wei, W., Yu, G., Wu, Q., Qin, M.
Journal of pediatric ophthalmology and strabismus. 2018;:1-8
Abstract
PURPOSE To investigate the difference in the optic canal diameter between children with autosomal recessive malignant infantile osteopetrosis and normal children, and to assess the influence of hematopoietic stem cell transplantation on the optic canal diameter. METHODS Twenty pediatric patients with malignant infantile osteopetrosis and 22 normal control children were included in this study. Eleven patients with malignant infantile osteopetrosis underwent hematopoietic stem cell transplantation. The measurements included optical canal diameter and flash visual evoked potential. Comparisons of these measurements between patients with malignant infantile osteopetrosis and normal controls as well as before and after hematopoietic stem cell transplantation were performed. The correlation between age and optic canal diameter was analyzed using Pearson correlation analysis. RESULTS The mean optic canal diameter before hematopoietic stem cell transplantation was 1.65 +/- 0.54 mm in patients with malignant infantile osteopetrosis and 3.38 +/- 0.60 mm in the control group (P < .001). The mean optic canal diameter after hematopoietic stem cell transplantation was 2.72 +/- 0.66 mm, which was significantly different from the pre-transplantation measurement (P < .001). The P2 latency for the flash visual evoked potential after hematopoietic stem cell transplantation (152.3 +/- 36.4 ms) was significantly less than that before transplantation (165.5 +/- 27.7 ms; P = .051). Pearson correlation analysis revealed a significant correlation between age and optic canal diameter (r = 0.722, P < .001). CONCLUSIONS The optic canal was narrower in pediatric patients with malignant infantile osteopetrosis than in age-matched normal controls. This condition can be relieved through hematopoietic stem cell transplantation and the impaired conductibility of the optic nerve can be improved in some cases. [J Pediatr Ophthalmol Strabismus. 201X;X(X):XX-XX.].