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Human leucocyte antigen-matched related haematopoietic stem cell transplantation using low-dose cyclophosphamide, fludarabine and thymoglobulin in children with severe aplastic anaemia
Alsultan, A., Abujoub, R., Alsudairy, R., Memon, S., Jarrar, M. S., Alafghani, S., Aldaama, S., Ballourah, W., Almanjomi, F., Essa, M. F.
British journal of haematology. 2023
Abstract
When human leucocyte antigen-matched related donors are available, haematopoietic stem cell transplantation (HSCT) in children with severe aplastic anaemia (SAA) represents the standard of care. Cyclophosphamide (Cy) 200 mg/kg and anti-thymocyte globulin (ATG) are frequently administered, but to-date, no standard conditioning regimen exists. In this study, we investigated the efficacy of a unified HSCT conditioning protocol consisting of low-dose Cy 80 mg/kg, fludarabine and ATG. Data were reviewed from children aged ≤14 years with either acquired SAA or non-Fanconi anaemia inherited bone marrow failure syndrome (IBMFS) between 2011 and 2022 at various Saudi institutions. Graft-versus-host disease (GVHD) prophylaxis included mycophenolate mofetil and calcineurin inhibitors. HSCT was performed in 32 children (17 females and 15 males). Nine patients had deleterious mutations (two ERCC6L2, two ANKRD26, two TINF2, one LZTFL1, one RTEL1 and one DNAJC21). Four patients had short telomeres. All 32 patients engrafted successfully. At 3 years post-transplant, the event-free survival was 93% and overall survival was 95%. Two patients experienced secondary graft failure or myelodysplastic syndrome. A low probability of GVHD was observed (one acute GVHD II and one mild chronic GVHD). These data highlight how HSCT using low-dose Cy as part of a fludarabine-based regimen is safe and effective in SAA/non-Fanconi anaemia IBMFS.
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Impact of Conditioning Regimen and Graft-versus-Host Disease Prophylaxis on The Outcome of Haploidentical Peripheral Blood Stem Cell Transplantation for High-Risk Severe Aplastic Anaemia in Children and Young Adults: A Report from the Pediatric
Kharya, G., Jaiswal, S. R., Bhat, S., Raj, R., Yadav, S. P., Dua, V., Sen, S., Bakane, A., Badiger, S., Uppuluri, R., et al
Transplantation and cellular therapy. 2022
Abstract
Allogenic hematopoietic cell transplant (HCT) is the best curative approach patients with severe aplastic anemia (SAA). Outcome of HCT from haploidentical family donor (HFD) has improved, making it a feasible option for patients lacking HLA-identical donor. However, data on HFD-HCT for younger patients with SAA is sparse. In multicentre retrospective study, we report outcome of 79 patients undergoing HFD-HCT for SAA. All were heavily pre-transfused, median time to HCT >12 months and 67% had failed previous therapies. Conditioning was based on Flu-Cy-ATG/TBI with or without thiotepa/melphalan (TT/Mel). Post-transplantation cyclophosphamide (PTCy) and CNI/Sirolimus were employed as GvHD prophylaxis with or without abatacept. Primary graft failure (PGF) was 16.43%, less in those conditioned with TT/Mel. Incidence of acute and chronic GVHD were 26.4% and 18.9%. At a median follow-up of 48 months, the overall survival (OS) and event free survival (EFS) were 61.6% and 58.1% respectively. Both OS/EFS were better in TT/Mel group and with abatacept as GVHD prophylaxis. On multivariate analysis, use of Abatacept was found to favourably impact the outcome variables including GVHD and EFS. Our study suggests that PTCy-based HFD-HCT is a reasonable option for young patients with high-risk SAA, where optimisation of conditioning and GVHD prophylaxis might improve outcomes further.
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Haploidentical Peripheral Stem Cell Transplantation for Young Patients with Severe Aplastic Anemia Using Post-Transplantation Cyclophosphamide and Methotrexate
Yang, K., Gong, S., Jiang, T., Liang, X., Hu, J., Zhu, P., Nie, L., Xu, Y., Fu, B.
Transplantation and cellular therapy. 2021;27(5):429.e1-429.e7
Abstract
Severe aplastic anemia (SAA) is a serious bone marrow failure disorder that is often cured with hematopoietic stem cell transplantation (HSCT). The absence of a matched related donor is common, however, and thus novel approaches are needed to safely expand the donor pool to include alternative donors, especially haploidentical related donors, for patients with SAA. This study aimed to explore a novel approach to HSCT for patients with SAA without an available HLA-identical sibling or a matched unrelated donor, termed haploidentical peripheral blood stem cell transplantation (haplo-PBSCT), using a conditioning regimen comprising cyclophosphamide, busulfan, and fludarabine (CBF) and a graft-versus-host disease (GVHD) prophylaxis regimen with post-transplantation cyclophosphamide (PTCy), low-dose methotrexate (LD-MTX), and calcineurin inhibitors. This prospectively designed nonrandomized study included 29 patients with SAA who underwent haplo-PBSCT between November 2017 and May 2020. The median patient age was 17 years (range, 14 to 30 years), and the median time to neutrophil recovery was 13 days (range, 13 to 15 days). There was 1 primary graft failure (GF) in the group receiving PTCy at a dose of 50 mg/kg and no GFs in the group receiving PTCy at a dose of 100 mg/kg. The median duration of follow-up was 736 days (95% confidence interval, 512 to 879 days). The estimated 1-year overall survival and disease-free survival were 91.7 ± 5.7% and 89.7 ± 5.7%, respectively. Only 1 of the 27 patients developed grade II acute GVHD. Four patients developed limited and mild chronic GVHD, involving only the skin or/and oral mucosa. Haplo-PBSCT following CBF and followed by PTCy and LD-MTX represents a novel approach for safely expanding the donor pool to include alternative donors for young patients with SAA.
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Donor-derived marrow mesenchymal stromal cell co-transplantation following a haploidentical hematopoietic stem cell transplantation trail to treat severe aplastic anemia in children
Wang, Z., Yu, H., Cao, F., Liu, Z., Liu, Z., Feng, W., Liu, X., Yu, Y., Xiao, Y., Li, L., et al
Annals of hematology. 2018
Abstract
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is associated with an increased risk of graft failure and severe graft-versus-host disease (GVHD). Recent studies have shown that mesenchymal stromal cells (MSCs) display potent immunosuppressive effects and can support normal hematopoiesis. In a multi-center trial, we co-transplanted culture-expanded donor-derived bone marrow MSCs (BM-MSCs) into 35 children with severe aplastic anemia (SAA) undergoing haplo-HSCT. All 35 patients (100%) achieved hematopoietic reconstitution and showed sustained full donor chimerism. The median time for myeloid engraftment was 14 days (range 10-22 days), while that for platelet engraftment was 18 days (range 9-36 days). The incidence of grade II-IV acute GVHD and chronic GVHD was 25.71 and 22.86%, respectively. The overall survival rate was 85.71% with a median of 22 months (range 3.5-37 months). The combined transplantation of haploidentical HSCs and BM-MSCs into children with SAA without an HLA-identical sibling donor is relatively safe and may represent an effective new therapy to improve survival rates and reduce the risk of graft failure.