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1.
Prospective study of a modified posttransplant cyclophosphamide regimen for severe aplastic anemia patients with HLA-haploidentical transplantation
Wu, L., Zhou, M., Li, Y., Chen, X., Mo, W., Wang, C., Xu, S., Zhou, W., Deng, T., Zhou, R., et al
Transplantation and cellular therapy. 2023
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative modality for severe aplastic anemia (SAA). The availability of haploidentical donors has expanded valid choices for SAA. However, previous posttransplantation cyclophosphamide (PTCy)-based protocols for HLA-haploidentical HSCT in SAA patients are associated with relatively delayed neutrophil and platelet engraftment. We prospectively studied HLA-haploidentical HSCT using bone marrow combined with peripheral blood stem cells as grafts and a modified PTCy regimen for treating SAA; we evaluated the efficacy and safety of this regimen, which had an increased dose (from 4.5 mg/kg to 6.0 mg/kg) and backward adjusted timing (from day -9 to -7 to day -5 to -3) of antithymocyte globulin (ATG) compared with previous PTCy protocols. Seventy-one eligible patients were included in this prospective study between July 2019 and June 2022. The median time to and cumulative incidence (CI) of neutrophil and platelet engraftment were 13 days (range, 11-19) and 97.2±2.2% and 12 days (range, 7-62) and 94.4 ± 2.9%, respectively. Five patients experienced graft failure (GF), including 2 with primary GF and 3 with secondary GF. The CI of GF was 7.0±3.1%. The interval between diagnosis and transplantation (≥1 year) was a risk factor for GF development (HR 8.40, 95% confidence interval (1.40-50.47), p=0.02). No patients developed grade IV acute graft-versus-host disease (aGVHD) or severe chronic GVHD (cGVHD). The 100-day CI of grade II-IV aGVHD and 2-year cGVHD were 13.4±4.2% and 5.9±2.9%, respectively. With a median follow-up of 580 days (range, 108-1014) for 63 survivors, the estimated 2-year overall survival (OS) and 2-year GVHD-free and failure-free survival (GFFS) were 87.3% (95% confidence interval, 79.4-96.0) and 83.8% (95% confidence interval, 74.9-93.7), respectively. In conclusion, the PTCy regimen with an increased dose and backward adjusted timing of ATG is an effective and feasible choice for treatment with HLA-haploidentical HSCT using BM combined with PBSCs as grafts, with a high rate of and faster engraftment, a low rate and intensity of aGVHD and cGVHD, and prolonged OS and GFFS.
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2.
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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3.
[Clinical Study of Haploid Allogeneic Hematopoietic Stem Cell Transplantation Combined with Post-transplant Cyclophosphamide in Severe Aplastic Anemia Patients]
Li, J. N., Li, P., Liu, L., Xiao, Q., Tang, X. Q., Zhang, H. B., Wang, X., Luo, X. H., Wang, L.
Zhongguo shi yan xue ye xue za zhi. 2022;30(1):227-231
Abstract
OBJECTIVE To evaluate the clinical effect of haploid allogeneic hematopoietic stem cell transplantation(haplo-HSCT) in the treatment of severe aplastic anemia (SAA), and to explore the efficacy different between post-transplant cyclophosphamide (PT/Cy) and standard-dose ATG. METHODS The clinical data of 38 patients with SAA in our hospital from January 2012 to December 2019 were collected and retrospectively analyzed. The efficacy was evaluated. The patients with haplo-HSCT were divided into low-dose ATG combined with PT/Cy group and standard-dose ATG group, and the blood cell hematopoietic reconstruction time, GVHD incidence, mortality and survival time of the patients in the two groups was compared. RESULTS Among the 32 patients, hematopoietic reconstitution were detected in 9375%(30/32) recipients. The median time of neutrophil and platelet engraftment was 15(10-22) days and 13(7-30) days, respectively. The incidence of GVHD was 21.89%, the incidence of infection was 93.75%, and the 2-year overall survival rate was 84.38%. The hematopoietic reconstitution time, incidence of GVHD, mortality rate and survival time were no statistical differences between the patients in the two groups(all P>0.05). CONCLUSION Haplo-HSCT is an effective method for the treatment of SAA,low-dose ATG combined with PT/Cy can lighten the economic burden on patients, it would be a feasible treatment plan for SAA with light side effect.
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4.
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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5.
Comparison of porcine ALG and rabbit ATG on outcomes of HLA-haploidentical hematopoietic stem cell transplantation for patients with acquired aplastic anemia
Chen, J., Zhang, Y., Chen, X., Pang, A., Zhao, Y., Liu, L., Ma, R., Wei, J., He, Y., Yang, D., et al
Cancer cell international. 2022;22(1):89
Abstract
OBJECTIVE To evaluate the efficacy and safety of P-ALG (porcine anti-lymphocyte globulin) and R-ATG (rabbit anti-thymocyte globulin) in the conditioning regime for patients with acquired aplastic anemia who underwent HLA-haploidentical hematopoietic stem cell transplantation (halpo-HSCT). METHODS A total of 91 patients with acquired aplastic anemia who received haplo-HSCT at our center between January 2014 and December 2020 were retrospectively reviewed. Twenty-eight patients were in the P-ALG group while sixty-three patients were in the R-ATG group. RESULTS The median time was 11 versus 13 days (P = 0.294) for myeloid engraftment and 12.5 versus 15 days (P = 0.465) for platelet engraftment in the P-ALG and R-ATG groups, respectively. There were no significant difference in 5-year overall survival (74.83% ± 8.24% vs 72.29% ± 6.26%, P = 0.830), GVHD-free, failure-free survival (71.05% ± 8.65% vs 62.71% ± 6.22%, P = 0.662), failure-free survival (74.83% ± 8.24% vs 66.09% ± 5.84%, P = 0.647) and transplantation-related mortality (25.17% ± 8.24% vs 26.29% ± 6.22%, P = 0.708) between the two groups. The incidence of aGVHD (acute graft versus host disease) (65.39% ± 9.33% vs 62.71% ± 6.30%, P = 0.653), II-IV aGVHD (38.46% ± 9.54% vs 35.64% ± 6.24%, P = 0.695), III-IV aGVHD (19.23% ± 7.73% vs 10.53% ± 4.07%, P = 0.291), cGVHD (chronic graft versus host disease) (22.22% ± 12.25% vs 22.31% ± 6.30%, P = 0.915), and moderate to severe cGVHD (5.56% ± 5.40% vs 9.28% ± 4.46%, P = 0.993) were not significantly different. Similar outcomes were observed between the P-ALG and R-ATG groups for severe bacterial infection (17.9% vs 25.4%, P = 0.431), invasive fungal diseases (3.6% vs 9.5%, P = 0.577) and graft rejection (0% vs 9.5%, P = 0.218). However, the incidence of cytomegalovirus infection and Epstein-Barr virus infection was significantly lower in the P-ALG group (46.4% vs 71.4%, P = 0.022; 3.6% vs 25.4%, P = 0.014). CONCLUSION The efficacy and safety of P-ALG were similar with R-ATG in the setting of haplo-HSCT for patients with acquired aplastic anemia patients. P-ALG could be an alternative for R-ATG.
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6.
Comparisons Between modified PTCY and G-CSF/ATG Regimens for Haploidentical Transplantation in Patients with Aplastic Anemia
Li, Y., Lu, X., Wang, N., Zhang, X., Cao, Y., Xiao, Y., Meng, F., Zhang, D., You, Y., Zou, L., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Haploidentical transplantation has become an alternative treatment option for aplastic anemia patients without matched sibling donors or matched unrelated donors. Recently, the post-transplantation cyclophosphamide (PTCY) regimen and granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG) regimen have become the most common protocols used worldwide. OBJECTIVE We designed this retrospective study to compare the outcomes of patients receiving a modified post-transplantation cyclophosphamide (mPTCY) regimen versus the G-CSF/ATG regimen. STUDY DESIGN We retrospectively reviewed and analyzed the clinical data of 130 aplastic anemia patients who underwent haplo-HSCT and received the mPTCY regimen (n=55) or G-CSF/ATG regimen (n=75) between Jan 2013 and Jun 2021 across seven transplant centers. RESULTS Neutrophil engraftment was successful in all patients within 30 days in the G-CSF/ATG group. The cumulative neutrophil engraftment rate in the mPTCY group was 96.36% (95% CI, 94.57-97.57, P=0.010). The median time of neutrophil engraftment in the G-CSF/ATG group was 10 (7-28) days, which was more rapid than that observed in the mPTCY group (P <0.001). There were no significant differences in the incidence of graft versus host disease (GVHD) between the two groups. The cumulative incidence of II-IV acute GVHD was 18.40% (95% CI, 4.27-40.31) in the mPTCY group and 19.32% (95% CI, 5.86-38.58) in the G-CSF/ATG group, while the cumulative incidence of III-IV acute GVHD was 7.31% (95% CI, 0.09-37.48) in the mPTCY group and 7.57% (95% CI, 0.20-34.19) in the G-CSF/ATG group. Similarly, no significant difference was observed between the two groups in terms of overall survival (OS), failure-free survival (FFS), and GVHD relapse-free survival (GRFS). The 2-year OS, FFS and GRFS rates were 95.91% (95% CI, 84.59-98.96), 92.25% (95% CI, 80.59-97.03) and 86.68% (95% CI, 73.98-93.44), respectively, in the mPTCY group and 86.67% (95% CI, 76.64-92.59), 81.28% (95% CI, 70.45-88.46) and 77.20% (95% CI, 65.89-85.16), respectively, in the G-CSF/ATG group. The transplantation-related mortality (TRM) rate was significantly higher in the G-CSG/ATG group than in the mPTCY group (13.33% in the G-CSG/ATG group versus 1.96% in the mPTCY group, P=0.022). In multivariate analysis, female donors, a higher hematopoietic cell transplantation comorbidity index (HCT-CI) and III-IV aGVHD were associated with worse survival outcomes. CONCLUSIONS In conclusion, the mPTCY and G-CSF/ATG regimens led to similar outcomes in AA patients, but quicker engraftment was observed with the ATG/G-CSF regimen, and a lower incidence of TRM was observed with the mPTCY regimen.
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7.
[Haploidentical Hematopoietic Stem Cell Transplantation with Co-Infusion of Mesenchymal Stromal Cells for Acquired Severe Aplastic Anemia: A Report of 127 Cases]
Han, D. M., Ding, L., Zheng, X. L., Yan, H. M., Xue, M., Liu, J., Zhu, L., Li, S., Wang, H. X.
Zhongguo shi yan xue ye xue za zhi. 2022;30(4):1230-1237
Abstract
OBJECTIVE To analyze the prognostic factors of haplo-HSCT combined with MSC in the treatment of SAA. METHODS 127 SAA patients who had undergone haplo-HSCT with co-infusion of MSC in our center from January 2014 to August 2019 were analyzed retrospectively. Median age was 11 (1-37) years, and median follow-up time was 39.8 (1-74) months. RESULTS The median time for neutrophil and platelet engraftment was 14 d and 18 d respectively. The cumulative incidences of grade III-IV aGVHD was 4.4%±1.9% at day +100. The 2-year cumulative incidence of extensive cGVHD was 8.3%± 2.7%. The estimated 3-year OS was 86.1%±3.1%. Univariate analysis showed that high-dose CD34(+) cells (>6.69×106/kg) could promote the engraftment of neutrophil (97.9%±0.05% vs 88.6%±0.13% at day +21, P=0.0006) and platelet (81.2%±0.33% vs 70.8%±0.26% at day +28, P=0.002) and did not increase the incidence of aGVHD (10.4%±0.1% vs 18.9%±0.1% at day +100, P=0.18). More nucleated cells (>12.78×10(8)/kg) caused a lower incidence of grade II-IV aGVHD (8.6%±0.13% vs 21.7%±0.25% at day+100, P=0.04) and a higher incidence of 3-year OS (91.3%±3.2% vs 78.1%±6.5%, P=0.03) than less nucleated cells (≤12.78×10(8)/kg). Younger patients (age≤12 y) had faster neutrophil engraftment (94.9%±0.06% vs 87.5%±0.24% at day+21, P=0.02), higher 3-year OS (93.6%±2.8% vs 75.9%±6.4%, P=0.006) and higher 3-year FFS (93.6%±2.8% vs 68.3%±7.1%, P=0.000) than older patients (age>12 y). The shorter the time from diagnosis to HSCT (≤29.5 months), the higher the 3-year FFS of patients (88.8%±3.5% vs 74.2%±7.2%, P=0.028). Male patients with female donors had higher cumulative incidence of extensive cGVHD than others (20.0%±0.8% vs 4.6%±0.1%, P=0.01). CONCLUSION In the haplo-HSCT of SAA, the prognosis of children patients is better than that of adults patients. More CD34(+) cells and nucleated cells can promote engraftment, reduce the incidence of aGVHD and improve OS. HSCT should be performed as early as possible, and the occurrence of cGVHD should be reduced in male patients by avoiding female donors.
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8.
Retrospective Comparison of Efficacy and Safety of Rabbit Anti-Thymocyte Globulin and Porcine Anti-Lymphocyte Globulin in Patients With Acquired Aplastic Anemia Undergoing Hematopoietic Stem Cell Transplantation From Matched Sibling Donors
Zhang, Y., Chen, X., Li, L., Li, Y., Lin, L., Cao, Y., Wang, N., Yang, D., Pang, A., Zhang, R., et al
Frontiers in immunology. 2022;13:889784
Abstract
We compared the efficacy and safety of porcine anti-lymphocyte globulin (pALG) (n=140) and rabbit anti-thymocyte globulin (rATG) (n=86) in patients with acquired aplastic anemia (AA) receiving hematopoietic stem cell transplantation (HSCT) from matched sibling donors (MSD) in two transplantation centers in China ranging from 2005 to 2020. The groups had similar baseline characteristics except for a higher number of infused mononuclear cells (P<0.001) and a higher proportion of peripheral blood stem cells as graft sources (P=0.003) in the pALG group. The rates of neutrophil engraftment at day 28 (P=1), platelet engraftment at day 28 (P=0.228), bloodstream infection before engraftment (P=0.867), invasive fungal diseases (P=0.362), cytomegalovirus viremia (P=0.667), and graft rejection (P=0.147) were similar in the two groups. A higher cumulative incidence of grades II-IV acute graft versus host disease (aGvHD) at 100 days occurred in the pALG group (19% vs. 8%, P=0.035) while no significant differences in grades III-IV aGvHD (P=0.572), mild to severe chronic GvHD (cGvHD) (P=0.181), and moderate to severe cGvHD (P=0.586) were observed. The actuarial 5-year overall survival (OS), failure-free survival (FFS), and GvHD-free, FFS rates of the pALG group were 87% (95% confidence interval [CI], 82-93), 85% (95% CI, 80-92), and 78% (95% CI, 72-92) versus 91% (95% CI, 86-99) (P=0.33), 88% (95% CI, 82-97) (P=0.428), and 79% (95% CI, 72-90) (P=0.824) in the rATG group, respectively. A busulfan-containing conditioning regimen was the only adverse risk factor for OS and FFS in multivariate analysis. In conclusion, pALG is an alternative to rATG in patients with severe AA receiving MSD-HSCT. A prospective, large-sample study is needed to explore this therapy further.
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9.
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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10.
Mesenchymal stromal cells as prophylaxis for graft-versus-host disease in haplo-identical hematopoietic stem cell transplantation recipients with severe aplastic anemia?-a systematic review and meta-analysis
Li, R., Tu, J., Zhao, J., Pan, H., Fang, L., Shi, J.
Stem cell research & therapy. 2021;12(1):106
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) are an emerging prophylaxis option for graft-versus-host disease (GVHD) in haplo-identical hematopoietic stem cell transplantation (haplo-HSCT) recipients with severe aplastic anemia (SAA), but studies have reported inconsistent results. This systematic review and meta-analysis evaluates the efficacy of MSCs as prophylaxis for GVHD in SAA patients with haplo-HSCT. METHODS Studies were retrieved from PubMed, EMBASE, Cochrane, Web of Science, and http://clinicaltrials.gov from establishment to February 2020. Twenty-nine single-arm studies (n?=?1456) were included, in which eight (n?=?241) studies combined with MSCs and eleven (n?=?1215) reports without MSCs in haplo-HSCT for SAA patients. The primary outcomes were the incidences of GVHD. Other outcomes included 2-year overall survival (OS) and the incidence of cytomegalovirus (CMV) infection. Odds ratios (ORs) were calculated to compare the results pooled through random or fixed effects models. RESULTS Between MSCs and no MSCs groups, no significant differences were found in the pooled incidences of acute GVHD (56.0%, 95% CI 48.6-63.5% vs. 47.2%, 95% CI 29.0-65.4%; OR 1.43, 95% CI 0.91-2.25; p?=?0.123), grade II-IV acute GVHD (29.8%, 95% CI 24.1-35.5% vs. 30.6%, 95% CI 26.6-34.6%; OR 0.97, 95% CI 0.70-1.32; p?=?0.889), and chronic GVHD (25.4%, 95% CI 19.8-31.0% vs. 30.0%, 95% CI 23.3-36.6%; OR 0.79, 95% CI 0.56-1.11; p?=?0.187). Furtherly, there was no obvious difference in 2-year OS (OR 0.98, 95% CI 0.60-1.61; p?=?1.000) and incidence of CMV infection (OR 0.61, 95% CI 0.40-1.92; p?=?0.018). CONCLUSIONS Our meta-analysis indicates that the prophylactic use of MSC co-transplantation is not an effective option for SAA patients undergoing haplo-HSCT. Hence, the general co-transplantation of MSCs for SAA haplo-HSCT recipients may lack evidence-based practice.