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1.
Busulfan for allogeneic hematopoietic stem cell transplantation in children with severe aplastic anemia: A retrospective study
Si, Y., Luo, R., Qin, M., Du, Z., Zhang, X., Wang, Y., Chen, W., Gu, W., Xing, G., Dou, L., et al
Acta haematologica. 2023
Abstract
Introduction This retrospective study aimed to compare a range of conditioning regimens in children with severe aplastic anemia (SAA) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) at the Seventh Medical Center of PLA General Hospital between January 2008 and June 2017. Methods Patients were categorized into the Bu (Bu + Flu + Cy + ATG-F regimen) and control (Flu + Cy + ATG-F) groups, with a median follow-up time after HSCT of 3.5 (range, 3.1-6.2) and 3.7 (3.2-5.9) years in the Bu and control groups, respectively. Results No differences were observed between the two groups regarding the median time of peripheral blood neutrophil and platelet engraftment (P = 0.538 and P = 0.491); the 28-day engraftment rates of neutrophils were similar (P = 0.199) although higher for platelets with Bu (P = 0.044). Additionally, graft failure was 0% and 20.0% in the Bu and control groups, respectively (P = 0.004). In both groups, the incidence of grades ⅡI-Ⅳ (or grades Ⅱ-Ⅳ) acute graft-versus-host disease (GVHD) and chronic GVHD was not significantly different (P > 0.05). Moreover, the 3-year overall survival and failure-free survival did not show significant differences (P = 0.670 and P = 0.908). Discussion In children with SAA undergoing allo-HSCT, conditioning regimen with Bu + Flu + Cy + ATG-F is capable of enhancing the myeloablation effect, promoting donor hematopoietic stem cell engraftment, and reducing the graft failure rate. Furthermore, it does not increase the incidence of complications, including GVHD.
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2.
Fludarabine-Based Low-Intensity Conditioning for Fanconi Anemia is Associated with Good Outcomes in Aplastic Anemia but not in MDS - a Single-Center Experience
Chattopadhyay, S., Lionel, S., Selvarajan, S., Devasia, A. J., Korula, A., Kulkarni, U., Na, F., Sindhuvi, E., Lakshmi, K. M., Srivastava, A., et al
Mediterranean journal of hematology and infectious diseases. 2023;15(1):e2023039
Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with Fanconi Anemia (FA) with hematological abnormalities. MATERIALS AND METHODS This is a retrospective analysis of patients with FA who underwent a matched-related donor HSCT. RESULTS Sixty patients underwent 65 transplants between 1999-2021 using a fludarabine-based low-intensity conditioning regimen. The median age at transplant was 11 years (range: 3-37). Aplastic anemia (AA) was the underlying diagnosis in 55 (84.6%), while 8 (12.4%) had myelodysplastic syndrome (MDS) and 2 (3%) had acute myeloid leukemia (AML). The conditioning regimen used was Fludarabine with low-dose Cyclophosphamide for aplastic anemia and Fludarabine with low-dose Busulfan for MDS/AML. Graft versus host disease (GVHD) prophylaxis consisted of Cyclosporine and methotrexate. Peripheral blood was the predominant stem cell graft source (86.2%). Engraftment occurred in all but one patient. The median time to neutrophil and platelet engraftment was 13 days (range: 9-29) & 13 days (range: 5-31), respectively. Day 28 chimerism analysis showed complete chimerism in 75.4 % and mixed chimerism in 18.5%. Secondary graft failure was encountered in 7.7%. Grade II-IV acute GVHD occurred in 29.2%, while Grade III-IV acute GVHD occurred in 9.2%. Chronic GVHD was seen in 58.5% and was limited in most patients. The median follow-up is 55 months (range: 2-144) & the 5-year estimated overall survival (OS) is 80.2 ± 5.1%. Secondary malignancies were noted in 4 patients. The 5-year OS was significantly higher in patients undergoing HSCT for AA (86.6 + 4.7%) as compared to MDS/AML (45.7+16.6%) (p= 0.001). CONCLUSION SCT using a fully matched donor provides good outcomes with low-intensity conditioning regimens in patients with FA who have aplastic marrow.
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3.
Adding 5-day decitabine to the conditioning regimen for haploidentical bone marrow transplantation in aplastic anaemia patients results in satisfactory clinical outcomes
Tang, L., Wu, Y., Lei, R., Liu, J., Guo, D., Zhao, Y., Li, H., Fan, S.
Bone marrow transplantation. 2022
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4.
A modified conditioning regimen based on low-dose cyclophosphamide and fludarabine for haploidentical hematopoietic stem cell transplant in severe aplastic anemia patients at risk of severe cardiotoxicity
Lin, F., Zhang, Y., Han, T., Cheng, Y., Mo, X., Wang, J., Chen, Y., Wang, F., Tang, F., Han, W., et al
Clinical transplantation. 2022;36(1):e14514
Abstract
Severe cardiotoxicity is a fatal complication during high-dose cyclophosphamide (Cy)-based conditioning in hematopoietic stem cell transplant (HSCT) for severe aplastic anemia (SAA). This study aimed to evaluate the feasibility and efficacy of a modified conditioning regimen in haploidentical HSCT (haplo-HSCT) for severe-cardiotoxic-risk SAA patients. This BuCy(low) Flu conditioning utilized busulfan (Bu, 3.2 mg/kg for 2 days), low-dose Cy (100 mg/kg), fludarabine (150 mg/m(2) ), and rabbit antithymocyte globulin (rATG, 10 mg/kg). Compared to BuCy conditioning using high-dose Cy of 200 mg/kg, Bu of 3.2 mg/kg for 2 days, and rATG of 10 mg/kg, the incidence of severe cardiotoxicity of BuCy(low) Flu conditioning was significantly decreased (2.17% vs 12.80%, p = .032). The engraftment rates (100% for neutrophil and 84.44% for platelet) were favorable. The probabilities of 100-day transplant-related mortality were similar in the BuCy(low) Flu and the BuCy group (8.75% vs 10.53%, p = .671). Both 1-year overall survival (88.79% vs 84.66%, p = .357) and 1-year failure-free survival (84.78% vs 81.70%, p = .535) were comparable. The BuCy(low) Flu group had higher rates of cytomegalovirus and Epstein-Barr virus reactivation. In conclusion, the BuCy(low) Flu provided reduced severe cardiotoxicity, and achieved favorable engraftment and survival. Our results suggest BuCy(low) Flu conditioning can be a feasible alternative for haplo-HSCT recipients at risk of severe cardiotoxicity.
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5.
Fludarabine/Cyclophosphamide Conditioning Regimen in Aplastic Anemia Patients Receiving Matched-Sibling Donor Transplant Is Non-inferior to ATG/Cyclophosphamide: A Single-Center Experience from Pakistan
Zaidi, U., Fatima, M., Samad, S. A., Shafique, K., Waseem, H. F., Farzana, T., Shamsi, T. S.
Stem cells international. 2022;2022:1442613
Abstract
The successful outcome of allogeneic hematopoietic stem cell transplant (HSCT) in aplastic anemia patients is driven by suitable donor selection, appropriate conditioning regimen, early intervention, and optimal supportive care after transplant. Pakistan, being a developing country, faces grave economic challenges due to meager health care budget; therefore, cost constraints remain the foremost impediment in optimizing transplant facilities for socioeconomically deprived patients. We conducted a single-center retrospective analysis of aplastic anemia patients (N = 130), who received matched sibling donor transplants from 2011 to 2019, treated with either fludarabine/cyclophosphamide (Flu/Cy) or antithymocyte globulin/cyclophosphamide (ATG/CY) conditioning regimen. Median age was 16 years (IQR, 11-20), and it ranged from 3 to 48 years. The median time from diagnosis to transplant was 3 months (IQR, 2 to 4), and it ranged from 1 to 8 months. The estimated overall survival (OS), relapse-free survival (RFS), and GvHD-free survival (GFS) were found to be 69.0%, 66.7%, and 64.3% in the ATG/Cy group while 76.1%, 72.7%, and 62.5% in the Flu/Cy group, respectively, after a median follow-up of 30 months (IQR, 8 to 55), and it ranged from 0 to 98 months for the study groups. The Flu/Cy regimen was well tolerated and was not associated with increased risk of GvHD. Hence, it may be an appropriate alternative conditioning regimen for developing countries with limited health care resources.
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6.
An Antithymocyte Globulin-Free Conditioning Regimen Using Fludarabine and Cyclophosphamide Is Associated with Good Outcomes in Patients Undergoing Matched Related Family Donor Transplantation for Aplastic Anemia
George, B., Lionel, S., Selvarajan, S., Abubacker, F. N., Korula, A., Devasia, A. J., Kulkarni, U., Lakshmi, K. M., Sindhuvi, E., Abraham, A., et al
Transplantation and cellular therapy. 2021;27(5):409.e1-409.e6
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) using fludarabine (Flu)-based conditioning regimens are being increasingly being used in patients with aplastic anemia (AA). We describe an antithymocyte globulin (ATG)-free conditioning regimen consisting of Flu and cyclophosphamide (Cy) in patients undergoing matched related donor (MRD) HSCT for AA. Between 2004 and 2019, 212 patients underwent MRD HSCT using Flu (30 mg/m(2)/day for 6 days) and Cy (60 mg/kg/day for 2 days) for conditioning. The graft source was peripheral blood stem cells in all patients. Graft-versus-host disease (GVHD) prophylaxis consisted mainly of cyclosporine and methotrexate, although 41 patients received post-transplantation Cy as part of a study. Engraftment occurred in 91% of patients at a median of 16 days, whereas 4 patients (1.8%) experienced primary graft failure and 15 (7.1%) died before achieving engraftment. Toxicity was minimal. The incidence of grade II-IV acute GVHD (aGVHD) was 27.9%, and that of grade III-IV aGVHD was 11.3%. Chronic GVHD occurred in 41.6%. 80% were free of immunosuppression at 60 months and long-term complications were seen in 8.4%. At a median of 46 months, 158 patients were alive and well, with a 5-year overall survival (OS) of 75.3 ± 3.0%. The 5-year OS was 80.6 ± 4.1% for patients age <20 years (n = 93), 74.5 ± 4.6% for those age 20 to 40 years (n = 91), and 59.7 ± 9.5% for those age >40 years (n = 28) (P = .11). Patients classified as low risk had better OS compared with those at high risk (93.2 ± 2.9% versus 65.7 ± 4.1%; P = .000). Factors affecting OS on multivariate analysis included aGVHD (P = .02) and graft failure (P = .000). This large series using Flu/Cy for conditioning before MRD HSCT confirms good outcomes in patients with AA, with excellent outcomes in low-risk patients. Suitable modifications are needed to improve outcomes in high-risk patients.
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7.
Optimizing conditioning regimen with low-dose irradiation or busulfan enables the outcome of transplantation from a 6-7/8 HLA-matched donor comparable to that from an 8/8 HLA-matched unrelated donor in severe aplastic anemia patients under 40 years
Qin, X., Zhu, Y. P., Luo, C. J., Zhou, M., Huang, K., Chen, C., Zhang, W. P., Sun, Y., Luo, R. M., Tang, X. F., et al
Annals of hematology. 2021
Abstract
With the dramatic improvements in outcomes following alternative donor hematopoietic stem cell transplantation (HSCT), interest in the use of alternative donors in severe aplastic anemia (SAA) is increasing. We conducted a multicenter prospective study to explore the efficiency and safety of upfront HSCT from a 6-8/8 HLA-matched unrelated donor (MUD) or 6-7/8 HLA-matched related donor (MRD) in acquired SAA patients under 40 years. Between August 2014 and July 2017, 115 patients were enrolled, including 48 (41.7%) patients receiving grafts from an 8/8 MUD, 25 (21.7%) from a 6-7/8 MRD, and 42 (36.5%) from a 6-7/8 MUD. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was higher in the 6-7/8 MUD group than in the 8/8 MUD group (42.9% vs. 12.8%, P=0.001). The corresponding incidence in the 6-7/8 MRD group was comparable to that in the 8/8 MUD group (21.7% vs. 12.8%, P=0.332). There was no significant difference in the incidence of chronic GVHD (24.3%, 13.6%, and 17.9%, P=0.676), graft failure (2.4%, 8.0%, and 6.3%, P=0.551), overall survival (85.7%, 96.0%, and 87.5%, P=0.424), and failure-free survival (83.3%, 88.0%, and 83.3%, P=0.885) among the three groups (6-7/8 MUD, 6-7/8 MRD, and 8/8 MUD). In multivariate analysis, conditioning regimen without low-dose irradiation or busulfan was associated with an inferior failure-free survival (HR=2.973, P=0.042). In conclusion, after an intensified conditioning regimen with additional low-dose irradiation or busulfan, the outcome of HSCT from a 6-7/8 MRD or 6-7/8 MUD is comparable to that from an 8/8 MUD.
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8.
Full dose Cyclophosphamide with the addition of Fludarabine for Matched Sibling transplants in Severe Aplastic Anemia: Flu/Cy conditioning for SAA
Fakih, R. E., Alhayli, S., Ahmed, S. O., Shaheen, M., Chaudhri, N., Alsharif, F., Hanbali, A., Alfraih, F., Alshaibani, A., Assiri, A., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND The recommended therapy for severe aplastic anemia (SAA) in younger patients with a matched sibling donor (MSD) is allogeneic hematopoietic cell transplantation (allo-HCT). A number of conditioning regimens and protocols have been utilized. Here we report a homogeneous cohort of SAA patients receiving a uniform transplant protocol. METHODS Retrospective analysis of 82 consecutive cases of SAA who underwent MSD allo-HCT at a single center. RESULTS The median follow-up time for survivors was 100 months, the 10 years OS was 87.5%, the 10 years EFS was 75.3%. OS for "mobilized" bone marrow was 97.4% and 78.9% for "non-mobilized" bone marrow recipients, p-value= 0.01. The cumulative incidence of aGvHD was 25.6%. The cumulative incidence of cGvHD was 27.16%. The cumulative incidence of graft failure was 16.2%. Recipient age =30 years and patients transplanted after more than six months from SAA diagnosis had a higher risk of events. CONCLUSION In the presence of a full matched sibling donor, allogeneic transplantation with "mobilized" bone marrow source and Flu-Cy conditioning is an efficacious and safe regimen. Early transplant is associated with a better outcome, emphasizing the importance of not delaying transplants in these patients. Prospective trials are needed to determine the optimal regimen.
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9.
Fludarabine-Cyclophosphamide-Based Conditioning with Antithymocyte Globulin Serotherapy Is Associated with Durable Engraftment and Manageable Infections in Children with Severe Aplastic Anemia
Salamonowicz-Bodzioch, M., Rosa, M., Fraczkiewicz, J., Gorczynska, E., Gul, K., Janeczko-Czarnecka, M., Jarmolinski, T., Kalwak, K., Mielcarek-Siedziuk, M., Olejnik, I., et al
Journal of clinical medicine. 2021;10(19)
Abstract
Severe aplastic anemia (SAA) is a bone marrow failure syndrome that can be treated with hematopoietic cell transplantation (HCT) or immunosuppressive (IS) therapy. A retrospective cohort of 56 children with SAA undergoing transplantation with fludarabine-cyclophosphamide-ATG-based conditioning (FluCyATG) was analyzed. The endpoints were overall survival (OS), event-free survival (EFS), cumulative incidence (CI) of graft versus host disease (GVHD) and CI of viral replication. Engraftment was achieved in 53/56 patients, and four patients died (two due to fungal infection, and two of neuroinfection). The median time to neutrophil engraftment was 14 days and to platelet engraftment was 16 days, and median donor chimerism was above 98%. The overall incidence of acute GVHD was 41.5%, and that of grade III-IV acute GVHD was 14.3%. Chronic GVHD was diagnosed in 14.2% of children. The probability of 2-year GVHD-free survival was 76.1%. In the univariate analysis, a higher dose of cyclophosphamide and previous IS therapy were significant risk factors for worse overall survival. Episodes of viral replication occurred in 33/56 (58.9%) patients, but did not influence OS. The main advantages of FluCyATG include early engraftment with a very high level of donor chimerism, high overall survival and a low risk of viral replication after HCT.
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10.
Total body irradiation-containing conditioning regimens without antithymocyte globulin in adults with aplastic anemia undergoing umbilical cord blood transplantation
Hiramoto, N., Yamazaki, H., Nakamura, Y., Uchida, N., Murata, M., Kondo, T., Yoshioka, S., Eto, T., Nishikawa, A., Kimura, T., et al
Annals of hematology. 2021
Abstract
Thus far, there have been no large cohort studies on total body irradiation (TBI)-containing conditioning regimens without antithymocyte globulin (ATG) in adults with aplastic anemia (AA) undergoing umbilical cord blood (UCB) transplantation (UCBT). We retrospectively analyzed 115 adults with idiopathic AA undergoing UCBT using TBI-containing reduced-intensity conditioning (RIC) regimens without ATG between 2000 and 2018 on behalf of the Adult Aplastic Anemia Working Group of the Japanese Society for Hematopoietic Cell Transplantation. We then compared transplantation outcomes between a fludarabine (Flu)- and melphalan (Mel)-based regimen (FM) and a Flu- and cyclophosphamide (Cy)-based regimen (FC). The median patient age at UCBT was 41 years. The median total nucleated cell and total CD34(+) cell doses in a UCB unit at cryopreservation were 2.5?×?10(7)/kg and 0.7?×?10(5)/kg, respectively. The median follow-up period for survivors was 47 months. The cumulative incidence rate of neutrophil engraftment was 76.5%, and the 4-year overall survival (OS) rate was 64.3%. In multivariate analysis, the covariates that were significantly associated with a higher neutrophil engraftment were total CD34(+) cell dose in an UCB unit (=?0.7?×?10(5)/kg; hazard ratio, 0.57, P?=?0.01) and total dose of TBI (4 Gy of TBI; hazard ratio, 0.32, P?=?0.01). There was no significant difference in the cumulative incidence of neutrophil engraftment and the 4-year OS between the FM and FC groups. In conclusion, TBI-containing RIC regimens without ATG are suitable for adults with AA undergoing UCBT. There were no significant differences in transplantation outcomes between the FM and FC groups.