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1.
Finding a balance in reduced toxicity hematopoietic stem cell transplantation for thalassemia: role of infused CD3+ cell count and immunosuppression
Meissner, B., Lang, P., Bader, P., Hoenig, M., Müller, I., Meisel, R., Greil, J., Sauer, M. G., Metzler, M., Corbacioglu, S., et al
Bone marrow transplantation. 2024
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Editor's Choice
Abstract
We performed a retrospective analysis on 124 patients with transfusion-dependent thalassemia who were registered in the German pediatric registry for stem cell transplantation. All patients underwent first allogeneic hematopoietic stem cell transplantation (HSCT) between 2011 and 2020 and belonged mainly to Pesaro risk class 1-2. Four-year overall (OS) and thalassemia-free survival (TFS) were 94.5% ± 2.9% and 88.0% ± 3.4% after treosulfan-fludarabine-thiotepa- and 96.9% ± 3.1% (P = 0.763) and 96.9% ± 3.1% (P = 0.155) after busulfan-fludarabine-based conditioning. Mixed chimerism below 75% occurred predominantly in treosulfan-based regimens (27.5% versus 6.2%). OS and TFS did not differ significantly between matched sibling, other matched family and matched unrelated donor (UD) HSCTs (OS: 100.0%, 100.0%, 96.3% ± 3.6%; TFS: 96.5% ± 2.4%, 90.0% ± 9.5%, 88.9% ± 6.0%). However, mismatched UD-HSCTs performed less favorable (OS: 84.7% ± 7.3% (P = 0.029); TFS: 79.9% ± 7.4% (P = 0.082)). We generated a scoring system reflecting the risk to develop mixed chimerism in our cohort. The main risk-reducing factors were a high CD3+ cell count (≥6 × 10(7)/kg) in the graft, busulfan-conditioning, pre-conditioning therapy and low-targeted ciclosporin A trough levels. Acute GvHD grade III-IV in treosulfan-based concepts predominantly occurred in patients with UD and reduced GvHD prophylaxis but not in the context of high CD3+ cell doses. Taken together, this information might be used to develop more risk-adapted HSCT regimens for thalassemia patients.
PICO Summary
Population
Children and young adults with transfusion-dependent thalassemia who underwent first allogeneic transplant between 2011 and 2020 and were registered in the German pediatric registry for stem cell transplantation. (n=124)
Intervention
Treosulfan-fludarabine-thiotepa based conditioning (n=92)
Comparison
Busulfan-fludarabine-based conditioning (n=32)
Outcome
Four-year overall (OS) and thalassemia-free survival (TFS) were 94.5% ± 2.9% and 88.0% ± 3.4% after treosulfan-fludarabine-thiotepa- and 96.9% ± 3.1% and 96.9% ± 3.1% after busulfan-fludarabine-based conditioning. Mixed chimerism below 75% occurred predominantly in treosulfan-based regimens (27.5% versus 6.2%). OS and TFS did not differ significantly between matched sibling, other matched family and matched unrelated donor (UD) HSCTs (OS: 100.0%, 100.0%, 96.3% ± 3.6%; TFS: 96.5% ± 2.4%, 90.0% ± 9.5%, 88.9% ± 6.0%). However, mismatched UD-HSCTs performed less favorable (OS: 84.7% ± 7.3%; TFS: 79.9% ± 7.4%). We generated a scoring system reflecting the risk to develop mixed chimerism in our cohort. The main risk-reducing factors were a high CD3+ cell count (≥6 × 10(7)/kg) in the graft, busulfan-conditioning, pre-conditioning therapy and low-targeted ciclosporin A trough levels. Acute GvHD grade III-IV in treosulfan-based concepts predominantly occurred in patients with UD and reduced GvHD prophylaxis but not in the context of high CD3+ cell doses.
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Reduced-intensity allogenic transplantation for children and adolescents with Philadelphia chromosome-positive acute lymphoblastic leukemia
Ishida, H., Arakawa, Y., Hasegawa, D., Usami, I., Hashii, Y., Arai, Y., Nishiwaki, S., Keino, D., Kato, K., Sato, M., et al
Annals of hematology. 2023
Abstract
Survival rates of patients with Philadelphia chromosome-positive ALL (Ph+ALL) have improved considerably with the introduction of tyrosine kinase inhibitors (TKI); however, hematopoietic stem cell transplantation (HSCT) continues to play an important role. Reduced-intensity conditioning (RIC) regimens have been widely applied particularly for older patients, but their validity for children and adolescents with Ph+ALL has not been investigated. In this study, data from patients receiving HSCT for de novo Ph+ALL in first or second remission at ages younger than 25 years and with a history of pre-HSCT TKI therapy were retrospectively collected through the nationwide registry in Japan. In 265 patients who received myeloablative conditioning (MAC) and 33 patients receiving RIC, 5-year leukemia-free survival (LFS) rates were 67.3% and 79.8%, respectively (p = 0.142). Multivariate analysis of LFS, focusing on patients with good performance status, identified RIC as a significant prognostic factor for LFS (hazard ratio 0.32, p = 0.032), as well as older age, higher leukocyte count at diagnosis, and disease with additional chromosomal abnormalities. These trends were similar when we focused on patients who received prophylactic post-HSCT TKI treatment, as 5-year LFS was 81.0% for MAC and 84.4% for RIC (p = 0.748). In summary, HSCT with RIC regimen showed at least comparable LFS to HSCT with MAC regimen, and RIC was an independent favorable prognostic factor on multivariate analysis adjusting potential prognostic factors. While patient numbers were limited, our data suggest that RIC may be safely applied in this group, particularly combined with prophylactic post-HSCT TKI maintenance therapy.
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Reduced Intensity Conditioning Mitigates Risk for Primary Ovarian Insufficiency but Does Not Decrease Risk for Infertility in Pediatric and Young Adult Survivors of Hematopoietic Stem Cell Transplant: Gonadal Toxicity and Fertility Following Pediatric HSCT
Bender, J. D., Toro, H. O., Benoit, J., Howell, J. C., Badia, P., Davies, S. M., Grimley, M. S., Jodele, S., Phillips, C., Burns, K., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Hematopoietic stem cell transplant (HSCT) is a curative therapy for many pediatric malignancies and non-malignant conditions. Gonadal insufficiency or infertility is present in almost all survivors of myeloablative conditioning (MAC). Reduced intensity conditioning (RIC) regimens are being increasingly used in medically fragile patients or in patients with non-malignant diagnoses to limit the toxicities associated with HSCT, however the short and long-term gonadal toxicity of RIC remains unknown in pediatric and young adult survivors. OBJECTIVES To compare the prevalence of gonadal insufficiency and infertility among pubertal and post-pubertal pediatric and young adult survivors of HSCT who underwent RIC versus MAC. STUDY DESIGN Twenty-three females (RIC=8, MAC=15) and 35 males (RIC=19, MAC=16) were included in this single center, retrospective, cross-sectional study. Eligible patients were defined as being ≥ 1 year post-HSCT and aged <40 years, having reached puberty, and having available laboratory results. FSH, LH, estradiol, and anti-Müllerian hormone (AMH) levels were measured in females and FSH, LH, total testosterone, and inhibin B in males. Twenty-one males (RIC=11, MAC=10) underwent semen analysis through a separate consent. Parametric and non-parametric analyses were undertaken to compare RIC versus MAC groups. RESULTS Female patients who underwent RIC were less likely than those who received MAC to develop primary ovarian insufficiency, as demonstrated by elevated FSH (p=0.02) and low estradiol (p=0.01) or elevated LH (p=0.09). Most RIC (75%) and MAC (93%) females demonstrated low AMH indicating low or absent ovarian reserve, with no significant difference between cohorts (p=0.53). In males, there were no significant differences seen in prevalence of abnormal FSH, LH, testosterone, or inhibin B between the 2 cohorts. Ten of 11 (91%) RIC males and 10/10 (100%) MAC males had azoospermia or oligospermia, at a median time to semen analysis from HSCT of 3.7 years (range: 1.3-12.2 years). CONCLUSIONS RIC may pose less risk for primary ovarian insufficiency than MAC among female survivors of HSCT. However, female and male patients undergoing either RIC or MAC are at high risk for infertility. In the largest reported series of semen analyses of pediatric and young adult male recipients of RIC, azoospermia or oligospermia was found in nearly all (91%) RIC survivors. All patients undergoing HSCT should receive counseling to outline the high risk of gonadal toxicity, and efforts should be made to preserve fertility in patients undergoing either RIC or MAC.
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Reduced-toxicity myeloablative conditioning regimen using fludarabine and full doses of intravenous busulfan in pediatric patients not eligible for standard myeloablative conditioning regimens: Results of a multicenter prospective phase 2 trial
Rialland, F., Grain, A., Labopin, M., Michel, G., Gandemer, V., Paillard, C., Pochon, C., Clement, L., Brissot, E., Jubert, C., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Data regarding the safety and efficacy of reduced-toxicity conditioning regimen (RTC) prior to allogeneic stem cell transplantation (allo-SCT) to treat hematological malignancies in pediatric patients are limited. This prospective multicenter, phase 2 trial investigated a RTC regimen based on the combination of intravenous busulfan (3.2 mg/kg/d x 4 days), fludarabine (30 mg/m(2)/d x 5 days) and antithymocyte globulin (Thymoglobulin®, Genzyme; 5 mg/kg total dose) with the aim of delivering high dose myeloablation that would allow optimal disease control while minimizing toxicity, in a subgroup of children at very high risk of non-relapse mortality (NRM). The primary endpoint was NRM at 1 year after allo-SCT. A total of 48 high risk patients were included (median age, 13 years; range, 3-24). At 1 year, the cumulative incidence of recurrence/disease progression and NRM were 33% and 8%, respectively. With a median follow-up of 23 months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) at 1 year were 69% and 58%, respectively. We conclude that the RTC regimen used in this prospective trial is safe, with a < 10% NRM rate noted among high-risk children and adolescents, paving the way for larger phase 3 trials incorporating novel agents pre- and post-allo-SCT.(ClinicalTrials.gov Identifier: NCT01572181).
PICO Summary
Population
Children and adolescents with haematological malignancies, but not eligible for standard myeloablative conditioning regimens, in 16 centres in France (n=48)
Intervention
30 mg/m2/d fludarabine for 5 consecutive days (day -6 to -2), 3.2 mg/kg/day IV Busulfan administered four times daily in a 2 h infusion for 4 consecutive days (day -5, -4, -3, and -2), and 2.5 mg/Kg/d antithymocyte globulin for 2 consecutive days (day -2 and -1).
Comparison
None
Outcome
At 1 year, the cumulative incidence of recurrence/disease progression and non-relapse mortality (NRM) were 33% and 8%, respectively. With a median follow-up of 23 months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) at 1 year were 69% and 58%, respectively.
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Reduced-Intensity/Reduced-Toxicity Conditioning Approaches Are Tolerated in XIAP Deficiency but Patients Fare Poorly with Acute GVHD
Arnold, D. E., Nofal, R., Wakefield, C., Lehmberg, K., Wustrau, K., Albert, M. H., Morris, E. C., Heimall, J. R., Bunin, N. J., Kumar, A., et al
Journal of clinical immunology. 2021;:1-10
Abstract
X-linked inhibitor of apoptosis (XIAP) deficiency is an inherited primary immunodeficiency characterized by chronic inflammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). Allogeneic hematopoietic cell transplantation (HCT) with fully myeloablative conditioning may be curative but has been associated with poor outcomes. Reports of reduced-intensity conditioning (RIC) and reduced-toxicity conditioning (RTC) regimens suggest these approaches are well tolerated, but outcomes are not well established. Retrospective data were collected from an international cohort of 40 patients with XIAP deficiency who underwent HCT with RIC or RTC. Thirty-three (83%) patients had a history of HLH, and thirteen (33%) patients had IBD. Median age at HCT was 6.5 years. Grafts were from HLA-matched (n?=?30, 75%) and HLA-mismatched (n?=?10, 25%) donors. There were no cases of primary graft failure. Two (5%) patients experienced secondary graft failure, and three (8%) patients ultimately received a second HCT. Nine (23%) patients developed grade II-IV acute GVHD, and 3 (8%) developed extensive chronic GVHD. The estimated 2-year overall and event-free survival rates were 74% (CI 55-86%) and 64% (CI 46-77%), respectively. Recipient and donor HLA mismatch and grade II-IV acute GVHD were negatively associated with survival on multivariate analysis with hazard ratios of 5.8 (CI 1.5-23.3, p?=?0.01) and 8.2 (CI 2.1-32.7, p?0.01), respectively. These data suggest that XIAP patients tolerate RIC and RTC with survival rates similar to HCT of other genetic HLH disorders. Every effort should be made to prevent acute GVHD in XIAP-deficient patients who undergo allogeneic HCT.
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Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases
Nishimura, A., Aoki, Y., Ishiwata, Y., Ichimura, T., Ueyama, J., Kawahara, Y., Tomoda, T., Inoue, M., Matsumoto, K., Inoue, K., et al
Journal of clinical immunology. 2021
Abstract
PURPOSE The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID). METHODS We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID. RESULTS The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival. CONCLUSIONS RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.
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Radiation-sparing reduced-intensity unrelated umbilical cord blood transplantation for rare hematological disorders in children
Sawada, A., Shimizu, M., Koyama-Sato, M., Higuchi, K., Okada, Y., Goto, K., Inoue, S., Yasui, M., Inoue, M.
International journal of hematology. 2021
Abstract
Graft failure is a major pitfall of unrelated umbilical cord blood transplantation (CBT) in children with rare hematological disorders other than acute leukemia, such as acquired and inherited bone marrow failure, myelodysplastic syndrome, juvenile myelomonocytic leukemia, and chronic myeloid leukemia. We developed a less-toxic conditioning regimen for CBT that achieves a higher rate of complete donor chimerism, and retrospectively compared it against two other conditioning regimens for CBT performed at our single institution. The engraftment rate with complete donor chimerism was 100% and 5-year event-free survival (5y-EFS) was 90.9% in patients using our latest regimen (n?=?11) of reduced-intensity conditioning (RIC) containing fludarabine (Flu) 180 mg/m(2), melphalan (MEL) 210 mg/m(2), and low-dose rabbit anti-thymocyte globulin (LD-rATG) 2.5 mg/kg without irradiation (regimen C). Outcomes were better than in patients (n?=?10) treated with previous regimens involving irradiation (5y-EFS 30.0%, p?=?0.004): regimen A, consisting of myeloablative conditioning containing cyclophosphamide (CY) and total body irradiation (TBI) with 8-12 Gy, or regimen B, consisting of RIC with Flu, CY, horse ATG, and thoracoabdominal irradiation (TAI) with 6 Gy. In conclusion, Flu/MEL/LD-rATG (regimen C) without TBI/TAI may be preferable as RIC for unrelated CBT in children with rare hematological disorders.
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Reduced-intensity single-unit unrelated cord blood transplant with optional immune boost for nonmalignant disorders
Vander Lugt, M. T., Chen, X., Escolar, M. L., Carella, B. A., Barnum, J. L., Windreich, R. M., Hill, M. J., Poe, M., Marsh, R. A., Stanczak, H., et al
Blood advances. 2020;4(13):3041-3052
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Abstract
Children with many inherited nonmalignant disorders can be cured or their condition alleviated by hematopoietic stem cell transplantation (HSCT). Umbilical cord blood (UCB) units are a rapidly available stem cell source and offer great flexibility in HLA matching, allowing nearly uniform access to HSCT. Although reduced-intensity conditioning (RIC) regimens promise decreased treatment-related morbidity and mortality, graft failure and infections have limited their use in chemotherapy-naive patients. We prospectively evaluated a novel RIC regimen of alemtuzumab, hydroxyurea, fludarabine, melphalan, and thiotepa with a single-unit UCB graft in 44 consecutive patients with inborn errors of metabolism, immunity, or hematopoiesis. In addition, 5% of the UCB graft was re-cryopreserved and reserved for cord donor leukocyte infusion (cDLI) posttransplant. All patients engrafted at a median of 15 days posttransplant, and chimerism was >90% donor in the majority of patients at 1-year posttransplant with only 1 secondary graft failure. The incidence of grade II to IV graft-versus-host disease (GVHD) was 27% (95% confidence interval [CI], 17-43) with no extensive chronic GVHD. Overall survival was 95% (95% CI, 83-99) and 85% (95% CI, 64-93) at 1 and 5 years posttransplant, respectively. No significant end-organ toxicities were observed. The use of cDLI did not affect GVHD and showed signals of efficacy for infection control or donor chimerism. This RIC transplant regimen using single-unit UCB graft resulted in outstanding survival and remarkably low rates of graft failure. Implementation of the protocol not requiring pharmacokinetic monitoring would be feasible and applicable worldwide for children with inherited disorders of metabolism, immunity, or hematopoiesis. This trial was registered at www.clinicaltrials.gov as #NCT01962415.
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Reduced Toxicity Conditioning for Non-Malignant Hematopoietic Cell Transplants
Contreras, C. F., Long-Boyle, J. R., Shimano, K. A., Melton, A., Kharbanda, S., Dara, J., Higham, C., Huang, J. N., Cowan, M. J., Dvorak, C. C.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Allogeneic hematopoietic cell transplantation (HCT) for children with non-malignant disorders is challenged by potential drug-related toxicities and poor engraftment. This retrospective analysis expands on our single pediatric medical center experience with targeted busulfan, fludarabine, and intravenous (IV) alemtuzumab as a low-toxicity regimen to achieve sustained donor engraftment. Sixty-two patients received this regimen for their first HCT for a non-malignant disorder between 2004 and 2018. Donors were matched sibling in 27%, 8/8 HLA allele-matched unrelated in 50%, and 7/8 HLA allele-mismatched in 23% (some of whom received additional immunoablation with thiotepa or clofarabine). Five patients experienced graft failure for a cumulative incidence of 8.4% (95% CI, 1-16%). In engrafted patients, the median donor chimerism in whole blood and CD3, CD14/15, and CD19 subsets at 1-year were 96%, 90%, 99%, and 99%, respectively. Only one patient received donor lymphocyte infusions (DLIs) for poor chimerism. Two patients died following disease progression despite 100% donor chimerism. The 3-year cumulative incidence of treatment-related mortality was 10% (95% CI, 2-17%). Overall survival and event-free-survival at 3-years were 87% (95% CI, 78-95%) and 80% (95% CI, 70-90%), respectively. The 6-month cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 7% (95% CI, 3-13%), while the 3-year cumulative incidence of chronic GVHD was 5% (95% CI, 0-11%). These results suggest that use of targeted busulfan, fludarabine and IV alemtuzumab offers a well-tolerated option for children with non-malignant disorders to achieve sustained engraftment with a low incidence of GVHD.
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10.
Reduced Toxicity (BuFlu) Conditioning Is Better Tolerated but Has Higher Second Transplant Rate Compared to Myeloablative Conditioning (BuCy) in Children with Inherited Metabolic Disorders
Gupta, A., Downey, M., Shanley, R., Jennissen, C., Miller, W. P., Lund, T. C., Orchard, P. J., Smith, A. R.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) is a primary treatment for various inherited metabolic diseases (IMDs). Achieving stable and sustained engraftment while minimizing transplant related morbidity and mortality is critical in optimizing outcome for IMDs. Traditional regimens have used myeloablative approaches, primarily Busulfan and Cyclophosphamide (BuCy), which is associated with significant regimen related toxicity (RRT). Alternatively, reduced toxicity regimens, such as Busulfan and Fludarabine (BuFlu), have been proposed to offer similar efficacy with reduced toxicities. We compared transplant related outcomes with BuCy and BuFlu based conditioning in patients with IMDs. METHODS We retrospectively analyzed University of Minnesota's transplant database for patients with IMDs who underwent HSCT using BuCy (with alemtuzumab) or BuFlu (with ATG) preparative regimen from March, 2008 to September,2017. Overall survival (OS), event free survival (EFS) and incidence of neutrophil and platelet recovery was determined using standard definitions. Complications such as graft failure, sinusoidal obstruction syndrome, hemorrhagic cystitis and respiratory failure were compared. Graft failure includes primary and secondary aplastic graft failure, with and without autologous recovery. Incidence of viral infections post-transplant comparing two regimens were also determined. RESULTS Total of 99 patients underwent HSCT for IMDs during the study period. Sixty-four received BuCy conditioning and 35 received BuFlu. Hurler syndrome (46%) and adrenoleukodystrophy (43%) were most common IMDs and umbilical cord blood was the most common graft source (74%). One-year OS was similar in both groups (81.2% in BuCy vs. 85.5% in BuFlu; p=0.8) with an EFS of 75% vs 63% respectively. Similar incidence of grade 3-4 acute GVHD(9% vs. 6%; p=0.5) and chronic GVHD(9% vs. 7%; p=0.67). Neutrophil and platelet recovery were similar in both groups with significantly shorter duration of hospital stay noted in BuFlu cohort (median 21 d vs. 34 d, p=0.002). Cumulative incidence of graft failure was higher with BuFlu group (29% vs 14%, p= 0.08). Significantly higher rates of second HCT was noted following BuFlu cohort (27% vs. 3%, p= 0.001). Incidence of adenoviral infection (14% vs. 0%, p=0.02) and hemorrhagic cystitis (23% vs. 3%, p=0.01) were higher in the BuCy group. T-cell engraftment occurred significantly sooner with BuCy conditioning until 1-year post transplant, donor myeloid engraftment was similar in both groups. CONCLUSION Reduced toxicity conditioning leads to lower rates of infections and other transplant related complications, but concerning for higher rate of graft failure in patients with IMDs. Alternate immune suppressive agents and novel techniques should be considered to minimize toxicities and reduce complications.