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1.
Addition of venetoclax to myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in high-risk AML
Cao, X. Y., Chen, J. Q., Wang, H., Ma, W., Liu, W. W., Zhang, F. F., Xue, S., Dong, L., Liu, T., Zhao, X. Z., et al
Annals of medicine. 2023;55(1):388-400
Abstract
BACKGROUND Venetoclax monotherapy is an effective option for patients with acute myeloid leukemia (AML). Venetoclax has also been used in non-myeloablative conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk AML with a tolerable toxicity profile. However, the efficacy and safety of a venetoclax-containing myeloablative conditioning (MAC) allo-HSCT regimen for high-risk AML have not been evaluated. OBJECTIVE To evaluate the safety and efficacy of a MAC regimen containing venetoclax for high-risk AML. STUDY DESIGN From 25 February 2021 to 4 September 2022, a total of 31 patients with high-risk AML who underwent allo-HSCT and a MAC regimen with venetoclax were analyzed. RESULTS At the time of transplantation, 21 patients were in first complete remission (CR1), 4 were in a second complete remission (CR2), and 6 in non-remission (NR). Twenty-four patients (77.4%) were minimal residual disease (MRD)-positive before transplant. The FLT3-ITD gene mutation was present in 51.6% of patients. NUP98 rearrangement, MLL rearrangement or MLL-PTD and DEK::CAN fusion genes were found in 5 (16.1%), 7(22.6%) and 2 (6.5%) patients, respectively. Twenty-nine (93.6%) patients underwent haploidentical allo-HSCT. The median follow-up time was 278 days (range: 52-632 days). The 100-day cumulative incidence of grade 3 to 4 acute graft-versus-host disease (aGVHD) was 16.1% (95%CI, 7.2-36.0%). The 180-day cumulative incidence of moderate to severe chronic graft-versus-host disease (cGVHD) was 7.1% (95%CI, 1.9-26.9%). Cumulative incidence of 100-day cytomegalovirus (CMV) viraemia and 100-day Epstein-Barr virus (EBV) viraemia was 61.6% (95%CI, 46.5-81.4%) and 3.2% (95%CI, 0.4-22.2%), respectively. The 600-day overall survival (OS) and leukemia-free survival (LFS) were 80.9% (95%CI, 63.5-93.6%) and 81.3% (95%CI, 64.2-93.7%), respectively. The 600-day relapse incidence (RI) and non-relapse mortality (NRM) was 6.9% (95%CI, 1.8-26.3%) and 11.7% (95%CI, 3.9-35.0%). CONCLUSION Our study shows that the addition of venetoclax to a MAC allo-HSCT was feasible, safe and effective for high-risk AML patients.
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2.
Characterising the autoantibody repertoire in systemic sclerosis following myeloablative haematopoietic stem cell transplantation
Ayoglu, B., Donato, M., Furst, D. E., Crofford, L. J., Goldmuntz, E., Keyes-Elstein, L., James, J., Macwana, S., Mayes, M. D., McSweeney, P., et al
Annals of the rheumatic diseases. 2023;82(5):670-680
Abstract
OBJECTIVES Results from the SCOT (Scleroderma: Cyclophosphamide Or Transplantation) clinical trial demonstrated significant benefits of haematopoietic stem cell transplant (HSCT) versus cyclophosphamide (CTX) in patients with systemic sclerosis. The objective of this study was to test the hypothesis that transplantation stabilises the autoantibody repertoire in patients with favourable clinical outcomes. METHODS We used a bead-based array containing 221 protein antigens to profile serum IgG autoantibodies in participants of the SCOT trial. RESULTS Comparison of autoantibody profiles at month 26 (n=23 HSCT; n=22 CTX) revealed antibodies against two viral antigens and six self-proteins (SSB/La, CX3CL1, glycyl-tRNA synthetase (EJ), parietal cell antigen, bactericidal permeability-increasing protein and epidermal growth factor receptor (EGFR)) that were significantly different between treatment groups. Linear mixed model analysis identified temporal increases in antibody levels for hepatitis B surface antigen, CCL3 and EGFR in HSCT-treated patients. Eight of 32 HSCT-treated participants and one of 31 CTX-treated participants had temporally varying serum antibody profiles for one or more of 14 antigens. Baseline autoantibody levels against 20 unique antigens, including 9 secreted proteins (interleukins, IL-18, IL-22, IL-23 and IL-27), interferon-α2A, stem cell factor, transforming growth factor-β, macrophage colony-stimulating factor and macrophage migration inhibitory factor were significantly higher in patients who survived event-free to month 54. CONCLUSIONS Our results suggest that HSCT favourably alters the autoantibody repertoire, which remains virtually unchanged in CTX-treated patients. Although antibodies recognising secreted proteins are generally thought to be pathogenic, our results suggest a subset could potentially modulate HSCT in scleroderma.
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3.
Appropriate pre-transplant strategy for patients with myelodysplastic syndromes receiving allogeneic haematopoietic stem cell transplantation after myeloablative conditioning
Wang, H., Wang, Q., Qi, J., Li, X., Chu, T., Qiu, H., Fu, C., Tang, X., Ruan, C., Wu, D., et al
Frontiers in immunology. 2023;14:1146619
Abstract
PURPOSE Appropriate pre-transplant strategies in patients with myelodysplastic syndromes (MDS) remain challenging. We sought to assess the effect of different pre-transplant therapies and transplantation interval times on patient prognosis. METHODS We retrospectively analysed clinical data for 371 consecutive MDS patients after myeloablative transplantation between 2007 and 2019. RESULTS The median age of the patients was 38 years (range, 12-64 years). A total of 114 patients (31%) received supportive care (SC), 108 (29%) hypomethylating agents (HMAs), and 149 (40%) chemotherapy-based therapy before transplantation. In patients who received HMA or SC, there was no significant difference in overall survival (OS; P=0.151) or relapse-free survival (RFS; P=0.330), except that HMA-treated patients had a lower rate of non-relapse mortality (5-year NRM: 18% vs. 32%, P=0.035). However, compared with patients who received HMA, those who received chemotherapy-based therapy had a lower 5-year OS rate (56% vs. 69%, P=0.020) and a slightly higher 5-year NRM rate (28% vs. 18%, P=0.067). Compared to the delayed transplant group (transplant interval ≥6 months), the early transplant group (transplant interval <6 months) had a superior 5-year OS (66% vs. 51%, P=0.001) and a lower 5-year cumulative incidence of NRM (22% vs. 36%, P=0.001). CONCLUSION The findings of the study indicate that receiving an appropriate pre-transplant strategy (SC/HMA + <6 months) significantly improves OS and decreases NRM in MDS patients after myeloablative transplantation.
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4.
Association Between the Magnitude of Intravenous Busulfan Exposure and Development of Hepatic Veno-Occlusive Disease in Children and Young Adults Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation
Bognàr, T., Bartelink, I. H., Egberts, T. C. G., Rademaker, C. M. A., Versluys, A. B., Slatter, M. A., Kletzel, M., Nath, C. E., Cuvelier, G. D. E., Savic, R. M., et al
Transplantation and cellular therapy. 2022;28(4):196-202
Abstract
Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight into the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen before allogeneic HCT. In this observational study we included all patients who underwent allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using nonlinear mixed effect modeling and expressed as the maximal concentration (Cmax; day 1 and day 1 to 4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier; therefore we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg × h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%; odds ratio [OR] = 2.95, 95% confidence interval [CI] 1.13 to 7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg × h/L) did not further increase the risk of VOD/SOS (15.4% versus 15.2%; OR = 1.03, 95% CI 0.61 to 1.75). The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk.
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5.
Examination of a nutritional treatment pathway according to pretreatment health status and stress levels of patients undergoing hematopoietic stem cell transplantation
Aoyama, T., Imataki, O., Notsu, A., Yurikusa, T., Ichimaru, K., Tsuji, M., Yoshitsugu, K., Fukaya, M., Enami, T., Ikeda, T.
PloS one. 2022;17(8):e0271728
Abstract
INTRODUCTION This study aimed to validate hematopoietic stem cell transplantation (HSCT) treatment via a tailored nutritional pathway in myeloablative conditioning (MAC), determine its efficacy in terms of remission, and explore associations between clinical outcomes and nutritional indicators. METHODS We included patients who underwent MAC for HSCT at the Shizuoka Cancer Center Stem Cell Transplantation between 2015 and 2019. We evaluated outcomes from the day before treatment initiation (transplant date: day 0) to day 42. RESULTS Among the 40 MAC cases (participant characteristics: 20/40 males, mean age of 52 years, and mean body mass index of 21.9 kg/m2), we found that the percent loss of body weight and loss of skeletal muscle mass were correlated with the basal energy expenditure rate (BEE rate; r = 0.70, p<0.001 and r = 0.49, p<0.01, respectively). Based on the receiver operating characteristics curves, the cutoff value for the BEE rate in terms of weight loss was 1.1. Salivary amylase levels did not significantly change during the treatment course. Continuous variables, including oral caloric intake and performance status, showed statistically significant correlations with nutrition-related adverse events during treatment (r = -0.93, p<0.01 and r = 0.91, p<0.01, respectively). Skeletal muscle mass before treatment initiation was an independent predictive variable for reduced 2-year survival (p = 0.04). CONCLUSION Our results support the validity of a safe nutritional pathway with a BEE rate of 1.1 for HSCT patients pretreated with MAC. Specifically, we found that this pathway could prevent weight loss in response to nutrition-related adverse events. Skeletal muscle mass before treatment was identified as an independent risk factor for reduced 2-year survival.
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6.
[A comparison of C+SCAV and SEAM conditioning regimens in efficacy and safety in autologous hematopoietic stem cell transplantation for non-Hodgkin's lymphoma patients]
Li, J. Q., Zhang, Y., Geng, H. Z., Jia, S. X., Wu, X. J., Zhou, J., Zong, X. P., Yang, Z., Chen, X. C., Ma, C., et al
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2022;43(8):668-673
Abstract
Objective: This study aimed to compare the efficacy and safety of cladribine, smustine, etoposide, cyclophosphamide, and cytarabine (C+SCAV) and smustine, etoposide, cytarabine, and melphalan (SEAM) conditioning regimens in autologous stem cell transplantation (auto-HSCT) for non-Hodgkin's lymphoma (NHL) . Methods: A retrospective analysis was conducted on 61 NHL patients who received auto-HSCT in the Department of Hematology, the First Affiliated Hospital of Suzhou University, from March 2018 to May 2021. The C + SCAV group and SEAM group had 19 and 42 patients, respectively. Results: ① Among the 61 patients with NHL, 37 were male and 24 were female. The median age was 48 (21-66) years old. There were 19 cases in the C+SCAV group and 42 cases in the SEAM group. There was no significant difference in the baseline characteristics between the two groups (P>0.05) . ② The median time to neutrophil and platelet engraftment in the C+SCAV cohort were 10 (8-15) days and 13 (9-22) days, respectively, which does not differ from the SEAM group (P=0.103, P=0.403) . ③ No differences existed between the two groups in terms of survival. The 1-year progression-free survival (PFS) was (76.5±10.3) % for patients receiving C+SCAV and (78.4±6.8) % for those who received SEAM (P=0.841) . The 1-year overall survival was 100.0% for the C+SCAV group and 95.2±3.3% for the SEAM group (P=0.339) . ④The 1-year PFS of patients with complete remission in the C+SCAV group was similar to those who in the SEAM group [ (92.3±7.4) % vs (82.5±7.2) %, P=0.406]. ⑤ The incidence of non-hematological serious adverse events (≥ grade 3) in the C+SCAV group and SEAM group were 10.5% (2/19) and 40.5% (17/42) (P=0.013) , the incidence of severe mucositis was 5.3% (1/19) and 31.0% (13/42) (P=0.015) , and the incidence of severe infection (≥ grade 3) was 10.5% (2/19) and 19.0% (8/42) (P=0.389) , respectively. Conclusion: C + SCAV conditioning regimen appeared to be no different from the SEAM regimen in terms of survival. It can lower the incidence of SAE and does not increase the risk of severe infection. As a result, it can be used as an alternative conditioning regimen for lymphoma patients undergoing auto-HSCT.
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7.
Clofarabine and busulfan myeloablative conditioning in allogeneic hematopoietic cell transplant for patients with active myeloid malignancies
Connor, M. P., Loren, A. W., Hexner, E. O., Martin, M. E., Gill, S. I., Luger, S. M., Mangan, J. K., Perl, A. E., McCurdy, S. R., Pratz, K. W., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplant (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and non-relapse mortality. A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been described to exhibit anti-leukemic activity with acceptable toxicity in patients ≤ 70 years old. OBJECTIVES To describe clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. STUDY DESIGN In a single-center, retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free (EFS) and overall survival (OS), cumulative incidence of relapse, non-relapse mortality (NRM), and incidence and severity of acute and chronic graft-versus-host disease (GVHD). RESULTS We identified 69 patients with a median age of 60 years (range 22-70). Most patients had relapsed/refractory or primary refractory acute myeloid leukemia (AML, n = 55), or refractory myelodysplastic syndrome (MDS, n = 12); one patient had chronic myeloid leukemia and one had blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 after transplant. Two-year EFS and OS were 30% (95% CI 20-44) and 40% (95% CI 29-54), respectively. Patients with AML had 2-year EFS and OS of 28% (95% CI 18-44) and 38% (95% CI 27-54), respectively; those with MDS had 2-year EFS and OS of 47% (95% CI 25-88) and 56% (95% CI 33-94), respectively. Cumulative incidence of relapse at 2 years was 39% (95% CI 27-51) for all patients: 45% (95% CI 31-58) in AML and 18% (95% CI 2-45) in MDS. NRM at 2 years was 31% (95% CI 20-42): 27% (95% CI 15-39) in AML and 35% (95% CI 10-63) in MDS. The total incidence of aGVHD of any severity was 80%. Incidence of grade 3-4 aGVHD at was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%, p = 0.05) and 2-year OS (39% versus 70%, p = 0.04) compared to those who did not. The 2-year cumulative incidence of cGVHD was 44% (95% CI 28-58). CONCLUSIONS Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplant strategy up to age 70, particularly for those with advanced MDS. High incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.
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8.
Allogeneic hematopoietic stem cell transplantation with the modified myeloablative conditioning regimen for children with chronic active Epstein-Barr virus infection
Luo, Y., Wei, A., Wang, B., Zhu, G., Zhang, R., Jia, C., Yan, Y., Zhou, X., Yang, J., Qin, M., et al
Pediatric investigation. 2022;6(4):250-259
Abstract
IMPORTANCE Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the only effective treatment for chronic active Epstein-Barr virus infection (CAEBV). The clinical efficacy and safety of allo-HSCT with different conditioning regimens in children with CAEBV remain unclear. OBJECTIVE To evaluate the effectiveness and safety of allo-HSCT with the modified myeloablative conditioning (MAC) regimen for children with CAEBV and also the factors affecting the outcomes. METHODS We retrospectively analyzed children with CAEBV who underwent allo-HSCT with the modified MAC regimen at Beijing Children's Hospital, Capital Medical University from October 2016 to June 2021. Data related to the clinical manifestations, engraftment, and outcome were extracted from the medical records. RESULTS The cohort comprised 41 patients (24 males, 17 females) with a median transplantation age of 92.6 (60.4, 120.7) months and a median follow-up time of 28.2 (15.3, 40.2) months. Four patients (9.8%) died, among which three died from primary disease relapse, and one died from grade IV acute graft-versus-host diseases (aGVHD) after stopping treatment. The 3-year overall survival (OS) and 3-year event-free survival (EFS) rates were 88.8% ± 5.4% and 85.0% ± 5.7%, respectively. The 3-year OS and EFS did not significantly differ between the patients with hemophagocytic lymphohistiocytosis (HLH) and the patient without HLH (87.7% ± 6.8% vs. 91.7% ± 8.0%, P = 0.790; 85.0% ± 6.9% vs. 84.6% ± 10.0%, P = 0.921), or among the patients with complete remission, partial remission, and activity disease before HSCT (all P > 0.05). Multivariate analysis showed that grade III-IV aGVHD was a risk factor for mortality (Hazards ratio: 11.65, 95% confidence interval: 1.00, 136.06; P = 0.050). INTERPRETATION Allo-HSCT with the modified MAC regimen is safe and effective for pediatric CAEBV. This treatment benefits patients with HLH or active disease. Patients with Grade III-IV aGVHD may be associated with worse outcomes.
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9.
ABO incompatibility does not affect transfusion requirements or clinical outcomes of unrelated cord blood transplantation after myeloablative conditioning for haematological malignancies
Chen, Y., Wan, X., Cao, Y., Wang, H., Han, D., Zhang, Y., Yao, W., Song, K., Fan, Q., Zhu, X., et al
Blood transfusion = Trasfusione del sangue. 2021
Abstract
BACKGROUND The effects of ABO incompatibility on cord blood transplantation (CBT) have not been confirmed. We retrospectively investigated the effect of ABO incompatibility on the clinical outcomes and changes of isoagglutinin titres of 261 consecutive patients who underwent CBT in a single centre. MATERIAL AND METHODS We studied patients with haematological malignancies undergoing unrelated CBT following myeloablative conditioning. There were 80 matched, 72 major mismatched, 72 minor mismatched, and 37 bidirectional mismatched transplants. Risk factors that could potentially influence the patients' outcomes were evaluated. Immunoglobulin M (IgM) isohaemagglutinin antibody (IHA) titres were determined 1 day before and 2, 4, 6 and 8 weeks after the transplant. RESULTS ABO mismatches did not influence engraftment, transfusion requirements, event-free survival or overall survival following CBT. The anti-donor IgM serum IHA titres fell to =1:8 at week 8 after CBT in all patients with ABO major and bidirectional mismatches. The percentages of patients requiring platelet and red blood cell transfusions in the period 31-61 days after CBT were markedly lower than in the period 0-30 days after CBT, being 15% vs 99% for platelets and 23% vs 78% for red blood cells, respectively. Of the 69 recipients of minor mismatched CBT tested, only three with AB blood type developed low titres of anti-recipient IHA after 5 months. DISCUSSION In this study ABO incompatibility did not affect clinical outcomes after CBT. A higher number of CD34(+) cells infused was correlated with earlier engraftment. Severe acute graft-versus-host disease was associated with poor overall survival. As the IHA titre decreased, so did the number of patients requiring blood transfusion. Rapidly decreasing anti-donor IHA titres and the non-production of donor anti-recipient A and/or B antibodies might contribute to a good outcome of ABO-incompatible CBT with myeloablative conditioning for haematological malignancies.
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10.
Impact of Total Body Irradiation-Based Myeloablative Conditioning Regimens in Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-Analysis
Khimani, F., Dutta, M., Faramand, R., Nishihori, T., Perez, A. P., Dean, E., Nieder, M., Perez, L., Mishra, A., Elmariah, H., et al
Transplantation and Cellular Therapy. 2021;27(7):620.e1-620.e9
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for patients with acute lymphoblastic leukemia (ALL). Both total body irradiation (TBI)-based and chemotherapy only-based myeloablative transplantation conditioning regimens have been applied, but the optimal regimen remains unclear. We performed a systematic review to assess the efficacy of TBI-based versus chemotherapy only-based myeloablative conditioning regimens. We searched PubMed, Embase, and Cochrane databases and meeting abstracts for all studies comparing TBI-based and chemotherapy only-based conditioning regimens in patients who underwent allo-HCT for ALL. Two authors independently reviewed all studies for inclusion and extracted data related to overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD). Eight studies were included in the final analysis. The overall methodological quality of the included studies was optimal. TBI-based regimens showed evidence of benefit compared with chemotherapy only-based conditioning regimens in terms of relapse (relative risk [RR], 0.82; 95% confidence interval [CI], 0.72 to 0.94; 6 studies, 5091 patients), OS (hazard ratio [HR], 0.76; 95% CI, 0.64 to 0.89; 7 studies, 4727 patients), and PFS (HR, 0.74; 95% CI, 0.63 to 0.85; 7 studies, 4727 patients). The TBI-based regimen did not increase the likelihood of grade II-IV acute GVHD (RR, 1.12; 95% CI, 0.92 to 1.36; 5 studies, 4996 patients) or chronic GVHD (RR, 1.10; 95% CI, 1.00 to 1.21; 5 studies, 4490 patients), or NRM (RR, 0.94; 95% CI, 0.69 to 1.28; 6 studies, 4522 patients). However, TBI-based regimens were associated with an increased risk of grade III-IV acute GVHD (RR, 1.29; 95% CI, 1.01 to 1.63; 3 studies, 3675 patients). A subgroup comparison of patients age ≥16 years showed similar results. This systematic review represents evidence supporting the use of TBI-based conditioning regimen in patients undergoing allo-HCT for ALL who are candidates for myeloablative conditioning, as it offers better OS, PFS, and less relapse with acceptable NRM.