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1.
Effect of conditioning regimens and GVHD prophylaxis on the outcomes of umbilical cord blood transplantation performed with cyclophosphamide/total-body irradiation-based regimens
Imahashi, N., Kurita, N., Konuma, T., Takahashi, S., Nishida, T., Tanaka, M., Nakamae, H., Kawakita, T., Ota, S., Doki, N., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Umbilical cord blood (UCB) is a valuable alternative donor source for allogeneic hematopoietic stem cell transplantation. Various conditioning regimens and graft-versus-host disease (GVHD) prophylaxis are explored to improve the outcomes of umbilical cord blood transplantation (UCBT). However, the differences in their effects remain unclear. OBJECTIVES To elucidate the differences in the effects of conditioning regimens and GVHD prophylaxis on UCBT outcomes by disease type in a nationwide, retrospective study. STUDY DESIGN We retrospectively analyzed the effects of conditioning regimens and GVHD prophylaxis on the outcomes of UCBT performed with cyclophosphamide/total-body irradiation (CY/TBI)-based regimens in patients with acute myeloid leukemia (AML; n=1126), acute lymphoblastic leukemia (ALL; n=620), myelodysplastic syndrome (MDS; n=170), and lymphoma (n=128). RESULTS Multivariate analysis for overall survival (OS) demonstrated the benefit of adding high-dose cytarabine to the CY/TBI regimen for the AML (relative risk [RR], 0.76; P=0.003) and lymphoma (RR, 0.54; P=0.02) groups, but not in the ALL and MDS groups. The benefit of adding etoposide to the CY/TBI regimen was tested in the ALL group; it was associated with a lower OS (RR, 1.45; P=0.03). In the case of GVHD prophylaxis, tacrolimus/methotrexate regimen resulted in a lower OS than the cyclosporine/methotrexate regimen in the AML group (RR, 1.26; P=0.01); this was not observed in the other groups. These differences in OS according to the conditioning regimen and GVHD prophylaxis were mainly attributable to differences in relapse risk. CONCLUSION The effects of conditioning regimens and GVHD prophylaxis on UCBT outcomes differed according to disease type. UCBT outcomes could be improved by selecting optimal conditioning regimens and GVHD prophylaxis for each disease type.
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The impacts of total body irradiation on umbilical cord blood hematopoietic stem cell transplantation
Wang, H., Berger, K. N., Miller, E. L., Fu, W., Broglie, L., Goldman, F. D., Konig, H., Lim, S. J., Berg, A. S., Talano, J. A., et al
Therapeutic advances in hematology. 2023;14:20406207231170708
Abstract
BACKGROUND Umbilical cord blood hematopoietic stem cells are commonly used for hematopoietic system reconstitution in recipients after umbilical cord blood transplantation (UCBT). However, the optimal conditioning regimen for UCBT remains a topic of debate. The exact impact of total body irradiation (TBI) as a part of conditioning regimens remains unknown. OBJECTIVES The aim of this study was to evaluate the impacts of TBI on UCBT outcomes. DESIGN This was a multi-institution retrospective study. METHODS A retrospective analysis was conducted on the outcomes of 136 patients receiving UCBT. Sixty-nine patients received myeloablative conditioning (MAC), in which 33 underwent TBI and 36 did not, and 67 patients received reduced-intensity conditioning (RIC), in which 43 underwent TBI and 24 did not. Univariate and multivariate analyses were conducted to compare the outcomes and the post-transplant complications between patients who did and did not undergo TBI in the MAC subgroup and RIC subgroup, respectively. RESULTS In the RIC subgroup, patients who underwent TBI had superior overall survival (adjusted hazard ratio [aHR] = 0.25, 95% confidence interval [CI]: 0.09-0.66, p = 0.005) and progression-free survival (aHR = 0.26, 95% CI: 0.10-0.66, p = 0.005). However, in the MAC subgroup, there were no statistically significant differences between those receiving and not receiving TBI. CONCLUSION In the setting of RIC in UCBT, TBI utilization can improve overall survival and progression-free survival. However, TBI does not show superiority in the MAC setting.
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Total body irradiation-based versus busulfan-based myeloablative conditioning for single-unit cord blood transplantation in adults
Konuma, T., Ooi, J., Monna-Oiwa, M., Isobe, M., Tomonari, A., Kato, S., Iseki, T., Nannya, Y., Tojo, A., Takahashi, S.
Leukemia & lymphoma. 2022;63(5):1191-1201
Abstract
Comparative studies between total body irradiation (TBI)-based and busulfan-based myeloablative conditioning (MAC) regimens for cord blood transplantation (CBT) have been limited. We retrospectively analyzed the results of single-unit CBT in 333 adult patients who received either TBI-based (n = 258) or busulfan-based (n = 75) MAC regimens at our institute. After adjusting for significant variables in the univariate analysis, there were no significant differences in neutrophil recovery (hazard ratio (HR), 0.88; p = .460), grade III-IV acute graft-versus-host disease (GVHD) (HR: 1.40, p = .410), extensive chronic GVHD (HR: 0.73, p = .380), relapse (HR: 0.61, p = .270), non-relapse mortality (HR: 1.38, p = .420), overall survival (HR: 1.18, p = .637), or event-free survival (HR: 1.08, p = .773), although platelet recovery was lower with marginal significance for the busulfan-based regimen (HR: 0.67, p = .068). In subgroup analysis, TBI-based regimens were superior to busulfan-based regimens in terms of survival for acute lymphoblastic leukemia, but not for myeloid malignancies. Further investigation is warranted even for CBT.
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Conditioning with 10 Gy Total Body Irradiation, Cyclophosphamide, and Fludarabine without ATG Is Associated with Improved Outcome of Cord Blood Transplantation in Children with Acute Leukemia
Cho, H. W., Ju, H. Y., Hyun, J. K., Lee, J. W., Sung, K. W., Koo, H. H., Lim, D. H., Yoo, K. H.
Journal of Korean medical science. 2021;36(19):e128
Abstract
BACKGROUND The optimal conditioning regimen in cord blood transplantation (CBT) needs to be determined. This study aimed to identify the impact of conditioning regimen on the outcome of CBT in children with acute leukemia. METHODS Medical records of patients with acute leukemia who received CBT were retrospectively reviewed. RESULTS A total of 71 patients were allocated into 2 groups; patients who received total body irradiation 10 Gy, cyclophosphamide 120 mg/kg, and fludarabine 75 mg/m² were named as TCF group (n = 18), while the non-TCF group (n = 53) included patients conditioned with regimens other than the TCF regimen. All patients in the TCF group were successfully engrafted, while 22.6% in the non-TCF group (n = 12) failed to achieve donor-origin hematopoiesis (P = 0.028). The incidence of cytomegalovirus diseases was 5.6% in the TCF group and 30.2% in the non-TCF group (P = 0.029). The 5-year overall survival rates of the TCF and non-TCF groups were 77.8% and 44.2%, respectively (P = 0.017). CONCLUSION Patients conditioned with the TCF regimen achieved better engraftment and survival rates, less suffering from cytomegalovirus disease. Our data suggest that the TCF regimen is a preferred option for CBT in children with acute leukemia.
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5.
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.
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6.
Engraftment of Double Cord Blood Transplantation after Nonmyeloablative Conditioning with Escalated Total Body Irradiation Dosing to Facilitate Engraftment in Immunocompetent Patients
Brunstein, C. G., DeFor, T. E., Fuchs, E. J., Karanes, C., McGuirk, J. P., Rezvani, A. R., Eapen, M., O'Donnell, P. V., Weisdorf, D. J.
Transplantation and cellular therapy. 2021;27(10):879.e1-879.e3
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Editor's Choice
Abstract
To improve accrual to a randomized clinical trial of double unrelated cord blood (dUCB) versus HLA-haploidentical bone marrow (haplo-BM) transplantation, patients with less previous therapy and potentially greater immunocompetence were enrolled. To reduce the risk of graft rejection, patients randomized to receive dUCB received a higher dose of total body irradiation (TBI) (300 cGy versus 200 cGy). In this study, we investigated whether the inclusion of recipients of 300 cGy TBI influenced the trial outcomes. This was a secondary analysis of dUCB recipients, 161 who received TBI 200 cGy and 18 who received TBI 300 cGy. Fine and Gray regression was used to evaluate the effect of TBI dose on relapse and nonrelapse mortality (NRM). Cox regression was used for evaluation of neutrophil engraftment and overall survival. Patient characteristics were similar in the 2 TBI dose subgroups. The probability of neutrophil engraftment was 100% for patients who received TBI 300 cGy versus 91% (95% confidence interval, 86% to 95%) for those who received TBI 200 cGy (P = .64), which was similar after regression analysis adjusting for age, total infused nucleated cell dose, HLA matching to the patient, and comorbidity score. We also investigated whether the lower survival probability and higher cumulative incidence of NRM observed in the dUCB arm of BMT CTN 1101 could be influenced by the TBI 300 cGy patient subset. There was no significant difference in the 1-year incidences of NRM and relapse or in 1-year survival, even after adjustment in multivariate analysis. Patients in BMT CTN 1101 who received TBI 300 cGy and 200 cGy had similar engraftment and early mortality. We conclude that inclusion of a modified regimen for dUCB transplantation had no demonstrable influence on this large randomized trial.
PICO Summary
Population
Adults aged up to 70 years with acute leukaemia or lymphoma, enrolled in BMT CTN 1101 trial, and who received a double cord blood (dUCB) graft (n=179)
Intervention
Total body irradiation (TBI) conditioning 200 cGy (n=161)
Comparison
Total body irradiation (TBI) conditioning 300 cGy (n=18)
Outcome
The probability of neutrophil engraftment was 100% for patients who received TBI 300 cGy versus 91% (95% confidence interval, 86% to 95%) for those who received TBI 200 cGy, which was similar after regression analysis adjusting for age, total infused nucleated cell dose, HLA matching to the patient, and comorbidity score. We also investigated whether the lower survival probability and higher cumulative incidence of NRM observed in the dUCB arm of BMT CTN 1101 could be influenced by the TBI 300 cGy patient subset. There was no significant difference in the 1-year incidences of NRM and relapse or in 1-year survival, even after adjustment in multivariate analysis. Patients in BMT CTN 1101 who received TBI 300 cGy and 200 cGy had similar engraftment and early mortality.
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Retrospective cohort study comparing the outcomes of intravenous busulfan vs. total-body irradiation after single cord blood transplantation
Tang, B., Zhu, X., Zheng, C., Liu, H., Hao, S., Huang, D., Lin, D., Li, N., Gao, S., Liang, X., et al
Bone marrow transplantation. 2019
Abstract
Limited to inadequate stem-cell doses, cord blood transplantation (UCBT) is accompanied by increased graft failure and delayed haematopoietic recovery. The conditioning regimen is critically important for engraftment, and numerous trials have been undertaken comparing the outcomes of IV Bu and TBI, but there are no comparative data for UCBT. We conducted a retrospective multicentre study to analyse the outcomes of IV Bu and TBI in UCBT patients with haematologic malignancies. Between 1 May, 2008 and 31 Mar, 31 2018, a total of 331 patients from the China Umbilical Cord Blood Transplantation Corporation (IV Bu, n = 131; TBI, n = 200) were evaluated. The cumulative incidence of neutrophil engraftment was 91.6% in the IV Bu/Cy cohort and 98.0% in the Cy/TBI cohort (P < 0.001). The median times to neutrophil engraftment were 16 and 19 days (P < 0.001), respectively. Multivariate analysis showed no statistical difference for nonrelapse mortality (hazard ratio [HR], 1.11; 95% confidence interval [CI], 0.66 to 1.86; P = 0.695), relapse (HR, 0.90; 95% CI, 0.50 to 1.60; P = 0.713) and overall survival (HR, 0.94; 95% CI, 0.61 to 1.44; P = 0.763) between the two conditioning regimens. Our results show that both IV Bu and TBI are valid myeloablative conditioning regimens for haematologic malignancy patients treated with UCBT.
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Impact of total body irradiation on successful neutrophil engraftment in unrelated bone marrow or cord blood transplantation
Nakasone, H., Fuji, S., Yakushijin, K., Onizuka, M., Shinohara, A., Ohashi, K., Miyamura, K., Uchida, N., Takanashi, M., Ichinohe, T., et al
American Journal of Hematology. 2017;92(2):171-178
Abstract
Total body irradiation (TBI) has been thought to promote donor cell engraftment in allogeneic hematopoietic cell transplantation (HCT) from alternative donors. However, recent progress in HCT strategies may affect the clinical significance of TBI on neutrophil engraftment. With the use of a Japanese transplant registry database, we analyzed 3933 adult recipients (>15 y.o.) who underwent HCT between 2006 and 2013 from an 8/8 HLA-matched unrelated bone marrow donor (MUD, n=1367), an HLA-mismatched unrelated bone marrow donor (MMUD, n=1102), or unrelated cord blood (CBT, n=1464). Conditioning regimens were divided into five groups: High-TBI-(>8Gy), Low-TBI- (<=8Gy), and no-TBI-myeloablative conditioning (MAC), and Low-TBI- and no-TBI-reduced-intensity conditioning (RIC). In both MUD and MMUD, neutrophil engraftment rate was >90% in each of the five conditioning groups, and TBI was not associated with prompt neutrophil engraftment in multivariate analyses. Conversely, in CBT, TBI regimens had a higher rate of day-30 neutrophil engraftment than no-TBI-regimens: 78% in High-TBI-MAC, 83% in Low-TBI-MAC, and 76% in Low-TBI-RIC versus 65% in No-TBI-MAC, and 68% in No-TBI-RIC (P<.001). Multivariate analyses in CBT demonstrated that TBI-regimens were significantly associated with a higher rate of neutrophil engraftment. Subsequently focusing on CBT patients alone, TBI-regimens were significantly associated with a higher rate of neutrophil engraftment in patients who received CBT with a 4/6 or less HLA allele-match, or who had anti-HLA antibodies. In summary, TBI-regimens had no impact on neutrophil engraftment in the current practice of unrelated bone marrow transplantation. However, in CBT, TBI is still necessary to enhance engraftment.
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Higher Early Monocyte and Total Lymphocyte Counts Are Associated with Better Overall Survival after Standard Total Body Irradiation, Cyclophosphamide, and Fludarabine Reduced-Intensity Conditioning Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation in Adults
Le Bourgeois, A., Peterlin, P., Guillaume, T., Delaunay, J., Duquesne, A., Le Gouill, S., Moreau, P., Mohty, M., Campion, L., Chevallier, P.
Biology of Blood & Marrow Transplantation. 2016;22(8):1473-9
Abstract
This single-center retrospective study aimed to report the impact of early hematopoietic and immune recoveries after a standard total body irradiation, cyclophosphamide, and fludarabine (TCF) reduced-intensity conditioning (RIC) regimen for double umbilical cord blood (dUCB) allogeneic stem cell transplantation (allo-SCT) in adults. We analyzed 47 consecutive patients older than 17 years who engrafted after a dUCB TCF allo-SCT performed between January 2006 and April 2013 in our department. Median times for neutrophil and platelet recoveries were 17 (range, 6 to 59) and 37 days (range, 0 to 164), respectively. The 3-year overall (OS) and disease-free survivals, relapse incidence, and nonrelapse mortality were 65.7%, 57.2%, 27.1%, and 19%, respectively. In multivariate analysis, higher day +30 monocyte (>615/mm(3); hazard ratio [HR], .04; 95% confidence interval [CI], .004 to .36; P < .01) and day +42 lymphocyte (>395/mm(3); HR, .16; 95% CI, .03 to .78; P = .02) counts were independently associated with better OS. These results suggest that early higher hematopoietic and immune recovery is predictive of survival after dUCB TCF RIC allo-SCT in adults. Factors other than granulocyte colony-stimulating factor, which was used in all cases, favoring expansion of monocytes or lymphocytes, should be tested in the future as part of the UCB transplantation procedure. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.