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1.
Comparison of fludarabine-based conditioning regimens in adult cord blood transplantation for myeloid malignancy: A retrospective, registry-based study
Kurita, N., Imahashi, N., Chiba, S., Tanaka, M., Kobayashi, H., Uchida, N., Kuriyama, T., Anzai, N., Nawa, Y., Nakano, N., et al
American journal of hematology. 2024
Abstract
Fludarabine/busulfan and fludarabine/melphalan are viable options as conditioning regimens. However, the optimal fludarabine-based conditioning in cord blood transplantation (CBT) remains unclear. Therefore, this retrospective, registry-based study aimed to analyze the impact of five fludarabine-containing conditioning regimens on 1395 adult patients (median age, 61 years) with acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia who underwent their first CBT. Treatment outcomes of fludarabine combined with melphalan (100-140 mg/m(2) ) and low-dose total body irradiation (TBI; FM140T); melphalan (80-99 mg/m(2) ) and TBI (FM80T); busulfan (12.8 mg/kg) and melphalan (FB4M); busulfan (12.8 mg/kg) and TBI (FB4T); and busulfan (6.4 mg/kg) and TBI (FB2T) were compared. The 3-year survival rate was 67%, 53%, 44%, 36%, and 39%, respectively (p < .0001). The FM140T survival rate was the most favorable after adjusting for confounders, and the hazard ratios (vs. FM140T) for overall mortality were as follows: FM80T, 1.6 (95% confidence interval [CI], 1.2-2.2); FB4M, 2.1 (95% CI, 1.6-2.8); FB4T, 2.7 (95% CI, 2.0-3.7); and FB2T, 2.2 (95% CI, 1.6-3.1). The better survival observed with FM140T, regardless of the disease, disease risk, age, or transplant year, was attributed to the lower relapse rate and lower non-relapse mortality (NRM) associated with fewer infectious deaths. Conversely, FB4T was associated with a higher relapse rate and higher NRM. The findings indicate that the outcomes of CBT in myeloid malignancies were highly dependent on both the alkylating agent and its dose in combination with fludarabine. Therefore, compared with fludarabine/busulfan-based conditioning, FM140T may be the preferred regimen.
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2.
Cost-Effectiveness of Unrelated Umbilical Cord Blood vs. HLA Haploidentical Related Bone Marrow Transplant: Evidence from BMT CTN 1101
Ramsey, S. D., Bansal, A., Li, L., O'Donnell, P. V., Fuchs, E. J., Brunstein, C. G., Eapen, M., Thao, V., Roth, J. A., Steuten, L.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND BMT CTN 1101 was a Phase III randomized controlled trial comparing reduced intensity conditioning followed by double unrelated umbilical cord blood (UCB) versus HLA-haploidentical related donor bone marrow (haplo-BM) transplantation for patients with high-risk hematologic malignancies. OBJECTIVE The objective of this study is to report the results of a parallel cost-effectiveness analysis. STUDY DESIGN Three hundred sixty-eight patients were randomized to unrelated UCB (n=186) or haplo-BM (n=182) transplant. We estimated healthcare utilization and costs using propensity score-matched BMT patients from the OptumLabs(Ⓡ) Data Warehouse for trial participants <65 years and Medicare claims for participants ≥65 years. Weibull models were used to estimate 20-year survival. EQ-5D surveys by trial participants were used estimate Quality-Adjusted Life Years (QALYs). RESULTS At 5-year follow-up, survival was 42% for haplo-BM versus 36% for UCB (P=.06). Over a 20-year time horizon, haplo-BM is expected to be more effective (+0.63 QALY) and more costly +$118,953) for persons under 65. For those over 65, haplo-BM is expected to be more effective and less costly. In one-way uncertainty analyses, for persons <65, the cost per QALY result was most sensitive to life years and health state utilities. For persons ≥65, life years were more influential than costs and health state utilities. CONCLUSION Compared to UCB, haplo-BM was moderately cost-effective for patients aged <65 years, and less costly and more effective for persons ≥65 years. Haplo-BM is a fair value choice for commercially insured patients with high-risk leukemia and lymphoma who require HCT. For Medicare enrollees, haplo-BM is a preferred choice when considering costs and outcomes.
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3.
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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4.
External validation and extended application of the transplant conditioning intensity score in acute myeloid leukemia
Yanada, M., Shimomura, Y., Mizuno, S., Matsuda, K., Kondo, T., Doki, N., Tanaka, M., Fukuda, T., Ara, T., Uchida, N., et al
Bone marrow transplantation. 2023
Abstract
This study aimed to validate the utility of the transplant conditioning intensity (TCI) score in 1714 patients with acute myeloid leukemia (AML) undergoing allogeneic bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT) and assess its applicability to 753 patients with AML undergoing umbilical cord blood transplantation (UCBT) both during first complete remission. Patients classified into a high TCI group accounted for 63% and 56% in the BMT/PBSCT and UCBT cohorts, respectively. In the BMT/PBSCT cohort, the risk of relapse was lower in patients in the high versus intermediate TCI group (P = 0.002), although non-relapse mortality (NRM) did not differ among the three TCI groups. In the UCBT cohort, both relapse and NRM did not differ among the TCI groups. Increasing cutoff points for intermediate and high TCI categories significantly improved the ability to predict relapse and NRM in the BMT/PBSCT cohort (P = 0.030 and 0.006, respectively), and relapse but not NRM in the UCBT cohort (P = 0.005 and 0.364, respectively). These findings highlight the difference in the threshold level of the TCI score for outcome discrimination between European and Japanese cohorts. The TCI scheme appears less effective for UCBT than for BMT/PBSCT.
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5.
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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6.
Advantages of a higher busulfan dose intensity in fludarabine-combined conditioning for patients with acute myeloid leukemia undergoing cord blood transplantation
Shibata, S., Arai, Y., Kondo, T., Mizuno, S., Harada, K., Miyakoshi, S., Uchida, N., Maruyama, Y., Eto, T., Katsuoka, Y., et al
Transplantation and cellular therapy. 2023
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Full text
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Editor's Choice
Abstract
Busulfan is an alkylating agent that is commonly used as conditioning in allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). However, a consensus has not yet been reached regarding the optimal dose of busulfan in cord blood transplantation (CBT). Therefore, we herein conducted a large nationwide cohort study to retrospectively analyze the outcomes of CBT in patients with AML receiving busulfan at intermediate (6.4 mg/kg iv; BU2) or higher doses (12.8 mg/kg iv; BU4) within a fludarabine/intravenous busulfan regimen (FLU/BU). Among 475 patients who underwent their first CBT following FLU/BU conditioning between 2007 and 2018, 162 and 313 received BU2 and BU4, respectively. A multivariate analysis identified BU4 as a significant factor for longer disease-free survival (HR, 0.85; 95% CI, 0.75-0.97; P = 0.014) and a lower relapse rate (HR, 0.84; 95% CI, 0.72-0.98; P = 0.030). No significant differences were observed in non-relapse mortality between BU4 and BU2 (HR, 1.05; 95% CI, 0.88-1.26; P = 0.57). Subgroup analyses showed that BU4 provided significant benefits for patients transplanted in non-complete remission (CR) and those younger than 60 years. The present results suggest that higher busulfan doses are preferable in CBT, particularly for non-CR and younger patients.
PICO Summary
Population
Patients aged 16 years or over with AML receiving cord blood transplant (CBT) with fludarabine/busulfan (FLU/BU) conditioning in Japan and reported to the TRUMP/JSTCT registry (n=475)
Intervention
Higher dose (12.8 mg/kg iv) of busulfan (BU4, n=313)
Comparison
Intermediate dose (6.4 mg/kg iv) busulfan (BU2, n=162)
Outcome
A multivariate analysis identified BU4 as a significant factor for longer disease-free survival (HR, 0.85; 95% CI, 0.75-0.97) and a lower relapse rate (HR, 0.84; 95% CI, 0.72-0.98). No significant differences were observed in non-relapse mortality between BU4 and BU2 (HR, 1.05; 95% CI, 0.88-1.26). Subgroup analyses showed that BU4 provided significant benefits for patients transplanted in non-complete remission (CR) and those younger than 60 years.
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Outcome of human umbilical cord blood stem cell transplantation (CBT) for acute myeloid leukemia in patients achieving first complete remission after one versus two induction courses: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
Nagler, A., Labopin, M., Cornelissen, J. J., Forcade, E., Chevallier, P., Fegueux, N., Sierra, J., Desmier, D., Labussière-Wallet, H., Byrne, J. L., et al
Bone marrow transplantation. 2022
Abstract
We compared transplantation outcomes of adult patients with AML that underwent cord blood transplantation (CBT) in CR1 following 1 versus 2 induction courses. Study included 325 patients, 243 (75%) with 1 and 82 (25%) with 2 induction courses. Engraftment was lower for patients achieving CR1 after 1 vs. 2 induction courses: 91% vs. 99% (p = 0.02). Incidence of acute GVHD was similar, 38% and 36% (p = 0.81), as was 2-year chronic GVHD at 23.4% and 27.5%, respectively (p = 0.65). Two-year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were not statistically different between patients achieving CR1 with 1 vs. 2 induction courses with 23% vs. 24% (p = 0.87), 25% vs. 30% (p = 0.4), 52% vs. 46% (p = 0.3), 59% vs. 50% (p = 0.2), and 44% vs. 41% (p = 0.66), respectively. Results were confirmed by multivariable analysis, NRM (hazard ratio (HR) = 1.1; 95% CI, 0.6-1.8, p = 0.7), RI (HR = 1.4; 95% CI, 0.9-2.3, p = 0.1), LFS (HR = 1.3; 95% CI, 0.9-1.8, p = 0.2), OS (HR = 1.3; 95% CI, 0.9-1.9, p = 0.1), and GRFS (HR = 1.1; 95% CI, 0.8-1.5, p = 0.5). Overall, outcomes of AML patients undergoing CBT in CR1 achieved after 1 or 2 induction courses are similar.
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Favorable Outcome with Conditioning Regimen of Flu/Bu4/Mel in Acute Myeloid Leukemia Patients in Remission Undergoing Cord Blood Transplantation
Mizuno, S., Takami, A., Kawamura, K., Shimomura, Y., Arai, Y., Konuma, T., Ozawa, Y., Sawa, M., Ota, S., Takahashi, S., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Cord blood transplantation (CBT) is a curative therapeutic option for patients with acute myeloid leukemia (AML) who do not have human leukocyte antigen-matched donors. The decline in early non-relapse mortality (NRM) after CBT has significantly improved overall survival (OS) during the past 20 years because of advances in CBT practices, such as more careful patient selection, use of safer conditioning regimens, better unit selection of cord blood, and improvement in supportive care. A previous study reported a conditioning regimen comprising fludarabine, busulfan, and melphalan (Flu/Bu4/Mel) developed for patients undergoing CBT in non-complete remission (CR) myeloid malignancies, which showed durable engraftment and remission with acceptable non-relapse mortality (NRM), leading to excellent survival outcomes. However, no prior study has focused on the role of Flu/Bu4/Mel in CBT conditioning and compared it with conventional myeloablative conditioning (MAC) for AML patients in CR. OBJECTIVES We aimed to investigate the efficacy and safety of Flu/Bu4/Mel compared to cyclophosphamide and total-body irradiation (CY/TBI)-based MAC for AML patients in CR who underwent CBT. STUDY DESIGN Patients were selected from the Japanese nationwide transplantation registry according to the following inclusion criteria: (1) patients with AML aged ≥16 years; (2) first transplantation of single-unit cord blood; (3) CR at the time of transplantation. RESULTS Of 477 eligible patients, 148 (31.0%) received CY/TBI, 223 (46.8%) received HDCA/CY/TBI, and 106 (22.2%) received Flu/Bu4/Mel. The probabilities of OS in the CY/TBI, HDCA/CY/TBI, and Flu/Bu4/Mel groups were 64.8% (95% confidence interval [CI]: 56.0%-72.3%), 65.1% (95% CI: 57.8%-71.4%), and 65.5% (95% CI: 53.7%-74.9%) at 3 years, respectively (P = 0.71). The cumulative incidences of relapse in the CY/TBI, HDCA/CY/TBI, and Flu/Bu4/Mel groups were 22.0% (95% CI: 15.2%-29.5%), 17.2% (95% CI: 12.2%-22.9%), and 18.0% (95% CI: 11.2%-26.2%) at 3 years, respectively (P = 0.40). The cumulative incidences of NRM in the CY/TBI, HDCA/CY/TBI, and Flu/Bu4/Mel groups were 17.2% (95% CI: 11.5%-24.0%), 20.7% (95% CI: 15.4%-26.7%), and 18.6% (95% CI: 11.4%-27.2%) at 3 years, respectively (P = 0.95). Multivariate analysis revealed that Flu/Bu4/Mel was a favorable factor for OS; however, it was not significantly favorable for relapse and NRM among the CY/TBI, HDCA/CY/TBI, and Flu/Bu4/Mel groups (hazard ratio [HR]: 0.50 [95% CI, 0.29-0.88]; P = 0.015, HR: 0.67 [95% CI, 0.31-1.46]; P = 0.31, and HR: 0.55 [95% CI, 0.26-1.18]; P = 0.12, respectively). Flu/Bu4/Mel was a favorable factor for neutrophil engraftment (1.51 [95% CI, 1.08-2.12]; P = 0.016). CONCLUSION The multivariate analysis showed that Flu/Bu4/Mel had a favorable prognostic impact on OS and neutrophil engraftment despite the non-TBI regimen. Our findings suggest that Flu/Bu4/Mel may sustain antileukemia effect with decreasing NRM and it could be a favorable CBT conditioning regimen for patients with AML in CR.
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Intensified conditioning regimens improved disease-free survival and engraftment after unrelated single-unit cord blood transplantation but not after matched sibling or matched unrelated donor allogeneic hematopoietic cell transplantation
Konuma, T., Kanda, J., Uchida, N., Nishijima, A., Tanaka, M., Ozawa, Y., MasashiSawa,, MakotoOnizuka,, Ota, S., Maruyama, Y., et al
Hematological oncology. 2022
Abstract
The impact of conditioning intensity on different donor groups has been unclear in allogeneic transplantation. The objective of this study was to clarify the effect of conditioning intensity on disease-free survival (DFS), relapse, non-relapse mortality (NRM), neutrophil engraftment, and graft-versus-host disease (GVHD) for each donor type. We retrospectively evaluated the effect of conditioning intensity on transplant outcomes for adult patients with acute leukemia or myelodysplastic syndrome aged between 16 and 60 years in Japan using the transplant conditioning intensity (TCI) scoring system. A total of 8,526 patients who received first allogeneic transplantation from 6/6 antigen-matched sibling donor (MSD, n=2768), 8/8 allele-matched unrelated donor (MUD, n=2357), and unrelated single-cord blood (UCB, n=3401) were eligible for the analyses. Compared to conditioning with TCI score 4.0, which was corresponds to conventional myeloablative conditioning, including cyclophosphamide with total body irradiation 12 Gy or busulfan 12.8 mg, and was considered as the reference group in the multivariate analyses, intensified conditioning with TCI score ≥4.5 improved DFS (hazard ratio [HR],0.81, P<0.001) and relapse rate (HR,0.70, P<0.001) but only after UCB transplants and not MSD and MUD transplants. In contrast, NRM was higher after intensified conditioning with TCI score ≥4.5 for MSD (HR,1.39, P=0.008) and MUD (HR,1.47, P=0.002) transplants but not UCB transplants (HR,1.12, P=0.240). Neutrophil engraftment was also significantly higher after intensified conditioning with TCI score ≥4.5 but only for UCB transplants (HR,1.24, P<0.001), whereas it was significantly lower after reduced- intensity conditioning with TCI score ≤3.5 for MSD transplants only (HR,0.82, P<0.001). These data demonstrated that an intensified conditioning regimen improved survival and engraftment rate only after a UCB transplants. Therefore, TCI scoring system could enable the optimization of conditioning intensity according to donor type, particularly in terms of survival and engraftment. This article is protected by copyright. All rights reserved.
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10.
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.