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1.
Intensified conditioning regimens with total marrow irradiation/etoposide/cyclophosphamide and busulfan/etoposide/cyclophosphamide overcome the impact of pre-transplant minimal residual disease on outcomes in high-risk acute lymphoblastic leukemia patients in complete remission
Zhao, X., Xu, Z., Li, Z., Zhou, X., Hu, Y., Wang, H.
Cancer medicine. 2024
Abstract
PURPOSE Among high-risk acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), those with positive minimal residual disease (MRD) are susceptible to poor outcomes. Therefore, it is necessary to determine the most suitable preparatory regimen for these patients. METHODS Data were analyzed from 141 patients who received allo-HSCT and were diagnosed with high-risk ALL. These patients underwent intensified conditioning regimens, including either total marrow and lymphoid irradiation (TMLI)-etoposide (VP16)-cyclophosphamide (CY) or busulfan (BU)-VP16-CY between October 2016 and November 2022. A total of 141 individuals were in complete remission (CR) before transplantation and, among all patients, 90 individuals exhibited a negative MRD status and 51 patients had a positive MRD status. RESULTS In patients who tested negative for MRD, the incidence of relapse within a 2-year timeframe was 25.0% (24.8%-25.5%), compared with 32.2% (31.2%-33.2%) in MRD-positive patients; however, this difference was not statistically significant. There were no significant differences in the 2-year disease-free survival (DFS) and 2-year overall survival (OS) rates between the MRD-negative and MRD-positive groups (DFS: 67.2% (57.9%-78.1%) vs. 55.5% (42.6%-72.3%); OS: 69.0% (61.9%-88.2%) vs. 66.7% (53.9%-82.5%)). Furthermore, no notable variations were observed in the occurrence of transplant-related mortality (TRM) and graft-versus-host disease (GVHD) across the two groups. CONCLUSION This study reveals the benefits of TMLI-VP16-CY and BU-VP16-CY conditioning regimens in high-risk ALL patients with CR and MRD-positive status. A large-scale prospective clinical trial is warranted in the future.
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2.
TBI, etoposide, and cyclophosphamide conditioning for intermediate-risk relapsed childhood acute lymphoblastic leukemia
Ueki, H., Ogawa, C., Goto, H., Nishi, M., Yamanaka, J., Mochizuki, S., Nishikawa, T., Kumamoto, T., Nishiuchi, R., Kikuta, A., et al
International journal of hematology. 2024
Abstract
BACKGROUND In children with intermediate-risk relapsed acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) has markedly improved the outcome of patients with an unsatisfactory minimal residual disease (MRD) response. Total body irradiation (TBI), etoposide (ETP), and cyclophosphamide (CY) have been shown to be equivalent to or better than TBI + ETP for conditioning, so we hypothesized that even greater survival could be achieved due to recent advances in HSCT and supportive care. PROCEDURE We prospectively analyzed the efficacy and safety of allo-HSCT with a unified conditioning regimen of TBI + ETP + CY in children with intermediate-risk relapsed ALL, based on MRD in the bone marrow after induction, from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-R08-II nationwide cohort (UMIN000002025). RESULTS Twenty patients with post-induction MRD ≥ 10(-3) and two not evaluated for MRD underwent allo-HSCT. Engraftment was confirmed in all patients, and no transplantation-related mortality was observed. The 3-year event-free survival and overall survival rates after transplantation were 86.4% ± 7.3% and 95.5% ± 4.4%, respectively. CONCLUSION Allo-HSCT based on post-induction MRD with TBI + ETP + CY conditioning was feasible in Japanese children with intermediate-risk relapsed ALL.
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3.
Reduced 8-Gray Compared to Standard 12-Gray Total Body Irradiation for Allogeneic Transplantation in First Remission Acute Lymphoblastic Leukemia: A Study of the Acute Leukemia Working Party of the EBMT
Spyridonidis, A., Labopin, M., Savani, B., Giebel, S., Bug, G., Schönland, S., Kröger, N., Stelljes, M., Schroeder, T., McDonald, A., et al
HemaSphere. 2023;7(1):e812
Abstract
In this registry-based study, we compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in adult patients with acute lymphoblastic leukemia (ALL) transplanted in first complete remission (CR-1), following conditioning with total body irradiation (TBI) at a standard 12-Gray or at a lower 8-Gray total dose. Patients received fludarabine (flu) as the sole chemotherapy complementing TBI. Eight-Gray TBI/flu was used in 494 patients and 12-Gray TBI/flu in 145 patients. Eighty-eight (23.1%) and 36 (29%) of the patients had Ph-negative B-ALL, 222 (58.3%) and 53 (42.7%) had Ph-positive B-ALL, 71 (18.6%) and 35 (28.2%) T-ALL, respectively (P = 0.008). Patients treated with 8-Gray were older than ones received 12-Gray (median 55.7 versus 40.3 years, P < 0.0001) and were more frequently administered in vivo T-cell depletion (71% versus 40%, P <0.0001). In a multivariate model adjusted for age, type of ALL, and other prognostic factors, leukemia-free survival (primary endpoint) as well as relapse, nonrelapse mortality, overall survival, and GVHD-free, relapse-free survival were not influenced by the TBI dose. These results were confirmed when we focused on patients <55 years of age (median 47 years). Patients with Ph-positive ALL or T-ALL had significantly better survival outcomes than ones with Ph-negative B-ALL, mainly due to significantly fewer relapses. We conclude that 8-Gray TBI is sufficient for adult patients with ALL transplanted in CR-1 with no additional benefit of augmenting the conditioning intensity to 12-Gray.
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4.
A comprehensive comparison between TBI vs non-TBI-based conditioning regimen in pediatric patients with acute lymphoblastic leukemia: A systematic review and meta-analysis
Ansari, F., Behfar, M., Jafari, L., Mohseni, R., Naji, P., Karamlou, Y., Amirzade-Iranaq, M. H., Hamidieh, A. A.
Leukemia research. 2023;135:107416
Abstract
INTRODUCTION We aimed to evaluate the efficacy, safety, and latent toxicity of total body irradiation (TBI)-based conditioning regimens compared to non-TBI regimens for pediatric patients (under 18 years old) with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). METHODS A systematic search was performed on MEDLINE, Scopus, WOS, and PMC. Also, a search for grey literature was performed on Google Scholar and relevant articles' references were included. Relevant articles which met the inclusion criteria were retrieved up to October 31th, 2022. CMA version 2 was used for the quantitative synthesis of the data. RESULTS Eight studies on efficacy and safety of TBI and non-TBI as a conditioning regimen were analyzed and six comparative studies on late toxicity were investigated. The meta-analysis revealed a hazard ratio (HR) of 1.508 (95% CI 0.96-2.35) for overall survival (OS) in instances of non-TBI conditioning. Also, an HR of 1.503 (95% CI 1.006-2.25) for disease-free- survival (DFS) favoring TBI-based conditioning. Late complications were reported to be significantly higher in the TBI conditioning regimen group than in the non-TBI group. CONCLUSION It appears that non-TBI regimens are as effective as TBI regimens in pediatrics with ALL regarding OS. Occurrence of latent toxicity is higher with TBI conditioning regimen. Conversely, TBI-based regimens are superior to non-TBI conditioning regimens regarding DFS. Considering all aspects, non-TBI conditioning regimens can be an alternative treatment option for pediatric ALL undergoing HSCT.
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5.
Total Body Irradiation Versus Chemotherapy Conditioning in Pediatric Acute Lymphoblastic Leukemia Patients Undergoing Hematopoietic Stem Cell Transplant: A Systematic Review and Meta-Analysis
Rehman, M. E. U., Chattaraj, A., Mahboob, A., Ijaz, Z., Franco, D., Farhan, M., Dharma, K., Mumtaz, H., Saeed, S., Basit, J., et al
Clinical lymphoma, myeloma & leukemia. 2023
Abstract
Allogeneic hematopoietic stem cell transplant (HSCT) is indicated in pediatric patients with acute lymphoblastic leukemia (ALL) who have relapsed or are at a very high risk of relapse during first complete remission. Two types of myeloablative conditioning are employed before allogeneic HSCT total body irradiation (TBI)-based regimens and chemotherapy (CHT) alone. This study compares the efficacy and safety of TBI-based regimens and CHT-based conditioning in pediatric, adolescent, and young adult patients with ALL (0-24 years old). TBI-based and CHT-conditioning regimens were evaluated in 4262 and 1367 patients, respectively, from 15 studies. Compared to CHT alone, TBI-based regimens were associated with better overall survival (OS), relative risk (RR) 1.21, better event-free survival (RR 1.34), and a reduced risk of relapse (RR 0.69). Both approaches had comparable risk of acute graft-versus-host disease (GVHD), grades 3 to 4 acute GVHD, chronic GVHD, and nonrelapse mortality (NRM). In the subgroup analysis for patients in first complete remission, TBI-based regimens and CHT alone had comparable OS and NRM. Our results demonstrate the superiority of TBI-based regimens compared to CHT alone in pediatric patients with ALL.
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6.
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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7.
Total body irradiation versus busulfan based intermediate intensity conditioning for stem cell transplantation in ALL patients >45 years-a registry-based study by the Acute Leukemia Working Party of the EBMT
Hirschbühl, K., Labopin, M., Polge, E., Blaise, D., Bourhis, J. H., Socié, G., Forcade, E., Yakoub-Agha, I., Labussière-Wallet, H., Bethge, W., et al
Bone marrow transplantation. 2023
Abstract
Allogeneic hematopoietic cell transplantation is a potentially curative treatment in high-risk acute lymphoblastic leukemia (ALL). Conditioning regimens based on ≥12 Gray total body irradiation (TBI) represent the current standard in patients ≤45 years, whereas elderly patients frequently receive intermediate intensity conditioning (IIC) to reduce toxicity. To evaluate the role of TBI as a backbone of IIC in ALL, a retrospective, registry-based study included patients >45 years transplanted from matched donors in first complete remission, who had received either fludarabine/TBI 8 Gy (FluTBI8, n = 262), or the most popular, irradiation-free alternative fludarabine/busulfan, comprising busulfan 6.4 mg/kg (FluBu6.4, n = 188) or 9.6 mg/kg (FluBu9.6, n = 51). At two years, overall survival (OS) was 68.5%, 57%, and 62.2%, leukemia-free survival (LFS) was 58%, 42.7%, and 45%, relapse incidence (RI) was 27.2%, 40%, and 30.9%, and non-relapse-mortality (NRM) was 23.1%, 20.7%, and 26.8% for patients receiving FluTBI8Gy, FluBu6.4, and FluBu9.6, respectively. In multivariate analysis, the risk of NRM, acute and chronic graft-versus-host disease was not influenced by conditioning. However, RI was higher after FluBu6.4 (hazard ratio [HR] [95% CI]: 1.85 [1.16-2.95]), and LFS was lower after both FluBu6.4 (HR: 1.56 [1.09-2.23]) and FluBu9.6 (HR: 1.63 [1.02-2.58]) as compared to FluTBI8. Although only resulting in a non-significant advantage in OS, this observation indicates a stronger anti-leukemic efficacy of TBI-based intermediate intensity conditioning.
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8.
Autologous versus allogeneic hematopoietic cell transplantation for older patients with acute lymphoblastic leukemia. An analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Giebel, S., Labopin, M., Houhou, M., Caillot, D., Finke, J., Blaise, D., Fegueux, N., Ethell, M., Cornelissen, J. J., Forcade, E., et al
Bone marrow transplantation. 2023;58(4):393-400
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) with reduced intensity conditioning (RIC) is an option for elderly patients with acute lymphoblastic leukemia (ALL). We retrospectively compared results of RIC-allo-HCT from either a matched sibling donor (MSD, n = 209) or matched unrelated donor (MUD, n = 209) with autologous (auto, n = 142) HCT for patients aged 55 years or more treated in first complete remission (CR1) between 2000 and 2018. The probabilities of leukemia-free survival (LFS) at 5 years were 34% for RIC-allo-HCT versus 39% for auto-HCT (p = 0.11) while overall survival (OS) rates were 42% versus 45% (p = 0.23), respectively. The incidence of relapse (RI) and non-relapse mortality (NRM) was 41% versus 51% (p = 0.22) and 25% versus 10% (p = 0.001), respectively. In a multivariate model, using auto-HCT as reference, the risk of NRM was increased for MSD-HCT (Hazard ratio [HR] = 2.1, p = 0.02) and MUD-HCT (HR = 3.08, p < 0.001), which for MUD-HCT translated into a decreased chance of LFS (HR = 1.55, p = 0.01) and OS (HR = 1.62, p = 0.008). No significant associations were found with respect to the risk of relapse. We conclude that for patients with ALL in CR1, aged above 55 years, auto-HCT may be considered a transplant option alternative to RIC-allo-HCT, although its value requires verification in prospective trials.
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9.
Fludarabine or cyclophosphamide in combination with total body irradiation as myeloablative conditioning prior to allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia: an analysis by the Acute Leukemia Working Party of the EBMT
Giebel, S., Labopin, M., Socié, G., Aljurf, M., Salmenniemi, U., Labussière-Wallet, H., Srour, M., Kröger, N., Zahrani, M. A., Lioure, B., et al
Bone marrow transplantation. 2023
Abstract
In this registry-based study we retrospectively compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with acute lymphoblastic leukemia (ALL) following conditioning with total body irradiation (TBI) combined with either cyclophosphamide (Cy) or fludarabine (Flu). TBI 12 Gy + Cy was used in 2105 cases while TBI 12 Gy + Flu was administered to 150 patients in first or second complete remission. In a multivariate model adjusted for other prognostic factors, TBI/Cy conditioning was associated with a reduced risk of relapse (HR = 0.69, p = 0.049) and increased risk of grade 2-4 acute graft-versus-host disease (GVHD, HR = 1.57, p = 0.03) without significant effect on other transplantation outcomes. In a matched-pair analysis the use of TBI/Cy as compared to TBI/Flu was associated with a significantly reduced rate of relapse (18% vs. 30% at 2 years, p = 0.015) without significant effect on non-relapse mortality, GVHD and survival. We conclude that the use of myeloablative TBI/Cy as conditioning prior to allo-HCT for adult patients with ALL in complete remission is associated with lower risk of relapse rate compared to TBI/Flu and therefore should probably be considered a preferable regimen.
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10.
Thiotepa-based regimens are a valid alternative to total body irradiation-based reduced-intensity conditioning regimens in patients with acute lymphoblastic leukemia: a retrospective study on behalf of the Acute Leukemia Working Party of the EBMT
Battipaglia, G., Labopin, M., Mielke, S., Ruggeri, A., Nur Ozkurt, Z., Henri Bourhis, J., Rabitsch, W., Yakoub-Agha, I., Grillo, G., Sanz, J., et al
Transplantation and cellular therapy. 2023
Abstract
INTRODUCTION Total body irradiation (TBI) at myeloablative doses is superior to chemotherapy-based regimens in young patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, in elderly and unfit patients, where reduced-intensity conditioning (RIC) regimens are preferred, whether a TBI- or chemotherapy-based approach is better, is unexplored. Thiotepa can be used as part of ALL conditioning regimens. The aim of the current study is to compare transplant outcomes after RIC with TBI- or thiotepa-based regimens in ALL. METHODS Included were patients aged ≥40 years undergoing allo-HSCT for ALL in first complete remission between 2000-2020, receiving a RIC regimen containing either TBI- (4-6 Gray, Gy) or thiotepa. RESULTS We identified a total of 265 patients, including 117 receiving TBI- and 148 receiving a thiotepa-based RIC regimen. In univariate analysis, no differences were observed in transplant outcomes (for TBI versus thiotepa: relapse, 23% versus 28%, p=0.24; non-relapse mortality, 20% versus 26%, p=0.61; leukemia-free survival, 57% versus 46%, p=0.12; overall survival, 67% versus 56%, p=0.18; graft-versus-host disease [GVHD]/relapse-free survival, 45% versus 38%, p=0.21; grade II-IV acute GVHD, 30% in both groups, p=0.84; grade III-IV acute GVHD, 9% versus 10%, p=0.89) except for chronic GVHD which was higher for TBI-based regimens (43% versus 29%, p=0.03). However, on multivariate analysis no differences in transplant outcomes were observed. CONCLUSION In patients ≥40 years receiving a RIC regimen, use of a thiotepa-based regimen may represent a valid alternative to TBI-based regimens as no differences were observed in the main transplant outcomes.