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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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Reduced intensity versus non-myeloablative conditioning regimen for haploidentical transplantation and post-transplantation cyclophosphamide in complete remission acute myeloid leukemia: a study from the ALWP of the EBMT
Devillier, R., Galimard, J. E., Labopin, M., Blaise, D., Raiola, A. M., Pavlu, J., Castagna, L., Socié, G., Chalandon, Y., Martino, M., et al
Bone marrow transplantation. 2022;57(9):1421-1427
Abstract
The optimal conditioning regimen prior haploidentical stem cell transplantation (Haplo-SCT) with post transplantation cyclophosphamide (PT-Cy) for acute myeloid leukemia (AML) remains unknown. A non-myeloablative conditioning (NMAC) regimen (cyclophosphamide + fludarabine + TBI 2 Gy [CyFluTBI]) is a safe approach, but relapse incidence remains high in this setting. Alternatively, a reduced intensity conditioning (RIC) regimen combining thiotepa and reduced-dose busulfan with fludarabine (TBF) may decrease AML relapse. However, an excess of toxicity may counterbalance this potential benefit. We retrospectively compared CyFluTBI vs. TBF in CR AML patients who underwent Haplo-SCT with PT-Cy, in two different populations based on age. We analyzed 490 patients. In patients aged <60 years (n = 203), we observed a higher RI (HR = 3.59, 95% CI = 1.75-7.37, p < 0.01), lower LFS (HR = 1.98, 95% CI = 1.22-3.22, p < 0.01) and lower OS (HR = 1.73, 95% CI = 1.04-2.88, p = 0.04) in the CyFluTBI group, without significant difference in NRM. In older patients (n = 287), we observed that conditioning regimen did not significantly influence LFS (HR = 0.90, 95% CI = 0.56-1.44, p = 0.65), OS (HR = 0.81, 95% CI = 0.49-1.32, p = 0.39) and RI (HR = 1.78, 95% CI = 0.90-3.50, p = 0.10), but showed that CyFluTBI was associated with a significantly lower risk of NRM (HR = 0.48, 95% CI = 0.25-0.92, p = 0.03). Thus, younger patients seem to benefit from conditioning intensification from CyFluTBI to TBF regimens prior PT-Cy Haplo-SCT for CR AML, while older ones do not.
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Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome using treosulfan based compared to other reduced-intensity or myeloablative conditioning regimens. A report of the chronic malignancies working party of the EBMT
Shimoni, A., Robin, M., Iacobelli, S., Beelen, D., Mufti, G. J., Ciceri, F., Bethge, W., Volin, L., Blaise, D., Ganser, A., et al
British journal of haematology. 2021
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Editor's Choice
Abstract
Allogeneic haematopoietic-cell transplantation (allo-HCT) is a potentially curative therapy for high-risk myelodysplastic syndrome (MDS). Reduced-intensity conditioning (RIC) is usually associated with lower non-relapse mortality (NRM), higher relapse rate and similar overall-survival (OS) as myeloablative-conditioning (MAC). Fludarabine/treosulfan (FT) is a reduced-toxicity regimen with intense anti-leukaemia activity and a favourable toxicity profile. We investigated post-transplant outcomes in 1722 MDS patients following allo-HCT with FT (n = 367), RIC (n = 687) or MAC (n = 668). FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51 years, respectively (P < 0·001) but other disease characteristics were similar. The median follow-up was 64 months (1-171). Five-year relapse rates were 25% (21-30), 38% (34-42) and 25% (22-29), after FT, RIC and MAC, respectively, (P < 0·001). NRM was 30% (25-35), 27% (23-30) and 34% (31-38, P = 0·008), respectively. Five-year OS was 50% (44-55), 43% (38-47), and 43% (39-47), respectively (P = 0·03). In multivariate analysis, FT was associated with a lower risk of relapse (HR 0·55, P < 0·001) and better OS (HR 0·72, P = 0·01). MAC was associated with higher NRM (HR 1·44, P = 0·001). In conclusion, FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved OS. FT may be the preferred regimen for allo-HCT in MDS.
PICO Summary
Population
Patients reported to the EBMT registry with a diagnosis of myelodysplastic syndrome, receiving allogeneic transplant (n=1722)
Intervention
Fludarabine/treosulfan based conditioning (FT, n=367)
Comparison
Other reduced intensity conditioning regimens (RIC, n=687) or myeloablative conditioning (MAC, n=668)
Outcome
FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51 years, respectively but other disease characteristics were similar. The median follow-up was 64 months (1-171). Five-year relapse rates were 25% (21-30), 38% (34-42) and 25% (22-29), after FT, RIC and MAC, respectively. NRM was 30% (25-35), 27% (23-30) and 34% (31-38), respectively. Five-year OS was 50% (44-55), 43% (38-47), and 43% (39-47), respectively. In multivariate analysis, FT was associated with a lower risk of relapse (HR 0·55) and better OS (HR 0·72). MAC was associated with higher NRM (HR 1·44).
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Sequential allogeneic hematopoietic stem cell transplantation for active refractory/relapsed myeloid malignancies: results of a reduced-intensity conditioning preceded by clofarabine and cytosine arabinoside, a retrospective study on behalf of the SFGM-TC
Le Bourgeois, A., Labopin, M., Marcais, A., de Latour, R. P., Blaise, D., Chantepie, S., N'Guyen, S., Maillard, N., Forcade, E., Yakoub-Agha, I., et al
Annals of hematology. 2020
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Editor's Choice
Abstract
Allogeneic stem cell transplantation (allo-SCT) represents the most beneficial treatment for patients with active relapsed/refractory (R/R) hematologic malignancies. Recently, sequential regimens combining debulking chemotherapy followed by reduced-intensity conditioning (RIC) have shown encouraging results for these patients. In this retrospective study, we report the extended results of a sequential regimen of clofarabine, cytosine arabinoside, and RIC in 131 adults with active R/R myeloid disease at transplant. Conditioning consisted of clofarabine (30 mg/m(2)/day) and cytosine arabinoside (1 g/m(2)/day) for 5 days, followed, after a rest of 3 days, by an RIC combining cyclophosphamide (60 mg/kg) for 1 day, iv busulfan (3.2 mg/kg/day) for 2 days, and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Between 2007 and 2016, 131 patients (males n = 75, median age: 52.6 years) were identified from the SFGM-TC registry. There were 111 acute myeloid leukemia (AML) patients and 20 cases with myelodysplastic or myeloproliferative syndrome. Status at transplant was known for all but 4 patients and was primary refractory (n = 81) and 1st or 2nd relapse (n = 46). All patients received allo-SCT from a matched donor (sibling n = 64, unrelated n = 67). Engraftment was observed in 105/122 (86%) evaluable cases and 63% of the patients achieved complete remission (CR) after transplant. The 1-year overall survival, disease-free survival, relapse incidence, non-relapse mortality, and graft-versus-host disease-free/relapse-free survival were 39.2%, 28.1%, 41.0%, 30.8%, and 22.2%, respectively. This study confirms that this sequential clofarabine-based regimen provides a high CR rate in this critical population, although relapse remains a matter of concern.
PICO Summary
Population
Adults with active relapsed/refractory (R/R) myeloid disease at transplant (n=131)
Intervention
Clofarabine, cytosine arabinoside regimen, followed by reduced intensity conditioning and matched donor allogeneic transplantation
Comparison
None
Outcome
Engraftment was observed in 105/122 (86%) evaluable cases and 63% of the patients achieved complete remission (CR) after transplant. The 1-year overall survival, disease-free survival, relapse incidence, non-relapse mortality, and graft-versus-host disease-free/relapse-free survival were 39.2%, 28.1%, 41.0%, 30.8%, and 22.2%, respectively.
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Reduced-intensity versus myeloablative conditioning in cord blood transplantation for AML (40-60 years) across highly mismatched HLA barriers - On behalf of Eurocord and the Cellular Therapy & Immunobiology Working Party (CTIWP) of EBMT
Sheth, V., Volt, F., Sanz, J., Clement, L., Cornelissen, J., Blaise, D., Sierra, J., Michallet, M., Saccardi, R., Rocha, V., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
The use of myeloablative conditioning (MAC) in umbilical cord blood transplantation (UCBT) has been associated with high non-relapse mortality (NRM) in patients >40 years, especially those having a high HLA disparity, thus limiting wider applications. We hypothesized that the NRM advantage of reduced intensity conditioning (RIC) and higher GVL associated with greater HLA disparities would expand its use for patients (40-60 years) without compromising efficacy, and compared outcomes between RIC versus MAC regimens. 288 patients aged 40 to 60 years, with de novo AML, receiving UCBT with at least 2 HLA mismatches with RIC (n=166) or MAC (n=122) regimens were included. As compared to RIC, the MAC cohort included relatively younger patients, having received more single UCBT, with lower total nucleated cell counts, and more in vivo T-cell depletion. Median time to neutrophil engraftment, infections (bacterial, viral and fungal), as well as grade II-IV acute and chronic graft-versus-host disease were similar in both groups. In the multivariate analysis, overall survival (HR-0.98, p=0.9), NRM (HR-0.68, p=0.2) and relapse (HR- 1.24, p=0.5) were not different between RIC and MAC. Refractory disease was associated with worse survival. Outcomes of UBCT for patients 40-60 years having =2 HLA mismatches are comparable after RIC or MAC regimen.
PICO Summary
Population
Patients with de novo AML aged 40 to 60 years (n=288)
Intervention
Cord blood transplantation with at least 2 mismatches, and reduced intensity conditioning (RIC, n=166)
Comparison
Cord blood transplantation with at least 2 mismatches, and myeloablative conditioning (MAC, n=122)
Outcome
As compared to RIC, the MAC cohort included relatively younger patients. Median time to neutrophil engraftment, infections (bacterial, viral and fungal), as well as grade II-IV acute and chronic graft-versus-host disease were similar in both groups. In the multivariate analysis, overall survival (HR-0.98), NRM (HR-0.68) and relapse (HR- 1.24) were not different between RIC and MAC. Refractory disease was associated with worse survival.
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Addition of Rituximab in Reduced Intensity Conditioning Regimens for B-Cell Malignancies Does Not Influence Transplant Outcomes: EBMT Registry Analyses Following Allogeneic Stem Cell Transplantation for B-Cell Malignancies
Tomaszewska, A., Jagasia, M., Beohou, E., van der Werf, S., Blaise, D., Kanfer, E., Milpied, N., Reményi, P., Ciceri, F., Bourhis, J. H., et al
Frontiers in immunology. 2020;11:613954
Abstract
Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell malignancies, not only to improve disease control, but also to prevent graft-versus-host disease (GVHD). There are no randomized prospective data to validate this practice, although single center data and the CIBMTR analysis have shown promising results. We aimed at validation of these findings in a large registry study. We conducted a retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell malignancies undergoing alloHCT (2001-2013) with either rituximab (R-RIC-9%) or non-rituximab (RIC-91%) reduced intensity regimens respectively. Median age and median follow up were 55 years (range 19.1-77.3) and 43.2 months (range 0.3-179.8), respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including 1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%), 1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4° (12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell malignancies had no significant impact on major transplant outcome variables. Of note, data on chronic GVHD was not available, limiting the conclusions that can be drawn from the present study.
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PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL
Dreger, P., Sureda, A., Ahn, K. W., Eapen, M., Litovich, C., Finel, H., Boumendil, A., Gopal, A., Herrera, A. F., Schmid, C., et al
Blood advances. 2019;3(3):360-369
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Abstract
This study retrospectively compared long-term outcomes of nonmyeloablative/reduced intensity conditioning (NMC/RIC) allogeneic hematopoietic cell transplantation (allo-HCT) from a haploidentical family donor (haplo-HCT) using posttransplant cyclophosphamide (PTCy) with those of matched sibling donor (MSD) and matched unrelated donor (MUD) with or without T-cell depletion (TCD+/TCD-) in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Adult patients with DLBCL who had undergone their first NMC/RIC allo-HCT between 2008 and 2015 were included. Recipients of haplo-HCT were limited to those receiving graft-versus-host disease (GVHD) prophylaxis with PTCy. GVHD prophylaxis in MSD was limited to calcineurin inhibitor (CNI)-based approaches without in vivo TCD, while MUD recipients received CNI-based prophylaxis with or without TCD. Outcome analyses for overall survival (OS) and progression-free survival (PFS), nonrelapse mortality (NRM), and disease relapse/progression were calculated. A total of 1438 patients (haplo, 132; MSD, 525; MUD TCD+, 403; and MUD TCD-, 378) were included. Patients with haplo donors were significantly older, had a better performance status and had more frequently received total body irradiation-based conditioning regimens and bone marrow grafts than MSD and MUD TCD+ or TCD-. 3-year OS, PFS, NRM and relapse/progression incidence after haplo-HCT was 46%, 38%, 22%, and 41%, respectively, and not significantly different from outcomes of matched donor transplants on multivariate analyses. Haplo-HCT was associated with a lower cumulative incidence of chronic GVHD compared with MSD, MUD TCD+/TCD-. NMC/RIC haplo-HCT with PTCy seems to be a valuable alternative for patients with DLBCL considered for allo-HCT but lacking a matched donor.
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Comparative Outcomes of Myeloablative and Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Therapy-Related Acute Myeloid Leukemia with Prior Solid Tumor: a report from the ALWP of the EBMT
Lee, C. J., Labopin, M., Beelen, D., Finke, J., Blaise, D., Ganser, A., Itala-Remes, M., Chevallier, P., Labussiere-Wallet, H., Maertens, J., et al
American journal of hematology. 2018
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Editor's Choice
Abstract
Therapy-related acute myeloid leukemia (t-AML) arises as a late complication following antecedent solid tumors or hematologic diseases and their associated treatments. There are limited data regarding risk factors and outcomes following allogeneic hematopoietic cell transplantation (HCT) for t-AML following a prior solid tumor, and furthermore, the impact of myeloablative (MAC) versus reduced-intensity conditioning (RIC) on survival is unknown. The Acute Leukemia Working Party (ALWP) of the European Society for Blood and Bone Marrow Transplantation (EBMT) performed a large registry study that included 535 patients with t-AML and prior solid tumor who underwent first MAC or RIC allogeneic HCT from 2000-2016. The primary endpoints of the study were OS and LFS. Patients receiving RIC regimens had an increase in relapse incidence (hazard ratio, 1.52; 95% CI 1.02 - 2.26; p = 0.04), lower LFS (hazard ratio, 1.52; 95% CI 1.12 - 2.05, p = 0.007) and OS (hazard ratio, 1.51; CI 1.09 - 2.09; p = 0.012). There were no differences in NRM and GRFS. Importantly, LFS and OS was superior in patients receiving ablative regimens due to a decrease in relapse. As NRM continues to decline in the current era, it is conceivable that outcomes of HCT for t-AML with prior solid tumor may be improved by careful patient selection for myeloablative regimens. This article is protected by copyright. All rights reserved.
PICO Summary
Population
100 patients with grade 2-4 aGvHD after haploidentical stem cell transplantation with post-transplant cyclophosphamide.
Intervention
Use of refined Minnesota risk score for aGvHD grading
Comparison
Keystone classification
Outcome
Grade 3-4 aGVHD according to the traditional Keystone classification was the main independent predictor of non-response to front-line treatment at day 28, while HR aGVHD by the new refined Minnesota score remained the main independent variable associated with adverse NRM and OS. It is not possible with this sample size to discriminate which system better predicts the outcome of patients with aGVHD in the setting of Haplo-SCT.
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Impact of antithymocyte globulin doses in reduced intensity conditioning before allogeneic transplantation from matched sibling donor for patients with acute myeloid leukemia: a report from the acute leukemia working party of European group of Bone Marrow Transplantation
Devillier, R., Labopin, M., Chevallier, P., Ledoux, M. P., Socié, G., Huynh, A., Bourhis, J. H., Cahn, J. Y., Roth-Guepin, G., Mufti, G., et al
Bone Marrow Transplantation. 2018;53(4):431-437
Abstract
Antithymocyte globulin (ATG) is commonly used for graft-vs.-host disease (GVHD) prophylaxis in unrelated donor allogeneic transplantation (Allo-HSCT). However, its use is still controversial in matched sibling donor (MSD) Allo-HSCT, notably after reduced intensity conditioning (RIC). ATG dose may influence the outcome, explaining in part the discordant conclusions in MSD Allo-HSCT. We, therefore, analyzed the impact of ATG doses in patients with acute myeloid leukemia in first complete remission undergoing RIC Allo-HSCT from a MSD. We analyzed 234 patients from the EBMT registry and compared outcome according to given ATG dose (high dose: ≥ 6 mg/kg, n = 39 or low dose: < 6 mg/kg, n = 195). No difference was found in the cumulative incidence of acute (grade 2-4: high dose vs. low dose: 21% vs. 13%, p = 0.334; adjusted hazard ratio (HR): 1.20, p = 0.712) and chronic GVHD (extensive: high dose vs. low dose: 19% vs. 18%, p = 0.897; adjusted HR: 1.01, p = 0.980). In contrast, high dose of ATG significantly increased the incidence of relapse (52% vs. 26%, p = 0.011; adjusted HR: 1.31, p = 0.001) leading to impaired outcome (HR progression-free survival (PFS): 1.23, p = 0.002; HR overall survival (OS): 1.17, p = 0.029; HR GVHD and relapse-free survival (GRFS): 1.20, p = 0.005). We conclude that an ATG dose <6 mg/kg is sufficient for GVHD prophylaxis, while higher doses impair disease control and outcome.
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Clofarabine/busulfan-based reduced intensity conditioning regimens provides very good survivals in acute myeloid leukemia patients in complete remission at transplant: a retrospective study on behalf of the SFGM-TC
Bourgeois, A. L., Labopin, M., Leclerc, M., de Latour, R. P., Bourhis, J. H., Ceballos, P., Orvain, C., Wallet, H. L., Bilger, K., Blaise, D., et al
Oncotarget. 2018;9(93):36603-36612
Abstract
Background: Clofarabine has been proved to have higher anti-leukemic myeloid activity compared to fludarabine, a drug extensively used as part of reduced intensity conditioning (RIC) for allogeneic stem cell transplantation (allo-SCT). Results: Eighty-four patients were included. The majority of patients had acute myeloid leukemia (AML, n = 63). Sixty-one patients were in complete remission (AML n = 55). With a median follow up of 31 months (range: 5.7-74.1), 2-year overall (OS) and disease-free (DFS) survivals, relapse incidence (RI), non-relapse mortality (NRM) and graft-versus-host disease (GVHD)/relapse free survival (GRFS) were 64.5% (53.8-75.2); 57.2% (46.2-68.2); 27.7% (18.2-37.9); 15.1% (8.2-23.9) and 43.6% (32.5-54.7), respectively. Considering AML in remission, 2-year OS, DFS, RI, NRM and GRFS were 74.2% (62-86.5); 66.8% (53.6-79.9); 23.4% (12.7-36); 9.8% (3.5-19.9) and 50.9% (36.9-64.9), respectively. Two-year outcomes were similar between CloB2A1 and CloB2A2 sub-groups. In multivariate analysis, active disease at transplant was the only factor adversely impacting 2 years outcomes. Conclusions: CloB2A2/A1 RIC regimen provides very good results for AML patients allografted in CR and could be retained as a new RIC platform for these patients. Materials and Methods: This was a retrospective study including all patients who received a clofarabine/busulfan based RIC allo-SCT for myeloid malignancies and reported within the SFGM-TC registry. RIC regimen consisted of clofarabine 30 mg/m(2)/day 4 to 5 days (Clo), busulfan 3.2 mg/kg/day 2 days (B2) and 2.5 mg/kg/day of rabbit anti-thymocyte globulin 1 or 2 days (A1 or A2). The primary objective of the study was to report the main outcomes of the whole cohort at 2 years.