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Sequential vs myeloablative vs reduced intensity conditioning for patients with myelodysplastic syndromes with an excess of blasts at time of allogeneic haematopoietic cell transplantation: a retrospective study by the chronic malignancies working party of the EBMT
Potter, V., Gras, L., Koster, L., Kroger, N., Sockel, K., Ganser, A., Finke, J., Labussiere-Wallet, H., Peffault de Latour, R., Koc, Y., et al
Bone marrow transplantation. 2023
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Editor's Choice
Abstract
The optimal conditioning for patients with higher risk MDS receiving potentially curative allogeneic haematopoietic stem cell transplant(allo-HCT) remains to be defined. This is particularly the case for patients with excess of blasts at time of allo-HCT. Sequential (Seq) conditioning, whereby chemotherapy is followed rapidly by transplant conditioning, offers an opportunity to decrease disease burden, potentially improving outcomes allo-HCT outcomes. Herein we present the only analysis comparing Seq to myeloablative (MAC) and reduced intensity conditioning (RIC) specifically focussed on MDS patients with excess of blasts at allo-HCT. 303 patients were identified in the EBMT registry, receiving RIC (n = 158), Seq (n = 105), and MAC (n = 40). Median follow-up was 67.2 months and median age at allo-HCT was 59.5 years (IQR 53.5-65.6). For the entire cohort, 3 y overall survival (OS) was 50% (95% CI 45-56%) and relapse free survival (RFS) 45% (95% CI 40-51%). No significant differences in OS (log-rank p = 0.13) and RFS (log-rank p = 0.18) were observed between conditioning protocols. On multivariable analysis, lower performance status, worse IPSS-R cytogenetics, sibling donor (compared to 8/8 MUD) and ≥20% blasts at allo-HCT were associated with worse outcomes. In conclusion, the Seq protocol did little to influence the outcome in this high-risk group of patients, with outcomes mostly determined by baseline disease risk and patient characteristics such as performance status.
PICO Summary
Population
Patients with myelodysplastic syndrome (MDS) with excess of blasts at allo-HCT, identified from the EBMT registry (n=303)
Intervention
Sequential conditioning, where chemotherapy is followed rapidly by transplant (Seq, n=105)
Comparison
Reduced intensity conditioning (RIC, n=158), or myeloablative conditioning (MAC, n=40).
Outcome
Median follow-up was 67.2 months and median age at allo-HCT was 59.5 years (IQR 53.5-65.6). For the entire cohort, 3 y overall survival (OS) was 50% (95% CI 45-56%) and relapse free survival (RFS) 45% (95% CI 40-51%). No significant differences in OS and RFS were observed between conditioning protocols. On multivariable analysis, lower performance status, worse IPSS-R cytogenetics, sibling donor (compared to 8/8 MUD) and ≥20% blasts at allo-HCT were associated with worse outcomes.
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Life expectancy and burden of late complications after reduced intensity conditioning allogeneic transplantation
Del Galy, A. S., Rousseau, A., Capes, A., Michonneau, D., Robin, M., de Fontbrune, F. S., Xhaard, A., Frieri, C., Adès, L., Raffoux, E., et al
Bone marrow transplantation. 2022;57(9):1365-1372
Abstract
Reduced intensity conditionings (RIC) before after allogeneic hematopoietic stem cell transplantation (HSCT) allow older or unfit patients of being transplanted, but survival expectancy and burden of late complications are poorly described in this setting. All patients (N = 456) who were alive and relapse-free 2 years after HSCT following RIC were included. Cumulative incidences (CI), standardized incidence, or mortality, ratio (SIR or SMR), and competing risk models were used. The 10-year CIs of relapse and non-relapse mortality incidences were 13.9 and 13.4%, respectively. Seventy-eight patients died, late relapse being the most frequent cause of death leading to a SMR of 6.38 (95% CI, 5.1-8.0; p < 0.001). Among non-relapsing patients (n = 412), 30 died (SMR 4.38; 95% CI, 3.3-5.8: p < 0.001). A total of 37 patients developed 41 SM leading to a 10-year cumulative incidence of 12.9%, and a significant SIR relative to the general population (1.4). Finally, we found high CI of cardiovascular (CVC) and venous thromboembolic complications (VTE) (10-year CI; 15.1% and 11.7%, respectively). Older age was the only significant risk factor for CVC and VTE in multivariable analysis. In conclusion, with life expectancy rate of 70%, late survivors after RIC warrants long-term follow-up and active intervention on averting cardiovascular disease and screening cancers.
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Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial
Beelen, D. W., Trenschel, R., Stelljes, M., Groth, C., Masszi, T., Remenyi, P., Wagner-Drouet, E. M., Hauptrock, B., Dreger, P., Luft, T., et al
The Lancet. Haematology. 2019
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Editor's Choice
Abstract
BACKGROUND Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. METHODS We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18-70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m(2) treosulfan daily applied as a 2-h infusion for 3 days (days -4 to -2) or 0.8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days -4 and -3. Both groups received 30 mg/m(2) intravenous fludarabine daily for 5 days (days -6 to -2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1.3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008-002356-18) and ClinicalTrials.gov (NCT00822393). FINDINGS Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15.4 months (IQR 8.8-23.6) for patients treated with treosulfan and 17.4 months (6.3-23.4) for those treated with busulfan. 2-year event-free survival was 64.0% (95% CI 56.0-70.9) in the treosulfan group and 50.4% (42.8-57.5) in the busulfan group (HR 0.65 [95% CI 0.47-0.90]; p<0.0001 for non-inferiority, p=0.0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. INTERPRETATION Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the treosulfan-fludarabine regimen suggest its potential to become a standard preparative regimen in this population. FUNDING medac GmbH.
PICO Summary
Population
Patients with acute myeloid leukaemia in first or consecutive complete haematological remission or myelodysplastic syndrome considered at an increased risk for standard myeloablative preparative regimens based on age (>/=50 years), an HSCT-specific comorbidity index of more than 2, or both. (n=460)
Intervention
Intravenous 10 g/m(2) treosulfan daily for 3 days followed by intravenous fludarabine daily for 5 days (n=221)
Comparison
0.8 mg/kg busulfan at 6-h intervals on days -4 and -3, followed by 30 mg/m(2) intravenous fludarabine daily for 5 days (n=240)
Outcome
Median follow-up was 15.4 months for patients treated with treosulfan and 17.4 months for those treated with busulfan. 2-year event-free survival was 64.0% in the treosulfan group and 50.4% in the busulfan group. The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (15% patients in the treosulfan group vs 15% in the busulfan group) and gastrointestinal disorders (11% patients vs 16% patients). Serious adverse events were reported for 8% of patients in the treosulfan group and 7% of patients in the busulfan group. Causes of deaths were generally transplantation-related.
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Late effects after hematopoietic stem cell transplantation for beta-thalassemia major: the French national experience
Rahal, I., Galambrun, C., Bertrand, Y., Garnier, N., Paillard, C., Frange, P., Pondarre, C., Dalle, J. H., Peffault de Latour, R., Michallet, M., et al
Haematologica. 2018
Abstract
In this retrospective study, we evaluate long-term complications in nearly all beta-thalassemia-major patients who successfully received, in France, allogeneic hematopoietic stem cell transplantation. 99 patients were analysed with a median age of 5.9 years at transplantation. The median duration of clinical follow-up was 12 years. All conditioning regimen were myeloablative, most often based on busulfan combined with cyclophosphamide and more than 90% of patients underwent a transplant from a matched sibling donor. After transplantation, 11% of patients developed thyroid dysfunction, 5% diabetes and 2% heart failure. Hypogonadism was present in 56% of females and 14% of males. Female patients who developed normal puberty after transplant were significantly younger at transplantation than those who experienced delayed puberty (median age 2.5 versus 8.7 years). Fertility was preserved in 9/27 females aged 20 and above and 2 other patients became pregnant following oocyte donation. In addition to patient's age and higher serum ferritin levels at transplantation, time elapsed since transplant was significantly associated with decreased height growth in multivariate analysis. Weight growth increased after transplantation particularly in females, 36% of adults being overweight at last evaluation. A comprehensive long-term monitoring especially of endocrine late-effects is required after hematopoietic stem cell transplantation for thalassemia.
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Reduced-intensity and non-myeloablative allogeneic stem cell transplantation from alternative HLA-mismatched donors for Hodgkin lymphoma: a study by the French Society of Bone Marrow Transplantation and Cellular Therapy
Gauthier, J., Castagna, L., Garnier, F., Guillaume, T., Socie, G., Maury, S., Maillard, N., Tabrizi, R., Marchand, T., Malfuson, J., et al
Bone Marrow Transplantation. 2017;52(5):689-696
Abstract
Allogeneic stem cell transplantation (allo-SCT) following a non-myeloablative (NMA) or reduced-intensity conditioning (RIC) is considered a valid approach to treat patients with refractory/relapsed Hodgkin lymphoma (HL). When an HLA-matched donor is lacking a graft from a familial haploidentical (HAPLO) donor, a mismatched unrelated donor (MMUD) or cord blood (CB) might be considered. In this retrospective study, we compared the outcome of patients with HL undergoing a RIC or NMA allo-SCT from HAPLO, MMUD or CB. Ninety-eight patients were included. Median follow-up was 31 months for the whole cohort. All patients in the HAPLO group (N=34) received a T-cell replete allo-SCT after a NMA (FLU-CY-TBI, N=31, 91%) or a RIC (N=3, 9%) followed by post-transplant cyclophosphamide. After adjustment for significant covariates, MMUD and CB were associated with significantly lower GvHD-free relapse-free survival (GRFS; hazard ratio (HR)=2.02, P=0.03 and HR=2.43, P=0.009, respectively) compared with HAPLO donors. In conclusion, higher GRFS was observed in Hodgkin lymphoma patients receiving a RIC or NMA allo-SCT with post-transplant cyclophosphamide from HAPLO donors. Our findings suggest they should be favoured over MMUD and CB in this setting.
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Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Societe Francophone de Greffe de Moelle et de Therapie Cellulaire
Decroocq, J., Itzykson, R., Vigouroux, S., Michallet, M., Yakoub-Agha, I., Huynh, A., Beckerich, F., Suarez, F., Chevallier, P., Nguyen-Quoc, S., et al
American Journal of Hematology. 2017
Abstract
Patients with acute myeloid leukemia (AML) in relapse or refractory to induction therapy have a dismal prognosis. Allogeneic hematopoietic stem cell transplantation is the only curative option. In these patients, we aimed to compare the results of a myeloablative transplant versus a sequential approach consisting in a cytoreductive chemotherapy followed by a reduced intensity conditioning regimen and prophylactic donor lymphocytes infusions. We retrospectively analyzed 99 patients aged 18-50 years, transplanted for a refractory (52%) or a relapsed AML not in remission (48%). Fifty-eight patients received a sequential approach and 41 patients a myeloablative conditioning regimen. Only 6 patients received prophylactic donor lymphocytes infusions. With a median follow-up of 48 months, 2-year overall survival was 39%, 95% confidence interval (CI) (24-53) in the myeloablative group versus 33%, 95% CI (21-45) in the sequential groups (p=0.39), and 2-year cumulative incidence of relapse was 57% versus 50% respectively (p=0.99). Non-relapse mortality was not higher in the myeloablative group (17% versus 15%, p=0.44). In multivariate analysis, overall survival, cumulative incidence of relapse and non-relapse mortality remained similar between the two groups. However, in multivariate analysis, sequential conditioning led to fewer acute grade II-IV graft versus host disease (GVHD) (HR for sequential approach = 0.37; 95% CI: 0.21-0.65; p<0.001) without a significant impact on chronic GVHD (all grades and extensive). In young patients with refractory or relapsed AML, myeloablative transplant and sequential approach offer similar outcomes except for a lower incidence of acute GvHD after a sequential transplant. This article is protected by copyright. All rights reserved.
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Reduced-intensity versus reduced-toxicity myeloablative fludarabine/busulfan-based conditioning regimens for allografted non-Hodgkin lymphoma adult patients: a retrospective study on behalf of the Societe Francophone de Greffe de Moelle et de Therapie Cellulaire
Le Bourgeois, A., Labopin, M., Blaise, D., Ceballos, P., Vigouroux, S., Peffault de Latour, R., Marcais, A., Bulabois, C. E., Bay, J. O., Chantepie, S., et al
Annals of Oncology. 2017;28(9):2191-2198
Abstract
Background: Fludarabine/busulfan-based conditioning regimens are widely used to perform allogeneic stem-cell transplantation (allo-SCT) in high-risk non-Hodgkin lymphoma (NHL) patients. The impact of the dose intensity of busulfan on outcomes has not been reported yet. Patients and methods: This was a retrospective with the aim to compare the outcomes of NHL patients who received before allo-SCT a fludarabine/busulfan conditioning regimen, either of reduced intensity (FB2, 2 days of busulfan at 4mg/kg/day oral or 3.2mg/kg/day i.v.) (n=277) or at a myeloablative reduced-toxicity dose (FB3/FB4, 3 or 4 days of busulfan at 4mg/kg/day oral or 3.2mg/kg/day i.v.) (n=101). Results: In univariate analysis, the 2-year overall survival (FB266.5% versus 60.3%, P=0.33), lymphoma-free survival (FB257.9% versus 49.8%, P=0.26), and non-relapse mortality (FB219% versus 21.1%, P=0.91) were similar between both groups. Cumulative incidence of grade III-IV acute graft versus host disease (GVHD) (FB211.2% versus 18%, P=0.08), extensive chronic GVHD (FB2: 17.3% versus 10.7%, P=0.18) and 2-year GVHD free-relapse free survival (FB2: 44.4% versus 42.8%, P=0.38) were also comparable. In multivariate analysis there was a trend for a worse outcome using FB3/FB4 regimens (overall survival: HR 1.47, 95% CI: 0.96-2.24, P=0.08; lymphoma-free survival: HR: 1.43, 95% CI: 0.99-2.06, P=0.05; relapse incidence: HR 1.54; 95% CI: 0.96-2.48, P=0.07). These results were confirmed using a propensity score-matching strategy. Conclusion: We conclude that reduced toxicity myeloablative conditioning with fludarabine/busulfan does not improve the outcomes compared with reduced-intensity conditioning in adults receiving allo-SCT for NHL.
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Allogeneic hematopoietic stem cell transplantation after reduced intensity conditioning regimen for elderly patients (60 years and older) with hematologic malignancies using unrelated donors: a retrospective study from the French society for stem cell transplantation (SFGM-TC)
El Cheikh, J., Sfumato, P., Sobh, M., Fegueux, N., Mohty, M., Vigouroux, S., Beguin, Y., Yakoub-Agha, I., Socie, G., Cornillon, J., et al
Haematologica. 2016;101(6):e262-5
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9.
Outcome after Transplantation According to Reduced-Intensity Conditioning Regimen in Patients Undergoing Transplantation for Myelofibrosis
Robin, M., Porcher, R., Wolschke, C., Sicre de Fontbrune, F., Alchalby, H., Christopeit, M., Cassinat, B., Zabelina, T., Peffault de Latour, R., Ayuk, F., et al
Biology of Blood & Marrow Transplantation. 2016;22(7):1206-11
Abstract
Allogeneic hematopoietic stem cell transplantation remains the sole curative option for myelofibrosis. Many transplantation recipients receive a reduced-intensity conditioning (RIC) regimen owing to age or comorbidities; however, there is little published evidence to guide the choice of RIC regimen. In this study, we compared outcomes in patients who received 1 of 2 frequently used RIC regimens for patients with myelofibrosis: fludarabine-busulfan (FB) and fludarabine-melphalan (FM). A total of 160 patients underwent a RIC allograft procedure (FB group, n = 105; FM group, n = 55). We have developed a complex statistical model involving weighting and adjustment to permit comparison between these 2 groups. After weighting, the incidence of acute graft-versus-host disease (GVHD) was 62% in the FM group and 31% in the FB group (P = .001), and the corresponding incidence of chronic GVHD was 49% and 53%, respectively. The 7-year progression-free survival was were 52% in the FM group versus 33% in the FB group, and the 7-year overall survival rate 52% in the FM group versus 59% in the FB group. Nonrelapse mortality (NRM) was 43% in the FM group and 31% in the FB group. Multivariable analyses revealed no significant differences in PFS between the 2 groups; however, the relapse rate was significantly lower in the FM group (hazard ratio, 9.21; P = .008), whereas a trend toward reduced NRM was seen in the FB group (hazard ratio, 0.51; P = .068). In conclusion, both regimens appear to be efficient in mediating disease control and can be used to successfully condition patients with myelofibrosis. The FM regimen appears to induce more NRM than the FB regimen, but with augmented control of disease, leading to comparable overall survival rates for both regimens. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.