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Etoposide plus cytarabine versus cyclophosphamide or melphalan in busulfan-based preparative regimens for autologous stem cell transplantation in adults with acute myeloid leukemia in first complete remission: a study from the Acute Leukemia Working Party of the EBMT
Sanz, J., Labopin, M., Pabst, T., Versluis, J., Van Gorkom, G., Meijer, E., Gedde-Dahl, T., Montoro, J., Arcese, W., Pérez-Simón, J. A., et al
Bone marrow transplantation. 2023
Abstract
We retrospectively compared the impact of the conditioning regimen in adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) that received high-dose myeloablative chemotherapy followed by autologous stem cell transplantation (ASCT) from 2010 to 2021 with either high-dose cytarabine, etoposide and busulfan (BEA), busulfan with cyclophosphamide (BUCY) or busulfan and high-dose melphalan (BUMEL) registered in the EBMT database. Overall 1560 patients underwent ASCT, of which 156, 1143 and 261 received BEA, BUCY and BUMEL, respectively. Compared to BUCY and BUMEL, BEA patients were younger (p < 0.001) and less frequently had NPM1 mutations (p = 0.03). Transplant outcomes at 5 years with BEA, BUCY and BUMEL were: cumulative incidence of relapse 41.8%, 46.6% and 51.6%; non-relapse mortality (NRM) 1.5%, 5.2% and 7.3%; probability of leukemia-free survival (LFS) 56.7%, 48.2% and 41.1%; and overall survival (OS) 71.3%, 62.3% and 56%, respectively. In multivariable analysis the BEA regimen showed significant improvement in OS compared to BUCY (hazard ratio [HR] 0.65; 95% CI, 0.42-0.83; p = 0.048) and BUMEL (HR 0.59; 95% CI, 0.37-0.94; p = 0.029). In conclusion, high-dose myeloablative combination chemotherapy with BEA offered improved outcomes compared to classical BUCY or BUMEL in patients with AML in CR1 undergoing ASCT.
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Autologous stem cell transplantation in adult patients with intermediate-risk acute myeloid leukemia in first complete remission and no detectable minimal residual disease. A comparative retrospective study with haploidentical transplants of the global committee and the ALWP of the EBMT
Chen, J., Labopin, M., Pabst, T., Zhang, X., Jiang, E., Tucci, A., Cornelissen, J., Meijer, E., Khevelidze, I., Polge, E., et al
Bone marrow transplantation. 2023
Abstract
In patients with acute myeloid leukemia (AML) of intermediate-risk (IR) in first remission (CR1) with no measurable residual disease (MRD negative), the choice of the best consolidation is questionable. 1122 adult patients from 196 centers, transplanted in 2010-21 were analyzed: 547 received an autologous stem cell transplantation (ASCT) and 575 a Haploidentical donor transplant. Because of a significant interaction, comparisons were done separately for patients with wild-type FLT3 (FLT3-wt) and FLT3-ITD mutation (FLT3-ITD). In FLT3-wt patients, haploidentical transplants had two year lower relapse incidence (RI) (16.9% versus 32.6%; HR = 0.40, p < 0.001), higher NRM higher (17.2% vs 3.5%; HR = 7.02, p < 0.001), similar LFS (65.9% vs 63.8%; p = 0.37) and lower OS (73.2% vs 80.6%; HR = 1.69, p = 0.018). In FLT3-ITD patients, haploidentical transplants had two year lower RI (8.2% vs 47.8%; HR = 0.14, p < 0.001) higher NRM (20.2% vs 5.6%; HR = 3.43, p = 0.002), better LFS (71.5% vs 46.6%; HR = 0.53, p = 0.007) and similar OS (73.5% vs 61.9%; p = 0.44). In IR AML patients with FLT3-wt in MRD negative CR1, autologous stem cell transplantation is a valid option, while in patients with FLT3-ITD, haploidentical transplant is better. Whether autologous transplantation is superior to chemotherapy in FLT3-wt patients and the role of maintenance therapy with FLT3 inhibitors remain to be studied.
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Autologous stem cell transplantation (ASCT) for acute myeloid leukemia in patients in first complete remission after one versus two induction courses: A study from the ALWP of the EBMT
Nagler, A., Galimard, J. E., Labopin, M., Blaise, D., Arcese, W., Trisolini, S. M., Wu, D., Pigneux, A., Van Gorkom, G., Rubio, M. T., et al
Cancer medicine. 2022
Abstract
BACKGROUND Achieving complete remission (CR) is the main goal in AML treatment and a prerequisite for successful autologous stem cell transplantation (ACT). METHODS Comparing results of peripheral blood ACT in patients with AML in CR1 attained following 1 versus 2 chemotherapy courses transplanted in 2000-2019. RESULTS Patients 1532 (84%) with one and 293 (16%) patients with two induction chemotherapies courses (a total of 1825 patients) were included in the study. Follow-up was 7.9 (95% CI: 7.4-8.4) and 7.7 (95% CI: 7.0-8.6) years (p = 0.8). Time from diagnosis to ACT was 4.7 (range, 3.9-5.8) versus 5.7 (range, 4.7-7.1) months (p < 0.001), respectively. Leukemia free survival (LFS) and overall survival (OS) at 5 years were inferior for patients achieving CR1 with 2 versus 1 course of chemotherapy: 26.6% versus 41.7% (HR = 1.42 [95% CI: 1.22-1.66], p < 0.001) and 36.2% versus 53.3%, (HR = 1.48 [95% CI: 1.25-1.75], p < 0.001), and 5-year relapse incidence (RI) was higher: 67.2% versus 52.3%, (HR = 1.46 [95% CI: 1.25-1.72], p < 0.001). Five-year non-relapse mortality (NRM) was 6.2% versus 6.0% for patients with 2 versus 1 chemotherapy courses, and did not differ significantly (HR = 1.31 [95% CI: 0.81-2.10], p = 0.27). CONCLUSIONS LFS and OS were inferior and relapse rate was higher in AML patients who received two inductions chemotherapy courses to reach CR1 before being autografted. AML patients who required 2 induction courses to achieve remission, may be offered allogeneic transplantation rather than an autologous one in an attempt to reduce their high RI and improve outcomes.
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Haematopoietic stem cell transplantation in adult soft-tissue sarcoma: an analysis from the European Society for Blood and Marrow Transplantation
Heilig, C. E., Badoglio, M., Labopin, M., Fröhling, S., Secondino, S., Heinz, J., Nicolas-Virelizier, E., Blaise, D., Korenbaum, C., Santoro, A., et al
ESMO open. 2020;5(5)
Abstract
BACKGROUND The role of high-dose chemotherapy with autologous stem cell transplantation (ASCT) in the treatment of soft-tissue sarcoma (STS) remains an unsettled issue. Prospective clinical trials failed to prove a benefit of the procedure but were limited by small and heterogeneous patient cohorts. Thus, it is unknown if ASCT may be a valuable treatment option in specific patient subgroups. METHODS The purpose of this study was to investigate the value of ASCT according to histological subtype in STS patients who were registered in the European Society for Blood and Marrow Transplantation database between 1996 and 2016. RESULTS Median progression-free (PFS) and overall survival (OS) in the entire cohort of 338 patients were 8.3 and 19.8 months, respectively, and PFS and OS at 5 years were 13% and 25%, respectively. Analysis of outcomes in different subgroups showed that younger age, better remission status before transplantation and melphalan-based preparative regimen were predictive of benefit from ASCT, whereas histology and grading had no statistically significant impact. CONCLUSIONS Outcomes after ASCT compared favorably to those of recent trials on conventional chemotherapies and targeted therapies in STS, including histology-tailored approaches. ASCT, thus, should be reinvestigated in clinical trials focusing on defined patient subgroups.
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Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party
Henes, J., Oliveira, M. C., Labopin, M., Badoglio, M., Scherer, H. U., Del Papa, N., Daikeler, T., Schmalzing, M., Schroers, R., Martin, T., et al
Haematologica. 2020
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Editor's Choice
Abstract
Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124.
PICO Summary
Population
Adult patients with severe systemic sclerosis (n=80)
Intervention
Autologous haematopoietic stem cell transplantation with cyclophosphamide plus antithymocyte globulins conditioning
Comparison
None
Outcome
At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time. By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival. CD34+-selection was associated with better response.
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Risk stratification using FLT3 and NPM1 in acute myeloid leukemia patients autografted in first complete remission
Shouval, R., Labopin, M., Bomze, D., Baerlocher, G. M., Capria, S., Blaise, D., Hanel, M., Forcade, E., Huynh, A., Saccardi, R., et al
Bone marrow transplantation. 2020
Abstract
FLT3-ITD and NPM1 mutation refine prognostic stratification in acute myeloid leukemia (AML) with intermediate-risk cytogenetics. However, data on their role in patients undergoing autologous stem cell transplantation (Auto-SCT) as post-remission therapy (PRT) are limited. We therefore sought to retrospectively evaluate the role of FLT3-ITD and NPM1 in a cohort of AML patients (n = 405) with intermediate-risk cytogenetics, autografted in first complete remission (CR1). Patients were transplanted between 2000 and 2014 and reported to the European Society for Blood and Marrow Transplantation (EBMT) registry. Leukemia-free survival (LFS) was the primary outcome. Median follow-up was 5.5 years. FLT3-ITD(neg)/NPM1(WT) was the leading molecular subtype (50%), followed by FLT3-ITD(neg)/NPM1(mut) (30%). In the univariate analysis, molecular subtype was associated with LFS, overall survival (OS), and relapse incidence (RI) (p < 0.001); 5-year LFS: FLT3-ITD(neg)/NPM1(mut) 62%, FLT3-ITD(pos)/NPM1(mut) 38%, FLT3-ITD(neg)/NPM1(WT) 32%, and FLT3-ITD(pos)/NPM1(WT) 21%. At 5 years, OS and RI in the FLT3-ITD(neg)/NPM1(mut) subtype were 74% and 35%, respectively. The corresponding OS and RI in other subtypes were below 48% and over 57%. In a Cox multivariable model, molecular subtype was the strongest predictor of LFS, OS, and relapse. In conclusion, AML patients with intermediate-risk cytogenetics and FLT3-ITD(neg)/NPM1(mut) experience favorable outcomes when autografted in CR1, suggesting that Auto-SCT is a valid PRT option.
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Autologous haematopoietic stem cell transplantation (AHSCT) in autoimmune disease adult patients in France: analysis of the long-term outcome from the French Society for Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)
Guillaume-Jugnot, P., Badoglio, M., Labopin, M., Terriou, L., Yakoub-Agha, I., Martin, T., Lioure, B., Marjanovic, Z., Blaise, D., Nguyen, S., et al
Clinical rheumatology. 2019
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Editor's Choice
Abstract
INTRODUCTION The use of autologous haematopoietic stem cell transplantation (AHSCT) in autoimmune disease (AD) patients has increased progressively worldwide. We retrospectively analysed the long-term outcome of AHSCT for AD reported to the French Society for Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). METHOD All French AD patients (≥ 18 years at transplant) with a first AHSCT between 1997 and 2013 were included. Primary data were derived from the European Society for Blood and Marrow Transplantation (EBMT) registry, and additional data were obtained through a specific questionnaire designed for the study. Primary end-point was overall survival (OS). Secondary end points were progression-free survival (PFS) and non-relapse mortality (NRM). RESULTS Ninety-four AD patients were included, of whom 71% suffered from rheumatologic diseases (n = 67, including 56 systemic sclerosis (SSc)), 16% from neurological disease (n = 15, including 14 multiple sclerosis (MS)) and 13% from various other AD (n = 12). After a median (interquartile range, IQR) follow-up of 83 months (38-130), OS at 5 and 10 years were 77% (95% CI 68.5-86.2) and 64% (95% CI 51.7-76.3), and for PFS 51% (95% CI 40.4-61.6) and 44% (95% CI 32.8-55.3), respectively. Overall, NRM was 8.7% (95% CI 4.0-15.5) at day 100, 9.8% (95% CI 4.8-16.9) at 5 years and 13.6% (95% CI 6.9-22.5) at 10 years. CONCLUSIONS This first SFGM-TC retrospective report shows long-term benefit of AHSCT in AD patients with acceptable toxicity.
PICO Summary
Population
Ninety-four adults suffering from autoimmune disease in France. Rheumatologic diseases (n=67), neurological disease (n = 15) or other AD (n = 12)
Intervention
Autologous haematopoietic stem cell transplantation
Comparison
None
Outcome
Overall Survival was 77% at 5 and 64% at 10 year. Non-Relapse Mortality was 8.7% at day 100, 9.8% at 5 years and 13.6% at 10 years.
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Individualized prediction of leukemia-free survival after autologous stem cell transplantation in acute myeloid leukemia
Shouval, R., Labopin, M., Gorin, N. C., Bomze, D., Houhou, M., Blaise, D., Zuckerman, T., Baerlocher, G. M., Capria, S., Forcade, E., et al
Cancer. 2019
Abstract
BACKGROUND Autologous stem cell transplantation (ASCT) is a potential consolidation therapy for acute myeloid leukemia (AML). This study was designed to develop a prediction model for leukemia-free survival (LFS) in a cohort of patients with de novo AML treated with ASCT during their first complete remission. METHODS This was a registry study of 956 patients reported to the European Society for Blood and Marrow Transplantation. The primary outcome was LFS. Multivariate Cox regression modeling with backward selection was used to select variables for the construction of the nomogram. The nomogram's performance was evaluated with discrimination (the area under the receiver operating characteristic curve [AUC]) and calibration. RESULTS Age and cytogenetic risk (with or without FMS-like tyrosine kinase 3 internal tandem duplication) were predictive of LFS and were used for the construction of the nomogram. Each factor in the nomogram was ascribed points according to its predictive weight. Through the calculation of the total score, the probability of LFS at 1, 3, and 5 years for each patient could be estimated. The discrimination of the nomogram, measured as the AUC, was 0.632 (95% confidence interval [CI], 0.595-0.669), 0.670 (95% CI, 0.635-0.705), and 0.687 (95% CI, 0.650-0.724), respectively. Further validation with bootstrapping showed similar AUCs (0.629 [95% CI, 0.597-0.657], 0.667 [95% CI, 0.633-0.699], and 0.679 [95% CI, 0.647-0.712], respectively), and this suggested that the model was not overfitted. Calibration was excellent. Patients were stratified into 4 incremental 5-year prognostic groups, with the probabilities of LFS and overall survival ranging from 25% to 64% and from 33% to 79%, respectively. CONCLUSIONS The Auto-AML nomogram score is a tool integrating individual prognostic factors to provide a probabilistic estimation of LFS after ASCT for patients with AML.
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Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE)
Sharrack, B., Saccardi, R., Alexander, T., Badoglio, M., Burman, J., Farge, D., Greco, R., Jessop, H., Kazmi, M., Kirgizov, K., et al
Bone marrow transplantation. 2019
Abstract
These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials.
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Post remission consolidation by autologous HCT for AML in CR1, negative implications for subsequent allogeneic HCT in CR2. A Study by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
Passweg, J. R., Labopin, M., Christopeit, M., Cornelissen, J., Pabst, T., Socie, G., Russel, N., Yakoub-Agha, I., Blaise, D., Gedde-Dahl, T., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
After autologous hematopoetic cell transplantation, (HCT in 1st complete remission (CR1), patients with acute myeloid leukemia (AML) may relapse and undergo allogeneic HCT in CR2. The aim of this study was to analyze outcome of allogeneic HCT performed in CR2 comparing patients with prior consolidation by autologous HCT vs. patients with chemotherapy consolidation. Included were 2619 adults, with allogeneic HCT in CR2, in 2000-2017 with (n=417) or without (n=2202) prior autologous HCT. Patient groups were not entirely comparable; patients with prior autologous HCT were younger, had less often a favorable cytogenetic profile, had more commonly donors other than matched siblings and more often received reduced intensity conditioning (RIC) conditioning. In multivariate analysis non relapse mortality (NRM) risks in patients with prior autologous HCT were 1.34 (1.07-1.67), p=0.01 after adjustment for age, cytogenetic risk, transplant year, donor, conditioning intensity, sex matching, interval diagnosis-relapse and relapse-allogeneic HCT as compared to chemotherapy consolidation. Similarly, risks of events in leukemia free survival and graft versus host disease, relapse free survival were higher with prior autologous HCT, 1.17 (1.01-1.35), p=0.03 and 1.18 (1.03-1.35) p= 0.02, respectively. Risk of death was also higher 1.13 (0.97-1.32) p=0.1 but this was not significant. Post remission consolidation with autologous HCT for AML in CR1 increases toxicity of subsequent allogeneic HCT in CR2.