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1.
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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2.
Prognostic impact of early-versus-late responses to different induction regimens in patients with myeloma undergoing autologous hematopoietic cell transplantation: results from the CALM study by the CMWP of the EBMT
Garderet, L., Sbianchi, G., Iacobelli, S., Blaise, D., Byrne, J. L., Remenyi, P., Apperley, J. F., Touzeau, C., Isaksson, C., Browne, P., et al
European journal of haematology. 2021
Abstract
BACKGROUND In autologous stem cell transplant (ASCT)-eligible myeloma patients, prolonged induction does not necessarily improve the depth of response. METHOD We analysed 1,222 ASCT patients who were classified based on (1) the interval between induction and stem cell collection, (2) the type of induction regimen: BID (Bortezomib, IMiDs and Dexamethasone), Bortezomib-based, or CTD (Cyclophosphamide, Thalidomide and Dexamethasone), and (3) the time to best response (Early i.e. best response within 4 or 5 months, depending on the regimen vs Late; Good i.e. VGPR or better vs Poor) RESULTS The length of induction treatment required to achieve a Good response did not affect PFS (p=0.65) or OS (p=0.61) post-ASCT. The three types of regimen resulted in similar outcomes: median PFS 31, 27.7 and 30.8 months (p=0.31), and median OS 81.7, 92.7, and 77.4 months, respectively (p=0.83). On multivariate analysis, neither the type nor the duration of the induction regimen affected OS and PFS, except for Early Good Responders who had a better PFS compared to Early Poor Responders (HR = 1.21, p value = 0.02). However, achieving a Good response at induction was associated with a better response (= VGPR) post-transplant CONCLUSION The kinetics of response did not affect outcomes.
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3.
Long-acting granulocyte colony-stimulating factor pegfilgrastim (lipegfilgrastim) for stem cell mobilization in multiple myeloma patients undergoing autologous stem cell transplantation
Danylesko, I., Sareli, R., Varda-Bloom, N., Yerushalmi, R., Shem-Tov, N., Magen, H., Shimoni, A., Nagler, A.
International journal of hematology. 2021
Abstract
Autologous stem cell transplantation (ASCT) is a standard of care in newly-diagnosed multiple myeloma (MM) patients. Several studies before the introduction of novel therapies in MM, demonstrated a pegylated G-CSF to be successful in mobilizing peripheral blood stem cells (PBSCs). Lipegfilgrastim is a novel long-acting G-CSF that is produced by the conjugation of a single 20-kDa polyethelene glycol to the natural O-glycosylation site of G-CSF. Twenty-four MM patients were included for PBSCs mobilization with a single SC injection of 6 mg lipegfilgrastim. PBSC collection was started when the CD34(+) count was > 10 × 10(6) cells/L. The target progenitor cells were 6 × 10(6) cells/kg. The median day of apheresis was + 3 (range 2-5) following lipegfilgrastim. Median peripheral blood CD34(+) count pre-mobilization was of 22.65 (range 3.36-105) × 10(6) cells/L. The median number of leukaphaeresis procedures was 2 (range 1-4). The median mobilized CD34(+) cells/kg were 8.26 (range 0.77-12.42). One patient failed to mobilize and two patients mobilized < 6 × 10(6) cells/kg. Toxicity was mild and transient. Twenty-three patients underwent ASCT following high dose melphalan. All patients engrafted. As lipegfilgrastim is administered only once, it is conceivable that it improves both compliance and quality-of-life (NCT02488382).
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4.
Maintenance therapy after second autologous hematopoietic cell transplantation for multiple myeloma. A CIBMTR analysis
Pasvolsky, O., Yeshurun, M., Fraser, R., Estrada-Merly, N., Rozovski, U., Shargian-Alon, L., Assal, A., Banerjee, R., Bumma, N., Gale, R. P., et al
Bone marrow transplantation. 2021
Abstract
The role of maintenance therapy after high-dose chemotherapy and first autologous transplantation in multiple myeloma (MM) is well established. We explored the effect of maintenance therapy on outcomes after salvage second autologous hematopoietic cell transplant (AHCT2) using the Center for International Blood and Marrow Transplant Research registry. Outcomes of interest included non-relapse mortality (NRM), relapse/progression (REL), progression-free and overall survival (PFS, OS). Of 522 patients who underwent AHCT2 between 2010 and 2018, 342 received maintenance therapy and 180 did not. Maintenance regimens included lenalidomide (42%), pomalidomide (13%), and bortezomib (13%). Median follow up was 58 months in the maintenance group and 61.5 months in the no-maintenance group. Univariate analysis showed superior outcomes at 5 years in maintenance compared to the no-maintenance group: NRM 2 (0.7-3.9)% vs 9.9 (5.9-14.9)%, (p?0.01), REL 70.2 (64.4-75.8)% vs 80.3 (73.6-86.3)% (p?0.01), PFS 27.8 (22.4-33.5)% vs. 9.8 (5.5-15.2)% (p?0.01), and OS 54 (47.5-60.5)% vs 30.9 (23.2-39.2)% (p?0.01), respectively. Use of maintenance therapy retained its association with improved outcomes in multivariate analysis. There was no difference in second cancers in the two groups (p?=?0.39). We conclude that maintenance after AHCT2 is associated with improved 5-year outcomes.
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5.
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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6.
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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7.
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.
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8.
Autologous Hematopoietic Stem Cell Transplantation for Systemic Sclerosis: a Systematic Review and Meta-Analysis
Shouval, R., Furie, N., Raanani, P., Nagler, A., Gafter-Gvili, A.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Autologous hematopoietic stem cell transplantation (AHSCT) has been proposed as a therapeutic modality for severe Systemic Sclerosis (SSc). We set to systematically review and meta-analyze the efficacy and safety of AHSCT in SSc. Randomized controlled trials (RCTs) and retrospective studies comparing AHSCT to standard immunosuppressive therapy were included. Of 363 titles screened from multiple databases, 15 were extracted for further investigation, and 4 met inclusion criteria (3 RCTs and 1 retrospective analysis). The control arm was monthly cyclophosphamide in all the RCTs and the majority of patients in the retrospective analysis (69%). Compared to the control, AHSCT reduced all-cause mortality (risk ratio [RR] 0.5 [95% CI 0.33-0.75]) and improved skin thickness (modified Rodnan Skin Score mean difference [MD] 10.62 [95% CI -14.21-7.03]), forced vital capacity (MD 9.58 [95% CI 3.89-15.18]), total lung capacity (MD 6.36 [95% CI 1.23-11.49]), and quality of life (physical SF-36 [MD 6.99 (95% CI 2.79-11.18)]). Treatment-related mortality considerably varied between trials but was overall higher with AHSCT (RR 9.00 [95%CI 1.57-51.69]). The risk of bias for studies included in the analysis was low. Overall, AHSCT reduces the risk of all-cause mortality and has properties of a disease-modifying anti-rheumatic treatment in SSc. Further investigation is warranted for refining patient selection and timing of transplantation.
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9.
Autologous stem cell transplantation for primary mediastinal B-cell lymphoma: long-term outcome and role of post-transplant radiotherapy. A report of the European Society for Blood and Marrow Transplantation
Avivi, I., Boumendil, A., Finel, H., Nagler, A., de Sousa, A. B., Santasusana, J. M. R., Vandenberghe, E., Afanasyev, B., Bordessoule, D., Moraleda, J. M., et al
Bone marrow transplantation. 2018
Abstract
The purpose of this retrospective registry study was to investigate the outcome of autoSCT for primary mediastinal B-cell lymphoma (PMBCL) in the rituximab era, including the effects of eventual post-transplant radiotherapy (RT) consolidation. Patients with PMBCL aged between 18 and 70 years who were treated with a first autoSCT between 2000 and 2012 and registered with the EBMT were eligible. Eighty-six patients with confirmed PMBCL and the full data set required for this analysis were evaluable. Sixteen patients underwent autoSCT in remission after first-line therapy (CR/PR1), 44 patients were transplanted with chemosensitive relapsed or primary refractory disease (CR/PR >1), and 24 patients were chemorefractory at the time of autoSCT. With a median follow-up of 5 years, 3-year estimates of relapse incidence, progression-free survival, and overall survival were 6%, 94%, and 100% for CR/PR1; 31%, 64%, and 85% for CR/PR >1; and 52%, 39%, and 41% for REF, respectively. Whilst there was no significant benefit of post-transplant RT in the CR/PR >1 group, RT could completely prevent disease recurrence post d100 in the refractory group. In conclusion, autoSCT with or without consolidating RT is associated with excellent outcome in chemoimmunotherapy-sensitive PMBCL, whereas its benefits seem to be limited in chemoimmunotherapy-refractory disease.
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10.
Treatment Intensification With Autologous Stem Cell Transplantation and Lenalidomide Maintenance Improves Survival Outcomes of Patients With Newly Diagnosed Multiple Myeloma in Complete Response
Mina, R., Petrucci, M. T., Corradini, P., Spada, S., Patriarca, F., Cerrato, C., De Paoli, L., Pescosta, N., Ria, R., Malfitano, A., et al
Clinical lymphoma, myeloma & leukemia. 2018
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Editor's Choice
Abstract
BACKGROUND High-dose therapy with autologous stem cell transplantation (HDT-ASCT) and maintenance treatment with novel agents are the best options for patients with newly diagnosed multiple myeloma, increasing the rate of complete response (CR) and prolonging progression-free survival (PFS) and overall survival (OS). Indeed, the achievement of a CR is a predictor of long-term survival among transplant-eligible patients. However, it is unclear whether patients reaching a CR after induction treatment could receive less intense consolidation or avoid maintenance therapy. PATIENTS AND METHODS We analyzed CR patients treated in 2 phase III trials, GIMEMA-RV-MM-PI-209 and RV-MM-EMN-441, to compare HDT-ASCT with an R-Alk (lenalidomide, alkylator) regimen as consolidation, and lenalidomide (R) maintenance with no maintenance. The primary endpoints were PFS, second PFS (PFS2), and OS from consolidation and maintenance (_m). RESULTS Overall, the data from 166 patients in CR were analyzed, 95 in the HDT-ASCT group and 71 in the R-Alk group. The CR patients who received HDT-ASCT had a better PFS (hazard ratio [HR], 0.55; P = .01), PFS2 (HR, 0.46; P = .02), and OS (HR, 0.42; P = .03) compared with patients randomized to R-Alk. The survival benefit with HDT-ASCT was confirmed among all the subgroups, according to age, International Staging System (ISS stage, cytogenetic profile, and receipt of maintenance therapy. CR patients who received lenalidomide maintenance had a better PFS_m (4 years: 54% vs. 19%; HR, 0.43; P = .02) compared with those who received no maintenance. However, no difference was observed in terms of PFS2_m (4 years: 72% vs. 58%; HR, 0.83; P = .67) and OS_m (4 years: 79% vs. 72%; HR, 0.82; P = .73) with maintenance therapy. CONCLUSION Even in CR patients, outcomes were improved by an intensified approach with HDT-ASCT consolidation and lenalidomide-based maintenance therapy.