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Multipotent mesenchymal stromal cells as treatment for poor graft function after allogeneic hematopoietic cell transplantation: A multicenter prospective analysis
Servais, S., Baron, F., Lechanteur, C., Seidel, L., Baudoux, E., Briquet, A., Selleslag, D., Maertens, J., Poire, X., Schroyens, W., et al
Frontiers in immunology. 2023;14:1106464
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Editor's Choice
Abstract
INTRODUCTION Poor graft function (PGF) is a rare but serious complication of allogeneic hematopoietic cell transplantation (alloHCT). Due to their hematopoietic supporting properties and immune regulatory effects, multipotent mesenchymal stromal cells (MSC) could be considered a good candidate to help to restore bone marrow (BM) niches homeostasis and facilitate hematopoiesis after alloHCT. METHODS We prospectively assessed the efficacy and safety of ex-vivo expanded BM-derived MSC from third-party donor in a series of 30 patients with prolonged severe cytopenia and PGF after alloHCT. This multicenter trial was registered at www.clinicaltrials.gov (#NTC00603330). RESULTS Within 90 days post-MSC infusion, 53% (95% CI, 35 - 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 10(9)/L, Hb > 80g/L and platelet count > 20 x 10(9)/L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively, p ≤0.001). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 10(9)/L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 - 88.5), with all but one of the patients who achieved CR being alive. A single infusion of third-party MSC appeared to be safe, with the exception of one deep vein thrombotic event possibly related to the intervention. DISCUSSION In conclusion, a single i.v. infusion of BM-derived MSC from third party donor seemed to improve hematological function after alloHCT, although spontaneous amelioration cannot be excluded. Comparative studies are warranted to confirm these encouraging results.
PICO Summary
Population
Adults with prolonged severe cytopenia and poor graft function (PGF) after allogeneic transplant in eight centres in Belgium (n=30).
Intervention
Single infusion of third-party donor mesenchymal stromal cells (MSC)
Comparison
None
Outcome
Within 90 days post-MSC infusion, 53% (95% CI, 35 - 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 10(9)/L, Hb > 80g/L and platelet count > 20 x 10(9)/L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 10(9)/L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 - 88.5), with all but one of the patients who achieved CR being alive.
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Use of chimerism analysis after allogeneic stem cell transplantation: Belgian guidelines and review of the current literature
Delie, A., Verlinden, A., Beel, K., Deeren, D., Mazure, D., Baron, F., Breems, D., De Becker, A., Graux, C., Lewalle, P., et al
Acta clinica Belgica. 2020;:1-9
Abstract
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment option in both adult and pediatric patients with malignant and non-malignant hematological diseases. Chimerism analysis, which determines the donor or recipient origin of hematopoietic cells in HSCT recipients, is an essential aspect of post-HSCT follow-up.Objectives: To review the current literature and develop Belgian consensus guidelines for the use of chimerism analysis in the standard of care after allogeneic HSCT.Methods: Non-systematic review of the literature in consultancy with the members of the BHS transplantation committee.Results: Clinical application with regards to prediction of graft failure or relapse as well as cell source are reviewed. A consensus guideline on the use of chimerism analysis after HSCT is presented.Conclusion: Monitoring of the dynamics or kinetics of a patient's chimerism status by serial analysis at fixed time points, as well as on suspicion of relapse or graft failure, is needed to monitor engraftment levels, as well as disease control and possible relapse.
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Allogeneic stem cell transplantation using HLA-matched donors for acute myeloid leukemia with deletion 5q or monosomy 5: a study from the Acute Leukemia Working Party of the EBMT
Poire, X., Labopin, M., Polge, E., Forcade, E., Ganser, A., Volin, L., Michallet, M., Blaise, D., Yakoub-Agha, I., Maertens, J., et al
Haematologica. 2019
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Editor's Choice
Abstract
Deletion 5q or monosomy 5 (-5/5q-) in acute myeloid leukemia is a common high-risk feature referred to allogeneic stem cell transplantation. However, -5/5q- is frequently associated with other high-risk cytogenetic aberrations such as complex karyotype, monosomal karyotype, monosomy 7 (-7), or 17p abnormalities (abn (17p)), the significance of which is unknown. In order to address this question, we studied adult patients with acute myeloid leukemia harboring -5/5q- having their first allogeneic transplantation between 2000 and 2015. Five hundred and one patients with -5/5q- have been analyzed. Three hundred thirty-eight patients (67%) were in first remission and 142 (28%) had an active disease at time of allogeneic transplantation. The 2-year probabilities of overall survival and leukemia-free survival were 27% and 20%, respectively. The 2-year probability of treatment-related mortality was 20%. We identified 4 different cytogenetic groups according to additional abnormalities with prognostic impact: -5/5q- without complex karyotype, monosomal karyotype or abn(17p), -5/5q- within a complex karyotype, -5/5q- within a monosomal karyotype and the combination of -5/5q- with abn(17p). In multivariate analysis, factors associated with worse overall survival and leukemia-free survival across the 4 groups were active disease, age, monosomal karyotype and abn(17p). The presence of -5/5q- without monosomal karyotype or abn(17p) was associated with a significantly better survival rate while -5/5q- in conjunction with monosomal karyotype or abn(17p) translated into a worse outcome. The patients harboring the combination of -5/5q- with abn(17p) showed very limited benefit from allogeneic transplantation.
PICO Summary
Population
Adult patients with acute myeloid leukemia harboring deletion 5q or monosomy 5 (-5/5q-) (n=501)
Intervention
First allogeneic transplantation between 2000 and 2015
Comparison
None
Outcome
The 2-year probabilities of overall survival and leukemia-free survival were 27% and 20%, respectively. The 2-year probability of treatment-related mortality was 20%. The presence of -5/5q- without monosomal karyotype or abn(17p) was associated with a significantly better survival rate while -5/5q- in conjunction with monosomal karyotype or abn(17p) translated into a worse outcome. The patients harboring the combination of -5/5q- with abn(17p) showed very limited benefit from allogeneic transplantation.
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The impact of concomitant cytogenetic abnormalities on acute myeloid leukemia with monosomy 7 or deletion 7q after HLA-matched allogeneic stem cell transplantation
Poire, X., Labopin, M., Polge, E., Volin, L., Finke, J., Ganser, A., Blaise, D., Yakoub-Agha, I., Beelen, D., Forcade, E., et al
American journal of hematology. 2019
Abstract
Monosomy 7 or deletion 7q (-7/7q-) is the most frequent adverse cytogenetic features reported in acute myeloid leukemia (AML) and is a common indication for allogeneic stem cell transplantation (SCT). Nevertheless, -7/7q- occurs frequently with other high-risk cytogenetic abnormalities such as complex karyotype (CK), monosomal karyotype (MK), monosomy 5 or deletion 5q (-5/5q-), 17p abnormalities (abn(17p)) or inversion of chromosome 3 (inv(3)), the presence of which may influence the outcomes after SCT. A total of 1,109 patients has been allocated to this study. Two-year probability of leukemia-free survival (LFS) and overall survival (OS) were 30% and 36%, respectively. Two-year probability of non-relapse mortality (NRM) was 20%. We defined 5 different cytogenetic subgroups: the "-7/7q- +/- CK group- designated group1", the "MK group-designated group 2", the "-5/5q- group- designated group 3", the 'abn(17p) group- designated group 4" and the "inv(3) group- designated group 5". The 2-year probability of LFS in first remission was 48% for group 1, 36.4% for group 2, 28.4% for group 3, 19.1% for group 4 and 17.3% for group 5, respectively (p<0.001). Multivariate analysis confirmed those significant differences across groups. SCT in -7/7q- AML provides durable response in one third of the patients. The presence of -7/7q- with or without CK in the absence of MK, abn(17p) or inv(3) is associated with a better survival after SCT. On the contrary, addition of MK, -5/5q-, abn(17p) or inv(3) identifies a sub-group of patients with poor prognosis even after SCT. This article is protected by copyright. All rights reserved.
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Impact of antithymocyte globulin on outcomes of allogeneic hematopoietic cell transplantation with TBI
Nagler, A., Labopin, M., Dholaria, B., Niittyvuopio, R., Maertens, J., Poire, X., Cornelissen, J., Remenyi, P., Bourhis, J. H., Beguin, Y., et al
Blood advances. 2019;3(13):1950-1960
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Abstract
The impact of the use of antithymocyte globulin (ATG) following a total body irradiation (TBI)-based myeloablative conditioning regimen has been poorly explored. We retrospectively analyzed 724 patients who underwent a first allogeneic hematopoietic cell transplantation (allo-HCT) following a TBI-based conditioning regimen for acute myeloid leukemia (AML) and compared the outcomes of 251 (35%) patients who received ATG (ATG group) with 473 (65%) patients who did not (non-ATG group). Median follow-up of surviving patients was 59 months (interquartile range, 28-83). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) for non-ATG and ATG groups in the first 100 days was 33% vs 24%, respectively (P = .0098). The 2-year cumulative incidence of chronic graft-versus-host disease (cGVHD) was reduced significantly in the ATG group in comparison with the non-ATG group (46% vs 34%, P = .003). Using multivariate analysis, in vivo T-cell depletion (ATG group) was independently associated with a decreased incidence of grade II-IV aGVHD (hazard ratio [HR], 0.28; P < .001), grade III-IV aGVHD (HR, 0.21; P < .001), cGVHD (HR, 0.63; P = .02), and nonrelapse mortality (NRM) (HR, 0.54; P = .02). Relapse risk, overall survival, and leukemia-free survival were similar between the 2 groups. Our results suggest that the addition of ATG to TBI-based myeloablative conditioning for allo-HCT in AML patients results in a significant reduction in aGVHD and cGVHD, translating into a significant reduction in NRM without increasing the relapse rate.
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Long-term outcome after allogeneic hematopoietic cell transplantation for myelofibrosis
Robin, M., de Wreede, L. C., Wolschke, C., Schetelig, J., Eikema, D. J., Van Lint, M. T., Knelange, N. S., Beelen, D., Brecht, A., Niederwieser, D., et al
Haematologica. 2019
Abstract
Allogeneic hematopoietic stem cell transplant remains the only curative treatment for myelofibrosis. Most post-transplantation events occur during the first 2 years and hence we aimed to analyze the outcome of 2-year disease-free survivors. 1055 patients with myelofibrosis transplanted between 1995 and 2014 and registered in the registry of the European Society for Blood and Marrow Transplantation were included. Survival was compared to the matched general population to determine excess mortality and the risk factors that are associated. In the 2-year survivors, Disease-free survival was 64% (60-68%) and Overall Survival was 74% (71-78%) at 10 years, better in younger individuals and in women. Excess mortality was 14% (8-21%) in patients < 45 years and 33% (13-53%) in patients ≥ 65 years. The main cause of death was relapse of the primary disease. Graft versus Host Disease before 2 years decreased the risk of relapse. Multivariable analysis of excess mortality showed that age, male sex recipient, secondary myelofibrosis and no GVHD prior to the 2-year landmark increased the risk of excess mortality. This is the largest study to date analyzing long-term outcome in patients with myelofibrosis undergoing transplant. Overall it shows a good survival in patients alive and in remission at 2-years but the occurrence of late complications, including late relapses, infectious complications and secondary malignancies highlights the importance of screening and monitoring of long-term survivors.
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Myeloablative and Reduced-intensity conditioned Allogeneic Haematopoietic Stem Cell Transplantation in Myelofibrosis: A Retrospective Study by the Chronic Malignancies Working Party of EBMT
McLornan, D., Szydlo, R., Koster, L., Chalandon, Y., Robin, M., Wolschke, C., Beelen, D., Socie, G., Bornhauser, M., Angelucci, E., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
This retrospective study by the EBMT analysed the outcome of 2224 Myelofibrosis patients who underwent allogeneic stem cell transplantation (allo-SCT) between 2000-2014; 781 (35%) underwent myeloablative conditioning (MAC) and 1443 (65%) reduced intensity conditioning (RIC). Median patient age was 52.9 years (r, 18-74) and 57.5 years (range(r), 21-76) in the MAC and RIC cohorts respectively. Donor type was similar: matched sibling donors (MAC- 317 (41%)) and RIC- 552 (38%) and unrelated donors (UD; MAC (464 (59%); RIC- 891 (62%)). Median time to both neutrophil and platelet (>20x10(9)/L) engraftment did not differ between cohorts. Rates of grade II-IV acute (a) GVHD were 28% (MAC) and 31% (RIC; (p=ns). Cumulative cGVHD rates (limited/ extensive) were 22%/27% (MAC) and 19%/ 31% (RIC; p=0.10). Cumulative incidences of Non-relapse mortality (NRM) at 1, 3 and 5-years were: 25.5%, 32.2% and 34.6% (MAC) and 26.3%, 32.8% and 34.4% (RIC). There was a trend towards a higher relapse rate with RIC regimens compared to MAC (p=0.08); rates at 1, 3 and 5-years were: 10.9%, 17.2% and 20.1% (MAC) and 14%, 19.7% and 23.2% (RIC), respectively. No significant difference in 5yr probabilities of overall survival (OS) was noted: MAC 53.0% (95% confidence intervals (CI) 49.1-56.9) and RIC 51.0% (95% CI: 48.3-53.7); p=0.78. Regarding the composite end point of GVHD-free/relapse-free survival (GRFS), the unadjusted Kaplan-Meier estimate of 5-year GRFS was 32.4% (95% CI: 29.0-36.1) in the MAC group and 26.1% (95% CI: 23.9-28.2) in the RIC group (p=0.001). In the MAC cohort, multivariable analysis confirmed worse OS and NRM with older age (>50 yrs), using an unrelated donor and a Karnofsky Performance Status (KPS) of 80 or less. For the RIC cohort, worse OS and NRM was associated with age 60- 70 years when compared to younger recipients, use of a mismatched donor and poor performance status. In conclusion, although similar OS rates existed for both cohorts overall, this study suggests that MAC should still be used for younger individuals suitable for such an approach due to a trend towards less relapse and an overall suggested advantage of improved GRFS; albeit this should be examined in a more homogeneous cohort. RIC allo-SCT still offers significant survival advantage in the older, fitter MF allograft patient and optimisation to reduce significant relapse and NRM rates are required.
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[Second allogeneic hematopoietic stem cell transplant: Guidelines from the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC)]
Yafour, N., Couturier, M. A., Azarnoush, S., Girault, S., Hermet, E., Masouridi Levrat, S., Schmidt, A., Michallet, M., Etancelin, P., Guillaume, T., et al
Bulletin du cancer. 2018
Abstract
Disease recurrence and graft dysfunction after allogeneic hematopoietic stem cell transplantation (allo-HSCT) currently remain among the major causes of treatment failure in malignant and non-malignant hematological diseases. A second allo-HSCT is a valuable therapeutic option to salvage those situations. During the 8th annual harmonization workshops of the french Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to elaborate unified guidelines on feasibility, indications, donor choice and conditioning in the case of a second allo-HSCT. In case of relapse, a second allo-HSCT with reduced intensity or non-myeloablative conditioning is a reasonable option, particularly in patients with a good performance status (Karnofsky/Lansky>80%), low co-morbidity score (EBMT score≤3), a longer remission duration after the first allo-HSCT (>6 months), and who present low disease burden at the time of second allo-HSCT. Matched related donors tend to be associated with better outcomes. In the presence of graft dysfunction (primary and secondary graft rejection), an immunoablative conditioning regimen is recommended. A donor change remains a valid option, especially in the absence of graft-versus-host disease after the first allo-HSCT.
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Allogeneic stem cell transplantation in adult patients with acute myeloid leukaemia and 17p abnormalities in first complete remission: a study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Poire, X., Labopin, M., Maertens, J., Yakoub-Agha, I., Blaise, D., Ifrah, N., Socie, G., Gedde-Dhal, T., Schaap, N., Cornelissen, J. J., et al
Journal of hematology & oncology. 2017;10(1):20
Abstract
BACKGROUND Acute myeloid leukaemia (AML) with 17p abnormalities (abn(17p)) carries a very poor prognosis due to high refractoriness to conventional chemotherapy, and allogeneic stem cell transplantation (allo-SCT) appears as the only potential curative option. METHODS To address outcomes after allo-SCT in patients with abn(17p), we retrospectively analysed de novo or secondary AML undergoing SCT between 2000 and 2013 from the EBMT registry. RESULTS One hundred thirty-nine patients with confirmed abn(17p) have been selected. At the time of transplant, one hundred twenty-five were in first remission (CR1). Median age was 54 years old. Abn(17p) was associated with a monosomal karyotype in 83% of patients, complex karyotype in 91%, monosomy 5 or 5q deletion (-5/5q-) in 55%, monosomy 7 (-7) in 39% and both -5/5q and -7 in 27%. Seventy-three patients (59%) had a reduced-intensity conditioning regimen. The 2-year overall survival (OS) and leukaemia-free survival (LFS) were 28 and 24%, respectively. The 2-year non-relapse mortality (NRM) was 15%, and 2-year relapse incidence (RI) was 61%. The cumulative incidence of grade II to IV acute graft-versus-host disease (GvHD) was 24% and that of chronic GvHD was 21%. In multivariate analysis, the presence of a -5/5q- in addition to abn(17p) was significantly and independently associated with worse OS, LFS and higher RI. Age and donor types did not correlate with outcome. Conditioning intensity was not statistically associated with OS, LFS and NRM when adjusted for patients' age. CONCLUSIONS In contrast to the dismal prognosis reported for AML patients harbouring abn(17p) undergoing conventional chemotherapy, allogeneic SCT provides responses in about 25% of those patients transplanted in CR1.
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Allogeneic stem cell transplantation benefits for patients >= 60 years with acute myeloid leukemia and FLT3-ITD; a study from the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT)
Poire, X., Labopin, M., Polge, E., Passweg, J., Craddock, C., Blaise, D., Cornelissen, J. J., Volin, L., Russell, N. H., Socie, G., et al
Haematologica. 2017
Abstract
Intermediate-risk cytogenetic acute myeloid leukemia with an internal tandem duplication of FLT3 (FLT3-ITD) is associated with a high risk of relapse and is now a standard indication for allogeneic stem cell transplantation. Nevertheless, most studies supporting this strategy have been performed in young patients. To address the benefit of allogeneic transplantation in elderly patients, we selected from the EBMT registry de novo intermediate-risk cytogenetic acute myeloid leukemia harboring FLT3-ITD in patients with an age equal or over the age of 60 years and transplanted from a related or unrelated donor between January 2000 and December 2015. Two hundred and ninety-one patients were identified. Most patients received a reduced-intensity conditioning (82%) and donor consisted of an unrelated donor in 161 (55%) patients. Two hundred twelve patients received their transplantation in first remission, 37 in second remission and 42 in more advanced stage of the disease. The 2-year leukemia-free survival was 56% in patients in first remission, 22% in those in second remission and 10% in patients with active disease, respectively (p<0.005). Non-relapse mortality for the entire cohort was 20%. In multivariate analysis, disease status at transplantation was the most powerful predictor of worse leukemia-free survival, graft-versus-host disease and relapse-free survival and overall survival. In this advanced age population, age was not associated with outcome. Based on the current results, allogeneic transplantation translates into a favorable outcome in fit patients >= 60 patients with FLT3-ITD acute myeloid leukemia in first remission, similarly to current treatment recommendation in younger patients.