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1.
Impact of in vivo T-cell depletion in patients with myelodysplastic syndromes undergoing allogeneic hematopoietic stem cell transplant: a registry study from the Chronic Malignancies Working Party of the EBMT
Forcade, E., Chevret, S., Finke, J., Ehninger, G., Ayuk, F., Beelen, D., Koster, L., Ganser, A., Volin, L., Sengeloev, H., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
While in vivo T-cell depletion (TCD) is widely used, its benefit in patients with MDS still remains a matter of debate. This study evaluates the impact of TCD on outcomes, and compares ATG and alemtuzumab, in patients with MDS. 1284 patients from the EBMT registry were included in this study with 470 patients in the no-TCD group and 814 in the TCD group (alemtuzumab N = 168; ATG N = 646). At 6 months, aGVHD III-IV cumulative incidences (CI) for no-TCD, ATG or alemtuzumab groups were 13% vs 14% vs 11% (ns), respectively. At 5 years, CI of chronic GVHD were 64% vs 52% vs 51% (p < 0.00017); and CI of relapse was 23% vs 25% vs 39% (p < 0.0001) for no TCD, ATG and alemtuzumab respectively; OS was 47% vs 46% vs 34% (p = 0.009) respectively; and GRFS was 21% vs 28% and 20% (p = 0.045) respectively. In multivariable analysis, ATG improved GRFS, and alemtuzumab decreased OS. Both ATG and alemtuzumab decreased risk of chronic GVHD, but the increased risk of relapse with alemtuzumab is associated with a poor GRFS and suggest to not use alemtuzumab in the setting of allo-SCT for high risk disease.
PICO Summary
Population
Patients with myelodysplastic syndromes undergoing allogeneic transplant and reported to the EBMT registry (n=1284)
Intervention
In vivo T-cell depletion (TCD, n=814: receiving alemtuzumab n=168 or ATG n=646)
Comparison
No in vivo T-cell depletion (No-TCD, n=470).
Outcome
At 6 months, aGVHD III-IV cumulative incidences (CI) for no-TCD, ATG or alemtuzumab groups were 13% vs 14% vs 11% (ns), respectively. At 5 years, CI of chronic GVHD were 64% vs 52% vs 51%; and CI of relapse was 23% vs 25% vs 39% for no TCD, ATG and alemtuzumab respectively; OS was 47% vs 46% vs 34% respectively; and GRFS was 21% vs 28% and 20% respectively. In multivariable analysis, ATG improved GRFS, and alemtuzumab decreased OS. Both ATG and alemtuzumab decreased risk of chronic GVHD, but the increased risk of relapse with alemtuzumab is associated with a poor GRFS
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Allogeneic hematopoietic stem cell transplantation for adult patients with t(4;11)(q21;q23) KMT2A/AFF1 B-cell precursor acute lymphoblastic leukemia in first complete remission: impact of pretransplant measurable residual disease (MRD) status. An analysis from the Acute Leukemia Working Party of the EBMT
Esteve, J., Giebel, S., Labopin, M., Czerw, T., Wu, D., Volin, L., Socié, G., Yakoub-Agha, I., Maertens, J., Cornelissen, J. J., et al
Leukemia. 2021
Abstract
Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with t(4;11)(q21;q23);KMT2A/AFF1 is a poor-prognosis entity. This registry-based study was aimed to analyze outcome of patients with t(4;11) BCP-ALL treated with allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1) between 2000 and 2017, focusing on the impact of measurable residual disease (MRD) at the time of transplant. Among 151 patients (median age, 38) allotransplanted from either HLA-matched siblings or unrelated donors, leukemia-free survival (LFS) and overall survival (OS) at 2 years were 51% and 60%, whereas relapse incidence (RI) and non-relapse mortality (NRM) were 30% and 20%, respectively. These results were comparable to a cohort of contemporary patients with diploid normal karyotype (NK) BCP-ALL with equivalent inclusion criteria (n?=?567). Among patients with evaluable MRD pre-alloHSCT, a negative status was the strongest beneficial factor influencing LFS (hazard ratio [HR]?=?0.2, p?0.001), OS (HR?=?0.14, p?0.001), RI (HR?=?0.23, p?=?0.001), and NRM (HR?=?0.16, p?=?0.002), with a similar outcome to MRD-negative NK BCP-ALL patients. In contrast, among patients with detectable pretransplant MRD, outcome in t(4;11) BCP-ALL was inferior to NK BCP-ALL (LFS: 27% vs. 50%, p?=?0.02). These results support indication of alloHSCT in CR1 for t(4;11) BCP-ALL patients, provided a negative MRD status is achieved. Conversely, pre-alloHSCT additional therapy is warranted in MRD-positive patients.
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Allogeneic hematopoietic cell transplantation for patients with TP53 mutant or deleted chronic lymphocytic leukemia: Results of a prospective observational study
Schetelig, J., Hoek, J., Stilgenbauer, S., Middeke, J. M., Andersen, N. S., Fox, C. P., Lenhoff, S., Volin, L., Shimoni, A., Schroyens, W., et al
Bone marrow transplantation. 2020
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4.
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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EBMT prospective observational study on allogeneic hematopoietic stem cell transplantation in T-prolymphocytic leukemia (T-PLL)
Wiktor-Jedrzejczak, W., Drozd-Sokolowska, J., Eikema, D. J., Hoek, J., Potter, M., Wulf, G., Sellner, L., Ljungman, P., Chevallier, P., Volin, L., et al
Bone marrow transplantation. 2019
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Editor's Choice
Abstract
Preliminary data suggest that allogeneic stem cell transplantation (allo-SCT) may be effective in T-prolymphocytic leukemia (T-PLL). The purpose of the present observational study was to assess the outcome of allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL. Patients were consecutively registered with the EBMT at the time of transplantation and followed by routine EBMT monitoring but with an extended dataset. Between 2007 and 2012, 37 evaluable patients (median age 56 years) were accrued. Pre-treatment contained alemtuzumab in 95% of patients. Sixty-two percent were in complete remission (CR) at the time of allo-SCT. Conditioning contained total body irradiation with 6 Gy or more (TBI6) in 30% of patients. With a median follow-up of 50 months, the 4-year non-relapse mortality, relapse incidence, progression-free (PFS) and overall survival were 32, 38, 30 and 42%, respectively. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM. This study confirms for the first time prospectively that allo-SCT can provide long-term disease control in a sizable albeit limited proportion of patients with T-PLL.
PICO Summary
Population
Allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL.
Intervention
Observational study
Comparison
None
Outcome
With a median follow-up of 50 months, the 4-year non-relapse mortality was 32%, relapse incidence 38%, progression-free (PFS) 30% and overall survival 42%. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM.
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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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Trends in patient outcome over the past two decades following allogeneic stem cell transplantation for acute myeloid leukemia. An ALWP/EBMT analysis
Canaani, J., Beohou, E., Labopin, M., Ghavamzadeh, A., Beelen, D., Hamladji, R. M., Niederwieser, D., Volin, L., Markiewicz, M., Arnold, R., et al
Journal of internal medicine. 2018
Abstract
BACKGROUND Outcomes for patients with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (allo-SCT) have significantly improved in recent years. OBJECTIVES To assess the incremental improvement of transplanted AML patients in the last two decades. METHODS Patients included in this analysis were adult AML patients who underwent allo-SCT from an HLA matched sibling donor (MSD) or matched unrelated donor (MUD) in first remission. Patient outcomes were assessed between three cohorts according to the year of transplant (1993-2002, 2003-2007, and 2008-2012). RESULTS The analysis comprised a total of 20187 patients of whom 4763 were transplanted between 1993-2002, 5835 in 2003-2007, and 9589 in 2008-2012. In multivariate analysis, leukemia free survival (LFS) rates were significantly improved in more recently transplanted patients compared to patients transplanted in 1993-2002 [Hazard ratio (HR)=0.84, confidence interval (CI) 95%, 0.77-0.92; P=0.003], a benefit which also extended to improved overall survival (OS) (HR=0.8, CI 95%, 0.73-0.89; P<0.0001), and decreased non-relapse mortality (NRM) rates (HR=0.65, CI 95%, 0.56-0.75; P<0.0001). Subset analysis revealed that in MSD, the rates of LFS, NRM, and OS significantly improved in patients in the more recent cohort with similar results also seen in MUD. Finally, the incidence of acute graft versus host disease (GVHD) was significantly reduced leading to improved GVHD-free/relapse-free survival (GRFS) rates in more recently transplanted patients. CONCLUSION Outcome of allo-SCT for AML patients has markedly improved in the last two decades owing to decreased non-relapse mortality and improved rates of leukemia-free survival resulting in significantly longer survival. This article is protected by copyright. All rights reserved.
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Relapse and survival after transplantation for complex karyotype acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and the University of Texas MD Anderson Cancer Center
Ciurea, S. O., Labopin, M., Socie, G., Volin, L., Passweg, J., Chevallier, P., Beelen, D., Milpied, N., Blaise, D., Cornelissen, J. J., et al
Cancer. 2018
Abstract
BACKGROUND Despite recent advances in allogeneic hematopoietic stem cell transplantation (AHSCT), the outcome of patients who have acute myeloid leukemia (AML) with a complex karyotype (CK) remains poor. The objective of this study was to identify prognostic factors associated with post-transplantation survival in a large cohort of patients with CK AML. METHODS In total, data on 1342 consecutively patients who underwent transplantation for CK (≥3 chromosomal abnormalities) AML were provided by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and from the University of Texas MD Anderson Cancer Center database were included in the analysis. The median patient age was 52 years. The donors were human leukocyte antigen-matched related donors (N = 749), matched unrelated donors (N = 513), and mismatched unrelated donors (N = 80). RESULTS Relapse was the main cause of treatment failure. Overall, 51% of patients relapsed, 17.6% died of treatment-related mortality, and 31.3% survived leukemia-free. In multivariate analysis, the factors associated with an increased risk of relapse were age (>40 years; hazard ratio [HR], 1.1 per 10 years; P = .02), secondary AML (HR, 1.35; P = .01), active disease at transplantation (HR, 1.98; P < .001), and deletion/monosomy 5 (HR, 1.5; P < .001); whereas age (HR, 1.15 per 10 years; P < .001), secondary AML (HR, 1.36; P = .001), active disease at transplantation (HR, 1.99; P < .001), deletion/monosomy 5 (HR, 1.24; P = .008), and deletion/monosomy 7 (HR, 1.44; P < .001) predicted for leukemia-free survival. CONCLUSIONS Disease relapse remains the most common cause of treatment failure for patients with CK AML after transplantation. Novel approaches to decrease the relapse rate and improve survival are needed in these patients. Cancer 2018. (c) 2018 American Cancer Society.
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AlloHSCT for inv(3)(q21;q26)/t(3;3)(q21;q26) AML: a report from the acute leukemia working party of the European society for blood and marrow transplantation
Halaburda, K., Labopin, M., Houhou, M., Niederwieser, D., Finke, J., Volin, L., Maertens, J., Cornelissen, J. J., Milpied, N., Stuhler, G., et al
Bone marrow transplantation. 2018
Abstract
Acute myeloid leukemia with inv(3)(q21;q26.2)/t(3;3)(q21;q26.2) (3q26 AML) is a rare disease with poor prognosis and median survival of <1 year. To evaluate allogeneic stem cell transplantation (alloHSCT) in the treatment of 3q26 AML, we studied 98 patients reported to the European Society for Blood and Marrow Transplantation between 1995 and 2013. Majority of patients were transplanted using peripheral blood, from unrelated donors and after myeloablative conditioning. Fifty-three patients were transplanted with active disease and 45 in complete remission. After a median follow-up of 47 months, 2 year leukemia-free survival (LFS), overall survival (OS), relapse incidence (RI), non-relapse mortality (NRM), and graft-versus-host disease-free, relapse-free survival (GRFS) probabilities were 20%, 26%, 64%, 16%, and 14%, respectively. Two-year LFS and OS probabilities for patients transplanted in CR vs. those transplanted in active disease were 23.8 vs. 17% (p = NS) and 34.9 vs. 18.9% (p = NS), respectively. In multivariate analysis CR was the only factor associated with a trend for better LFS (p = 0.05, HR 0.64) and OS (p = 0.06, HR 0.65). CR also significantly influenced GRFS (p = 0.01; HR 0.55) and NRM (p = 0.02; HR 0.27). The results suggest that a proportion of patients might benefit from the procedure, especially if performed in CR.
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10.
Family mismatched allogeneic stem cell transplantation for Myelofibrosis: Report from the Chronic Malignancies Working Party of EBMT
Raj, K., Eikema, D. J., McLornan, D. P., Olavarria, E., Blok, H. J., Bregante, S., Ciceri, F., Passweg, J., Ljungman, P., Schaap, N., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
This analysis includes 56 Myelofibrosis (MF) patients transplanted from family mismatched donor between 2009-2015 enrolled in the European Society for Blood and Marrow Transplantation (EBMT) database. The median age was 57 years (range, 38-72); 75% had primary MF and 25% had secondary MF. JAK2 V617F was mutated in 61%. Donors were HLA mismatched at 2 or more loci. Stem cells were sourced from bone marrow in 66% and peripheral blood in 34%. The median CD34+ cell dose was 4.8x10(6)/kg (1.7-22.9x10(6)/kg) (n=43). Conditioning was predominantly myeloablative (MAC) in 70% and reduced intensity (RIC) in the remainder. Regimens were heterogeneous with Thiotepa, Busulphan Fludarabine (TBF) and post-transplant cyclophosphamide (PTCy) used in 59%. The incidence of neutrophil engraftment by 28 days was 82% (range, 70-93%), at a median of 21 days (range,19-23). At 2 yrs. the CI of primary Graft failure was 9% (1-16%) and secondary graft failure was 13% (4-22%).The cumulative incidence (CI) of grades II-IV acute GvHD (aGvHD) and III-IV was 28% (16-40%) and 9% (2-17%) at 100 days. The CI of chronic GvHD (cGvHD) at 1 year was 45% (32-58%) but CI of death without cGVHD by 1 year was 20% (10-31%). With a median follow up of 32 months, the 1- and 2-year OS was 61% (48-74%) and 56% (41-70%) respectively. The 1- and 2- year PFS was 58% (45-71%) and 43% (28-58%) with a 2-year CI of relapse of 19% (7-31%). The 2-year non-relapse mortality (NRM) was 38% (24-51%). This retrospective study of MF allo-SCT utilising family mismatched donors, demonstrates feasibility of the approach, timely neutrophil engraftment in over 80% of cases and acceptable OS and PFS rates with relapse rates not dissimilar to the unrelated donor setting. However, strategies to minimise the risk of graft failure and the relatively high NRM need to be employed, ideally in a multicentre prospective fashion.