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1.
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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2.
Long-term outcome after allogeneic stem cell transplantation in multiple myeloma
Luoma, S., Silvennoinen, R., Rauhala, A., Niittyvuopio, R., Martelin, E., Lindström, V., Heiskanen, J., Volin, L., Ruutu, T., Nihtinen, A.
Annals of hematology. 2021
Abstract
The role of allogeneic hematopoietic stem cell transplantation (allo-SCT) in multiple myeloma is controversial. We analyzed the results of 205 patients transplanted in one center during 2000-2017. Transplantation was performed on 75 patients without a previous autologous SCT (upfront-allo), on 74 as tandem transplant (auto-allo), and on 56 patients after relapse. Median overall survival (OS) was 9.9 years for upfront-allo, 11.2 years for auto-allo, and 3.9 years for the relapse group (p = 0.015). Progression-free survival (PFS) was 2.4, 2.4, and 0.9 years, respectively (p < 0.001). Non-relapse mortality at 5 years was 8% overall, with no significant difference between the groups. Post-relapse survival was 4.1 years for upfront-allo and auto-allo, and 2.6 years for the relapse group (p = 0.066). Survival of high-risk patients was reduced. In multivariate analysis, the auto-allo group had improved OS and chronic graft-versus-host disease was advantageous in terms of PFS, OS, and relapse incidence. Late relapses occurred in all groups. Allo-SCT resulted in long-term survival in a small subgroup of patients. Our results indicate that auto-allo-SCT is feasible and could be considered for younger patients in the upfront setting.
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3.
Meta-Analysis of Genome-Wide Association and Gene Expression Studies Implicates Donor T Cell Function and Cytokine Pathways in Acute GvHD
Hyvarinen, K., Koskela, S., Niittyvuopio, R., Nihtinen, A., Volin, L., Salmenniemi, U., Putkonen, M., Buno, I., Gallardo, D., Itala-Remes, M., et al
Frontiers in immunology. 2020;11:19
Abstract
Graft-vs.-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation that causes mortality and severe morbidity. Genetic disparities in human leukocyte antigens between the recipient and donor are known contributors to the risk of the disease. However, the overall impact of genetic component is complex, and consistent findings across different populations and studies remain sparse. To gain a comprehensive understanding of the genes responsible for GvHD, we combined genome-wide association studies (GWAS) from two distinct populations with previously published gene expression studies on GvHD in a single gene-level meta-analysis. We hypothesized that genes driving GvHD should be associated in both data modalities and therefore could be detected more readily through their combined effects in the integrated analysis rather than in separate analyses. The meta-analysis yielded a total of 51 acute GvHD-associated genes (false detection rate [FDR] <0.1). In support of our hypothesis, this number was significantly higher than that in a permutation meta-analysis involving the whole data set, as well as in separate meta-analyses on the GWAS and gene expression data sets. The genes indicated by the meta-analysis were significantly enriched in 277 Gene Ontology terms (FDR < 0.05), such as T cell function and cytokine-mediated signaling pathways, and the results highlighted several established immune mediators, such as interleukins and JAK-STAT signaling, and presented TRAF6 and TERT as potential effector candidates. Altogether, the results support the chosen methodological approach, implicate a role of gene-level variation in donors' key immunological regulators predisposing patients to acute GVHD, and present potential targets for therapeutic intervention.
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4.
Allogeneic stem cell transplantation in AML with t(6;9)(p23;q34);DEK-NUP214 shows a favourable outcome when performed in first complete remission
Diaz-Beya, M., Labopin, M., Maertens, J., Alijurf, M., Passweg, J., Dietrich, B., Schouten, H., Socie, G., Schaap, N., Schwerdtfeger, R., et al
British journal of haematology. 2020
Abstract
Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is a poor-risk entity, commonly associated with FLT3-ITD (internal tandem duplication). Allogeneic stem-cell tranplantation (allo-SCT) is recommended, although studies analysing the outcome of allo-SCT in this setting are lacking. We selected 195 patients with t(6;9) AML, who received a first allo-SCT between 2000 and 2016 from the EBMT (European Society for Blood and Marrow Transplantation) registry. Disease status at time of allo-SCT was the strongest independent prognostic factor, with a two-year leukaemia-free survival and relapse incidence of 57% and 19% in patients in CR1 (first complete remission), 34% and 33% in CR2 (second complete remission), and 24% and 49% in patients not in remission, respectively (P < 0.001). This study, which represents the largest one available in t(6;9) AML, supports the recommendation to submit these patients to allo-SCT in CR1.
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5.
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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6.
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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Comparable Long-Term Outcome after Allogeneic Stem-Cell Transplantation from Sibling and Matched Unrelated Donors in AML Patients Older than 50 years. A Report on Behalf of the ALWP of EBMT
Shimoni, A., Labopin, M., Savani, B., Byrne, M., Volin, L., Finke, J., Niederwieser, D., Ehninger, G., Blaise, D., Beelen, D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Allogeneic stem-cell transplantation (SCT) is potentially curative therapy in acute myeloid leukemia (AML). Marked improvement has been achieved with SCT from matched unrelated-donors (MUD) in recent years. However, there is limited data comparing the long-term outcomes (beyond 10 years) after SCT from sibling donors and MUDs in older AML patients. We analyzed these outcomes in a large cohort of AML patients (n=1134), age ≥50 years, who were alive and leukemia-free 2 years after SCT from matched siblings (n=848) or MUD (n=286), with a median follow up 8.9 years. The median age was 56 and 58 years, after SCT from sibling and MUDs, respectively (P=0.005). 77%, 12% and 11% in the sibling group were in CR1, CR2 and active leukemia at SCT compared to 50%, 25% and 25% in the MUD group, respectively (P<0.001). 61% of sibling, and 62% of MUDs had reduced-intensity conditioning (P=0.78). The 10-year leukemia-free survival (LFS) of patients surviving leukemia-free 2 years after SCT was 72% and 62%, respectively (P=0.30). Multivariate-analysis identified active leukemia at SCT (HR 1.86, P=0.0001) or CR2 (HR 1.51, P=0.02) compared to CR1, female recipient (HR 0.71, P=0.006), adverse cytogenetics (HR 2.52, P=0.01) and prior GVHD (HR 1.31, P=0.04) as independent factors predicting LFS. Donor and conditioning type were not significant. The cumulative incidence of late relapse was 15% and 17% (P=0.97) and of late non-relapse mortality, 13% and 21%, respectively (P=0.15). Long-term LFS is similar and patients who are leukemia-free 2 years after SCT can expect favorable outcomes with both donor types.
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9.
Role of age and hematopoietic cell transplantation-specific comorbidity index in myelodysplastic patients undergoing an allotransplant. A retrospective study from the CMWP (Chronic Malignancies Working Party) of the EBMT
Carre, M., Porcher, R., Finke, J., Ehninger, G., Koster, L., Beelen, D., Ganser, A., Volin, L., Lozano, S., Friis, L., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Allogeneic stem cell transplantation (HSCT) remains the only potentially curative option for myelodysplastic syndromes (MDS) but is severely limited by non-relapse mortality (NRM), especially in this mostly old population. Comorbidity assessment is crucial to predict NRM and often assessed with the Hematopoietic cell transplantation-specific comorbidity index (HCT-CI). Moreover, the impact of age on NRM still remains a matter of debate. In recent years the age at which transplants are made has been progressively increasing and patients with comorbidities have become more common. Extricating the respective roles of age and comorbidities in toxic mortality is all the more important. This study of the European Group for Blood and Marrow Transplantation (EBMT) registry included 1245 adult patients who underwent a first allogeneic stem cell transplantation for MDS between 2003 and 2014. Overall, 4-year NRM and overall survival were 32% and 47% respectively. When considered as continuous predictors, HCT-CI score and age were associated with an increased hazard ratio for NRM. In multivariate analysis, age-band (HR 1.13; 95% CI, 1.02 to 1.25, p=0.016), HCT-CI ≥ 3 (HR 1.34; 95% CI, 1.04 to 1.73, p=0.022) and KPS ≤80 (HR 2.03; 95% CI, 1.52 to 2.73, p<0.0001) were significantly predictive of a worse NRM. In our large cohort, both comorbidities, evaluated by the original HCT-CI score, and chronological age significantly affected NRM. Thus, age should be part of the transplant decision-making process and should be integrated in future scoring systems predicting outcomes of HSCT in MDS.
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10.
The prognostic impact of the cytomegalovirus serostatus in patients with chronic hematological malignancies after allogeneic hematopoietic stem cell transplantation: a report from the Infectious Diseases Working Party of EBMT
Schmidt-Hieber, M., Tridello, G., Ljungman, P., Mikulska, M., Knelange, N., Blaise, D., Socie, G., Volin, L., Blijlevens, N., Fegueux, N., et al
Annals of hematology. 2019
Abstract
It has been shown recently that donor and/or recipient cytomegalovirus (CMV) seropositivity is associated with a significant overall survival (OS) decline in acute leukemia patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We now analyzed the prognostic impact of the donor/recipient CMV serostatus in 6968 patients with chronic hematological malignancies who underwent allo-HSCT. Donor and/or recipient CMV seropositivity was associated with a significantly reduced 2-year progression-free survival (PFS, 50% vs. 52%, p = 0.03) and OS (62% vs. 65%, p = 0.01). Multivariate Cox regression analyses showed an independent negative prognostic impact of donor and/or recipient CMV seropositivity on PFS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.03), OS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.003), and non-relapse mortality (HR, 1.2; 95% CI, 1.0-1.3; p = 0.02). OS decline was strongest for CMV-seropositive recipients with a CMV-seronegative donor (HR, 1.2; 95% CI, 1.1-1.3), followed by CMV-seropositive patients with a CMV-seropositive donor (HR, 1.1; 95% CI, 1.0-1.2). Conversely, OS did not differ significantly between CMV-seronegative recipients allografted from a CMV-seropositive donor (HR, 1.0; 95% CI, 0.9-1.2) and patients with donor/recipient CMV seronegativity (p = 0.001 for the four groups together). Non-relapse mortality was also significantly (p = 0.01) higher for CMV-seropositive patients with a CMV-seronegative graft (HR, 1.2; 95% CI, 1.1-1.4) than for CMV-seropositive patients with a CMV-seropositive graft (HR, 1.1; 95% CI, 0.9-1.2) or CMV-seronegative recipients with a CMV-seropositive graft (HR, 1.0; 95% CI, 0.8-1.2). Donor and/or recipient CMV seropositivity still results in an OS decline in patients with chronic hematological malignancies who have undergone allo-HSCT. However, this OS decline seems to be lower than that described for acute leukemia patients previously.