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1.
Cytogenetic risk score maintains its prognostic significance in AML patients with detectable measurable residual disease undergoing transplantation in remission: on behalf of the ALWP/EBMT
Nagler, A., Labopin, M., Canaani, J., Niittyvuopio, R., Socie, G., Kroger, N., Itala-Remes, M., Yakoub-Agha, I., Labussiere-Wallet, H., Gallego-Hernanz, M. P., et al
American journal of hematology. 2020
Abstract
While evidence for measurable residual disease (MRD) is a harbinger of inferior outcome in acute myeloid leukemia (AML) patients referred for allogeneic stem cell transplantation (allo-SCT), the exact clinical trajectory of specific patient subsets in this clinical setting is undefined. Using a recently published prognostic cytogenetic model (Leukemia 2019) we evaluated whether this model applied also to studies of patients with positive MRD. The analysis comprised MRD(+) patients in first complete remission undergoing allo-SCT from a matched sibling donor or unrelated donor. Seven hundred and seventy-five patients were evaluated with a median follow-up duration of 22 months. Cytogenetic risk score was favorable, intermediate/FLT3(wt) intermediate/FLT3-ITD, and adverse in 15%, 28.3%, 37% and 19.7% of the patients, respectively. Favorable and intermediate/FLT3(wt) risk patients had 2-year leukemia-free survival rates of 78% and 61%, respectively, compared with only 50% and 37% for intermediate FLT3-ITD and adverse risk patients, respectively (p<0.0001). In multivariate analysis adverse and intermediate/FLT3-ITD risk patients were more likely to experience disease relapse compared with favorable risk patients [Hazard ratio (HR)=3.9, 95% confidence interval (CI), 2.1-7.3; p<0.0001, and HR=4.4, CI 95%, 2.4-7.8; p<0.0001, respectively]. The EBMT cytogenetic risk score is a valuable adjunct for risk stratification of MRD(+) AML patients. This article is protected by copyright. All rights reserved.
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2.
Outcome of Patients with Fanconi Anemia developing myelodysplasia and acute leukemia who received Allogeneic Hematopoietic Stem Cell Transplantation: A retrospective analysis on Behalf of EBMT group
Giardino, S., Peffault de Latour, R., Aljurf, M., Eikema, D. J., Bosman, P., Bertrand, Y., Tbakhi, A., Holter, W., Bornhauser, M., Rossig, C., et al
American journal of hematology. 2020
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative for bone marrow failure in patients with Fanconi anemia (FA), but the presence of a malignant transformation is associated with a poor prognosis and the management of these patients is still challenging. We analyzed outcome of 74 FA patients with a diagnosis of myelodysplastic syndrome (n = 35), acute leukemia (n = 35) or with cytogenetic abnormalities (n = 4), who underwent allo-HSCT from 1999 to 2016 in EBMT network. Type of diagnosis, pre-HSCT cytoreductive therapies and related toxicities, disease status pre-HSCT, donor type, and conditioning regimen were considered as main variables potentially influencing outcome. The 5-year OS and EFS were 42% (30-53%) and 39% (27-51%), respectively. Patients transplanted in CR showed better OS compared with those transplanted in presence of an active malignant disease (OS:71%[48-95] vs 37% [24-50],P = .04), while none of the other variables considered had an impact. Twenty-two patients received pre-HSCT cytoreduction and 9/22 showed a grade 3-4 toxicity, without any lethal event or negative influence on survival after HSCT(OS:toxicity pre-HSCT 48% [20-75%] vs no-toxicity 51% [25-78%],P = .98). The cumulative incidence of day-100 grade II-IV a-GvHD and of 5-year c-GvHD were 38% (26-50%) and 40% (28-52%). Non-relapse-related mortality and incidence of relapse at 5-years were 40% (29-52%) and 21% (11-30%) respectively, without any significant impact of the tested variables. Causes of death were transplant-related events in most patients (34 out of the 42 deaths, 81%). This analysis confirms the poor outcome of transformed FA patients and identifies the importance of achieving CR pre-HSCT, suggesting that, in a newly diagnosed transformed FA patient, a cytoreductive approach pre-HSCT should be considered if a donor have been secured. This article is protected by copyright. All rights reserved.
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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.
Inferior outcome of allogeneic stem cell transplantation for secondary acute myeloid leukemia in first complete remission as compared to de novo acute myeloid leukemia
Schmaelter, A. K., Labopin, M., Socie, G., Itala-Remes, M., Blaise, D., Yakoub-Agha, I., Forcade, E., Cornelissen, J., Ganser, A., Beelen, D., et al
Blood cancer journal. 2020;10(3):26
Abstract
Following chemotherapy, secondary acute myeloid leukemia (sAML), occurring after antecedent hematologic diseases, previous chemotherapy or radiation, has an inferior prognosis compared with de novo AML. To define the outcome of sAML in the context of allogeneic stem cell transplantation (alloSCT), a retrospective, registry-based comparison was performed, including 11,439 patients with de novo and 1325 with sAML. Among transplants in first complete remission (CR1) (n = 8,600), the 3-year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) was 28.5% and 16.4% for de novo, and 35% and 23.4% for sAML. Three-year overall survival (OS), leukemia-free survival (LFS) and Graft-versus-Host Disease/relapse-free survival (GRFS) was 60.8%, 55.1%, and 38.6% for de novo, and 46.7%, 41.6%, and 28.4% for sAML, respectively. In multivariate analysis, sAML was associated with a lower OS (HR = 1.33 [95% CI = 1.21-1.48]; p < 10(-5)), LFS (HR = 1.32 [95% CI = 1.19-1.45]; p < 10(-5)) and GRFS (HR = 1.2 [95% CI = 1.1-1.31]; p < 10(-4)) and higher NRM (HR = 1.37 [95% CI = 1.17-1.59]; p < 10(-4)) and RI (HR = 1.27 [95% CI = 1.12-1.44]; p < 10(-3)). Results of the Cox model were confirmed in a matched-pair analysis. In contrast, results did not differ between de novo and sAML after alloSCT in induction failure or relapse. Hence, this analysis identified sAML as an independent risk factor for outcome after alloSCT in CR1.
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5.
Comparison of DIPSS and MYSEC-PM for prediction of outcome in post-PV and ET myelofibrosis after allogeneic stem-cell transplantation
Gagelmann, N., Eikema, D. J., de Wreede, L. C., Koster, L., Wolschke, C., Arnold, R., Kanz, L., McQuaker, G., Marchand, T., Socie, G., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC- PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C >0.5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (34-54 months) being different in post-PV (45 months) and post-ET myelofibrosis (38 months). Survival at one, two, and four years was 70% (63-77%), 61% (53- 69%) and 52% (43-61%) for the total cohort, 70% (59-80%), 61% (49-73%) and 51% (38-64%) for post-PV, and 71% (61-81%), 61% (50-72%) and 54% (42-66%) for post-ET myelofibrosis (p=0.78). Overall, the DIPSS was not significantly predictive of outcome (p=0.28). With respect to the MYSEC-PM, overall survival at four years was 69% for the low-risk, 55% for the intermediate-1-risk, 47% for the intermediate-2-risk, and 22% (0-45%) for the high-risk group. The prognostic model was predictive of survival overall (p=0.05) while groups with intermediate-2 and high risk showed no significant difference (p=0.44). Assessment of prognostic utility yielded C-index of 0.575 (0.502-0.648) for the DIPSS while assessment of the MYSEC-PM resulted in C-statistics of 0.636 (0.563-0.708) indicating improvement in prediction of posttransplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (p=0.04) and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (p=0.01) showed worse survival. In conclusion, incorporating transplant-specific as well as clinical and mutational information together with the MYSEC-PM may enhance risk stratification.
PICO Summary
Population
Patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. (n=159)
Intervention
MYelofibrosis SECondary to PV and ET prognostic model (MYSEC- PM)
Comparison
Dynamic International Prognostic Scoring System (DIPSS)
Outcome
Overall, the DIPSS was not significantly predictive of outcome. MYSEC-PM was predictive of survival overall, while groups with intermediate-2 and high risk showed no significant difference. Assessment of prognostic utility yielded C-index of 0.575 for the DIPSS while assessment of the MYSEC-PM resulted in C-statistics of 0.636, indicating improvement in prediction of posttransplant survival using the new MYSEC-PM.
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Allogeneic stem cell transplantation for blast crisis chronic myeloid leukemia in the era of tyrosine kinase inhibitors - A retrospective study by the EBMT Chronic Malignancies Working Party
Radujkovic, A., Dietrich, S., Blok, H. J., Nagler, A., Ayuk, F., Finke, J., Tischer, J., Mayer, J., Koc, Y., Sora, F., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
The prognosis of patients with blast crisis (BC) chronic myeloid leukemia (CML) is still dismal. Allogeneic stem cell transplantation (alloSCT) represents the only curative treatment option, but data on transplant outcomes are scarce. We therefore conducted a retrospective, registry based study of adult patients allografted for BC CML focusing on patients with active disease at transplant and pre-transplant prognostic factors. A total of 170 patients allografted for BC CML after tyrosine kinase inhibitor pre-treatment between 2004 and 2016 were analyzed. Prior to transplant, 95 patients were in remission, whereas 75 patients had active BC. In multivariable analysis of the entire cohort, active BC at transplant was the strongest factor associated with decreased overall survival (OS, HR 1.87, P=0.010) and shorter leukemia-free survival (LFS, HR 1.69, P=0.017). For patients with BC in remission at transplant, advanced age (≥45 years), lower performance status (≤80%), longer interval from diagnosis BC to transplant (>12 months), myeloablative conditioning, and unrelated donor (UD) transplant were risk factors for inferior survival. In patients with active BC, only UD transplant was significantly associated with prolonged LFS and trended towards improved OS. In summary, survival of patients allografted for BC CML was strongly dependent on the pre-transplant remission status. In patients with remission of BC, conventional prognostic factors remained the major determinants of outcome, whereas in those with active BC at transplant, UD transplantation was associated with prolonged LFS in our study.
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The impact of anti-thymocyte globulin on the outcomes of Patients with AML with or without measurable residual disease at the time of allogeneic hematopoietic cell transplantation
Nagler, A., Dholaria, B., Labopin, M., Socie, G., Huynh, A., Itala-Remes, M., Deconinck, E., Yakoub-Agha, I., Cahn, J. Y., Bourhis, J. H., et al
Leukemia. 2019
Abstract
Measurable residual disease (MRD) status pre-allogeneic hematopoietic cell transplantation (allo-HCT) has been shown to predict transplant outcomes. We investigated the effect of Anti-Thymocyte Globulin (ATG) on acute myelogenous leukemia (AML) relapse by pretransplant MRD status. AML patients undergoing allo-HCT in first complete remission from either a matched sibling or unrelated donor during the 2006-2017 period were selected. Outcomes of 1509 patients (MRD(+), n = 426) were studied. ATG was used in 561 (52%) and 239 (58%) patients within the MRD(-) and MRD(+) cohorts, respectively. In MRD(-) patients, ATG did not affect relapse incidence (RI) (HR = 0.80, p = 0.17), but was associated with reduced incidence of grade II-IV acute GVHD, grade II-IV and chronic GVHD, reduced nonrelapse mortality (HR = 0.66, p = 0.05), improved leukemia-free survival (HR = 0.74, p = 0.02), overall survival (HR = 0.69, p = 0.01), and GVHD-relapse free survival (HR = 0.62, p < 0.01). In MRD(+) patients, ATG was associated with a lower incidence of chronic GVHD (total, HR 0.56 p = 0.03; extensive, HR 0.40 P = 0.01), without an impact on other allo-HCT outcome parameters, including RI(HR = 1.02, p = 0.92). The use of ATG was associated with reduced risk for GVHD. ATG did not increase RI, even in high-risk AML patients who were MRD(+) before allo-HCT.
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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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Impact of primary disease on outcome after allogeneic stem cell transplantation for transformed secondary acute leukaemia
Kroger, N., Eikema, D. J., Koster, L., Beelen, D., de Wreede, L. C., Finke, J., Koenecke, C., Niederwieser, D., Bornhauser, M., Schoenland, S., et al
British journal of haematology. 2019
Abstract
Myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukaemia (CMML) can progress to secondary acute myeloid leukaemia (sAML). We compared the outcome of 4214 sAML patients who received allogeneic haematopoietic stem cell transplantation (allo-HSCT) from an unrelated (62%) or human leucocyte antigen (HLA)-identical sibling donor (38%) according the underlying disease: MDS (n = 3541), CMML (n = 251) or MPN (n = 422). After a median follow up of 46.5 months, the estimated 3-year progression-free (PFS) and overall survival (OS) for the entire group was 36% (34-37%) and 41% (40-43%), respectively. The cumulative incidence of relapse and non-relapse mortality (NRM) was 37% (35-39%) and 27% (26-29%), respectively. In a multivariable analysis for OS, besides age (P < 0.001), unrelated donor (P = 0.011), cytomegalovirus +/- constellation (P = 0.007), Karnofsky index ≤ 80 (P < 0.001), remission status (P < 0.001), peripheral blood as stem cell source (P = 0.009), sAML from MPN (P = 0.003) remained a significant factor in comparison to sAML from MDS, while worse outcome of sAML from CMML did not reach statistical significance (P = 0.06). This large registry study demonstrates a major impact of the underlying disease on outcome of sAML after allo-HSCT.
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Graft-versus-host disease and graft-versus-leukaemia effects in secondary acute myeloid leukaemia: a retrospective, multicentre registry analysis from the Acute Leukaemia Working Party of the EBMT
Baron, F., Labopin, M., Savani, B. N., Beohou, E., Niederwieser, D., Eder, M., Potter, V., Kroger, N., Beelen, D., Socie, G., et al
British journal of haematology. 2019
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Editor's Choice
Abstract
We assessed the susceptibility of secondary acute myeloid leukaemia (sAML) to graft-versus-leukaemia effects. Data from 2414 sAML patients in first (n = 2194) or second (n = 220) complete remission were included. They were given grafts from human leucocyte antigen (HLA)-matched sibling (MSD, n = 1085), 10/10 unrelated donor (MUD, n = 1066) or 9/10 mismatched unrelated donor (MMUD, n = 263). The 100-day incidence of grade II-IV acute graft-versus-host disease (GVHD) was 25% while 2-year incidence of chronic GVHD was 38%. Relapse rates declined steadily by duration of follow-up and were significantly lower in patients with chronic GVHD (P < 0.001). Limited (hazard ratio [HR] = 0.66, P < 0.001) and extensive (HR = 0.52, P < 0.001) chronic GVHD were associated with a lower incidence of relapse. Each grade III-IV acute (HR = 7.04, P < 0.001) as well as limited (HR = 1.42, P = 0.03) and extensive (HR = 3.97, P < 0.001) chronic GVHD were associated with higher non-relapse mortality (NRM). This translated to better overall survival (OS; HR = 0.61, P < 0.001) in patients with limited chronic GVHD. In contrast, grade III-IV acute and extensive chronic GVHD were associated with worse OS (HR = 3.16, P < 0.001 and HR = 1.21, P = 0.03, respectively). Further, in comparison to HLA-identical sibling recipients, MUD recipients had a lower risk of relapse (HR = 0.82, P = 0.03) but higher NRM (HR = 1.38, P = 0.004). In conclusion, these data demonstrate that sAML is susceptible to graft-versus-leukaemia effects.
PICO Summary
Population
Patients with secondary acute myeloid leukaemia (sAML) (n=2414)
Intervention
Allo-transplant from human leucocyte antigen (HLA)-matched sibling (MSD, n = 1085), 10/10 unrelated donor (MUD, n = 1066) or 9/10 mismatched unrelated donor (MMUD, n = 263)
Comparison
None
Outcome
The 100-day incidence of grade II-IV acute graft-versus-host disease (GVHD) was 25% while 2-year incidence of chronic GVHD was 38%. Relapse rates declined steadily by duration of follow-up and were significantly lower in patients with chronic GVHD. Limited and extensive chronic GVHD were associated with a lower incidence of relapse. Each grade III-IV acute as well as limited and extensive chronic GVHD were associated with higher non-relapse mortality (NRM). This translated to better overall survival (OS) in patients with limited chronic GVHD. In contrast, grade III-IV acute and extensive chronic GVHD were associated with worse OS. Further, in comparison to HLA-identical sibling recipients, MUD recipients had a lower risk of relapse but higher NRM.