-
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.
-
2.
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.
-
3.
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
-
-
-
Free full text
-
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.
-
4.
Tandem autologous stem cell transplantation improves outcome in newly diagnosed multiple myeloma with extramedullary disease and high-risk cytogenetics: a study from the Chronic Malignancies Working Party of EBMT
Gagelmann, N., Eikema, D. J., Koster, L., Caillot, D., Pioltelli, P., Lleonart, J. B., Remenyi, P., Blaise, D., Schaap, N., Trneny, M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
-
-
-
Free full text
-
Editor's Choice
Abstract
Although high-dose therapy and autologous stem cell transplantation combined with novel agents is still the hallmark of first-line treatment in newly diagnosed transplant-eligible multiple myeloma, the impact of tandem autologous or autologous/reduced-intensity allogeneic transplant for patients with extramedullary disease and high-risk cytogenetics is not defined yet. Here, we analyzed clinical and cytogenetic data from 488 adult myeloma patients with extramedullary disease undergoing single autologous (n=373), tandem autologous (n=84), or autologous-allogeneic transplantation (n=31) between 2003 and 2015. At least one high-risk abnormality was present in 41% (n=202), with del(17p) (40%) and t(4;14) (45%) being the most frequent. More than one high-risk abnormality was found in 54%. High-risk cytogenetics showed worse 4-year overall survival and progression-free survival of 54% and 29% vs. 78% and 49% for standard-risk (p<0.001, respectively). Co-segregation of high-risk abnormalities did not seem to affect outcome. Regarding transplant regimen, overall and progression-free survival were 70% and 43% for single autologous vs. 83% and 52% for tandem autologous and 88% and 58% for autologous-allogeneic (p=0.06 and p=0.30). In multivariate analysis, high-risk cytogenetics were associated with worse survival (HR, 2.00; p=0.003) while tandem autologous significantly improved outcome vs. single autologous transplant (hazard ratios, 0.46 and 0.64; p=0.02 and p=0.03). Autologous-allogeneic transplant did not significantly differ in outcome but appeared to improve survival while results were limited due to small population (hazard ratio, 0.31). In conclusion, high-risk cytogenetics is frequently observed in newly diagnosed myeloma with extramedullary disease and significantly worsens outcome after single autologous while tandem autologous transplant strategy may overcome onset poor prognosis.
PICO Summary
Population
Adult myeloma patients with extramedullary disease (n=488).
Intervention
Tandem autologous transplantation (n=84) or autologous-allogeneic transplantation (n=31)
Comparison
Single autologous transplantation (n=373)
Outcome
Overall and progression-free survival were 70% and 43% for single autologous vs. 83% and 52% for tandem autologous and 88% and 58% for autologous-allogeneic. In multivariate analysis, high-risk cytogenetics were associated with worse survival, while tandem autologous significantly improved outcome vs. single autologous transplant. Autologous-allogeneic transplant did not significantly differ in outcome but appeared to improve survival while results were limited due to small population.
-
5.
Prognostic significance of recurring chromosomal abnormalities in transplanted patients with acute myeloid leukemia
Canaani, J., Labopin, M., Itala-Remes, M., Blaise, D., Socie, G., Forcade, E., Maertens, J., Wu, D., Malladi, R., Cornelissen, J. J., et al
Leukemia. 2019
-
-
-
Full text
-
Editor's Choice
Abstract
Baseline cytogenetic studies at diagnosis remain the single most important determinant of outcome in patients with acute myeloid leukemia (AML). However, the prognostic role of the complete gamut of cytogenetic aberrations in AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently undefined. In addition, their significance in conjunction with FLT3-ITD status has not been addressed thus far. Using the ALWP/EBMT registry we conducted a retrospective analysis to determine the clinical outcomes of AML patients undergoing allo-HSCT with respect to specific recurring cytogenetic abnormalities complemented with FLT3-ITD status. We analyzed a cohort consisting of 8558 adult AML patients who underwent allo-HSCT from either a matched sibling or a matched unrelated donor. Patients with inv(3)(q21q26)/t(3;3)(q21;q26), del(5q), monosomy 7, chromosome 17p abnormalities, t(10;11)(p11-14;q13-23), t(6;11)(q27;q23), as well as those patients with a monosomal or complex karyotype experienced significantly inferior leukemia-free survival (LFS) compared to patients with a normal karyotype. Trisomy 14, del(9q), and loss of chromosome X were associated with improved LFS rates. A novel prognostic model delineating 5 distinct groups incorporating cytogenetic complexity and FLT3-ITD status was constructed with significant prognostic implications. Our analysis supports the added prognostic significance of FLT3-ITD to baseline cytogenetics in patients undergoing allo-HSCT.
PICO Summary
Population
8558 adult AML patients who underwent allo-HSCT from either a matched sibling or a matched unrelated donor, reported to the ALWP/EBMT registry.
Intervention
Patients with monosomal karyotype (n=533) or complex karyotype (n= 507) or other abnormalities
Comparison
Patients with a normal karyotype (n=4530)
Outcome
Patients with inv(3)(q21q26)/t(3;3)(q21;q26), del(5q), monosomy 7, chromosome 17p abnormalities, t(10;11)(p11-14;q13-23), t(6;11)(q27;q23), as well as those patients with a monosomal or complex karyotype experienced significantly inferior leukemia-free survival (LFS) compared to patients with a normal karyotype. Trisomy 14, del(9q), and loss of chromosome X were associated with improved LFS rates. This analysis supports the added prognostic significance of FLT3-ITD to baseline cytogenetics in patients undergoing allo-HSCT.
-
6.
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
-
-
-
Free full text
-
Full text
-
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.
-
7.
Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: A study from the Chronic Malignancies Working Party of the EBMT
Gagelmann, N., Eikema, D. J., Iacobelli, S., Koster, L., Nahi, H., Stoppa, A. M., Masszi, T., Caillot, D., Lenhoff, S., Udvardy, M., et al
Haematologica. 2018
Abstract
We investigated extramedullary disease in newly diagnosed multiple myeloma patients and its impact on outcome following first line autologous stem cell transplantation. We identified 3744 adult myeloma patients who received upfront single (n = 3391) or tandem transplantation (n = 353) between 2005 and 2014 with available data on extramedullary in-volvement at diagnosis. The overall incidence of extramedullary disease was 18.2% (n = 682) and increased per year from 6.5% (2005) to 23.7% (2014). Paraskeletal involvement was found in 543 (14.5%) and extramedullary organ involvement in 139 (3.7%) while the majority of 3062 (81.8%) patients had no extramedullary disease. More patients with extramedul-lary organ involvement had multiple involved sites (≥2;) (p < 0.001). In patients with single sites compared to patients without the disease, upfront transplantation resulted in at least similar 3-year progression-free survival (paraskeletal: p = 0.86, and extramedullary organ: p = 0.88). In single paraskeletal involvement, this translated less clearly into 3-year overall survival (p = 0.07) while single organ involvement was significantly worse (p = 0.001). Multiple organ sites were associated with worse outcome (p < 0.001 and p = 0.01). First line treatment with tandem compared with single transplantation resulted in similar survival in patients with extramedullary disease at diagnosis (p = 0.13, respectively).
-
8.
Early CD8+-recovery independently predicts low probability of disease relapse but also associates with severe GVHD after allogeneic HSCT
Ranti, J., Kurki, S., Salmenniemi, U., Putkonen, M., Salomaki, S., Itala-Remes, M.
PloS one. 2018;13(9):e0204136
Abstract
In this single-center study we retrospectively evaluated the impact of early reconstitution of different lymphocyte subsets on patient outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that CD8+ T-cell counts exceeding 50x106/l as early as on day 28 post-transplantation correlated significantly with decreased relapse risk, with three-year relapse rates of 17.0% and 55.6% (P = 0.002), but were also associated with severe acute and chronic GVHD. Incidence of grade III-IV acute GVHD was 30.5% for those with early CD8+ T-cell recovery compared to 2.1% for those with lower CD8+ T-cell counts on day 28 post-transplant (HR = 20.24, P = 0.004). Early CD8+ T-cell reconstitution did not, however, affect the overall survival. Multivariate analysis showed that slow CD8+ T-cell reconstitution was strongly associated with increased risk of relapse (HR = 3.44, P = 0.026). A weaker correlation was found between CD4+ reconstitution and relapse-risk, but there was no such association with CD19+ B-cells or NK-cells. In conclusion, the early CD8+ T-cell recovery on day 28 post-transplant is associated with the lower risk of relapse but also predicts the impending severe GVHD, and thus could be useful in guiding timely treatment decisions.
-
9.
Genomic prediction of relapse in recipients of allogeneic haematopoietic stem cell transplantation
Ritari, J., Hyvarinen, K., Koskela, S., Itala-Remes, M., Niittyvuopio, R., Nihtinen, A., Salmenniemi, U., Putkonen, M., Volin, L., Kwan, T., et al
Leukemia. 2018
-
-
Free full text
-
Full text
-
Editor's Choice
Abstract
Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the most informative variants while controlling against overfitting. Our results show that germline genetic polymorphisms in patients entail a significant contribution to relapse risk, as judged by the predictive performance of the model (AUC = 0.72 [95% CI: 0.63-0.81]). Furthermore, the top contributing variants were predictive in two independent replication cohorts (n = 258 and n = 125) from the same population. The results can help elucidate relapse mechanisms and suggest novel therapeutic targets. A computational genomic model could provide a step toward individualized prognostic risk assessment, particularly when accompanied by other data modalities.
-
10.
Graft Immune Cell Composition Associates with Clinical Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with AML
Impola, U., Larjo, A., Salmenniemi, U., Putkonen, M., Itala-Remes, M., Partanen, J.
Frontiers in Immunology. 2016;7:523
Abstract
Complications of allogeneic hematopoietic stem cell transplantation (HSCT) have been attributed to immune cells transferred into the patient with the graft. However, a detailed immune cell composition of the graft is usually not evaluated. In the present study, we determined the level of variation in the composition of immune cells between clinical HSCT grafts and whether this variation is associated with clinical outcome. Sizes of major immune cell populations in 50 clinical grafts from a single HSCT Centre were analyzed using flow cytometry. A statistical comparison between cell levels and clinical outcomes of HSCT was performed. Overall survival, acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), and relapse were used as the primary endpoints. Individual HSCT grafts showed considerable variation in their numbers of immune cell populations, including CD123+ dendritic cells and CD34+ cells, which may play a role in GVHD. Acute myeloid leukemia (AML) patients who developed aGVHD were transplanted with higher levels of effector CD3+ T, CD19+ B, and CD123+ dendritic cells than AML patients without aGVHD, whereas grafts with a high CD34+ content protected against aGVHD. AML patients with cGVHD had received grafts with a lower level of monocytes and a higher level of CD34+ cells than those without cGVHD. There is considerable variation in the levels of immune cell populations between HSCT grafts, and this variation is associated with outcomes of HSCT in AML patients. A detailed analysis of the immune cell content of the graft can be used in risk assessment of HSCT.