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1.
Impact of comorbidities and body mass index on the outcomes of allogeneic hematopoietic cell transplantation in myelofibrosis: A study on behalf of the Chronic Malignancies Working Party of EBMT
Polverelli, N., Bonneville, E. F., de Wreede, L. C., Koster, L., Kröger, N. M., Schroeder, T., Peffault de Latour, R., Passweg, J., Sockel, K., Broers, A. E. C., et al
American journal of hematology. 2024
Abstract
Investigating the evaluation of eligibility for transplant in myelofibrosis (MF): The role of HCT-CI and BMI. HCT-CI emerges as a key prognostic factor, while BMI shows limited impact. This study expands insights for better clinical decision-making in MF allo-HCT.
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2.
Circulating T cell profiles associate with enterotype signatures underlying hematological malignancy relapses
Vallet, N., Salmona, M., Malet-Villemagne, J., Bredel, M., Bondeelle, L., Tournier, S., Mercier-Delarue, S., Cassonnet, S., Ingram, B., Peffault de Latour, R., et al
Cell host & microbe. 2023
Abstract
Early administration of azithromycin after allogeneic hematopoietic stem cell transplantation was shown to increase the relapse of hematological malignancies. To determine the impact of azithromycin on the post-transplant gut ecosystem and its influence on relapse, we characterized overtime gut bacteriome, virome, and metabolome of 55 patients treated with azithromycin or a placebo. We describe four enterotypes and the network of associated bacteriophage species and metabolic pathways. One enterotype associates with sustained remission. One taxon from Bacteroides specifically associates with relapse, while two from Bacteroides and Prevotella correlate with complete remission. These taxa are associated with lipid, pentose, and branched-chain amino acid metabolic pathways and several bacteriophage species. Enterotypes and taxa associate with exhausted T cells and the functional status of circulating immune cells. These results illustrate how an antibiotic influences a complex network of gut bacteria, viruses, and metabolites and may promote cancer relapse through modifications of immune cells.
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3.
The impact of pre-transplantation diabetes and obesity on acute graft-versus-host disease, relapse and death after allogeneic hematopoietic cell transplantation: a study from the EBMT Transplant Complications Working Party
Gjærde, L. K., Ruutu, T., Peczynski, C., Boreland, W., Kröger, N., Blaise, D., Schroeder, T., Peffault de Latour, R., Gedde-Dahl, T., Kulagin, A., et al
Bone marrow transplantation. 2023
Abstract
Obesity and diabetes can modulate immune responses, which may impact allogeneic HCT outcomes and GvHD. From the EBMT registry, we included 36,539 adult patients who underwent allogeneic HCT for a hematological malignancy between 2016 and 2020. Of these, 5228 (14%) had obesity (BMI ≥ 30 kg/m(2)), 1415 (4%) had diabetes (requiring treatment with insulin or oral hypoglycemics), and 688 (2%) had obesity + diabetes pre-transplantation. Compared with patients without diabetes or obesity, the hazard ratio (HR) of grade II-IV acute GvHD was 1.00 (95% confidence interval [CI] 0.94-1.06, p = 0.89) for patients with obesity, 0.95 (CI 0.85-1.07, p = 0.43) for patients with diabetes, and 0.96 (CI 0.82-1.13, p = 0.63) for patients with obesity + diabetes. Non-relapse mortality was higher in patients with obesity (HR 1.08, CI 1.00-1.17, p = 0.047), diabetes (HR 1.40, CI 1.24-1.57, p < 0.001), and obesity + diabetes (HR 1.38, CI 1.16-1.64, p < 0.001). Overall survival after grade II-IV acute GvHD was lower in patients with diabetes (HR 1.46, CI 1.25-1.70, p < 0.001). Pre-transplantation diabetes and obesity did not influence the risk of developing acute GvHD, but pre-transplantation diabetes was associated with poorer survival after acute GvHD.
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4.
Artificial intelligence methods to estimate overall mortality and non-relapse mortality following allogeneic HCT in the modern era: an EBMT-TCWP study
Mussetti, A., Rius-Sansalvador, B., Moreno, V., Peczynski, C., Polge, E., Galimard, J. E., Kröger, N., Blaise, D., Peffault de Latour, R., Kulagin, A., et al
Bone marrow transplantation. 2023
Abstract
Allogeneic haematopoietic cell transplantation (alloHCT) has curative potential counterbalanced by its toxicity. Prognostic scores fail to include current era patients and alternative donors. We examined adult patients from the EBMT registry who underwent alloHCT between 2010 and 2019 for oncohaematological disease. Our primary objective was to develop a new prognostic score for overall mortality (OM), with a secondary objective of predicting non-relapse mortality (NRM) using the OM score. AI techniques were employed. The model for OM was trained, optimized, and validated using 70%, 15%, and 15% of the data set, respectively. The top models, "gradient boosting" for OM (AUC = 0.64) and "elasticnet" for NRM (AUC = 0.62), were selected. The analysis included 33,927 patients. In the final prognostic model, patients with the lowest score had a 2-year OM and NRM of 18 and 13%, respectively, while those with the highest score had a 2-year OM and NRM of 82 and 93%, respectively. The results were consistent in the subset of the haploidentical cohort (n = 4386). Our score effectively stratifies the risk of OM and NRM in the current era but do not significantly improve mortality prediction. Future prognostic scores can benefit from identifying biological or dynamic markers post alloHCT.
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5.
Azithromycin promotes relapse by disrupting immune and metabolic networks after allogeneic stem cell transplantation
Vallet, N., Le Grand, S., Bondeelle, L., Hoareau, B., Corneau, A., Bouteiller, D., Tournier, S., Lew-Derivry, L., Bohineust, A., Tourret, M., et al
Blood. 2022
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Editor's Choice
Abstract
Administration of azithromycin after allogeneic hematopoietic stem cell transplantation for hematological malignancies has been associated with relapse in a randomized phase 3 controlled clinical trial. Studying 240 samples from patients randomized in this trial is a unique opportunity to better understand the mechanisms underlying relapse, the first cause of mortality after transplantation. We used multi-omics on patients' samples to decipher immune alterations associated with azithromycin intake and post-transplant relapsed malignancies. Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In vitro, azithromycin exposure inhibited T cells cytotoxicity against tumor cells and impaired T cells metabolism through glycolysis inhibition, mitochondrial genes downregulation, and immunomodulatory genes upregulation, notably SOCS1. These results highlight that azithromycin directly affects immune cells that favor relapse, which raises caution about long-term use of azithromycin treatment in patients at high risk of malignancies.
PICO Summary
Population
Participants with haematological malignancies enrolled in the ALLOZITHRO trial (n=240)
Intervention
Azithromycin 250 mg x 3/week (n=123)
Comparison
Placebo (n=117)
Outcome
Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In vitro, azithromycin exposure inhibited T cells cytotoxicity against tumor cells and impaired T cells metabolism through glycolysis inhibition, mitochondrial genes downregulation, and immunomodulatory genes upregulation, notably SOCS1.
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6.
Immune landscape after allo-HSCT: TIGIT and CD161-expressing CD4 T cells are associated with subsequent leukemia relapse
Gournay, V., Vallet, N., Peux, V., Vera, K., Bordenave, J., Lambert, M., Corneau, A., Michonneau, D., Peffault de Latour, R., Caillat-Zucman, S., et al
Blood. 2022
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Editor's Choice
Abstract
Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is the most effective treatment for selected patients with acute myeloid leukemia (AML) and relies on a "graft-versus-leukemia" effect (GVL) where donor T lymphocytes mediate control of malignant cell growth. However, relapse remains the major cause of death after allo-HSCT. In various malignancies, several immunoregulatory mechanisms have been shown to restrain antitumor immunity, including ligand-mediated engagement of inhibitory receptors on effector cells, and induction of immunosuppressive cell-subsets such as regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs). While relapse after HSCT remains a major therapeutic challenge, immunoregulatory mechanisms involved in restraining the GVL effect need to be better deciphered in humans. We used mass cytometry to comprehensively characterize circulating leukocytes in two cohorts of patients after allo-HSCT. We first longitudinally assessed various immunoregulatory parameters highlighting specific trends, such as opposite dynamics between MDSCs and Tregs. More generally, the immune landscape was rather stable from month-3 to 6, while many variations occurred from month-6 to 12 post-HSCT. Comparison with healthy individuals revealed that profound alterations in the immune equilibrium persisted 1-year post-HSCT. Importantly, we found that high levels of TIGIT and CD161 expression on CD4 T cells at month 3 post-HSCT were distinct features significantly associated with subsequent AML relapse in a second cross sectional cohort. Altogether, these data provide global insights into the immunoregulatory landscape reconstitution following HSCT, and highlight non-canonical inhibitory receptors associated with relapse, which could open the path towards new prognostic tools or therapeutic targets to restore subverted anti-AML immunity.
PICO Summary
Population
Adults with acute myeloid leukaemia or myelodysplastic syndrome, undergoing allogeneic transplant
Intervention
Measurement of peripheral blood mononuclear cells at months 3, 6 and 12 after transplant (n=37)
Comparison
Comparison cohort of healthy volunteers (n=20)
Outcome
More generally, the immune landscape was rather stable from month-3 to 6, while many variations occurred from month-6 to 12 post-HSCT. Comparison with healthy individuals revealed that profound alterations in the immune equilibrium persisted 1-year post-HSCT. Importantly, we found that high levels of TIGIT and CD161 expression on CD4 T cells at month 3 post-HSCT were distinct features significantly associated with subsequent AML relapse in a second cross sectional cohort.
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7.
Hematopoietic stem cell transplantation for acute lymphoblastic leukemia: why do adolescents and young adults outcomes differ from those of children? A retrospective study on behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC)
Grain, A., Rialland-Battisti, F., Chevallier, P., Blin, N., Dalle, J. H., Michel, G., Dhédin, N., Peffault de Latour, R., Pochon, C., Yakoub-Agha, I., et al
Journal of cancer research and clinical oncology. 2022
Abstract
PURPOSE In the acute lymphoblastic leukemia (ALL) landscape, adolescents and young adults (AYA) often present high-risk diseases and increased chemotherapy-related toxicity. Studies analyzing the outcomes of AYA after hematopoietic stem cell transplantation (HSCT) are scarce. Our study aimed to compare the outcomes of children and AYA with ALL after HSCT and to determine the factors influencing potential differences. METHOD 891 patients, from the SFGM-TC registry, aged between 1 and 25 years who received HSCT between 2005 and 2012 were included. The outcomes of AYA were compared to the ones of their younger counterparts. RESULTS Five-year OS and GRFS were lower in AYA: 53.1% versus 64% and 36% versus 47% (p = 0.0012 and p = 0.007, respectively). WhileCIR was similar in both groups, 5 year-treatment related mortality was higher in AYA: 19% versus 13% (p = 0.04). The lower GRFS in AYA was mainly explained by a higher chronic graft versus host disease (cGvHD) incidence: 32% versus 19% (p < 0.001). Use of peripheral blood stem cells and use of anti-thymoglobulin appeared to be the main factors impacting cGvHD occurrence in AYA. CONCLUSION AYA have worse outcomes than children after HSCT for ALL because of a greater risk of TRM due to cGvHD. HSCT practices should be questioned in this population.
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8.
Prospective external validation of biomarkers to predict acute graft-versus host disease severity
Robin, M., Porcher, R., Michonneau, D., Taurines, L., Sicre de Fontbrune, F., Xhaard, A., Oriano, B., Sutra Del Galy, A., Peffault de Latour, R., Socié, G., et al
Blood advances. 2022
Abstract
Acute GVHD is still the major contributor to comorbidities and mortality after allogeneic hematopoietic stem cell transplantation (HSCT. The use of plasmatic biomarkers to predict early outcomes have been advocated in the last decade. The purpose of this prospective non interventional study was to test the ability of panels including 7 biomarkers (Elafin, HGF, IL2RA, IL8, REG3, ST2 and TNFRI), to predict Day 28 (D28)-complete response to steroid, D180-overall survival (OS) and D180-non-relapse mortality (NRM). Using previous algorithms developed by the Ann Arbor / MAGIC consortium, 204 patients with acute GVHD were prospectively included and biomarkers were measured at GVHD onset for all of them. Initial GVHD grade and bilirubin level were significantly associated with all those outcomes. After adjustment on clinical variables, biomarkers were associated with survival and NRM. In addition to clinical variables, biomarkers slightly improved the prediction of overall survival and NRM (concordance [C] and net reclassification indexes). The potential benefit of adding biomarkers panel to clinical parameters was also investigated by decision curve analyses. The benefit of adding biomarkers to clinical parameters was however marginal for the D28 non-response and mortality endpoints.
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9.
Long-term outcomes and risk factor analysis of steroid-refractory graft versus host disease after hematopoietic stem cell transplantation
Pagliuca, S., Prata, P. H., Xhaard, A., Frieri, C., Giannoni, L., Sutra Del Galy, A., Brignier, A., Sicre de Fontbrune, F., Michonneau, D., Dhedin, N., et al
Bone marrow transplantation. 2020
Abstract
Steroid-refractory graft versus host disease (GVHD) represents a fearsome complication after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a retrospective study on outcomes and risk factors associated with acute and chronic steroid-refractory GVHD in a large cohort of 1207 patients receiving HSCT in Saint Louis Hospital between 2007 and 2017. Among patients who developed an acute and/or a chronic GVHD, the cumulative incidences of acute and chronic steroid-refractory disease were 31% and 48%, respectively, at day +100 and 1-year post-HSCT. Through a multivariable analysis we selected several risk factors associated with the development of a steroid-refractory disease. For acute GVHD steroid refractoriness, we identified (1) a very high disease risk index, (2) an unrelated donor, (3) the absence of in vivo T-depletion as GVHD prophylaxis, and (4) a reduced intensity conditioning regimen. For chronic GVHD, (1) the use of peripheral blood stem cells, (2) unrelated donors, and (3) absence of in vivo T-depletion were more likely associated with a steroid-refractory disease. After the construction of a multistate dynamic model, we found that the probability of being alive without relapse after the resolution of all GVHD episodes was about 36% in the long term.
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10.
Expansion of circulating CD49b+LAG3+ type 1 regulatory T (Tr1) cells in human chronic graft-versus-host disease
Talvard-Balland, N., Sutra Del Galy, A., Michonneau, D., Le Buanec, H., Chasset, F., Robin, M., Peffault de Latour, R., Xhaard, A., Sicre de Fontbrune, F., Parquet, N., et al
The Journal of investigative dermatology. 2020