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Decrease of lethal infectious complications in the context of causes of death (COD) after hematopoietic cell transplantation: COD-2 and COD-1 study of the Infectious Diseases Working Party EBMT
Styczynski, J., Tridello, G., Koster, L., Knelange, N., Wendel, L., van Biezen, A., van der Werf, S., Mikulska, M., Gil, L., Cordonnier, C., et al
Bone marrow transplantation. 2023
Abstract
We previously analyzed trends in incidence and factors associated with lethal complications in ALL/AML/CML patients (causes of deaths; COD-1 study). The objective of this study was the analysis of incidence and specific causes of death after HCT, with focus on infectious deaths in two time periods, 1980-2001 (cohort-1) and 2002-2015 (cohort-2). All patients with HCT for lymphoma, plasma cell disorders, chronic leukemia (except CML), myelodysplastic/myeloproliferative disorders, registered in the EBMT-ProMISe-database were included (n = 232,618) (COD-2 study). Results were compared to those in the ALL/AML/CML COD-1 study. Mortality from bacterial, viral, fungal, and parasitic infections decreased in very early, early and intermediate phases. In the late phase, mortality from bacterial infections increased, while mortality from fungal, viral, or unknown infectious etiology did not change. This pattern was similar for allo- and auto-HCT in COD-1 and COD-2 studies, with a distinct and constant lower incidence of all types of infections at all phases, after auto-HCT. In conclusion, infections were the main cause of death before day +100, followed by relapse. Mortality from infectious deaths significantly decreased, except late phase. Post-transplant mortality has significantly decreased in all phases, from all causes after auto-HCT; it has decreased in all phases after allo-HCT except late phase.
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Impact of the SARS-CoV-2 pandemic on hematopoietic cell transplantation and cellular therapies in Europe 2020: a report from the EBMT activity survey
Passweg, J. R., Baldomero, H., Chabannon, C., Corbacioglu, S., de la Cámara, R., Dolstra, H., Glass, B., Greco, R., Mohty, M., Neven, B., et al
Bone marrow transplantation. 2022;:1-11
Abstract
In 2020, 45,364 HCT in 41,016 patients, 18,796 (41%) allogeneic and 26,568 (59%) autologous in 690 centers were reported. Changes observed were as follows: total number of HCT -6.5%, allogeneic HCT -5.1%, autologous HCT -7.5%, and were more pronounced in non-malignant disorders for allogeneic HCT and in autoimmune disease for autologous HCT. Main indications were myeloid malignancies 10,441 (25%), lymphoid malignancies 26,120 (64%) and non-malignant disorders 2532 (6%). A continued growth in CAR-T cellular therapies to 1874 (+65%) patients in 2020 was observed. In allogeneic HCT, the use of haploidentical donors increased while use of unrelated and sibling donors decreased. Cord blood HCT increased by 11.7% for the first time since 2012. There was a significant increase in the use of non-myeloablative but a drop in myeloablative conditioning and in use of marrow as stem cell source. We interpreted these changes as being due to the SARS-CoV-2 pandemic starting early in 2020 in Europe and provided additional data reflecting the varying impact of the pandemic across selected countries and larger cities. The transplant community confronted with the pandemic challenge, continued in providing patients access to treatment. This annual report of the EBMT reflects current activities useful for health care planning.
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3.
Impact of gut fungal and bacterial communities on the outcome of allogeneic hematopoietic cell transplantation
Malard, F., Lavelle, A., Battipaglia, G., Gaugler, B., Dulery, R., Brissot, E., Mediavilla, C., Jegou, S., Rolhion, N., Ledraa, T., et al
Mucosal immunology. 2021
Abstract
Patients receiving allogeneic hematopoietic cell transplantation (alloHCT) were previously shown to display a bacterial gut dysbiosis; however, limited data are available regarding the role of fungal microbiota in these patients. We evaluated the bacterial and fungal composition of the fecal microbiota at day 0 of alloHCT. Higher bacterial diversity was associated with an improved overall survival (OS) and disease-free survival (DFS). While fungal diversity had no impact on patient outcomes, we observed that high versus low relative abundance of Candida albicans in alloHCT patients at day 0 was associated with a significantly lower OS, DFS and graft-versus-host-free, relapse-free survival (GRFS) (p?=?0.0008, p?=?0.0064 and p?=?0.026, respectively). While these results are limited by low patient numbers and low fungal read counts in some samples, they suggest a potentially important role for C albicans in alloHCT.
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4.
Compatibility at amino acid position 98 of MICB reduces the incidence of graft-versus-host disease in conjunction with the CMV status
Carapito, R., Aouadi, I., Pichot, A., Spinnhirny, P., Morlon, A., Kotova, I., Macquin, C., Rolli, V., Cesbron, A., Gagne, K., et al
Bone marrow transplantation. 2020
Abstract
Graft-versus-host disease (GVHD) and cytomegalovirus (CMV)-related complications are leading causes of mortality after unrelated-donor hematopoietic cell transplantation (UD-HCT). The non-conventional MHC class I gene MICB, alike MICA, encodes a stress-induced polymorphic NKG2D ligand. However, unlike MICA, MICB interacts with the CMV-encoded UL16, which sequestrates MICB intracellularly, leading to immune evasion. Here, we retrospectively analyzed the impact of mismatches in MICB amino acid position 98 (MICB98), a key polymorphic residue involved in UL16 binding, in 943 UD-HCT pairs who were allele-matched at HLA-A, -B, -C, -DRB1, -DQB1 and MICA loci. HLA-DP typing was further available. MICB98 mismatches were significantly associated with an increased incidence of acute (grade II-IV: HR, 1.20; 95% CI, 1.15 to 1.24; P < 0.001; grade III-IV: HR, 2.28; 95% CI, 1.56 to 3.34; P < 0.001) and chronic GVHD (HR, 1.21; 95% CI, 1.10 to 1.33; P < 0.001). MICB98 matching significantly reduced the effect of CMV status on overall mortality from a hazard ratio of 1.77 to 1.16. MICB98 mismatches showed a GVHD-independent association with a higher incidence of CMV infection/reactivation (HR, 1.84; 95% CI, 1.34 to 2.51; P < 0.001). Hence selecting a MICB98-matched donor significantly reduces the GVHD incidence and lowers the impact of CMV status on overall survival.
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5.
The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR T-cell therapy
Ljungman, P., Mikulska, M., de la Camara, R., Basak, G. W., Chabannon, C., Corbacioglu, S., Duarte, R., Dolstra, H., Lankester, A. C., Mohty, M., et al
Bone marrow transplantation. 2020;55(11):2071-2076
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Editor's Choice
Abstract
The new coronavirus SARS-CoV-2 has rapidly spread over the world causing the disease by WHO called COVID-19. This pandemic poses unprecedented stress on the health care system including programs performing allogeneic and autologous hematopoietic cell transplantation (HCT) and cellular therapy such as with CAR T cells. Risk factors for severe disease include age and predisposing conditions such as cancer. The true impact on stem cell transplant and CAR T-cell recipients in unknown. The European Society for Blood and Marrow Transplantation (EBMT) has therefore developed recommendations for transplant programs and physicians caring for these patients. These guidelines were developed by experts from the Infectious Diseases Working Party and have been endorsed by EBMT's scientific council and board. This work intends to provide guidelines for transplant centers, management of transplant candidates and recipients, and donor issues until the COVID-19 pandemic has passed.
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Pre-emptive rituximab treatment for Epstein-Barr virus reactivation after allogeneic hematopoietic stem cell transplantation is a worthwhile strategy in high-risk recipients: a comparative study for immune recovery and clinical outcomes
Stocker, N., Labopin, M., Boussen, I., Paccoud, O., Bonnin, A., Malard, F., Amiel, C., Gozlan, J., Battipaglia, G., Dulery, R., et al
Bone marrow transplantation. 2019
Abstract
This retrospective study evaluated the impact of a pre-emptive rituximab (RTX) strategy for Epstein-Barr virus (EBV) reactivation on immune recovery and outcomes of 219 high-risk recipients undergoing allogeneic stem cell transplantation (allo-SCT) for hematological malignancies or bone marrow failure. One-hundred and seven patients received pre-emptive RTX for EBV reactivation (RTX group) and 112 did not (control group). The median onset time of EBV reactivation was 49 days (range, 14-561), including five patients who developed post-transplant lymphoproliferative disorder (EBV-PTLD). RTX and control groups were pair-matched to assess the impact of RTX on all endpoints. In RTX patients, CD19 + B cells were significantly decreased until 1-year post-transplant, so were immunoglobulin levels. Twenty-one patients (17%) developed RTX-related neutropenia. There was, in the RTX group, a trend towards a lower cumulative incidence of chronic GvHD (P = 0.059). Overall survival, progression-free survival, non-relapse mortality, relapse incidence, and incidence of overall infections at 2 years following allo-SCT were comparable in the two groups. We conclude that pre-emptive RTX, despite inducing a delayed B-cell reconstitution and a high risk of RTX-related neutropenia, may be considered as a worthwhile treatment, given the absence of negative impact on post allo-SCT outcomes and a low incidence of EBV-PTLD.
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Features of Toxoplasma gondii reactivation after allogeneic hematopoietic stem-cell transplantation in a high seroprevalence setting
Paccoud, O., Guitard, J., Labopin, M., Surgers, L., Malard, F., Battipaglia, G., Dulery, R., Hennequin, C., Mohty, M., Brissot, E.
Bone marrow transplantation. 2019
Abstract
We performed a single-centre retrospective study to evaluate the effectiveness of Toxoplasma gondii prevention strategies after allogeneic stem-cell transplantation. The charts of 138 allogeneic stem-cell recipients over a 4-year period were reviewed. Forty-nine percent of patients were not receiving optimal trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis at day +30, mainly due to persistent cytopenia. Six months after transplantation, the rate of toxoplasmosis reactivation was 11.6%, including nine cases of Toxoplasma infection and seven cases of Toxoplasma disease. Fifty-six percent of cases of reactivation occurred before day +30. Thirty-eight percent occurred in patients receiving atovaquone prophylaxis. In 57% of patients presenting with Toxoplasma disease, signs of disease were present at first evidence of Toxoplasma DNA in peripheral blood samples. This study illustrates the limitations inherent to currently used toxoplasmosis prevention strategies and argues for the use of a combined prophylactic and preemptive approach. After performing the initial study, we limited the use of atovaquone in favour of TMP-SMZ when possible, and implemented an early prevention strategy consisting of the introduction of prophylaxis starting on day of engraftment. Over the following 16 months, 88.9% of eligible Toxoplasma-seropositive patients were receiving TMP-SMZ at day +30, and the rate of early Toxoplasma reactivation was 1.5%.
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Infectious complications after post-transplantation cyclophosphamide and anti-thymocyte globulin-based haploidentical stem cell transplantation
Mohty, R., Brissot, E., Battipaglia, G., Ruggeri, A., Dulery, R., Bonnin, A., Mediavilla, C., Sestili, S., Belhocine, R., Vekhoff, A., et al
British journal of haematology. 2019
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Incidence, Risk Factors and Long-Term Outcome of Acute Leukemia Patients with Early Candidemia after Allogeneic Stem Cell Transplantation. A Study by the Acute Leukemia and Infectious Diseases Working Parties of EBMT
Cesaro, S., Tridello, G., Blijlevens, N., Ljungman, P., Craddock, C., Michallet, M., Martin, A., Snowden, J. A., Mohty, M., Maertens, J., et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018
Abstract
Objectives: To assess the incidence of, and risk factors for, Candida infection in the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT) and the impact on long-term survival. Methods: outcome analysis of 28,542 acute leukemia patients who underwent HSCT from 2000 to 2012: 347 with candidemia by day +100, and 28,195 without candidemia or any other type of Candida infection. Results: The incidence of candidemia by day +100 was 1.2% (347/28542) and occurred at a median of 22 days after HSCT (range 1-100). A higher 100-day non-relapse-mortality (NRM) (HR 3.0, p <0.0001), and a lower 100-day overall-survival (OS) (HR 2.5, p<0.0001) were observed in patients with candidemia. The case fatality rate by day +100 in patients with candidemia was 22% (76/347). Factors associated with candidemia occurrence were: gender female, bone marrow or cord blood stem cell source, T-cell depletion, use of total body irradiation, and acute graft versus host disease. Among the patients alive at day +100, the 5-year NRM and OS after a median follow-up of 5.6 years (95% CI 5.5 - 5.7) for patients with and without candidemia were 22.5% vs. 13.5%, p <0.0001, and 45.6% vs. 53.4%, p=0.0003, respectively. In multivariate analysis, the occurrence of a candidemia episode by day +100 was an independent risk factor for higher NRM, HR 1.7, p=0.001, and lower OS, HR 1.4, p=0.001. Conclusions: despite the general improvements in prophylaxis and treatment, the early occurrence of candidemia after HSCT is still associated with higher NRM and lower short-and-long-term OS.
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10.
Influence of pre-existing invasive aspergillosis on allo-HSCT outcome: a retrospective EBMT analysis by the Infectious Diseases and Acute Leukemia Working Parties
Penack, O., Tridello, G., Hoek, J., Socie, G., Blaise, D., Passweg, J., Chevallier, P., Craddock, C., Milpied, N., Veelken, H., et al
Bone Marrow Transplantation. 2016;51(3):418-23
Abstract
Historically, invasive aspergillosis (IA) has been a major barrier for allogeneic hematopoietic stem cell transplantation (allo-HSCT). The influence of invasive IA on long-term survival and on transplant-related complications has not been investigated in a larger patient cohort under current conditions. Our aim was to analyze the long-term outcome of patients undergoing allo-HSCT with a history of prior IA. We used European Society for Blood and Marrow Transplantation database data of first allo-HSCTs performed between 2005 and 2010 in patients with acute leukemia. One thousand one hundred and fifty patients with data on IA before allo-HSCT were included in the analysis. The median follow-up time was 52.1 months. We found no significant impact of IA on major transplant outcome variables such as overall survival, relapse-free survival, non-relapse mortality, cumulative incidence of acute GvHD grade II-IV, chronic GvHD, pulmonary complications and leukemia relapse. However, we found a trend toward lower overall survival (P=0.078, hazard ratio (HR) (95% confidence interval (CI)): 1.16 (0.98, 1.36)) and higher non-relapse mortality (P=0.150, HR (95% CI): 1.19 (0.94, 1.50)) in allo-HSCT recipients with pre-existing IA. Our data suggest that a history of IA should not generally be a contraindication when considering the performance of allo-HSCT in patients with acute leukemia.