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A day 14 endpoint for acute GVHD clinical trials
Spyrou, N., Akahoshi, Y., Kowalyk, S., Morales, G., Beheshti, R., Aguayo-Hiraldo, P., Malki, M. M. A., Ayuk, F., Bader, P., Baez, J., et al
Transplantation and cellular therapy. 2024
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Editor's Choice
Abstract
The overall response (ORR) rate 28 days after treatment has been adopted as the primary endpoint for clinical trials of acute graft versus host disease (GVHD). However, physicians often need to modify immunosuppression earlier than day (D) 28, and non-relapse mortality (NRM) does not always correlate with ORR at D28. We studied 1144 patients that received systemic treatment for GVHD in the Mount Sinai Acute GVHD International Consortium and divided them into a training set (n=764) and a validation set (n=380). We used a recursive partitioning algorithm to create a Mount Sinai model that classifies patients into favorable or unfavorable groups that predicted 12 month NRM according to overall GVHD grade at both onset and D14. In the Mount Sinai model grade II GVHD at D14 was unfavorable for grade III/IV GVHD at onset and predicted NRM as well as the D28 standard response model. TheMAGIC algorithm probability (MAP) is a validated score that combines the serum concentrations of suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3-alpha (REG3α) to predict NRM. Inclusion of the D14 MAP biomarker score with the D14 Mount Sinai model created three distinct groups (good, intermediate, poor) with strikingly different NRM (8%, 35%, 76% respectively). This D14 MAGIC model displayed better AUC, sensitivity, positive and negative predictive value, and net benefit in decision curve analysis compared to the D28 standard response model. We conclude that this D14 MAGIC model could be useful in therapeutic decisions and may offer an improved endpoint for clinical trials of acute GVHD treatment.
PICO Summary
Population
Adults with acute GvHD receiving systemic treatment at a single center in USA (n=1144)
Intervention
Creation of a model that classifies patients into favorable or unfavorable groups, predicting 12 month non-relapse mortality
Comparison
Training set (n=764); Validation set (n=380)
Outcome
In the Mount Sinai model grade II GVHD at D14 was unfavorable for grade III/IV GVHD at onset and predicted NRM as well as the D28 standard response model. TheMAGIC algorithm probability (MAP) is a validated score that combines the serum concentrations of suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3-alpha (REG3α) to predict NRM. Inclusion of the D14 MAP biomarker score with the D14 Mount Sinai model created three distinct groups (good, intermediate, poor) with strikingly different NRM (8%, 35%, 76% respectively). This D14 MAGIC model displayed better AUC, sensitivity, positive and negative predictive value, and net benefit in decision curve analysis compared to the D28 standard response model.
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Risk factors for a severe disease course in children with SARS-COV-2 infection following hematopoietic cell transplantation in the pre-Omicron period: a prospective multinational Infectious Disease Working Party from the European Society for Blood and Marrow Transplantation group (EBMT) and the Spanish Group of Hematopoietic Stem Cell Transplantation (GETH) study
Averbuch, D., de la Camara, R., Tridello, G., Knelange, N. S., Bykova, T. A., Ifversen, M., Dobsinska, V., Ayas, M., Hamidieh, A. A., Pichler, H., et al
Bone marrow transplantation. 2023;:1-9
Abstract
Risk factors for severe SARS-Cov-2 infection course are poorly described in children following hematopoietic cell transplantation (HCT). In this international study, we analyzed factors associated with a severe course (intensive care unit (ICU) admission and/or mortality) in post-HCT children. Eighty-nine children (58% male; median age 9 years (min-max 1-18)) who received an allogeneic (85; 96%) or an autologous (4; 4%) HCT were reported from 28 centers (18 countries). Median time from HCT to SARS-Cov-2 infection was 7 months (min-max 0-181). The most common clinical manifestations included fever (37; 42%) and cough (26; 29%); 37 (42%) were asymptomatic. Nine (10%) children following allo-HCT required ICU care. Seven children (8%) following allo-HCT, died at a median of 22 days after SARS-Cov-2 diagnosis. In a univariate analysis, the probability of a severe disease course was higher in allo-HCT children with chronic GVHD, non-malignant disease, immune suppressive treatment (specifically, mycophenolate), moderate immunodeficiency score, low Lansky score, fever, cough, coinfection, pulmonary radiological findings, and high C-reactive protein. In conclusion, SARS-Cov-2 infection in children following HCT was frequently asymptomatic. Despite this, 10% needed ICU admission and 8% died in our cohort. Certain HCT, underlying disease, and SARS-Cov-2 related factors were associated with a severe disease course.
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Mother donors improve outcomes after HLA haploidentical transplantation: A Study by the Cellular Therapy and Immunobiology Working Party of the EBMT
Ruggeri, L., Eikema, D. J., Bondanza, A., Noviello, M., van Biezen, A., de Wreede, L. C., Crucitti, L., Vago, L., Ciardelli, S., Bader, P., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND Trans-placental trafficking of maternal and foetal cells during pregnancy establishes long-term, reciprocal micro-chimerism in both mother and child. As a consequence, the immune system of the mother may become sensitized to paternal histocompatibility antigens. It has been hypothesized that mother's "exposure" to paternal HLA haplotype antigens during pregnancy may affect transplantation outcomes when the mother acts as donor for the child. In T-cell depleted HLA haploidentical hematopoietic transplants, maternal donors have been shown to improve transplantation outcomes (Stern et al. Blood, 2008;112: 2990-2995). OBJECTIVES AND STUDY DESIGN The present retrospective multicenter study was conducted on behalf of Cellular Therapy and Immunobiology Working Party of the EBMT. It involved 409 patients (102 pediatric and 307 adult) with acute leukemia who were given HLA-haploidentical hematopoietic transplants. The goal of the study was to evaluate the role of maternal donors in a large cohort of haploidentical transplants. RESULTS Transplants from maternal donors were associated with lower relapse incidence in T-cell depleted (HR: 2.13 (1.16-3.92), p= 0.018) as well as in a limited series of unmanipulated, in vivo T-cell depleted transplants (HR: 4.15 (0.94-18.35), P=0.06) and also better graft-vs-host disease/relapse-free survival in T-cell depleted transplants (HR: 1.67 (1.02-2.73), p = 0.04). CONCLUSION These results indicate that the mother should be the preferred donor in order to provide better graft-vs-host disease/relapse-free survival in T-cell depleted HLA-haploidentical transplants for acute leukemia.
PICO Summary
Population
Adults and children with acute leukemia who underwent HSCT from a haploidentical family donor and were reported to the EBMT registry (n=409; 102 paediatric and 307 adult)
Intervention
Maternal donor (n=96)
Comparison
Other family donor (n=313)
Outcome
Transplants from maternal donors were associated with lower relapse incidence in T-cell depleted (HR: 2.13 (1.16-3.92) as well as in a limited series of unmanipulated, in vivo T-cell depleted transplants (HR: 4.15 (0.94-18.35) and also better graft-vs-host disease/relapse-free survival in T-cell depleted transplants (HR: 1.67 (1.02-2.73).
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Reg3α levels at day of allogeneic stem cell transplantation predict outcome and correlate with early antibiotic use
Weber, D. A., Weber, M., Meedt, E., Ghimire, S., Wolff, D., Edinger, M., Poeck, H., Hiergeist, A., Gessner, A., Ayuk, F. A., et al
Blood advances. 2022
Abstract
The intestinal microbiome diversity plays an important role in the pathophysiology of acute gastrointestinal (GI) Graft-versus-Host Disease (aGvHD) and influences the outcome of patients after allogeneic stem cell transplantation (SCT). We analyzed clinical data and blood samples taken pre-conditioning and on the day of allogeneic SCT from 587 patients from seven German centers of the Mount Sinai Acute GvHD International Consortium (MAGIC), dividing them into a single-center test cohort (n=371) and a multicenter validation cohort (n=216). Reg3α serum concentration of day 0 correlated with clinical data as well as urinary 3-Indoxylsulfate and Clostridiales group XIVa, indicators of intestinal microbiome diversity. High Reg3α concentration at day 0 of allogeneic SCT was associated with higher 1-year transplant-related mortality (TRM) in both cohorts (p<0.001). Cox regression analysis revealed high Reg3α at day 0 as an independent prognostic factor for 1-year TRM (HR=2.9, 95%CI=1.8-4.8, p<0.001). Multivariable analysis showed an independent correlation of high Reg3α concentrations at day 0 and early systemic antibiotic treatment (OR=3.1, 95% CI = 2.0-4.8, p<0.001). Urinary 3-Indoxylsulfate (p=0.04) and Clostridiales group XIVa (p=0.004) were lower in patients with high Reg3α day 0 concentrations than in low Reg3α patients. In contrast, Reg3α concentrations prior to conditioning therapy correlated with neither TRM nor disease or treatment-related parameters. Reg3α, a known biomarker of acute GI GvHD correlates with intestinal dysbiosis induced by early antibiotic treatment in the period of pretransplant conditioning. Serum concentrations of Reg3α measured on the day of graft infusion are predictive of the risk for TRM of allogenic SCT recipients.
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Hematopoietic stem cell transplantation in children and adolescents with GATA2-related myelodysplastic syndrome
Bortnick, R., Wlodarski, M., de Haas, V., De Moerloose, B., Dworzak, M., Hasle, H., Masetti, R., Starý, J., Turkiewicz, D., Ussowicz, M., et al
Bone marrow transplantation. 2021
Abstract
GATA2 deficiency is a heterogeneous multi-system disorder characterized by a high risk of developing myelodysplastic syndrome (MDS) and myeloid leukemia. We analyzed the outcome of 65 patients reported to the registry of the European Working Group (EWOG) of MDS in childhood carrying a germline GATA2 mutation (GATA2(mut)) who had undergone hematopoietic stem cell transplantation (HSCT). At 5 years the probability of overall survival and disease-free survival (DFS) was 75% and 70%, respectively. Non-relapse mortality and relapse equally contributed to treatment failure. There was no evidence of increased incidence of graft-versus-host-disease or excessive rates of infections or organ toxicities. Advanced disease and monosomy 7 (-7) were associated with worse outcome. Patients with refractory cytopenia of childhood (RCC) and normal karyotype showed an excellent outcome (DFS 90%) compared to RCC and -7 (DFS 67%). Comparing outcome of GATA2(mut) with GATA2(wt) patients, there was no difference in DFS in patients with RCC and normal karyotype. The same was true for patients with -7 across morphological subtypes. We demonstrate that HSCT outcome is independent of GATA2 germline mutations in pediatric MDS suggesting the application of standard MDS algorithms and protocols. Our data support considering HSCT early in the course of GATA2 deficiency in young individuals.
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Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation
Uppugunduri, C. R. S., Huezo-Diaz Curtis, P., Nava, T., Rezgui, M. A., Mlakar, V., Mlakar, S. J., Waespe, N., Théoret, Y., Gumy-Pause, F., Bernard, F., et al
The pharmacogenomics journal. 2021
Abstract
Acute Graft versus Host Disease (aGvHD) grades 2-4 occurs in 15-60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2-4 in 60 pediatric patients. The cumulative incidence of aGvHD 2-4 was 12% (n?=?7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2-4 [Odds ratios?=?14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3-191.8), respectively, multiple testing corrected p?=?0.001]. Upon evaluation in an extended cohort (n?=?182) with an incidence of aGvHD 2-4 of 22% (n?=?40), only MGMT rs10764881 (G>A) remained significant (adjusted HR?=?2.05 [95% CI: 1.06-3.94]; p?=?0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.
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Risk factors for mixed chimerism in children with hemophagocytic lymphohistiocytosis after reduced toxicity conditioning
Wustrau, K., Greil, J., Sykora, K. W., Albert, M. H., Burkhardt, B., Lang, P., Meisel, R., Wossmann, W., Beier, R., Schulz, A., et al
Pediatric blood & cancer. 2020;:e28523
Abstract
BACKGROUND Reduced toxicity conditioning for hematopoietic stem cell transplantation of patients with hemophagocyticlymphohistiocytosis (HLH) results in favorable survival, however at the expense of relevant rates of mixed chimerism. Factors predisposing to mixed chimerism remain to be determined. PROCEDURE Patients with primary HLH transplanted 2009-2016 after treosulfan- or melphalan-based conditioning regimens were analyzed in a retrospective multicenter study for survival, engraftment, chimerism, and adverse events. Mixed chimerism was considered substantial if < 25% donor chimerism occurred and/or if secondary cell therapy was administered. Donor type, graft source, type of alkylating agent, type of serotherapy, and remission status were analyzed as potential risk factors in a multivariable logistic regression model. RESULTS Among 60 patients, engraftment was achieved in 95%, and the five-year estimated overall survival rate was 75%. Prevalence of any recipient chimerism was 48%. Substantial recipient chimerism was recorded in 32% of patients. Secondary post-HSCT cell therapy was administered in 30% of patients. A human leukocyte antigen (HLA)-mismatched donor (< 10/10) was the only significant risk factor for the occurrence of substantial recipient chimerism (P = 0.01; odds ratio, 5.8; CI 95%, 1.5-26.3). CONCLUSION The use of an HLA-matched donor is the most important factor to avoid substantial recipient chimerism following treosulfan -or melphalan-based conditioning in primary HLH.
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Prognostic impact of EBV serostatus in patients with lymphomas or chronic malignancies undergoing allogeneic HCT
Styczynski, J., Tridello, G., Gil, L., Ljungman, P., Mikulska, M., Ward, K. N., Cordonnier, C., de la Camara, R., Averbuch, D., Knelange, N., et al
Bone marrow transplantation. 2019
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Editor's Choice
Abstract
The influence of the donor (D) and recipient (R) pre-transplant Epstein-Barr Virus (EBV) serostatus on transplant outcomes (overall survival, relapse-free survival, relapse incidence, non-relapse mortality, acute and chronic GVHD) in 12,931 patients with lymphomas or chronic malignancies undergoing allogeneic hematopoietic cell transplant (allo-HCT) between 1997-2016 was analyzed. In multivariate analysis, the risk of development of chronic GVHD was increased for EBV R+/D+ (HR = 1.26; p = 0.003), R+/D- (HR = 1.21; p = 0.044), and R-/D + (HR = 1.21; p = 0.048) in comparison to R-/D- transplants. No significance was shown for other transplant outcomes; however, in univariate analysis, EBV-seropositive patients receiving grafts from EBV-seropositive donors (EBV R+/D+transplants) had inferior transplant outcomes in comparison to EBV-seronegative recipients of grafts from EBV-seronegative donors (EBV R-/D-): inferior overall survival (59.6% vs 65.9%), inferior relapse-free survival (51.1% vs 57.5%), increased incidence of chronic GVHD (49.5% vs 41.8%), and increased incidence of de novo chronic GVHD (30.5% vs 24.0%). In conclusion, an EBV-negative recipient with lymphoma or chronic malignancy can benefit from selection of an EBV-negative donor in context of chronic GVHD, while there are no preferences in donor EBV serostatus for EBV-seropositive recipient.
PICO Summary
Population
Patients with lymphomas or chronic malignancies undergoing allogeneic hematopoietic cell transplant between 1997-2016 (n=12,931)
Intervention
Epstein-Barr virus seropositive donors (D+) and/or recipients (R+)
Comparison
Epstein-Barr virus seronegative donors (D-) and/or recipients (R-)
Outcome
In multivariate analysis, the risk of development of chronic GVHD was increased for EBV R+/D+, R+/D- and R-/D + in comparison to R-/D- transplants. No significance was shown for other transplant outcomes; however, in univariate analysis, EBV-seropositive patients receiving grafts from EBV-seropositive donors (EBV R+/D+transplants) had inferior transplant outcomes in comparison to EBV-seronegative recipients of grafts from EBV-seronegative donors (EBV R-/D-): inferior overall survival (59.6% vs 65.9%), inferior relapse-free survival (51.1% vs 57.5%), increased incidence of chronic GVHD (49.5% vs 41.8%), and increased incidence of de novo chronic GVHD (30.5% vs 24.0%).
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Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors
Styczynski, J., Tridello, G., Koster, L., Iacobelli, S., van Biezen, A., van der Werf, S., Mikulska, M., Gil, L., Cordonnier, C., Ljungman, P., et al
Bone marrow transplantation. 2019
Abstract
Information on incidence, and factors associated with mortality is a prerequisite to improve outcome after hematopoietic stem cell transplantation (HSCT). Therefore, 55'668 deaths in 114'491 patients with HSCT (83.7% allogeneic) for leukemia were investigated in a landmark analysis for causes of death at day 30 (very early), day 100 (early), at 1 year (intermediate) and at 5 years (late). Mortality from all causes decreased from cohort 1 (1980-2001) to cohort 2 (2002-2015) in all post-transplant phases after autologous HSCT. After allogeneic HSCT, mortality from infections, GVHD, and toxicity decreased up to 1 year, increased at 5 years; deaths from relapse increased in all post-transplant phases. Infections of unknown origin were the main cause of infectious deaths. Lethal bacterial and fungal infections decreased from cohort 1 to cohort 2, not unknown or mixed infections. Infectious deaths were associated with patient-, disease-, donor type, stem cell source, center, and country- related factors. Their impact varied over the post-transplant phases. Transplant centres have successfully managed to reduce death after HSCT in the early and intermediate post-transplant phases, and have identified risk factors. Late post-transplant care could be improved by focus on groups at risk and better identification of infections of "unknown origin".
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Presence of centromeric but absence of telomeric group B KIR haplotypes in stem cell donors improve leukaemia control after HSCT for childhood ALL
Babor, F., Peters, C., Manser, A. R., Glogova, E., Sauer, M., Potschger, U., Ahlmann, M., Cario, G., Feuchtinger, T., Gruhn, B., et al
Bone marrow transplantation. 2019
Abstract
Although allogeneic hematopoietic stem-cell transplantation (HSCT) provides high cure rates for children with high-risk acute lymphoblastic leukaemia (ALL), relapses remain the main cause of treatment failure. Whereas donor killer cell immunoglobulin-like receptor (KIR) genotype was shown to impact on relapse incidence in adult myeloid leukaemia similar studies in paediatric ALL are largely missing. Effect of donor KIR genotype on transplant outcome was evaluated in 317 children receiving a first myeloablative HSCT from an HLA-matched unrelated donor or sibling within the prospective ALL-SCT-BFM-2003 trial. Analysis of donor KIR gene polymorphism revealed that centromeric presence and telomeric absence of KIR B haplotypes was associated with reduced relapse risk. A centromeric/telomeric KIR score (ct-KIR score) integrating these observations correlated with relapse risk (hazard ratio (HR) 0.58; P = 0.002) while it had no impact on graft-versus-host disease or non-relapse mortality. In multivariable analyses ct-KIR score was associated with reduced relapse risk (HR 0.58; P = 0.003) and a trend towards improved event-free survival (HR 0.76; P = 0.059). This effect proved independent of MRD level prior to HSCT. Our data suggest that in children with ALL undergoing HSCT after myeloablative conditioning, donor selection based on KIR genotyping holds promise to improve clinical outcome by decreasing relapse risk and prolonged event-free survival.