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1.
Influence of invasive aspergillosis during acute leukaemia treatment on survival after allogeneic stem cell transplantation: a prospective study of the EBMT Infectious Diseases Working Party
Penack, O., Tridello, G., Salmenniemi, U., Martino, R., Khanna, N., Perruccio, K., Fagioli, F., Richert-Przygonska, M., Labussière-Wallet, H., Maertens, J., et al
EClinicalMedicine. 2024;67:102393
Abstract
BACKGROUND Infections are the main reason for mortality during acute leukaemia treatment and invasive aspergillosis (IA) is a major concern. Allogeneic stem cell transplantation (alloSCT) is a standard therapy and often is the only live-saving procedure in leukaemia patients. The profound immunodeficiency occurring after alloSCT led to high IA-associated mortality in the past. Therefore, patients with IA were historically considered transplant-ineligible. Recently, there has been improvement of anti-fungal management including novel anti-fungal agents. As a result, more leukaemia patients with IA are undergoing alloSCT. Outcome has not been prospectively assessed. METHODS We performed a prospective study in acute leukaemia patients undergoing alloSCT to analyse the impact of a prior history of probable or proven IA (pre-SCT IA). The primary endpoint was 1-year non-relapse mortality (NRM). Relapse free survival and overall survival were analysed as secondary endpoints. FINDINGS 1439 patients were included between 2016 and 2021. The incidence of probable or proven pre-SCT IA was 6.0% (n = 87). The cumulative incidence of 1-year NRM was 17.3% (95% CI 10.2-26.0) and 11.2% (9.6-13.0) for patients with and without pre-SCT IA. In multivariate analyses the hazard ratio (HR) for 1-year NRM was 2.1 (1.2-3.6; p = 0.009) for patients with pre-SCT IA. One-year relapse-free survival was inferior in patients with pre-SCT IA (59.4% [48.3-68.9] vs. 70.4 [67.9-72.8]; multivariate HR 1.5 [1.1-2.1]; p = 0.02). Consequently, 1-year overall survival was lower in patients with pre-SCT IA (68.8% [57.8-77.4] vs. 79.0% [76.7-81.1]; multivariate HR 1.7 [1.1-2.5]; p = 0.01). INTERPRETATION Pre-SCT IA remains to be significantly associated with impaired alloSCT outcome. On the other hand, more than two thirds of patients with pre-SCT IA were alive at one year after alloSCT. IA is not anymore an absolute contraindication for alloSCT because the majority of patients with IA who undergo alloSCT benefit from this procedure. FUNDING There was no external funding source for this study.
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2.
Cytogenetic abnormalities predict survival after allogeneic hematopoietic stem cell transplantation for pediatric acute myeloid leukemia: a PDWP/EBMT study
Sharma, A., Galimard, J. E., Pryce, A., Bhoopalan, S. V., Dalissier, A., Dalle, J. H., Locatelli, F., Jubert, C., Mirci-Danicar, O., Kitra-Roussou, V., et al
Bone marrow transplantation. 2024
Abstract
Poor-risk (PR) cytogenetic/molecular abnormalities generally direct pediatric patients with acute myeloid leukemia (AML) to allogeneic hematopoietic stem cell transplant (HSCT). We assessed the predictive value of cytogenetic risk classification at diagnosis with respect to post-HSCT outcomes in pediatric patients. Patients younger than 18 years at the time of their first allogeneic HSCT for AML in CR1 between 2005 and 2022 who were reported to the European Society for Blood and Marrow Transplantation registry were subgrouped into four categories. Of the 845 pediatric patients included in this study, 36% had an 11q23 abnormality, 24% had monosomy 7/del7q or monosomy 5/del5q, 24% had a complex or monosomal karyotype, and 16% had other PR cytogenetic abnormalities. In a multivariable model, 11q23 (hazard ratio [HR] = 0.66, P = 0.03) and other PR cytogenetic abnormalities (HR = 0.55, P = 0.02) were associated with significantly better overall survival when compared with monosomy 7/del7q or monosomy 5/del5q. Patients with other PR cytogenetic abnormalities had a lower risk of disease relapse after HSCT (HR = 0.49, P = 0.01) and, hence, better leukemia-free survival (HR = 0.55, P = 0.01). Therefore, we conclude that PR cytogenetic abnormalities at diagnosis predict overall survival after HSCT for AML in pediatric patients.
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Multivariate Analysis of Immune Reconstitution and Relapse Risk Scoring in Children Receiving Allogeneic Stem Cell Transplantation for Acute Leukemias
Spadea, M., Saglio, F., Tripodi, S. I., Menconi, M., Zecca, M., Fagioli, F.
Transplantation direct. 2021;7(11):e774
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Abstract
A timely and effective immune reconstitution after hematopoietic stem cell transplantation (HSCT) is of crucial importance to enhance graft-versus-leukemia reaction in hematological malignancies. Several factors can influence the yield of this process, and new mathematical models are needed to describe this complex phenomenon. METHODS We retrospectively analyzed immune reconstitution in the early post-HSCT period in a multicenter cohort of 206 pediatric patients affected by acute lymphoblastic leukemia, acute myeloblastic leukemia, and myelodysplastic syndrome who received their first allo-HSCT. All patients were in complete morphological remission at transplantation and were followed-up at least 26 mo post-HSCT. Blood samples for analysis of lymphocyte subset numbers were collected at day 100 (±20 d). RESULTS The 2-y cumulative incidence of relapse was 22.2% (95% confidence interval [CI], 17.3-27). Using principal component analysis, we identified based on 16 input variables a new multivariate model that enables patients' description in a low-dimensional model, consisting of the first 2 principal components. We found that the numbers of CD3(+)/CD4(+)/CD8(+) lymphocyte subsets at day 100 post-HSCT and acute graft-versus-host disease had the greatest impact in preventing relapse. We ultimately derived a risk score defining high- or medium-low-risk groups with 2-y cumulative incidence of relapse: 35.3% (95% CI, 25.6-45) and 15.6% (95% CI, 10.1-20.7), respectively (P ?=?0.001*). CONCLUSIONS Our model describes immune reconstitution and its main influencing factors in the early posttransplantation period, presenting as a reliable model for relapse risk prediction. If validated, this model could definitely serve as a predictive tool and could be used for clinical trials or for individualized patient counseling.
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Allelic HLA Matching and Pair Origin Are Favorable Prognostic Factors for Unrelated Hematopoietic Stem Cell Transplantation in Neoplastic Hematologic Diseases: An Italian Analysis by the Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti
Picardi, A., Sacchi, N., Miotti, V., Lorentino, F., Oldani, E., Rambaldi, A., Sessa, M., Bruno, B., Cerno, M., Vago, L., et al
Transplantation and cellular therapy. 2021;27(5):406.e1-406.e11
Abstract
HLA molecules are important for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti promoted a retrospective observational study to evaluate HLA matching and the impact of allelic HLA mismatching and non-HLA factors on unrelated Italian HSCT outcomes. From 2012 to 2015, 1788 patients were enrolled in the study. The average donor age was 29 years and the average recipient age was 49 years. As a conditioning regimen, 71% of the patients received myeloablative conditioning. For GVHD prophylaxis, 76% received either antithymocyte or anti-T lymphocyte globulin, cyclosporine A, and methotrexate. Peripheral blood was the stem cell source in 80%. The median duration of follow-up was 53 months. Regarding HLA matching, 50% of donor-recipient pairs were 10/10 matched, 38% had 1 mismatch, and 12% had 2 or more mismatches. A total of 302 pairs shared Italian origin. Four-year overall survival (OS), progression-free survival, GVHD-free relapse-free survival, and relapse rates were 49%, 40%, 22%, and 34%, respectively. The 4-year NRM was 27%, and the 100-day cumulative incidence of grade =II acute GVHD (aGVHD) was 26%. In multivariate analysis, 9/10 and =8/10 HLA allele-matched pairs were associated with worse OS (P = .04 and .007, respectively), NRM (P = .007 and P < .0001, respectively), and grade III-IV aGVHD (P = .0001 and .01, respectively). Moreover, the incidences of grade II-IV aGVHD (P = .001) and chronic GVHD (P = .002) were significantly lower in Italian pairs. In conclusion, 10/10 HLA matching is a favorable prognostic factor for unrelated HSCT outcome in the Italian population. Moreover, the presence of 2 HLA-mismatched loci was associated with a higher NRM (P < .0001) and grade II-IV aGVHD (P = .006) and a poorer OS (P = .001) compared with 1 HLA-mismatched locus in early or intermediate disease phases. Finally, we found that Italian donor and recipient origin is a favorable prognostic factor for GVHD occurrence.
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Hematopoietic stem cell transplantation for isolated extramedullary relapse of acute lymphoblastic leukemia in children
Gabelli, M., Zecca, M., Messina, C., Carraro, E., Buldini, B., Rovelli, A. M., Fagioli, F., Bertaina, A., Lanino, E., Favre, C., et al
Bone marrow transplantation. 2018
Abstract
Relapse of acute lymphoblastic leukemia (ALL) may occur in extramedullary sites, mainly central nervous system (CNS) and testis. Optimal post-remissional treatment for isolated extramedullary relapse (IEMR) is still controversial. We collected data of children treated with hematopoietic stem cell transplantation (HSCT) for ALL IEMR from 1990 to 2015 in Italy. Among 281 patients, 167 had a relapse confined to CNS, 73 to testis, 14 to mediastinum, and 27 to other organs. Ninety-seven patients underwent autologous HSCT, 79 received allogeneic HSCT from a matched family donor, 75 from a matched unrelated donor, and 30 from an HLA-haploidentical donor. The 10-year overall survival was 56% and was not influenced by gender, ALL blast immune-phenotype, age, site of relapse, duration of first remission, and type of HSCT. In multivariable analysis, the only prognostic factors were disease status at HSCT and year of transplantation. Patients transplanted in third or subsequent complete remission (CR) had a risk of death 2.3 times greater than those in CR2. Children treated after 2000 had half the risk of death than those treated before that year. Our results suggest that both autologous and allogeneic HSCT may be considered for the treatment of pediatric ALL IEMR after the achievement of CR2.
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Analysis of Mesenchymal Stromal Cell Engraftment After Allogeneic HSCT in Pediatric Patients: A Large Multicenter Study
Castello, L. M., Leone, M., Adamini, A., Castiglia, S., Mareschi, K., Ferrero, I., Marco, G., Carnevale-Schianca, F., Fagioli, F., Berger, M.
Journal of pediatric hematology/oncology. 2018
Abstract
The mesenchymal stem cell (MSC) role after allogeneic hematopoietic stem cell transplantation (HSCT) is still a matter of debate; in particular, MSC engraftment in recipient bone marrow (BM) is unclear. A total of 46 patients were analyzed for MSC and hemopoietic stem cell engraftment after HSCT. The majority of patients had the BM as the stem cell source, and acute leukemia was the main indication for HSCT. Mesenchymal and hematopoietic stem cell chimerism analysis was carried out through specific polymorphic tandemly repeated regions. All patients reached complete donor engraftment; no evidence of donor-derived MSC engraftment was noted. Our data indicate that MSCs after HSCT remain of recipient origin despite the following: (i) myeloablative conditioning; (ii) the stem cell source; (iii) the interval from HSCT to BM analysis; (iv) the underlying disease before HSCT; and (v) the patients' or the donors' age at HSCT.
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Pre- and post-transplant minimal residual disease predicts relapse occurrence in children with acute lymphoblastic leukaemia
Lovisa, F., Zecca, M., Rossi, B., Campeggio, M., Magrin, E., Giarin, E., Buldini, B., Songia, S., Cazzaniga, G., Mina, T., et al
British journal of haematology. 2018;180(5):680-693
Abstract
Relapse remains the leading cause of treatment failure in children with acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem cell transplantation (HSCT). We retrospectively investigated the prognostic role of minimal residual disease (MRD) before and after HSCT in 119 children transplanted in complete remission (CR). MRD was measured by polymerase chain reaction in bone marrow samples collected pre-HSCT and during the first and third trimesters after HSCT (post-HSCT1 and post-HSCT3). The overall event-free survival (EFS) was 50%. The cumulative incidence of relapse and non-relapse mortality was 41% and 9%. Any degree of detectable pre-HSCT MRD was associated with poor outcome: EFS was 39% and 18% in patients with MRD positivity <1 × 10(-3) and ≥1 × 10(-3) , respectively, versus 73% in MRD-negative patients (P < 0·001). This effect was maintained in different disease remissions, but low-level MRD had a very strong negative impact only in patients transplanted in second or further CR. Also, MRD after HSCT enabled patients to be stratified, with increasing MRD between post-HSCT1 and post-HSCT3 clearly defining cohorts with a different outcome. MRD is an important prognostic factor both before and after transplantation. Given that MRD persistence after HSCT is associated with dismal outcome, these patients could benefit from early discontinuation of immunosuppression, or pre-emptive immuno-therapy.
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Pentraxin 3 plasma levels at graft-versus-host disease onset predict disease severity and response to therapy in children given haematopoietic stem cell transplantation
Dander, E., De Lorenzo, P., Bottazzi, B., Quarello, P., Vinci, P., Balduzzi, A., Masciocchi, F., Bonanomi, S., Cappuzzello, C., Prunotto, G., et al
Oncotarget. 2016;7(50):82123-82138
Abstract
Acute Graft-versus-Host Disease (GvHD) remains a major complication of allogeneic haematopoietic stem cell transplantation, with a significant proportion of patients failing to respond to first-line systemic corticosteroids. Reliable biomarkers predicting disease severity and response to treatment are warranted to improve its management. Thus, we sought to determine whether pentraxin 3 (PTX3), an acute-phase protein produced locally at the site of inflammation, could represent a novel acute GvHD biomarker. Using a murine model of the disease, we found increased PTX3 plasma levels after irradiation and at GvHD onset. Similarly, plasma PTX3 was enhanced in 115 pediatric patients on day of transplantation, likely due to conditioning, and at GvHD onset in patients experiencing clinical symptoms of the disease. PTX3 was also found increased in skin and colon biopsies from patients with active disease. Furthermore, PTX3 plasma levels at GvHD onset were predictive of disease outcome since they resulted significantly higher in both severe and therapy-unresponsive patients. Multiple injections of rhPTX3 in the murine model of GvHD did not influence the disease course. Taken together, our results indicate that PTX3 constitutes a biomarker of GvHD severity and therapy response useful to tailor treatment intensity according to early risk-stratification of GvHD patients.