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Tesi etd-11102018-140214

Type of thesis
Corsi integrativi di I livello
Author
DI GANGI, ALESSANDRO
URN
etd-11102018-140214
Title
The impact of CMV reactivation on hematopoietic stem cell transplantation in children with malignancies: a 13 years single center experience
Structure
Cl. Sc. Sperimentali - Medicina
Course
SCIENZE MEDICHE - Medicina e chirurgia (DM 270)
Committee
Membro Dott. MEOLA, MARIO
Presidente Prof. RECCHIA, FABIO ANASTASIO
Membro Prof. PASSINO, CLAUDIO
Membro Prof. EMDIN, MICHELE
Membro Prof. LIONETTI, VINCENZO
Membro Dott.ssa ANGELONI, DEBORA
Membro Dott.ssa PETRUCCI, ILARIA
Relatore Dott.ssa MENCONI, MARIACRISTINA
Membro Prof. COCEANI, FLAVIO
Keywords
  • cytomegalovirus
  • hematopoietic stem cell transplantation
  • outcomes
  • pediatrics
Exam session start date
;
Availability
parziale
Abstract
After the introduction of pre-emptive therapy, the incidence of CMV disease (CMVD) dramatically decreased in HSCT recipients, while indirect effects of CMV infection (CMVI) are still under investigation. Therefore, our aim was to critically evaluate indirect effects of CMVI in pediatric HSCT for malignancies.<br>We retrospectively analyzed children (aged&lt;18 years) who underwent first allogeneic HSCT for malignancies at our institution between 01/2003 and 12/2016. CMVI was defined as virus isolation or detection of viral proteins (antigen pp65) or nucleic acid in any body fluid or tissue specimen while the definition of CMVD required specific organ signs/symptoms combined with CMV documented in the involved tissue by virus isolation, rapid culture, histopathology, immunohistochemistry or DNA hybridization techniques. Patients were classified according to the presence of CMVI. 5-years probabilities of OS, DFS, GVHD-free relapse-free survival (GRFS) and infection were calculated using the Kaplan-Meier method and the log-rank test. Cumulative incidence procedure, Pepe and Mori’s test and Gray’s test were used to assess differences in relapse, NRM, acute graft versus host disease (aGVHD) grades 2-4, extensive cGVHD (e-cGVHD), neutrophils and platelets engraftment. Cox regression was applied for univariate and multivariate analysis.<br>Ninety-two patients were included (CMVI N=40). Groups were homogeneous for age, sex, diagnosis, donor (MSD N=13, MUD N=31, MMUD N=22, haploidentical (HAPLO) N=12, UCBU N=15), stem cell source and graft composition with the exception of lower median cellularity in UCBU. Eleven HAPLO were lymphocyte-depleted (6 α/β+ and 5 CD3+/CD19+) while one received post-transplantation cyclophosphamide. HAPLO received mainly chemotherapy-based reduced-intensity conditioning regimens and grafts from peripheral blood while others received predominantly irradiation-based myeloablative regimens and bone marrow grafts.<br>No significant differences were reported for OS, DFS, infections, GRFS, relapse, NRM, and both neutrophils and platelets engraftment (p&gt;0.05). The mean day of CMVI diagnosis was 39.6 (28.2-51.0). Although statistically non-significant, aGVHD grade 2-4 was higher in CMVI+, suggesting a possible association. Moreover, the competing risk analysis on relapse has demonstrated that long-term rates of competing risks are similar among groups, while all the competing risk for aGVHD occurred early after HSCT in CMVI- when compared to CMVI+ suggesting that CMV reactivation is more likely a consequence of another event. Noticeable, aGVHD has often preceded CMVI (N=7 vs N=1). Furthermore, the use of steroids is significantly higher in CMVI+ when compared to CMVI- patients and this is not in relation to CMVI itself since steroids are avoided when possible in case of CMVI. Therefore, we suggest that steroids should be taken into consideration as the major risk factor for CMVI regardless of the presence of an active aGVHD. Pre-engraftment viremia was associated with delayed engraftment (median day +33 and +19 respectively for pre and post-engraftment viremia). Of note, stratification based on the onset of viremia was not performed for other outcomes. <br>The use of pre-emptive therapy ameliorates CMV indirect effects in pediatric HSCT recipients but the role of pre-engraftment viremia should be investigated. Moreover, we suggest the possibility to start a double anti-CMV regimen in patients at high risk of a “long-term” treatment with steroids for aGVHD. However, a prospective evaluation with a careful assessment of the safety profile is required.
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