Risk Factors and Measures to Prevent Liver and Pancreas Complications in Pediatric Patients After HSCT

Hematopoietic Stem Cell Transplantation (HSCT) is currently a standard procedure for a wide range of blood-oncological diseases and genetic disorders. Recent improvements in transplant technologies, infection prevention and graft-versus-host-disease (GVHD) management procedures have significantly reduced the transplant-related mortality (TRM). However, approximately 50% of pediatric patients may develop liver dysfunction before HSCT and 74% to 85.5% after HSCT, with a TRM related to liver dysfunction reaching 46%. The liver and pancreas complications still remain too high for the difficulties and diagnostic inefficiencies and, consequently, for the lack of targeted and safer therapies. The diagnostic problems can be summarized in 3 major points: a) the histological examination of liver and pancreas parenchyma cannot be routinely performed because of the organ anatomy and the relative risk of the bioptic procedures; b) the lack of specific biomarkers or advanced imaging techniques appropriate for the diagnosis of HSCT complications; c) the multifactorial causes of organ complications, as well as drug toxicities, GVHD, siderosis, ductopenia (considered as an index of hepatic GVHD), the accumulation of potentially toxic substances favored by siderosis and ductopenia. In more than 50% of HSCT patients, siderosis and/or ductopenia may represent common pathological conditions. Furthermore, international guidelines issued by onco-hematology and transplantation scientific societies recommend a chelating treatment with deferasirox in all hematological and oncological patients undergoing an intense transfusion regimen. However, in the presence of siderosis and marked ductopenia, patients receiving deferasirox may experience both severe renal and hematological toxicities and lack of effectiveness of the chelating treatment.

Therefore, the principal aim of the present retrospective study will be the evaluation of the transplant-related mortality (TRM) in patients requiring a chelation treatment according to the Italian guidelines in pediatric patients

The present retrospective study will be conducted at the Bone Marrow Transplant Center, IRCCS Burlo Garofolo, Trieste, Italy. All pediatric patients who underwent one or more allogeneic HSCTs between 2010 and 2018 will be enrolled according to inclusion/exclusion criteria.

The following data will be collected in a retrospective manner:

* Data on the underlying disease (diagnosis, therapeutic protocol, transfusion regimen, possible relapses, type of transplant, conditioning regimen, infectious complications, immunosuppressive treatment, including use of steroids);
* Pre-transplant liver and pancreatic function, as well as quantification of iron content by nuclear magnetic resonance (MRI);
* Pre-transplant histological evaluation of liver parenchyma in case of pre-existing liver disease;
* Post-transplant liver and pancreatic function and the evaluation of parenchymal accumulation of Fe+;
* Length and doses of DFX treatment, and corresponding drug plasma concentrations as per routine drug monitoring protocols;
* Treatment tolerability according to CTC-AE grading V5.0, November 27, 2017 The post-transplant data will be collected within 2 years from HSCT (or the last HSCT when more than one).

The data entered in an appropriate anonymous database will be processed by descriptive statistics and uni- multivariate statistical analyses according to study endpoints. DFX plasma concentrations will be analyzed by means of to a nonlinear mixed effect modeling approach to elaborate a population pharmacokinetic (POP/PK) model. POP/PK findings will be further analyzed together with clinical and laboratory data.

Eligibility Criteria:
Inclusion Criteria:

* one or more allogeneic HSCT
* any type of disease (blood-oncological or genetic), from any type of donor (sibling, MUD, haploidentical) and with any source of stem cells (spinal cord, peripheral blood stem cells, cord blood)
* diagnosis of moderate-to-severe siderosis (by nuclear magnetic resonance imaging, MRI) and who needed a chelation treatment with deferasirox
* one or more liver biopsies in the post-transplant period to perform histological examinations
* Complete results from lab analyses
* 2-year follow-up after HSCT
* therapeutic drug monitoring (TDM) protocol for deferasirox plasma concentration as per clinical routine
* Sign of the informed consent by the parents or legal representatives

Exclusion Criteria:

* Lack of liver biopsies after transplantation, results from laboratory analyses or TDM or MRI
* Lack of informed consent