The first patient was a 4-year-old male child (whose mother was an Ethiopian) affected by acute lymphoblastic leukemia who underwent allo-HSCT after total body irradiation (TBI)-based myeloablative conditioning. GVHD prophylaxis was performed with tacrolimus only. Prophylaxis of liver complications was performed with ursodeoxycholic acid (UDCA), 30 mg/kg/day, from the first day of conditioning. During the pre-transplant work-up, the child was subjected to abdominal magnetic resonance evaluation of abdominal organ iron concentration. He was found to have severe IO with an iron concentration value higher than 200 micromol/g (normal value: <40 micromol/g) in three of the four organs evaluated (ie, in spleen, bone, and liver, except pancreas), and the child underwent chelation therapy with deferoxamine (30 mg/kg/day, continuous intravenous infusion) during the entire stay in the Transplant Unit.
The post-transplantation period was complicated by a severe VOD, with a complete inversion of the portal flow and an important ascite (Figure 1). The severity of the clinical picture was further complicated by a hyperacute GVHD, characterized by hypertransaminasemia with aspartate aminotransferase and an alanine aminotransferase value higher than 800 U/L (normal values: <38 U/L and <25 U/L, respectively). The portal flow returned to normal after 10 days of defibrotide treatment. Hepatic GVHD resolved completely after three doses of infliximab.
After ascites resolution, a liver biopsy was performed and a histological evaluation showed the presence of central ischemic-hemorrhagic necrosis suggestive of VOD and a high degree of IO. Another histological feature was ductopenia (absence of interlobular bile ducts in portal tracts) suggestive of liver GVHD (Figure 2).
The patient underwent a second MRI-based iron load evaluation before discharge from our Transplant Unit and showed a general worsening of iron accumulation. All four abdominal organs evaluated had an abnormal iron concentration. The liver, spleen, and bone showed a higher degree of siderosis compared to pre-transplant values. Ferritin values stabilized around 3,000 ng/mL (normal range: 20-300 ng/mL).
Therefore, the patient was treated with DFX at a dosage of 375 mg/day (17.6 mg/kg). One month later, he was readmitted to our Unit with a marked deterioration of clinical conditions. He experienced fatigue, weakness, nausea, vomiting, abdominal pain, and anorexia that had begun one week before. Laboratory investigations on admission showed a normal white blood cell count with mild neutropenia, a normal platelets count, and hemoglobin concentration. His liver and renal function was mildly deranged. Furthermore, he was found to have a metabolic acidosis.
Primary disease recurrence was excluded. Prednisone at a dosage of 1 mg/kg was added to tacrolimus as systemic GVHD was suspected. To correct acidosis, the patient was hydrated by administering electrolyte solution enriched with bicarbonate.
Measurement, by high performance liquid chromatography (HPLC) assay, previously described and validated, of DFX plasma concentration confirmed a moderate increase of the drug plasmatic level (Ctrough =27 microM; normal Ctrough value <20 microM; CDFX/DDFX ratio =0.56). Tacrolimus therapeutic plasma concentrations were maintained at about 10 ng/mL.
He continued to demonstrate mild liver and renal dysfunction during the following month, while metabolic acidosis progressively worsened. The child underwent another liver biopsy that showed a histological feature suggestive of drug-induced liver injury (DILI) (Figure 3). After 79 days of chelation treatment, DFX was immediately stopped. His biochemical parameters normalized rapidly after discontinuation of DFX and the bicarbonate supplement was stopped two weeks later (see Table 1).