In the past, much research had been focused on iron overload and its adverse effects caused solely by multiple blood transfusions in diseases such as beta-thalassemia major and other chronic anemia (11
). Recently, as the number of survivors with high-risk malignancy increases, particularly after SCT which requires multiple transfusions during pre- and post-SCT period, iron overload has become an increasingly important risk factor for outcome in these patients (14
). Iron overload in SCT recipients may have different, more severe manifestations and must therefore be evaluated differently from that in chronic anemia patients who do not receive chemoradiotherapy. It is well established that a higher pre-SCT iron level is associated with more frequent various toxicities during SCT and a higher toxic death rate (15
). However, studies for iron status and its late adverse effects during post-SCT follow-up are very limited (18
). Thus, our primary objective was to demonstrate the trend of iron levels during follow-up at various time points after tandem HDCT/autoSCT in children with high-risk neuroblastoma and factors contributing to its sustained levels, as well as major organ functions affected by iron overload.
Because HDCT/autoSCT recipients do not need RBC transfusion after engraftment, iron levels are expected to decrease over time, particularly in growing children. Indeed, ferritin levels steadily decreased without iron chelation after HDCT/autoSCT in the present study. Nevertheless, when the number of CD34+ cells transplanted was low, patients required prolonged RBC transfusion after HDCT/autoSCT, and accordingly, their ferritin levels at 1 yr after tandem HDCT/autoSCT were high. There was a strong correlation between the number of CD34+ cells and RBC transfusion amount during the post-SCT period. A lower CD34+ cell number was associated with a greater need of RBC transfusion, which in turn led to higher serum ferritin levels at 1 yr after tandem HDCT/autoSCT. The number of CD34+ cells was an independent factor affecting the ferritin level at 1 yr after tandem HDCT/autoSCT. Most clinical reports concerning SCT have used neutrophil and platelet recovery as parameters for hematologic recovery after SCT. However, findings in the present study suggest that RBC recovery should also be considered as a significant parameter assessing the hematologic recovery and outcome after SCT.
About half of the patients in the present study maintained ferritin levels > 1,000 ng/mL at 1 yr after the tandem HDCT/autoSCT. In these patients, renal glomerular function was significantly worse than their counterparts (ferritin levels < 1,000 ng/mL) at 1 yr after tandem HDCT/autoSCT. There was no difference in glomerular function prior to HDCT/autoSCT between the two groups. These findings suggest a possible correlation between high ferritin levels and impairment of glomerular function during post-SCT follow-up. However, at present, it is not clear if hyperferritinemia is directly responsible for impaired glomerular function during post-SCT follow-up because all of our patients had received intensive induction and HDCT with various nephrotoxic agents, and therefore might already have subclinical renal dysfunction after tandem HDCT/autoSCT. Longer follow-up and a larger cohort of patients may be needed to elucidate if heperferritinemia is responsible for impairment of glomerular function during post-SCT follow-up.
We previously showed that deferasirox treatment prior to tandem HDCT/autoSCT is effective at lowering pre-SCT serum ferritin levels, thereby lowering the frequency of hepatic veno-occlusive disease and infection during tandem HDCT/autoSCT in children with neuroblastoma and brain tumors (19
). However, at present, experience of iron chelation treatment after SCT, particularly with deferasirox, is very limited. Elevation of serum creatinine levels during deferasirox treatment has frequently been reported (19
), and the US Food and Drug Administration (FDA) black box warning for deferasirox includes renal failure (21
). This poses as a challenge in using deferasirox to treat iron overload in HDCT/autoSCT recipients, as they may be more susceptible to possible adverse effects of iron chelation treatment than chronic anemia patients due to previous chemoradiotherapy. Furthermore, the present study showed that renal glomerular function at 1 yr after tandem HDCT/autoSCT was already lower in patients with high ferritin levels. Taken together, findings in the present study suggest that the use of iron chelators such as deferasirox should be approached with caution in patients who underwent HDCT/autoSCT.
We used serum ferritin as a measure of iron overload in the present study because repeated measurements can be performed without difficulty to establish trends in iron burden over time. However, previous publications have suggested that this may not be a reliable indicator of iron overload (22
). Serum ferritin may be increased due to liver dysfunction, may act as an acute phase reactant of infectious complications, and may be increased in other SCT-related complications. More specific measures of iron overload include liver MRI and liver biopsy. Therefore, it may be important in further testing our hypothesis to use liver biopsy or MRI to better quantify iron overload.
In summary, we demonstrated for the first time that ferritin levels sustained high even at 1 yr after tandem HDCT/autoSCT when the number of CD34+ cells transplanted was low, and accordingly, patients required prolonged RBC transfusion after HDCT/autoSCT. We acknowledge the limitations present in our small single-institution study and believe that further validation in patients with other solid tumors and a longer follow-up period for assessing organ function are necessary. Nonetheless, our results strongly support the notion that further modalities of collecting more CD34+ cells must be researched in order to reduce RBC transfusion amount, lower ferritin level, and possibly decrease organ dysfunction related to iron overload in patients with high-risk solid tumors.