Estimating systemic iron stores in stem cell transplant patients is challenging. Serum ferritin has frequently been used as an estimate of systemic iron stores, but is prone to false elevation in the setting of inflammation and malignancy . Other blood markers, such as transferrin saturation and soluble transferrin receptor, have proven to be even less successful in establishing the diagnosis of iron overload [14, 15]. Non-invasive imaging techniques, such as T2* MRI, show promise for determining tissue iron stores but have not been extensively studied in transplant patients . The current "gold standard" for assessing systemic iron overload remains dependent on liver biopsy . However, invasive procedures are often not practical in patients awaiting stem cell transplant, as thrombocytopenia and neutropenia are common. Because of these difficulties, there is no consensus on how to best determine iron status in the transplant setting .
We identified three clinical markers of iron overload that were associated with decreased survival: (1) transfusion burden, (2) serum ferritin, and (3) bone marrow iron stores. Intuitively, each of these is a marker of transfusion related iron overload, and all have been used separately to estimate iron overload in transplant and non-transplant studies [5, 6, 19]. Each marker we identified also has the advantage of being readily available in the clinical setting, as exemplified by the high availability within our study.
In comparison to individual iron parameters, the Transplant Iron Score was more closely associated with transplant outcomes. Specifically, the iron score was more closely associated with survival than ferritin quartiles, which have previously been used to estimate pre-transplant iron overload . Additionally, the iron score identified 35 percent of our study patients as having a "high" score, whereas quartiles by definition only identify the highest 25 percent. This suggests the Transplant Iron Score may be simultaneously more accurate and more inclusive than other proposed markers of iron overload in the transplant setting. Further evidence of the potential power of the iron score was seen in multivariate analysis, where the iron score maintained significance while controlling for other risk factors.
Using the Transplant Iron Score, we investigated the mechanism by which iron overload influences transplant survival. Classically, excess iron accumulates over decades resulting in progressive heart and liver dysfunction and eventually leading to premature death . In contrast, our results demonstrate that iron overload at the time of transplant results in early mortality, and suggest that this process is not dependent on end-organ damage. Also differing from "classic" iron overload, our data suggests that a relatively low systemic iron burden is sufficient to substantially alter transplant survival. In adults, transfusion with more than 100 units of blood is generally required prior to clinical evidence of iron overload [20, 21]. Meanwhile, even our patients with a high iron score had only 46 units of pRBCs on average. Taken together, our results suggest that iron overload in the transplant setting influences mortality by an alternate mechanism of action, differing from the classic model of chronic free-radical induced organ damage. Interestingly, the degree of iron overload necessary to impact transplant survival appears to be sub-clinical, underscoring the need for a more sensitive clinical marker of iron such as the Transplant Iron Score.
To further explore the mechanism by which iron overload influences survival, we closely examined the cause of death for each of the transplant recipients. We observed that treatment related mortality occurred more frequently in those patients with a high iron score. The majority of these deaths resulted from infection, thereby suggesting that lethal infection is the dominant mechanism by which iron overload influences transplant survival. While it has been suggested that iron overload predisposes to infection [4, 5, 22], to our knowledge, this is the first report showing an independent association between iron overload and infection related mortality.
In addition to adding insight into the mechanism of action of transplant iron overload, our study also helps to define its clinical applicability. Specifically, our study simultaneously compares the impact of iron overload in both the autologous and allogeneic transplant setting. Using the Transplant Iron Score to define iron overload in both groups, we found allogeneic transplant patients to be at a disproportionately high risk of death associated with iron overload. Our data suggests that iron overload as a prognostic marker may be limited to, or at least more pronounced in, patients undergoing allogeneic stem cell transplant.
We acknowledge the limitations inherent in our small single-institution study and believe that validation of the Transplant Iron Score is necessary prior to its incorporation into clinical practice. Nevertheless, our results strongly support the notion that iron overload prior to transplant is detrimental and provide rationale to study chelation therapy within the transplant setting. Typically, there is only a small window of opportunity between when a patient is identified as needing transplantation and when the transplant is undertaken. If patients with iron overload are detected early in this process, it is conceivable that iron chelation could minimize the negative impact of iron overload on transplant survival. This exciting possibility merits study in a prospective randomized fashion.