In this issue of Blood, Maradei and colleagues investigate the role of prehematopoietic stem cell transplantation hyperferritinemia as a risk factor for sinusoidal obstruction syndrome.1 They show that increased levels of ferritin (presumptively reflecting increased iron stores) increases the incidence of this complication after allogeneic transplantation.
Iron is the 6th most abundant element in the universe comprising most of the constituents of the Earth (35%).2 Going from the big picture of the universe to the smaller theater of human life, iron is important in many biologic processes. Iron biology and potential implications of iron overload have not received much attention in hematopoietic stem cell transplantation (HSCT), largely due to the lack of practical ways to address excess body iron during the peritransplantation period. Consequently, there has been a discrepancy between the explosion of biologic and genetic knowledge and clinical application as it pertains to iron overload significance and treatment in HSCT.
Ferritin keeps iron in a nonreactive state, preventing the Fenton chemical reaction that leads to the formation of oxygen radicals. Although most ferritin is kept intracellularly, the circulating fraction is used as a surrogate for iron stores. Interestingly, little is known about the role of serum ferritin compared to transferrin.3 Moreover, ferritin is an acute phase reactant and may be elevated for a variety of reasons.
Maradei et al show that a pretransplant ferritin level above 1000 ng/dL is an independent risk factor for decreased 5-year survival and is associated with a high incidence of hepatic sinusoidal obstruction syndrome (SOS, also referred to as veno-occlusive disease or VOD), a poorly understood but often deadly complication of HSCT. Allogeneic transplantation, busulfan-based conditioning regimen, and use of imatinib before HSCT completed the list of SOS-associated risk factors identified by multivariate analysis.
The authors had pretransplant ferritin levels from most of the patients from their institution and used a standard clinical definition of SOS. No transfusion information was provided, and there were no other measurements of iron stores, such as MRI of the liver.4 The rate of SOS was high, a phenomenon frequently seen when busulfan is given orally without dose adjustments. The high rates of SOS likely allowed the statistical detection of the ferritin effect. The limitations in estimating the actual iron stores here raise an issue: If the ferritin elevation does not reflect iron stores, what does this association tell us? In addition, the increased risk of SOS with pre-SCT imatinib observation is potentially important (although based on a small subgroup), and deserves evaluation in larger cohorts.
If iron overload jeopardizes transplant outcomes, will iron chelation be beneficial, analogous to what is observed in thalassemia? This is a complex question to study in a clinical trial. Chelation is not a quick process, which limits its use before transplantation for aggressive hematologic malignancies. Side effects and drug interactions will have to be considered as well, especially after HSCT where multiple medications are the rule. Another important issue is the extent to which the innate immune system is affected by excess iron or by pharmacologic treatment. Chelation may be feasible before HSCT for indolent malignant and nonmalignant conditions, although data supporting the efficacy of this approach are lacking in most diseases. A trial of posttransplantation chelation is unlikely to be effective in preventing SOS, which is an early complication of transplantation. Furthermore, proving that chelation will improve long-term survival will require large studies with extended follow-up.
Until such prospective trials are completed, it seems prudent to include pre-HSCT ferritin level as a risk factor for patients undergoing allogeneic transplantation, as suggested by Maradei in this issue of Blood, or by Armand et al among others.5 Hopefully, the rapid advances in the field of iron biology will lead to new therapeutic/prophylaxis paradigms, which, in turn, will help us better understand hepatic toxicity in HSCT.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■
