Does Iron Overload Really Matter in Stem Cell Transplantation?

Abstract

Abstract 3029 Background:In patients with hematologic malignancies undergoing myeloablative hematopoietic stem cell transplantation (HSCT), an elevated serum ferritin prior to HSCT has been consistently associated with increased mortality. While serum ferritin is strongly correlated with liver iron content (LIC), to date no study has directly examined the effect of elevated LIC on HSCT outcomes. Furthermore, there are no studies of pre-transplantation chelation in this population. We conducted 2 prospective studies in patients with AML, ALL, or MDS undergoing HSCT. In the first, 45 patients were followed for >1 year with serial measurements of serum iron parameters and liver and cardiac iron (by MRI). In the second, we treated patients with severe iron overload (ferritin ≥ 1000 ng/ml and liver iron content (LIC) ≥ 5 mg/gdw) with deferoxamine 50 mg/kg/d starting in the weeks prior to transplantation and continuing until day -1, with the goal of controlling labile plasma iron (LPI) and especially the expected conditioning-induced rise in LPI. Results:The baseline characteristics of the patients on the observational study have been described in a prior publication (Armand et al., BBMT 2011). 5 patients (2 with AML in CR, 2 with AML and active disease, 1 with MDS) were enrolled on the chelation study; the median serum ferritin was 3, 746 ng/ml, and LIC 11.7 mg/gdw. They received deferoxamine for a median of 19 days before stem cell infusion. No significant drug-related toxicity occurred except for one episode of transient hypotension. There was no significant change in LIC after this short course of chelation. None of the 5 patients had a positive LPI assay before chelation or at the onset of conditioning; however, despite deferoxamine treatment, 2/5 had elevated LPI post-conditioning. Among those 5 patients, there was no disease relapse or death at a median follow-up of 20 months; only 1 patient developed grade II acute GVHD, and no patient developed VOD.Among the 50 patients in both studies combined, there was no significant change in serum ferritin, LIC or cardiac T2* in the first year after HSCT. After a median follow-up of 24 months, the estimated 2y overall survival (OS) and progression-free survival were 54% and 46%, respectively. When patients on the chelation study were excluded, there was a significant difference in OS for patients with pre-HSCT ferritin > 2, 500 ng/ml (2y OS 21% versus 62%, p =0.03) (Figure, panel A), similar to prior studies. However, there was no difference in OS, PFS, relapse or NRM for patients stratified by pre-HSCT LIC, regardless of the cutoff used and whether or not chelated patients were included (Figure, panel B). There was also no discernible impact of LIC on acute GVHD or VOD incidence. The difference in OS based on ferritin was apparent even among the patients with LIC<5 mg/gdw. Those results were confirmed in multivariable analyses. [Display omitted] Conclusion:We confirmed prospectively that pre-HSCT ferritin is an important prognostic marker in patients with AML, ALL or MDS undergoing HSCT. However, despite the strong correlation between ferritin and LIC, elevated LIC does not itself appear to be associated with survival. Thus, the prognostic value of ferritin may reflect other factors, such as inflammatory state, rather than iron burden. This calls into question the negative adverse impact attributed to iron overload in this population. Pre-transplantation chelation is challenging and does not reliably prevent the rise in LPI with conditioning. Despite this, our results in a very small number of patients raise the question of a possible beneficial effect of deferoxamine administered before HSCT that may be independent of parenchymal or labile iron chelation. Disclosures:Armand:Novartis Oncology: Research Funding. Neufeld:Novartis: Research Funding; Ferrokin BioSciences: Research Funding.