Iron Overload In Adult Allogeneic Hematopoietic Stem Cell Transplantation Survivors: Quantification of Iron Burden by Determining Non-Transferrin-Bound Iron.

Iron overload (IO) is a relatively common complication in allogeneic hematopoietic stem cell transplant (AHSCT) recipients who frequently need red blood cell transfusions. The estimation of IO is currently based on serum ferritin (SF) level, but in HSCT recipients, many confounding factors can result in ferritin overestimation. Non-transferrin-bound iron (NTBI), which is detected in conditions of iron overload when transferrin becomes fully saturated and unable to bind excess iron, is thought to catalyze the formation of reactive radicals. We studied the prevalence of IO in adult AHSCT survivors and quantified IO by determining NTBI.

A total of 116 patients were enrolled in this study, who underwent their first AHSCT in our institute, survived ≥100 days from AHSCT in continuous remission and were returning for follow-up at our institute between August 2009 and March 2010.

The median age at AHSCT was 37 (range, 17–65) years. Primary diagnosis included acute leukemia/myelodysplastic syndrome (n=77) and aplastic anemia (n=14). Conditioning regimens were myeloablative (n=81) and reduced intensity (n=35). Donors were HLA-matched (n=99) and mismatched (n=17), and related (n=48) and unrelated (n=68). Graft sources were bone marrow (n=89), peripheral blood (n=18) and cord blood (n=9). Graft-versus-host disease (GVHD) prophylaxis consisted of a combination of short-term methotrexate and tacrolimus (n=66) or cyclosporine (n=50). The incidence of grade II-IV acute GVHD was 22%, and that of chronic GVHD was 49%. The median SF level was 911 (range, 14–10, 500) ng/ml, and 49 patients (42%) had hyperferritinemia (HF) (SF>1000 ng/ml). The median time from HSCT to SF assessment was 1276 (range, 134–4213) days, and was similar between patients with and without HF. No significant correlation was found between HF and the presence of cGVHD (p=0.48). There was a moderate correlation between SF level and the number of packed red blood cell units transfused from the diagnosis of underlying disease (ρ=0.69, p<0.0001). Only 22 of the 67 patients (33%) without HF had at least 1 abnormal liver function test (LFT), including aspartate aminotransferase (AST), alanine aminotransferase (ALT), gammaglutamyl transpeptidase (γ-GTP) and alkaline phosphatase (ALP), whereas 31 of the 49 patients (63%) with HF (p=0.001). The median AST, ALT, and γ-GTP values determined at the time of iron status assessment were significantly higher in patients with HF. In multivariate analysis, HF was a significant risk factor for the presence of abnormal LFTs (OR=3.5; 95% CI=1.6-7.6). Six patients with HF evaluated by MRI all had findings suggesting liver hemosiderosis. The rate of diabetes showed a higher tendency in patients with HF compared to those without HF (27% versus 12%; p=0.053). The median NTBI value was significantly higher in patients with HF (median, 0.72 μmol/l; range, 0.28–2.09 μmol/l) compared to those without it (median, 0.28 μmol/l; range, 0.04–0.55 μmol/l) (p<0.0001). In addition, there was a statistically significant correlation between SF and the NTBI level (ρ=0.74, p<0.0001). All of the patients with HF showed more than the normal range of NTBI (male: 0.206 ± 0.091; female: 0.212 ± 0.095 mmol/l).

At first, we assume that SF after AHSCT is affected by alloimmune reaction and infection and SF could not be used for precise monitoring of IO. However, the current study demonstrated that SF was well correlated with NTBI and that SF can be used for monitoring IO after AHSCT. Humans do not have any physiological mechanisms to excrete excess iron, and the current study showed that many long-term survivors after AHSCT, independently of RBC transfusion, had HF and high NTBI levels. It suggested that IO is a common feature after AHSCT. HF is an independent risk factor for abnormal LFTs in AHSCT survivors as well as diabetes to a lesser extent. These results prompt us to further evaluate the benefit of iron chelating therapy or phlebotomy for patients who suffer from liver dysfunction or diabetes.

Sasaki: Novartis Pharma K. K.: Research Funding. Kohgo: Novartis Pharma K. K.: Research Funding.