Iron overload is a common complication in allogeneic hematopoietic cell transplantation (HCT). We studied the prevalence of iron overload using serum ferritin from 122 allogeneic HCT survivors who had survived a median of 1259 (range 134-4261) days. We also quantified iron overload by determining non-transferrin-bound iron (NTBI), which reflects iron overload more directly than ferritin, and compared the results with those of the ferritin assay. Fifty-two patients (43 %) showed hyperferritinemia (HF) (serum ferritin >1000 ng/mL), and there was a moderate correlation between serum ferritin and the number of transfused red blood cell units (ρ = 0.71). In multivariate analyses, HF was a significant risk factor for liver dysfunction (P = 0.0001) and diabetes (P = 0.02), and was related to a lesser extent with performance status (P = 0.08). There was a significant correlation between serum ferritin and NTBI (ρ = 0.59); however, the association of NTBI with these outcomes was weaker than that of serum ferritin. In conclusion, serum ferritin is a good surrogate marker of iron overload after allogeneic HCT, and reflects organ damage more accurately than NTBI.

Hemophagocytic syndrome (HPS) induced by uncontrolled macrophage activation and subsequent graft failure is a frequent and prominent complication after allogeneic stem cell transplantation (allo-SCT), a cause of severe morbidity and death, and a therapeutic challenge. Liposome-incorporated dexamethasone, dexamethasone palmitate (DP), shows greater efficacy against macrophages as compared to dexamethasone sodium phosphate (DSP). Based on our findings that DP achieves significantly larger decrease than DSP on the viability of primary human macrophages compared in vitro, we tested the effects of DP in patients with HPS. A decrease in number of macrophages in the bone marrow and prevention of engraftment failure were observed in all patients without any severe complications. In conclusion, these data provide a rationale for testing DP as a first-line treatment for patients with HPS after allo-SCT.

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Little is known regarding the chimerism status after reduced-intensity conditioning transplantation when bone marrow is used as a stem cell source. We prospectively analyzed lineage-specific chimerism and retrospectively evaluated clinical outcomes in 80 adult patients who underwent unrelated donor bone marrow transplantation (URBMT) with fludarabine plus melphalan (FM) as the conditioning regimen. Mixed donor chimerism (MDC) was seen in 43 and 10 % of patients at days 14 and 28, respectively. Melphalan at ≤130 mg/m(2) was associated with an increased incidence of MDC at day 28 (P = 0.03). Patients with MDC at day 14 showed a marginally increased risk of primary graft failure and a marginally decreased risk of graft-versus-host disease. In multivariate analysis, MDC at day 14 was associated with higher overall mortality (hazard ratio (HR) = 2.1; 95 % confidence interval (CI), 1.1-4.2; P = 0.04) and relapse rate (HR = 3.0; 95 % CI, 1.2-7.5; P = 0.02), but not with non-relapse mortality (HR = 1.8; 95 % CI, 0.70-4.6; P = 0.23). Thus, the FM regimen yields prompt complete donor chimerism after URBMT, but the melphalan dose significantly impacts the kinetics of chimerism. Chimerism status evaluation at day 14 may be instrumental in predicting relapse after URBMT with the FM regimen.

3455 Background: 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. Methods: 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. Results: 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). Conclusion: 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. Disclosures: Sasaki: Novartis Pharma K. K.: Research Funding. Kohgo: Novartis Pharma K. K.: Research Funding.