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.

Iron overload is a common complication of allogeneic hematopoietic cell transplantation(HCT) ; however, its management remains to be studied. We retrospectively analyzed the efficacy and safety of low-dose deferasirox treatment in four HCT survivors with iron overload and measured serum ferritin levels, liver iron concentrations (LIC) , and non-transferrin-bound iron(NTBI)levels. Patients who had become transfusion-independent after HCT were treated using 10 mg／kg／day deferasirox. Their median age was 36.5 years(range, 27-39) , and they had survived a median of 66 months(range, 27-101)after HCT. After a median of 23.5 months(range, 16-34)of deferasirox treatment, serum ferritin levels and LIC decreased in all patients, and NTBI decreased in three patients. The median ferritin levels, LIC, and NTBI levels decreased from 6135 (range, 3720-10,500) to 1782 ng／mL (range, 775-6840) , 24.6(range, 9.6-43.0)to 7.8 mg／g(range, 2.8-42.3) , and 1.26(range, 0.89-2.09)to 0.82μmol／L (range, 0.64-1.54) , respectively. Abnormal liver function tests improved in all patients after deferasirox treatment. On the other hand, all patients experienced an increase in serum creatinine levels. In conclusion, treatment with low-dose deferasirox might be an effective alternative for allogeneic HCT survivors with iron overload.

Cord blood is an alternative graft source for patients lacking sibling or unrelated marrow donors, however since there has been no affiliation with cord blood banks overseas, foreign cord blood unit(CBU)is not available in Japan. Here we report the first successful case of cord blood transplantation coordinated through the National Marrow Donor Program(NMDP)for a 34-year-old Filipina of mixed race with AML, weighning 78.5 kg. She underwent a conventional preparative regimen and was infused with a 4／6 serologically HLA-matched Asian female CBU with sufficient total nucleated cells and CD34 ＋ cell count. Neutrophil recovery was delayed as late as on 42 days post transplantation. This was caused by a low viability of only 31.5% measured in our facility before infusion, whereas the viability before cryopreservation at the cord blood bank was reportedly 91.0%. The patient developed no fatal complications including graft-versus-host disease. The duration of the coordination process is expected to become shorter with the full collaboration between the cord blood banks in Japan and NMDP. Relatively high nucleated cell number of CBU in NMDP also serves to overcome the difficult task of finding a donor for patients with heavy weight. The great cost is also a major problem. (Journal of Hematopoietic Cell Transplantation 5 (1) : 18-21, 2016.)

Introduction Delayed engraftment and subsequent engraftment failure cause fatal complications including severe infection and lead to poor prognosis after allogeneic hematopoietic stem cell transplantation (allo-SCT). We have previously reported that hemophagocytic syndrome (HPS) induced by uncontrolled macrophage activation in bone marrow had high mortality due to engraftment failure (BMT.2012;47:387–394). Macrophages are phagocytic cells with abilities of phagocytosis, antigen-presenting, and secretion of cytokines. Although phagocytosis reflects only a part of their activation, their morphological changes or increased cell counts can be used for evaluating their activation. Our hypothesis was that macrophage activation would have intrinsic value whether it would meet diagnostic criteria for HPS or not. In this study, we analyzed the clinical impact of activated macrophages in bone marrow during the peri-enrgaftment period in patients with delayed engraftment and engraftment failure. Patients and Methods We retrospectively reviewed 212 adult patients who received a first allo-SCT for hematological diseases from January 2006 to December 2011 in our institution. Delayed engraftment was defined that neutrophil engraftment was achieved later than day 15, 20 and 27 post peripheral blood stem cell, bone marrow and cord blood transplantation, respectively, whereas engraftment failure was defined that engraftment was never observed including those who received second allo-SCT. Bone marrow clot sections of day 14±7 and day 28±7 post allo-SCT were analyzed by staining macrophages with anti-CD163 monoclonal antibody. CD163 is a member of the scavenger receptor cystein-rich superfamily and is an exclusive marker for macrophages, playing a major role in the scavenging components of damaged cells. Recently macrophages with an unrestrained proinflammatory activation state along with highly expressed CD163 were reported (JCI.2011;121:985–97). Therefore, the total number of CD163 positive-macrophages was counted in three fields at a 200-fold magnification. We calculated the ratio of macrophages (mac ratio), dividing the number of macrophages by the total cell counts per field. Total area of CD163 positive-macrophages was measured with a digital microscope (BZ-9000, Keyence, Japan). The size of a macrophage was estimated total area of CD163+/ number of CD163 positive-macrophages. Results Delayed engraftment and engraftment failure were observed in 17 (8.0%) and 7 (3.3%) out of 212 patients, respectively. Median mac ratio of day 14 marrow was 0.09 (0.03-0.28), 0.54 (0.15-0.82) and 0.57 (0.46-0.65), whereas that of day 28 marrow was 0.05 (0.02-0.08), 0.25 (0.14-0.70) and 0.53 (0.33-0.82) in normal engraftment, delayed engraftment and engraftment failure groups, respectively. Both delayed engraftment and engraftment failure groups had significantly higher mac ratio in both day 14 and 28 than normal engraftment group (p=0.0002, 0.002 at day 14, p=0.0000, 0.0004 at day 28, respectively). Between delayed engraftment and engraftment failure groups, mac ratio was significantly higher in engraftment failure group in day 28 marrow (p=0.04), while no difference was observed in day 14 marrow (p=0.64). Higher mac ratio than 0.5 could predict delayed engraftment or engraftment failure in day14 marrow (p=0.002), and engraftment failure in day 28 marrow (p=0.000). Only 1 patient of 7 engraftment failure patients (14%) met the criteria of HPS, while mac ratio of 5 patients (71%) was >0.5 at day14. The size of macrophages at day 14 was significantly larger in delayed engraftment and engraftment failure groups than normal engraftment group (p=0.03; 1682.2 μm2 in engraftment failure, 1537.1 μm2 in delayed engraftment and 1054.3 μm2 in normal engraftment, respectively), which indicated the activation of macrophages. Conclusion Increased number of activated macrophages in bone marrow during the peri-engraftment period post allo-SCT was associated with subsequent delayed engraftment and engraftment failure. Our data also suggest that delayed engraftment and engraftment failure could be predicted by the mac ratio of day 14 and 28 marrow, which could be more sensitive marker than the criteria of HPS. This study suggests rationale for macrophage-targeted therapy among patients with the proliferation of activated macrophages in their bone marrow to prevent engraftment failure. Disclosures: No relevant conflicts of interest to declare.

In allogeneic hematopoietic stem cell transplantation (allo-HSCT) from unrelated donors, delays in donor search are adversely associated with patient outcome. However, the optimal duration for either waiting for an unrelated donor or selecting alternative sources remains undetermined. Using data from the Japan Marrow Donor Program (JMDP) registry, we retrospectively analyzed 349 adult patients who had searched for unrelated donors. Two hundred and three patients received allo-HSCT from JMDP donors (Group A) with a median of 140 days required to identify a donor, 60 received allo-HSCT from alternative sources (Group B) after a median of 111.5 days at which point either all donor candidates had failed or the patient achieved a second or subsequent complete remission, and 77 suspended allo-HSCT (Group C) after a median of 310 days. The 5-year overall survival (OS) rate in Group A was superior to that of Group C (48.6 vs 38.5%, P = 0.001). Although Group B included more patients with high or very high disease risk index (DRI) at the time of allo-HSCT compared with Group A, the 5-year OS was not significantly different between Groups A and B (48.6 vs 40.9%, P = 0.07), indicating that switching to alternative donors may benefit patients with high DRI.