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Fetomaternal microchimerism has been demonstrated, and immunologic tolerance to unshared HLA antigens between mother and offspring may be suggested. We used T-cell-repleted bone marrow transplantation (BMT) from their HLA-haploidentical mothers to treat 6 patients with fatal nonmalignant diseases. The number of mismatched HLA loci in the graft -versus-host disease (GVHD) direction was 3 in 4 patients and 2 in 2 patients. The number in the host-versus-graft direction was 3 in 4 patients, 2 in 1 patient, and 1 in 1 patient. Microchimerism of inherited paternal antigens was demonstrated in 5 donors, and microchimerism of noninherited maternal antigens was detected in 3 recipients. GVHD prophylaxis consisted of short-course methotrexate, tacrolimus, and mycophenolate mofetil (3 patients) or short-course methotrexate, tacrolimus, and methylprednisolone (1 patient). Engraftment was achieved in 5 patients who had received preconditioning, and T-cell engraftment was confirmed in 1 patient with severe combined immunodeficiency. Acute GVHD developed in 3 patients: grade 1 in 2 patients and grade 2 in 1 patient. Chronic GVHD was observed in 5 patients: localized type in 3 patients and extended type in 2 patients. Five patients were alive 11 to 30 months after BMT and 1 patient died of chronic GVHD. Unmanipulated haploidentical BMT from a maternal donor may be the treatment of choice of poor-prognosis nonmalignant diseases.

Background: Changes in thyroid function among young patients who received bone marrow transplantation (BMT) were evaluated. Methods: The study included 91 patients (50 males) who underwent BMT from 1985 to 1995 at the age of 0.6−21 years. Sixty patients had neoplastic disease such as leukemia or lymphoma, and the remainder had non-neoplastic diseases. Preconditioning regimen for BMT included 12 Gy of fractionated-total body irradiation (TBI) for patients with neoplastic disease and 3−8 Gy of irradiation for the remaining patients, in addition to chemotherapy. Evaluation of thyroid function was performed by serial assessment of basal serum FT4, FT3, TSH concentrations as well as by TRH test. Results: No patient had overt hypothyroidism or elevated basal TSH concentrations (>10 mU/L). However, 6 (7%) of patients experienced exaggerated peak TSH response to TRH stimulation several years after BMT. In 33 patients whose thyroid status was evaluated before, within 3 months, and 1 year after BMT, serum FT3 concentrations as well as peak TSH response to TRH stimulation significantly decreased immediately after BMT (

The present study compares immune reconstitution after allogeneic cord blood transplantation (CBT) and CD34+ stem cell transplantation (CD34-SCT) with that after bone marrow transplantation (BMT). Eighty-eight children who underwent CBT (20 patients), BMT (58), and CD34-SCT (10) were enrolled, and lymphocytes and T-, B-, and natural killer—lymphocyte subsets were monitored for more than 5 years after transplantation. CBT recipients showed significant increases in (1) total lymphocyte counts (P < .001), (2) CD4+/CD8+ cell ratios (P < .01), (3) CD4+ and CD4+CD45RA+ cells (P < .001), (4) CD8+CD11b+ cells (P < .001), and (5) CD19+ and CD19+CD5+ cells (P < .0001) and marked decreases in the frequencies of CD8+ and CD8+CD11b- cells (P < .0001). CD34-SCT recipients showed lower lymphocyte counts in the first 6 months and an emergence of lymphocyte and CD4+CD45RA+ cells at approximately 9 months and 1 year. Both CBT and CD34-SCT recipients showed increased frequencies of CD56+ cells at 1 month (CD34-SCT versus BMT, P < .001) but decreased frequencies after 6 months (CBT versus BMT, P < .001). Lymphoproliferative responses to exogenous interleukin 2 were constantly lower in CBT and CD34-SCT recipients than in BMT recipients.These results suggest that the delay in immune reconstitution after CBT in the early phase was mainly qualitative and related to the immaturity of cells, whereas the delay in CD34-SCT was mainly quantitative in the first several months. Int J Hematol. 2003;77:399-407.

Two kinds of high power actuator film materials prepared by PVD process were developed. One is the The Fe-Pd alloy film, which shows large magnetostriction and high magnetostrictive susceptibility at low magnetic field from earth magnetic field to 1 kOe. Another is the hydrogen storage La-Ni alloy film on a polyimide substrate, which was prepared using a flash evaporation method. The hydrogen storage alloy film showed the reversible shape change, which operated by hydrogen absorption and desorptions. This bi-material actuator was driven by the large volume expansion of hydrogen storage La-Ni alloy film. In this study, the strain changes were measured under different loading stresses. The powers of these two actuator materials were larger than that of Ni-Ti alloy commercially used.

New high responsive Fe-Pd magnetostrictive films with high power were developed and prepared by magnetron sputtering. The in-plane magnetization of Fe-Pd thin film was larger than that of the Tb 0.3 Dy 0.7 Fe 2 alloy film. The Fe-Pd magnetostrictive films show large magnetostriction and high magnetostrictive susceptibility at low magnetic field from earth magnetic field to 1 kOe. The high magnetostrictive susceptibility of the Fe-Pd alloy films obtained was appropriate as a remote actuator in low magnetic field. If an ideal Fe-Pd magnetostrictive films are developed to apply the micro-machine, offering the advantages of low cost, lightweight and relatively simple design. In order to apply these properties to a practical actuator, load dependence of magnetostrictive susceptibility was serious potential problems. In this study, the magnetostrictive susceptibility changes were measured under different loading stresses. As a result, Fe-Pd alloy film showed high magnetostrictive susceptibility under high film loading stress above 50 MPa. Keywords : magnetostriction, actuator, high power, magnetostrictive susceptibility, Fe-Pd, alloy, film, magnetron sputtering, magnetization, Tb

A human leukocyte antigen (HLA)-matched unrelated bone marrow transplantation (BMT) was performed in a 13-year-old patient with the congenital immunodeficiency syndrome, Wiskott-Aldrich syndrome. The patient had a history of acyclovir (ACV)-resistant (ACV(r)) herpes simplex virus type 1 (HSV-1) infections prior to BMT. After BMT, the skin lesions caused by HSV-1 relapsed on the face and genito-anal areas. Ganciclovir (GCV) therapy was initiated, but the mucocutaneous lesions worsened. An HSV-1 isolate recovered from the lesions during this episode was resistant to both ACV and GCV. The ACV(r) isolate was confirmed to have the same mutation in the viral thymidine kinase (TK) gene as that of the previously isolated ACV(r) isolates from the patient. After treatment switch to foscarnet (PFA), there was a satisfactory remission but not a complete recovery. Although the mucocutaneous lesions improved, a PFA-resistant (PFA(r)) HSV-1 was isolated 1 month after the start of PFA therapy. The PFA(r) HSV-1 isolate coded for the same mutation in the viral TK gene as the ACV(r) HSV-1 isolates. Furthermore, the PFA(r) isolate also expressed a mutated viral DNA polymerase (DNA pol) with an amino acid (Gly) substitution for Val at position 715. This is the first report on the clinical course of a BMT-associated ACV(r) HSV-1 infection that subsequently developed resistance to foscarnet as well.

Magnetic resonance (MR) imaging (MRI) has the advantage of demonstrating lesions not visualized by other radiologic modalities. We present a case involving pediatric malignancy where MR-guided bone biopsy confirmed correct histologic diagnosis and was used to plan additional treatment. A 2-year, 9-month-old boy had a history of spontaneous regression of stage 4S neuroblastoma. 123 I-metaiodobenzylguanidine scintigraphy showed a hot spot at his right lower leg; however, neither plain radiograph 99m Tc diphosphonate bone scan was positive. Only MRI depicted a lesion at the distal third of his right tibia, and a subsequent MR-guided bone biopsy was diagnostic of bone marrow metastasis. After 6 courses of intensive chemotherapy, he has been in complete remission. MR-guided biopsy technique is likely to be particularly useful for the resection of invisible metastatic lesions, especially those that are only visible using MRI.

Successful allo-HSCT with a minimal myeloablative conditioning regimen in an adult patient with Fanconi’s anemia

Objective We examined cell subsets with respect to cutaneous graft-vs-host disease by cell sorting selection of subsets of human mononuclear cells and injecting the subsets subcutaneously in a mouse model. Materials and Methods Cell suspensions containing cultured human epidermal cells and dermal fibroblasts from a single donor mixed with lymphoid cell subsets positively selected using the FACSVantage cell sorting instrument and/or MACS cell isolation kits from unrelated individuals were injected into immunodeficient mice. This model is known to generate human skin with histologic findings similar to human graft-vs-host disease. Results Donor T-cell subsets CD4 + and CD8 + plus either host or donor CD14 + cells were necessary to cause acute cutaneous graft-vs-host disease. Although graft-vs-host disease can result from recognition of class I antigens expressed on human cutaneous cells by donor peripheral blood mononuclear cells, additional recognition of class II antigens expressed on host mononuclear cells resulted in more severe histologic manifestations. Dendritic cells that differentiated from donor and host monocytes also showed competent accessory cell function in this system. Conclusions Based on this model, human cutaneous graft-vs-host disease was caused by donor CD4 + cells and CD8 + cells activated through recognition of host antigens, including class I and class II antigens presented by either donor or host CD14 + cells or dendritic cells.

Three types of magnetic field operated shape memory ceramics have been developed. Namely, the shape memory movements can be operated by changes in magnetic flux density. The reversible shape memory effects are often induced by magnetostriction and magnetic field induced twin formation for Fe-Pd alloys. The former shows the precise shape change, whereas the later shows the large shape change expected. The strain value was about 182 ppm at 0.3 kOe at room temperature. The high magnetostrictive susceptibility was detected at low magnetic field. It was higher than that of Tb0.3Dy0.7Fe2 thin film developed. The other magnetic field operated shape change is recently found on softening near critical temperature of superconductors. The softening induced shape memory effect (SSME) has been found from 9.5 K to 20 K in pure metallic niobium.© (2001) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

To clarify the role of dose escalation of donor leukocyte infusion (DLI) in the treatment of relapsed leukemia after allogeneic bone marrow transplant (BMT), data from 100 patients were collected from 46 facilities in Japan and analyzed with respect to indications and infused cell dose. Complete remission (CR) was achieved in 11 of 12 (91%) patients with relapsed chronic myelogenous leukemia (CML) in the chronic phase, 3 of 11 (27%) with CML in the acute phase, 8 of 21 (38%) with acute myelogenous leukemia (AML), 6 of 23 (25%) with acute lymphoblastic leukemia (ALL), and 5 of 11 (45%) with myelodysplastic syndrome (MDS). The probability of remaining in CR at 3 years was 82% in CML patients in the chronic phase, but 0% in those with CML in the acute phase, 7% in those with AML, 0% with ALL, and 33% with MDS. Acute graft-versus-host disease (GVHD) (> or = 2) developed in 31 of 89 (34%) patients with human leukocyte antigen identical related donors and was fatal for 7 (7%). A leukocyte dose of 1 x 10(7)/kg of recipient body weight with CML in the chronic phase, 3 x 10(7)/kg of recipient body weight with MDS, and 1 x 10(8)/kg of recipient body weight with acute leukemia appeared to be optimal as an initial dose of DLI. However, the minimal dose of leukocyte developing fatal GVHD was 7 x 10(7)/kg of recipient body weight. These suggest that a relatively small dose of DLI ranging from 1 x 10(7)/kg to 5 x 10(7)/kg of recipient body weight should be administered initially then the infused escalating dose 2 or 3 months later in patients with CML in the chronic phase and MDS. However, a large number of leukocytes around 1 x 10(8)/kg are needed to induce graft versus leukemia effects in patients with acute leukemia despite a 7% fatality in GVHD.

The objectives were as follows: Firstly, to estimate the overall probability of event-free survival (EFS) and isolated CNS relapse in the studies for children with acute lymphoblastic leukemia (ALL) during the 1980s and 1990s. Secondly, to report the EFS according to presenting features and lineage. Thirdly, to evaluate the treatment results re-classified by the risks of NCI criteria. Four consecutive protocol studies were performed in the Tokyo Children's Cancer Study Group: L81-10 protocol (1981-1984, 189 patients), L84-11 (1984-1989, 484 patents), L89-12 (1989-1992, 418 patients) and L92-13 (1992-1995, 347 patients). Overall EFS at 5 years in each protocol was 56.5 +/- 3.8(1 s.e.)%, 71.0 +/- 2.1%, 67.8 +/- 2.3%, and 63.4 +/- 2.7%, respectively. The cumulative isolated CNS relapse rate at 5 years was 8.1 +/- 2.1%, 3.5 +/- 0.9%, 3.6 +/- 1.0%, 1.0 +/- 0.6. The EFS in SR/HR (standard risk/high risk) according to the NCI criteria in B-precursor ALL at 5 years was 61.9 +/- 4.3%/41.4 +/- 7.4% (lineage was not confirmed.), 72.5 +/- 2.6%/63.4 +/- 5.0%, 77.4 +/- 2.7%/56.3 +/- 4.7%, and 67.8 +/- 3.4%/56.7 +/- 5.4% in each protocol. Also EFSs according to NCI SR/HR at 5 years of T-ALL in protocols L84-11, L89-12 and L92-13 were 55.6 +/- 16.6%/60.9 +/- 10.1%, 72.7 +/- 13.4%/51.6 +/- 9.1%, and 77.1 +/- 14.4%/53.6/10.1%, respectively. The truncation of maintenance therapy to 6 months resulted in a decreased EFS in L92-13, particularly due to an increase of bone marrow relapse after cessation of therapy in SR and HR. The NCI risk criteria work properly even in the patients treated by different intensities, so that it makes the comparison possible among the patients in various groups. The overall EFSs in childhood ALL improved in 1980s, but it seemed stable or decreased in 1990s. The short maintenance therapy resulted in poor outcome in SR on the L92-13 protocol. Many of these late relapsers were effectively rescued and overall survival remained at a high level. The proportion of patients who received cranial irradiation reduced without any increase of the CNS events.

To the editor: Capillary leak syndrome (CLS) is a severe complication of allogeneic stem cell transplantation (SCT) characterized by weight gain, generalized edema, hypotension, and hypoalbuminemia.[1][1] The main CLS pathogenesis is injury of the capillary endothelium resulting in a loss of

AIM—To examine the long term effect of bone marrow transplantation (BMT) on ovarian function in girls. METHODS—Eighteen girls who underwent BMT before menarche, had been disease free for more than six years, and were over 14 years of age at the time of study were investigated. The preparative regimen consisted of irradiation and chemotherapy. The occurrence of menarche and changes in basal serum follicle stimulating hormone (FSH) concentrations were studied. RESULTS—Twelve patients achieved menarche at a median age of 12.8 years. Age at transplant was significantly younger in patients who achieved menarche than in those who did not (mean (SD), 7.2 (0.5) v 11.1 (1.7) years). Basal FSH began to rise to menopausal concentrations after 10 years of age, and the girls who did not experience menarche had a sustained rise in FSH concentrations. Among those with raised FSH concentrations, five girls experienced menarche while serum FSH values were decreasing and four achieved menarche while FSH remained raised. CONCLUSIONS—The high incidence of menarche suggests a favourable outcome of ovarian function in girls who undergo BMT at a young age.

Chronic restrictive lung disease in a 9-year-old boy with dyskeratosis congenita (DC) 7 years after allogeneic bone marrow transplantation (BMT) is described. When he was 1 year and 10 months old, severe aplastic anemia developed. He received a marrow transplant from his HLA serologically identical, but HLA-DP mismatched brother. He developed grade II acute graft-versus-host disease (GVHD) and thereafter chronic GVHD of progressive type, and was treated with both prednisolone and azathioprine resulting in clinical improvement. Thereafter he complained of dyspnea, and bilateral noncircumscribed interstitial shadows on chest CT scan were present. His pulmonary function showed restrictive changes. Prednisolone was not effective and he died of respiratory failure. Post-mortem examination confirmed interstitial fibrosis, lymphocytic infiltration of the bronchioles and alveoli with luminal fibrosis. There was no evidence of chronic GVHD in the skin and the liver. These findings raise the possibility that this pulmonary complication was associated with DC itself.

Background Sinusoidal obstruction syndrome (SOS) is well known as one of potentially lethal complications after hematopoietic stem cell transplantation (HSCT). To determine the incidence, risk factors and outcomes of SOS after allogeneic HSCT, we conducted a retrospective study among registering centers for the Japan Society for Hematopoietic Cell Transplantation (JSHCT). Patients and Methods One hundred and seventeen centers of the JSHCT participated in this study. A total of 4171 patients (4290 transplants) who underwent HSCT performed in those 117 centers between 1999 and 2010 were retrospectively analyzed. Additional data on the diagnosis, clinical presentation, and update of follow-up of 618 cases who developed SOS were collected. Median age of patients at transplant was 41 years (range, 0-76). The diagnosis included AML (n=1575), ALL (n=943), MDS (n=433), lymphoid malignancy (n=493), plasmacytic malignancy (n=54), CML/MPN (n=365), bone marrow failure (n=157), and others (n=270). 1166 patients were transplanted from a related donor (BM, n=501, PB, n=664, CB, n=1), and 3124 were transplanted from an unrelated donor (BM, n=2100, CB, n=1024). Conditioning regimen consisted of myeloablative regimen (MAC, n=2809) and reduced-intensity regimen (RIC, n=1367). The diagnosis of SOS was established clinically based on the Seattle criteria (presence before day 30 after HSCT, of at least two of the following features: (1) jaundice (2) hepatomegaly and right upper quadrant pain and (3) ascites and/or unexplained weight gain (≥ 2%)) or on the Baltimore criteria (hyperbilirubinemia ≥ 2 mg/dl before day 21 after HSCT and at least, two of the following features: (1) hepatomegaly (2) ascites and (3) weight gain (≥ 5%)). Complete response for SOS (CR) was defined as resolution of all the signs and symptoms of SOS diagnostic criteria. Results A total of 462 patients developed SOS fulfilling the Seattle criteria (cumulative incidence 11.0% [95% confidence interval [CI], 10.1-12.0]), and 161 out of 462 patients met the Baltimore criteria. The median time from the day of transplant to diagnosis of SOS was 12 days (range, -2-30). The signs and symptoms at diagnosis were weight gain (91%), jaundice (69%), hepatomegaly (61%), right upper abdominal pain (58%), ascites (48%), respiratory failure (25%), renal failure (23%), and encephalopathy (12%). CR rate was 45% in all SOS patients (52% and 30% in patients with SOS diagnosed by the Seattle but did not fulfill the Baltimore criteria and in patients who fulfilled the Baltimore criteria, respectively (P40; RR 0.95, 95%CI, 0.72-1.25, P=0.70, reference 0-15 y), PS 2-4 (RR 2.00, 95%CI, 1.57-2.54, P Conclusions This retrospective survey showed that the cumulative incidence of SOS was 11.0% in Japanese population, which was similar to previous reports from western countries. Patients with SOS had significantly poor prognosis. Therefore, we should establish strategies for SOS prevention and treatment for high risk patients in order to improve overall survival. Disclosures: No relevant conflicts of interest to declare.

Introduction Adrenoleukodystrophy (ALD) is an autosomal recessive disorder with progressive neurodegeneration caused by the mutation of ABCD1 gene and allogeneic stem cell transplantation (SCT) at its early stage is recognized as the only effective treatment modality to control the neurological symptoms. But the transplant outcome according to the conditioning regimen is not well understood so far. Here we analyzed the transplant outcome of patients with ALD using the clinical data accumulated in the Japan Society of Hematopoietic Cell Transplantation and tried to find the favorable conditioning regimen. Methods From 1988 to 2010, 76 patients with ALD were transplanted and their age at transplant was 1-34 years old (median 8). Stem cell sources the patients received were bone marrow (sibling 26, non-sibling related donor 5, unrelated volunteer donor 17), and cord blood (sibling 1, unrelated 28). Conditioning regimen was classified into four categories of A: busulfan + cyclophosphamide +/- others, (n=25), B: melphalan + total lymphoid irradiation (TLI) / thoraco-abdominal irradiation (TAI) +/- fludarabine +/- anti-thymocyte globulin (n=23), C: fludarabine + melphalan +low dose total body irradiation (TBI) (n=18), and D: others (n=10). Results Sustained engraftment was obtained in 59 patients (77.8%) and it was significantly higher in bone marrow transplant (BMT) patients than cord blood transplant (CBT) patients (87.8% vs 60.7%, P=0.001). The incidence of acute graft-versus-host disease (GVHD), chronic GVHD and treatment related mortality of all patients were 7.9%, 19.3%, and 11.9%, respectively. Ten year overall survival (OS) and event free survival (EFS) of all patients were 83.7% and 64.1%, respectively. Ten patients died of either disease progression (n=2), or transplant related complications (n=8). Five year OS and EFS according to the conditioning regimen was A: 91.6% and 75.8%, B: 85.7% and 60.9%, C: 100% and 83.3%, D: 77.8% and 48.0%, respectively and they were not significant (P=0.379 in OS and P=0.183 in EFS, respectively). TBI was given to 22 patients with median dose of 4Gy (range 2-10.2) and sustained engraftment was obtained in 19 patients and all of 22 patients are alive. In patients who were not given TBI (n=54), 41 patients obtained engraftment and 44 patients are alive. OS according to presence or absence of TBI was 100% with TBI (n=22) and 86.1% without TBI (n=54) (P=0.091). By multivariate analysis for EFS, BMT and TBI were identified as good prognostic factors compared to CBT or non-TBI (HR 3.303, P=0.005, and HR 3.257, P=0.038, respectively), but OS of CBT was improved after 2005 compared to before 2004 (94.7% vs 68.6%, P=0.090). Conclusion Our results showed that conditioning regimen which includes TBI, even at low dose could provide better transplant outcome and the result of CBT improved after 2005 even though it was proved to be a significantly poor risk factor in the analysis of entire cohort. CBT enables urgent SCT when family donor is not available, and immediate transplant is essential for patients with ALD because of its nature. More precise assessment with brain MRI and neuropsychological examination is mandatory to evaluate the transplant outcomes of patients with ALD. Disclosures: No relevant conflicts of interest to declare.

Long-term survivors of acquired aplastic anemia (AA) have an increased risk of developing clonal evolution after immunosuppressive therapy (IST). We previously reported that the duration of granulocyte colony-stimulating factor (G-CSF) treatment and non-response to IST at 6 months were risk factors for clonal evolution. In 2008, the revised World Health Organization (WHO) classification proposed a new entity, “refractory cytopenia of childhood” (RCC), which is often difficult to differentiate from aplastic anemia (AA). The spectrum of patients with RCC is wide, ranging from patients with severe hypocellular bone marrow (BM) with mild dysplasia to those with normocellular BM with distinct dysplasia meeting the criteria for refractory cytopenia with multilineage dysplasia (RCMD) in adults. Few studies have investigated the correlation between morphological classifications of bone marrow failure (BMF) and clonal evolution. Before introducing the criteria of RCC, we conducted a prospective study with antithymocyte globulin (ATG) and cyclosporine for patients with acquired BMF (AA 97 study), which provided a unique opportunity both to compare the long-term outcome of patients with RCC and AA and to analyze risk factors for clonal evolution. We retrospectively reviewed BM morphology in 186 children (median age, 8 years;range, 1–16 years) who were enrolled in the AA 97 study between July 1999 and November 2008. The median follow-up period was 87 months (range, 1–146 months). Fifty patients had non-severe, 54 had severe, and 82 had very severe disease. RCC criteria were defined as persistent cytopenia with 2 cell lineages or >10% within 1 cell lineage. RCMD criteria were defined as persistent cytopenia with 10% dysplastic changes in >2 cell lineages. Morphologically, 62 patients (33%) were classified as AA, 94 (49%) as RCC, and 34 (18%) as RCMD. Disease severity differed among the three groups as follows: 76% of the AA patients had very severe disease, while 41% of the RCMD patients had non-severe disease (p40 days was a significant risk factor for the development of monosomy 7 (p=0.016). Death, relapse, development of myelodysplastic syndrome or acute myeloid leukemia (AML), or disease progression requiring clinical intervention was considered to represent treatment failure. A second therapeutic intervention was required in some children. A second IST was therefore performed in 20 children, including five with AA, 11 with RCC, and four with RCMD. Hematopoietic stem cell transplantation was performed in 64 children, including 25 with AA, 29 with RCC, and 10 with RCMD. The rate of failure-free survival at 10 years was not significantly different among the three groups. On the other hand, the rate of overall survival at 10 years was significantly lower in the AA group (85±5.1%) than in the RCC (97±1.9%) and RCMD (100%) groups (p=0.01). Two patients died due to AML, and five patients died due to transplantation-related complications in the AA group. To confirm these results, we are currently conducting a prospective study involving IST in patients with acquired BMF classified according to WHO classification before treatment. Disclosures: No relevant conflicts of interest to declare.

Recently, intravenous busulfan (iv-BU) has replaced oral-BU, which can suppress variety of bioavailability. Also, iv-BU showed less hepatic toxicity by avoiding the hepatic first-pass effect of oral-BU. Previous reports showed that the use of iv-BU reduced early complications and decreased early non-relapse mortality (NRM). Some reports demonstrated that iv-BU may provide better overall survival (OS) in adult with malignant diseases. Although several reports have been published on pediatric patients using iv-BU, the number of patients included was small, and the reports mainly focused on acute toxicity or early clinical outcome because of a short follow-up period. Thus, the role of iv-BU in HSCT for pediatric patients with acute leukemia is yet to be determined. In this study, to compare clinical outcome of HSCT with iv-BU and oral-BU, we retrospectively analyzed HSCT based on data reported to the Japan Society for Hematopoietic Cell Transplantation (JSHCT) registry. The patients were selected according to the following criteria: (1) patients diagnosed with either acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML), (2) aged 15 years or younger when receiving HSCT, (3) BU-based myeloablative (more than 8 mg/kg) preconditioning regimens, and (4) HSCT performed between 2000 and 2010. Therefore, we analyzed 460 children with iv-BU (n = 198) or oral busulfan (BU) (n = 262) receiving hematopoietic stem cell conditioning transplantation (HSCT) with BU-based myeloablative conditioning for acute leukemia. The median age at HSCT was 4 years (range, 0–15 years). The median follow-up period was 1,828 days (range, 85–4,619 days) after HSCT in all the surviving patients, and 1,185 days (range, 100–3,759 days) after HSCT in the iv-BU patients. Although OS with iv-BU and oral-BU at day 100 after HSCT was 72.5 ± 3.2% and 66.9 ± 2.9%, respectively, OS at 3 years after HSCT was similar (iv-BU, 53.4 ± 3.7%; oral-BU, 55.1 ± 3.1% ), and the log-rank test for OS did not show statistically significant difference (p = 0.77) (Figure 1a). The result was concordant even when an analysis was limited to patients with ALL or AML. OS at 3 years for patients with ALL using iv-BU (n = 90) and oral-BU (n = 151) was 56.4 ± 5.5% and 54.6 ± 4.1, respectively (p = 0.51) (Figure 1b). OS at 3 years for patients with AML using iv-BU (n = 108) and oral-BU (n = 111) was 51.0 ± 5.0% and 55.8 ± 4.8%, respectively (p = 0.83) (Figure 1c). The similarity of OS was reproduced even with the limited cohort of 247 patients who received HSCT after 1st CR or 2nd CR without prior HSCT. OS at 3 years was 78.3 ± 4.2% for iv-BU patients (n = 98) and 78.7 ± 3.4% for oral-BU patients (n = 149) and the difference was not statistically significant (p = 0.66). Multivariate analysis also showed no significant survival advantage with iv-BU. Cumulative incidence of relapse at 3 years with iv-BU was similar with that of oral-BU (39.0 ± 3.6% and 36.4 ± 3.1%, respectively) (p = 0.67). Cumulative incidence of NRM at 3 years was 16.6 ± 2.7% with iv-BU and 18.3 ± 2.5% with oral-BU (p = 0.51). The iv-BU group showed a tendency toward higher engraftment probability at day 60 (96.0 ± 1.5%) compared with the oral-BU group (89.3 ± 2.0%), but the difference was not statistically significant (p = 0.22) This study was a retrospective study using registry data, and there are some limitations of our data. For example, as selection of iv-BU or oral-BU was strongly associated with the transplantation period, which may have introduced bias. Further prospective studies are required to establish an optimal allogeneic HSCT treatment strategy for pediatric patients with acute leukemia. In conclusion, our study provides valuable information on the role of iv-BU in myeloablative HSCT for pediatric acute leukemia. In children, iv-BU could not show significant survival improvement in outcome of acute leukemia. Disclosures: No relevant conflicts of interest to declare.

A 15 year old boy with a past history of chickenpox in infancy was complicated by lethal varicella during the course of chemotherapy against recurrent acute myeloblastic leukemia. He had received allo-bone marrow transplantation and had overcome a graft-versus-host disease. The skin eruptions were hemorrhagic and progressive during the last 3 weeks, with numerous intranuclear inclusions histologically confirmed in the involved epidermis, hair follicles and endothelial cells. Immunohistochemical and electron microscopic studies confirmed the infection of varicella-zoster virus.

Abstract 4185 Background: Since the clinical implication of anti-lymphocyte globulin (ATG/ALG) in allogeneic stem cell transplantation (allo-SCT) is not fully understood, we tried to identify the clinical impact of ATG/ALG in patients with acute leukemia who received allo-SCT in Japan. Patients and Methods: We analyzed patients with ALL (n=5494) and AML (n=8115) who received first allogeneic SCT from 1983 to 2009 with (n=356) or without (n=13253) ATG/ALG. Their stem cell sources were bone marrow (BM, n=9056), peripheral blood (PB, n=1918), and cord blood (CB, n=2575) and they were transplanted at 1st complete remission (CR1, n=5681), 2nd CR (CR2, n=2495), and advanced stages (>CR3, n=5033). Results: Five year overall survival (5y OS) of all patients with or without ATG/ALG was 33.6% vs 44.5%, respectively (P Conclusion: In allogeneic stem cell transplantation for patients with ALL and AML, ATG/ALG contribute in reducing acute and chronic GVHD without affecting relapse rates but it was a risk factor of OS for patients who received BM or CB. Disclosures: No relevant conflicts of interest to declare.

Abstract 959 Survival after bone marrow transplantation (BMT) in children with aplastic anemia (AA) has improved markedly over the last 3 decades. However, we have experienced a certain number of patients who presented with bone marrow aplasia with full donor chimerism after BMT (donor-type aplasia), especially in the recent years. Since the 2000s, fludarabine (FLU)-based conditioning regimen has been often used for Japanese children with AA. The present study therefore evaluated whether patient and transplantation characteristics (especially the FLU regimen) could associate with donor-type aplasia in a large population of children with AA. To identify the risk factors for donor-type aplasia, we reviewed the clinical data of 660 patients (< 20 years) with AA who received BMT from 1980 to 2010 and whose records were available in the Japan Society for Hematopoietic Cell Transplantation Registry. The influence of potential risk factors on donor-type aplasia was assessed according to patient and transplantation characteristics, including the conditioning regimen. The median age at transplantation was 11 years, and 238 patients received immunosuppressive therapy (IST) before BMT. The median interval between diagnosis and BMT was 9 months. Regarding transplantation, 419 patients received BMT from related donors, whereas 241 received BMT from unrelated donors. Totally, 220 patients received a regimen that included FLU. Primary graft failure was observed in 25 patients. Of the 635 patients who achieved primary engraftment, 46 developed secondary graft failure or relapse: 11 were of the recipient-type and 35 were of the donor-type. The cumulative incidence of donor-type aplasia was 5.7%, and the 10-year overall survival of patients who presented with donor-type aplasia was 87%. Notably, the incidence of donor-type aplasia was significantly higher in FLU regimen group than in non-FLU regimen group (11.6% vs. 2.7%; P < 0.0001), and multivariate analysis confirmed that the FLU regimen was an independent risk factor for donor-type aplasia. Low infused cells (≤ 3×108/kg) (P = 0.008) and IST before BMT (P = 0.04) were also associated with a high incidence of donor-type aplasia. Age at BMT, gender, etiology, severity, interval between diagnosis and BMT, transfusion times, donor type (related or unrelated), human leukocyte antigen disparity, acute or chronic graft versus host disease (GVHD), GVHD prophylaxis, and viral reactivation or infection did not influence the incidence of donor-type aplasia in multivariate analysis. When FLU was introduced in the regimen for Japanese children with AA, the dose of cyclophosphamide (CY) was reduced by half, to reduce the toxicity; the conventional dose of CY was 200 mg/kg before the introduction of FLU. Therefore, we investigated the impact of the dose reduction of CY in the FLU regimen group. In patients receiving the FLU regimen, the incidence of donor-type aplasia in the CY half-dose group (n = 175) was 14%, whereas donor-type aplasia was not observed in the CY full-dose group (n = 35) (P = 0.04). In contrast, the addition of antithymocyte globulin or irradiation did not influence the incidence of donor-type aplasia in the FLU regimen group. Of note, the incidence of heart failure as a result of CY administration was higher in the CY full-dose group (5.7%) than in the CY half-dose group (0.6%), although this difference was not statistically significant. In conclusion, the FLU regimen was identified as an independent risk factor for donor-type aplasia in children with AA, which could possibly be ascribed to the CY dose reduction. However, the high incidence of heart failure associated with the regimen including a full dose of CY is an important issue that needs to be resolved. To develop optimal treatment, the conditioning regimen for children with AA needs to be reconsidered. Disclosures: No relevant conflicts of interest to declare.

Abstract 3487 Introduction: Increasing evidence supports the notion that aplastic anemia (AA) defined as peripheral blood pancytopenia and bone marrow hypoplasia is an autoimmune disease mediated by T-cells attacking hematopoietic progenitor cells. Around 10% of acquired AA is associated with acute hepatitis, yet a causative virus has not been identified in most patients. Like other autoimmune disorders, adult AA is associated with human leukocyte antigen (HLA)-DR15. However, HLA-DR15 is not significantly associated in children with AA (Fuhrer et al. Pediatric Blood Cancer 2007 and Yoshida et al. Br J Haematol 2008). Human leukocyte antigen associations might differ between children and adults with AA. We therefore investigated the HLA types among patients with idiopathic aplastic anemia, hepatitis-associated aplastic anemia and fulminant hepatic failure who underwent liver transplantation. Patients and methods: We investigated data from 321 children (male, n = 202; female, n = 119; median age, 10 [range 0 – 18] years) with severe and very severe AA. All patients were enrolled in the AA-92 or AA-97 study from 1992 to 2010 and received immunosuppressive therapy (IST) using antithymocyte globulin and cyclosporine. Two hundred and sixty nine children had idiopathic AA and 52 had AA associated with hepatitis. The HLA alleles of 25 children with fulminant hepatic failure who underwent liver transplantation between 2006 and 2011 were characterized. Differences in all HLA alleles between the patients and healthy controls in the Japanese population were statistically analyzed at the phenotype level by χ2 and t tests using PRISM software. Results: The prevalence of HLA-B61 was significantly higher in idiopathic AA (21.9%, P < 0.0001), hepatitis associated AA (19.2%, P = 0.0089) and fulminant hepatic failure (20%, P = 0.0008) than in healthy Japanese controls (10.7%). No other HLA class I and II alleles including HLA-DR15 significantly differed between children with AA and healthy controls. Furthermore, HLA distribution did not significantly differ between patients who responded completely or partially to immunosuppressive therapy (IST) and non-responders. Conclusions: We did not uncover a significant association between AA and HLA-DR15 in children. Associations between HLA and disease might differ between children and adults with AA. HLA-B61 was positively associated with idiopathic aplastic anemia, hepatitis-associated aplastic anemia and fulminant hepatic failure in pediatric patients. These findings suggest that a common autoimmune mechanism is responsible for both hepatic- and bone marrow-related pathologies in children. Disclosures: No relevant conflicts of interest to declare.

Abstract 3113 During pregnancy, women can develop both cytotoxic and regulatory immune cells against inherited paternal alloantigens of their fetus. Such immune cells reactive against fetal alloantigens can persist postpartum and may confer beneficial effects when the mother is used as a donor for hematopoietic cell transplantation (HCT) for her offspring. However, there have been few studies that aimed to evaluate the effects of parental donor type on outcomes after HCT performed with T-cell-replete grafts in a relatively large cohort of patients. Using datasets obtained fromthe Japan Society for Hematopoietic Cell Transplantation, we compared the outcomes of 477 patients who received T-cell-replete HCT from a maternal donor (n=305) or a paternal donor (n=172) between 1999 and 2009 as treatment for acute myeloid leukemia (n=203), acute lymphoblastic leukemia (n=213), chronic myelogenous leukemia (n=37), and myelodysplastic syndrome (n=24); in vivo T-cell depletion was employed in 48 patients. Patients who underwent HCT using ex vivo T-cell-depleted grafts were not included in the study. Cox proportional-hazard models were used to evaluate variables that may affect overall mortality, whereas Fine and Gray regression models were used to evaluate variables that may affect incidences of graft-versus-host disease (GVHD), relapse, and treatment-related death. Recipients of maternal donor HCT and paternal donor HCT had similar background characteristics with respect to age group, diagnosis, disease status, stem cell source, type of conditioning regimen, and type of GVHD prophylaxis. Proportions of male recipients (61% of maternal donor HCT vs 51% of paternal donor HCT, p=0.044) and patients given a graft with HLA mismatch in the GVH vector (70% vs 60%, p=0.031) were higher in maternal donor HCT compared with paternal donor HCT. Unadjusted overall survival at 3 years after transplantation were 49.6% after maternal donor HCT and 37.9% after paternal donor HCT (p=0.118). Multivariate analysis revealed a significantly lower oveall mortality after maternal donor HCT compared with paternal donor HCT [hazard ratio (HR) of maternal donor transplant vs paternal donor transplant, 0.70; p=0.008]; the use of a maternal donor was associated with a lower risk of treatment-related mortality (TRM) (HR, 0.62; p=0.018) and a higher incidence of chronic GVHD (HR, 1.43; p=0.036), whereas the incidence rates of grade 2–4 acute GVHD (HR, 1.06; p=0.690) and relapse (HR, 1.05; p=0.763) were similar between the two groups. Intriguingly, if the analysis is confined to 241 patients who developed grades 2 to 4 acute GVHD, the use of a maternal donor was associated with a lower TRM compared with the use of a paternal donor (HR, 0.55; p=0.028), suggesting protective effects of maternal grafts in the setting of acute GVHD. Of 159 patients who received grafts without mismatch at HLA-A, -B, and -DR antigens in the GVH vector, overall mortality (HR, 0.86; p=0.535) and TRM (HR, 0.98; p=0.956) were similar between the two groups. Of 318 patients who received grafts with 1 (n=202) or more (n=116) HLA antigen mismatch in the GVH vector, the use of maternal grafts was associated with a lower overall mortality (HR, 0.63; p=0.004) and a lower TRM (HR, 0.53; p=0.005) compared with the use of paternal grafts. Collectively, these results indicate that the use of an HLA-mismatched mother as a donor for T-cell-replete HCT can be a reasonable option in selected patients who lack a suitable conventional stem cell source. Disclosures: No relevant conflicts of interest to declare.

3046 Systemic corticosteroid therapy is recommended as a first-line treatment for grade II or higher acute graft-versus-host disease (GVHD). Several clinical factors have been reported to be predictive of response to corticosteroid therapy in retrospective studies in which most or all patients received bone marrow transplantation. However, stem cell sources for allogeneic hematopoietic cell transplantation (HCT) dramatically changed with the frequent use of peripheral blood stem cells (PBSCs) and umbilical cord blood (UCB), and no study has compared the response rates of corticosteroid therapy among these stem cell sources. A retrospective study to identify clinical factors affecting the response of grade II-IV acute GVHD to systemic corticosteroid therapy was performed using the national registry data for Japanese patients who received first allogeneic HCT with bone marrow (BM) (n=2004), PBSCs (n=685), and UCB (n=863). Data were analyzed by STATA ver.12 statistical software. This study was approved by the ethical committees of the Nagoya University School of Medicine. Acute GVHD improved in 2259 (63.6%) of the 3552 patients. On multivariate logistic regression analysis, various factors were identified to predict corticosteroid response ([Table 1][1]). Interestingly, UCB was significantly associated with a higher probability of improvement, whereas HLA-matched unrelated BM and HLA-mismatched stem cell sources other than UCB were significantly associated with a lower probability of improvement; HLA-matched related PBSC was not significantly different from HLA-matched related BM. The cumulative incidence of non-relapse mortality (NRM) was significantly higher in patients without than with improvement of acute GVHD with corticosteroid therapy ( P < 0.0001). On competing risk regression analysis, patients without improvement with corticosteroid therapy were more likely to have NRM than those with improvement [HR, 2.50; 95% CI, 2.18–2.88]. Other factors associated with significantly worse NRM included age 16–49 y and ≥ 50 y (vs. < 16 y), grade III and IV acute GVHD (vs. grade II), and liver involvement of acute GVHD (vs. no involvement). Overall survival (OS) was significantly lower in patients without improvement with corticosteroid therapy than in patients with improvement (29.5% vs. 42.5% at 15y after transplantation) ( P < 0.0001). After adjustment by patient age, disease, grade of acute GVHD, and liver involvement of acute GVHD, OS was significantly lower in patients without than in patients with improvement with corticosteroid therapy [HR, 1.63; 95% CI, 1.46–1.81]. The present study demonstrated, for the first time, a higher probability of improvement in grade II-IV acute GVHD with systemic corticosteroid therapy in patients after UCB transplantation than in those after BM and PBSC transplantation. This finding should be considered in the design of future clinical trials of acute GVHD treatment. The response rate to corticosteroid therapy in Japanese patients (63.6%) was comparable to that in Caucasian patients (50–60%) and, when it is ineffective, Japanese patients also show high NRM and low OS. Thus, another important message of this study is that the establishment of a second-line treatment for corticosteroid-refractory acute GVHD is required for not only Caucasian patients but also for Japanese patients. A prospective study to validate the present findings is warranted. | Factor | Relative risk[*][2] (95% CI) | P | |:-------------------------------:| ---------------------------- | ------ | | Patient age (y) | | | | day14 | 1.21 (1.02–1.44) | 0.033 | | Grade of acute GVHD | | | | II | 1 | | | III | 0.48 (0.39–0.58) | 1.0 indicate higher probability of improvement; values < 1.0 indicate lower probability. Table 1. Factors predicting the response of grade II-IV acute GVHD to systemic corticosteroid therapy Disclosures: No relevant conflicts of interest to declare. [1]: #T1 [2]: #fn-1 [3]: #xref-fn-1-1

Abstract 958 Primary graft failure (pGF) is associated with considerable morbidity and mortality in hematopoietic stem cell transplantation (HSCT). Salvage HSCT can rescue pGF patients, however, prospective controlled trials are difficult and the optimal preconditioning regimen and stem cell source have not been established, because of the rarity of pGF and emergent condition of the patients. In this study, to investigate prognostic factors of salvage allogeneic HSCT and to obtain fundamental information for establishing a standard approach for pediatric pGF, we performed retrospective analysis of a salvage HSCT for pGF after allogeneic HSCT in children. A total of 102 patients were analyzed based on data reported to the Japan Society for Hematopoietic Cell Transplantation (JSHCT) registry. The patients were selected according to the following criteria: (1) aged 18 years or younger at salvage HSCT; (2) engraftment not achieved by a prior allogeneic HSCT, and salvage allogeneic HSCT performed; (3) salvage HSCT performed within 60 days after the first HSCT; (4) both the first and salvage HSCTs performed between 1982 and 2010. The median follow-up period in the surviving patients was 1502 days (range, 37–9101) after salvage HSCT. The estimated OS probability and standard error at 1 year after salvage HSCT was 53.3% ± 5.0%. The cumulative incidence of engraftment at 60 days was 55.7% ± 5.0%, whereas non-relapse mortality (NRM) at 1 year was 31.7% ± 4.7. Donor sources of the 102 salvage HSCT were 29 of HLA matched or 1-antigen mismatched related donor (rMM01), 42 of HLA 2- or 3-antigen mismatched related donor (rMM23), and 31 of cord blood (CB). The engraftment rate at 60 days was 57.7% ± 10.1% for rMM01, 57.1% ± 7.7% for rMM23, and 42.2% ± 9.4% for CBT (p = 0.24, Figure 1). The rMM01 group showed the highest OS (68.8% ± 8.6%), whereas OS was similar in the rMM23 (47.6% ± 7.7%) and CB (45.7% ± 8.6%) groups (Figure 2). The median time for neutrophil engraftment after CBT was 22 days, which was significantly longer than those for rMM01 (15 days) and rMM23 (15 days) (p = 0.02 and 0.0007, respectively). Thirty-one salvage CBTs were performed in our cohort. The median total nuclear cell (TNC) count was 5.3 (range, 2.2–13.3) × 107 cells/kg, and the median CD34-positive cell count was 1.6 (range, 0.13–5.3) × 105 cells/kg. There was no association between the cell counts and engraftment. HLA antigen mismatch did not result in inferior engraftment. Fludarabine, alkylating agents, anti-thymocyte/lymphocyte globulin, and irradiation were frequently used with various combinations, and all these components provided better engraftment probability. Alkylating agents was associated with better survival rate (p = 0.004). Multivariate analysis showed that rMM01 was significantly correlated with better engraftment and survival. The hazards for engraftment and survival were not different between rMM23 and CBT. Multivariate analysis showed also an advantage of FLU and irradiation in engraftment. On the other hand, alkylating agents had a major impact on survival probability, and the usage of alkylating agents was related with superiority in survival. A previous report including a small number of pediatric pGF patients showed an advantage of PBSC from mismatched related donors, whereas our analysis demonstrated that the survival curve for CBT was superimposed on the curve for HSCT from a mismatched related donor, although engraftment achievement tended to be lower and engraftment was later. In our cohort, the median TNC count of CB was considerably higher than that reported previously. The small body size of children allows a relatively high number of CB to be obtained. Of note, this study was a retrospective and uncontrolled study. Further prospective studies in a large cohort are therefore required to further improve the treatment of pediatric pGF patients. In conclusion, our study provides valuable information on the role of the second salvage HSCT for pediatric pGF. This study included the largest number of children with pGF investigated till date, and showed that rMM01 donor was the most suitable donor for salvage HSCT, and that CBT was an equally important option compared with a haploidentical related donor for patients without a well matched related donor. Disclosures: No relevant conflicts of interest to declare.

Abstract 2364 Background: Survival after immunosuppressive therapy (IST) for aplastic anemia (AA) depends on disease severity, which is classified according to polymorphic neutrophil (PMN) count as follows: nonsevere AA (nSAA; PMN > 0.5 × 109/L); severe AA (SAA; PMN 0.2 – 0.5 × 109/L); and very severe AA (vSAA; PMN < 0.2 × 109/L). Although patients with fulminant AA, defined as PMN = 0 for > 2 weeks, generally have poor outcome, no data are available for a large cohort. Therefore, we evaluated the outcome of children with fulminant AA who were enrolled in an AA-97 study and received ATG, cyclosporine, and granulocyte colony-stimulating factor (G-CSF). Patients and Methods: A total of 288 children newly diagnosed with AA (median age, 8 years) were enrolled into an AA-97 study between 1997 and 2006 and treated with a combination of horse antithymocyte globulin (Lymphoglobulin®) and cyclosporine. For patients with PMN < 0.2 × 109/L, G-CSF was added. Patients were classified into 3 groups according to disease severity as follows: fulminant (PMN 0, n = 35); vSAA (PMN 0 – 0.2 × 109/L, n = 129); and SAA (PMN 0.2 – 0.5 × 109/L, n = 124). Of the 35 patients with fulminant AA, 8 had a history of acute hepatitis at the time of diagnosis. One case was considered to be drug-induced AA. The remaining 26 patients had unknown etiology. We evaluated the response rate (RR) at 6 months, 5-year overall survival (OS), and 5-year failure free survival (FFS). Treatment failure was defined as death due to any cause, a requirement for a secondary therapy, relapse, clonal evolution to myelodysplastic syndrome/acute myelocytic leukemia, and paroxysmal nocturnal hemoglobinuria. Results: The children with fulminant AA showed a significantly lower RR than those with vSAA and SAA (40.0%, 62.8%, and 64.5%, respectively; p =.023). Of the 20 non-responders in the fulminant AA group, 11 were rescued by alternative donor stem cell transplantation, and 5 achieved a late response after 6 months. As a result, no significant difference was noted in 5-year OS and 5-year FFS among the children with fulminant AA, vSAA, and SAA (88.5%/48.2%, 95.8%/65.1%, and 96.8%/68.1%, respectively). Conclusion: In consideration of favorable OS, the choice of IST is indicated in children with fluminant AA who lack an HLA-matched family donor. Disclosures: No relevant conflicts of interest to declare.

Patients who undergo bone marrow transplantation (BMT) frequently experience impaired pituitary function, but precise assessment using repeated provocative tests has not been described. We studied 32 children (16 boys) who had BMT after receiving preparative irradiation. Assessment of pituitary function was performed by infusing insulin, luteinizing hormone-releasing hormone (LHRH), and thyrotropin-releasing hormone (TRH) on several occasions at various intervals during the follow-up period. Serum free thyroxine (FT4) and thyrotropin (TSH) levels tended to be low during the early period following BMT. Serum FT4 concentrations reverted to the low-normal range 1 year after transplant, and eight of 29 patients had subnormal and delayed TSH response to TRH consecutively. No children showed overt hypothyroidism. Basal and peak serum gonadotropin levels in response to LHRH were elevated in the patients who had received transplant around the time of puberty. Leydig cell function assessed by human chorionic gonadotropin test was normal. Three girls experienced menarche, and one male patient fathered a normal boy 7 years after BMT. Pituitary-adrenal function and prolactin secretion were not affected. A high incidence of transient hypothyroidism which did not require replacement therapy and gonadal failure among pubertal children were observed. Shielding of gonads should be attempted, if possible, at the time of preparative irradiation to prevent resultant hypogonadism.

The current role of surgery was evaluated in seven consecutive patients with high-risk neuroblastoma (six stage 4 patients and one stage 3, abdominal origin, and all over 12 months of age at diagnosis) treated with new modalities utilizing bone marrow transplantation (BMT). In six of these seven patients, a grossly complete excision of the primary tumor was achieved, and four have survived for 133, 69, 39, and 28 months with no further evidence of disease. The remaining patient with celiac neuroblastoma only underwent a biopsy during a second-look laparotomy after chemoradiotherapy, and thereafter developed local and distant recurrences and ultimately succumbed to the tumor. The timing of surgical intervention varied, either before or after chemotherapy, and did not appear to affect the ultimate survival. Although surgical excision of the primary tumor remains a very high priority in the overall treatment scheme, the most important factor remains the eradication of the tumor by well-planned courses of intensive chemotherapy (e.g., Al Protocol of the Study Group of Japan). Thus, after having induced complete remission, for consolidation, it is necessary to kill all remaining tumor cells by giving supralethal doses of chemotherapy including total body irradiation (TBI) assisted by BMT.

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Abstract 53 The revised 2008 WHO classification contains the newly proposed term, “refractory cytopenia of childhood (RCC)”. This term applies to children with myelodysplastic syndrome (MDS), which is characterized by a low blast count. RCC is defined as persistent cytopenia with 2 cell lineages or >10% within 1 cell lineage. The distinction between RCC and aplastic anemia (AA) is normally difficult to make, especially when the bone marrow is hypoplastic and no chromosomal abnormalities can be detected. The spectrum of patients defined as having RCC is quite wide. Cases range from patients with severe hypocellular marrow and mild dysplasia in hematopoietic cells to patients with normocellular marrow and severe dysplasia that meets the criteria of refractory cytopenia with multilineage dysplasia (RCMD) in adult MDS. However, there are few studies that have focused on the difference between these two diseases. Therefore, in order to determine the specific clinical differences between AA and RCC, we retrospectively reviewed bone marrow samples of 117 bone marrow failure syndrome children (males: 69, females: 48) who were administered the same immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine. These patients were classified into AA, RCC and RCMD groups. AA patients exhibited no morphologically dysplastic changes in any of their hematopoietic cell lineages, while RCC patients had 2 cell lineages, or >10% in 1 cell lineage. Patients classified as RCMD exhibited >10% of the dysplastic changes in >2 cell lineages. In accordance with the internationally defined criteria for AA, patients were further subdivided on the basis of severity, with 26 classified as non-severe, 35 as severe and 56 as very severe. At the time of initial presentation, 16 patients had a history of acute hepatitis, while one patient had the chromosomal abnormality 49,XY,+8,+16,+18. Out of the 117 patients enrolled, 58 (50%) were classified as AA, 47 (40%) as RCC and 12 (10%) as RCMD. AA and RCC patients tended to exhibit severe hypoplastic bone marrow cellularity, while the RCMD patients were normal or only exhibited mild hypoplastic marrow. The median ages in the AA, RCC, and RCMD groups were 9, 8 and 10 years, respectively. While most of the patients in the AA group (73%) had very severe disease, more than half of the RCMD patients (58%) only had non-severe disease (p Since the RCMD group exhibited a significantly high CI for clonal evolution, this suggests that the RCMD criteria should be applied to childhood MDS. However, the FFS and OS rates did not differ among these three groups. Thus, in order to definitively determine whether these three diseases are different entities, it will be necessary to use newly developed methods, such as whole exome analysis, to prospectively compare the clinical outcomes and biological findings in a larger number of the AA, RCC and RCMD patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 831 The first-line therapy for children with severe aplastic anemia (AA) is allogeneic hematopoietic stem cell transplantation (HSCT) from an human leukocyte antigen (HLA)-matched family donor, and immunosuppressive therapy (IST) is indicated for patients without HLA-matched family donors. While the standard therapy for children who fail to respond to IST is allogeneic HSCT from an HLA-matched unrelated donor, HSCT from an HLA-mismatched family donor has also been indicated. Compared with unrelated donors, an HLA-mismatched family donor has some advantages especially for children who need urgent transplantation. We analyzed the clinical outcome of 578 children (325 boys and 253 girls) with AA (age, The probability of severe acute GVHD (grade III–IV) in patients transplanted from 1MMRD (26.9% ± 7.4%) was significantly higher than that in patients transplanted from MRD (4.9% ± 1.3%) (p < 0.001). The probability of 5-year overall survival (5y OS) of patients transplanted from 1MMRD (93.1% ± 3.9%) was comparable to that of patients transplanted from MRD (93.1% ± 1.5%) (p = not significant, NS), but it was significantly better than that of patients transplanted from haploidentical donors (66.7% ± 15.7%, p =.016) and MUD (79.0% ± 2.9%, p =.014). In the subgroup analysis of 1MMRD, no significant difference was observed between HLA class I-mismatched (n = 32) and class II-mismatched patients (n = 12) (5y OS; 93.8% ± 4.3% vs. 91.7% ± 8.0%, p = NS). Comparison of the survival outcome based on the transplant period (1990–1999 vs. 2000–2009) revealed that the probability of 5y OS of patients transplanted from 1MMRD was not significantly different (92.3% ± 5.2% (n = 26) vs. 94.4% ± 5.4% (n = 18), p = NS), while that of patients transplanted from MUD significantly improved in the same period as we reported previously (67.1% ± 5.5% (n = 73) vs. 86.1% ± 3.1% (n = 140), p =.001)(Yagasaki et al., Blood 2011). In multivariate analysis, haploidentical donors (p In summary, our analysis revealed that an HLA-mismatched related donor, especially 1MMRD, could be selected as a donor candidate for children with AA who need urgent transplantation. Disclosures: No relevant conflicts of interest to declare.

Abstract 3421 Bone marrow transplantation (BMT) from an HLA-matched family donor (MFD) is the treatment of choice for severe aplastic anemia (SAA) in children. For children without an MFD, immunosuppressive therapy (IST) with a combination of antithymocyte globulin and cyclosporine has been successful. However, this treatment approach is based on the results of comparative studies between these therapies conducted in the 1980s, and the outcomes of both BMT and IST have improved markedly over the past three decades. Therefore, updated evidence for treatment decisions in pediatric SAA is required. In the present study, we compared the outcomes of children with SAA who received IST (subjects enrolled in the prospective multicenter trials of IST conducted by the Japan Childhood Aplastic Anemia Study Group) or BMT from an MFD (subjects registered in the Transplant Registry Unified Management Program conducted by the Japan Society for Hematopoietic Cell Transplantation). The influence of potential risk factors on overall survival (OS) and failure-free survival (FFS) was assessed according to first-line treatment, time period of treatment (1992–1999 and 2000–2009), age and other variables related to each treatment. FFS was defined as survival with treatment response. Death, primary or secondary graft failure, relapse and secondary malignancy were considered treatment failures in patients who received BMT. Death, relapse, disease progression requiring stem cell transplantation from an alternative donor or 2nd IST, clonal evolution and evolution to paroxysmal nocturnal hemoglobinuria were considered treatment failures in patients who received IST. Between 1992 and 2009, 599 children with SAA younger than 17 years received BMT from an MFD (n=213) or IST (n=386) as first-line treatment. While the OS did not differ between patients receiving IST and BMT (88±2% vs. 90±2% at 15 years), FFS was significantly inferior in patients receiving IST as compared to those receiving BMT (54±3% vs. 84±3% at 15 years, P Disclosures: No relevant conflicts of interest to declare.

Abstract 2400 Introduction: Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) plus cyclosporine A (CyA) has been the standard therapy for aplastic anemia (AA) patients. Recently, telomerase shortening was observed in constitutional marrow failure and some acquired AA patients. In addition, constitutional marrow failure syndrome of variable severity may be present in otherwise phenotypically normal individuals and can masquerade as acquired AA. Calado et al. reported that androgens increased telomerase activity in vitro. The addition of androgens to immunosuppressive therapy may increase the response rate by the effect for these hidden patients. Because all patients in the AA-92 study received danazol and patients in AA 97 study did not receive danazol, we have a unique chance to evaluate the effects of androgen. In this report we present results comparing AA-92 (ATG+CyA+danazol) with AA-97 (ATG+CyA) protocol for children with AA using a matched-pair analysis. Patients and Methods: We conducted two prospective multicenter studies: the AA-92 and AA-97, which began in November 1992 and October 1997, respectively. From 1992 to 2009, 530 children with AA were treated with IST. IST consisted of horse ATG (15 mg/kg/day, days 1 to 5), CyA (6 mg/kg/day, days 1 to 180) and methylprednisolone. All patients in the AA-92 study received danazol at a dose of 5 mg/kg/day for 6 months. We selected pairs of patients treated with either AA-92 or AA-97 by matching the variables of disease severity, age, sex, and duration from diagnosis to IST. We assessed hematologic response at 3 and 6 months after initiation of therapy as well as overall survival and failure-free survival. Definition of treatment failure was death, relapse, disease progression requiring stem cell transplantation or second IST, and clonal evolution. Results: Among 530 patients, 104 pairs were matched and their disease severity was very severe (VSAA) (n=43), severe (SAA) (n=34), and non-severe (NSAA) (n=27). Median age was 8 years (1–15) and 53 (51.0%) were male. In the AA-92 study, the response rates at 3 and 6 months were 48/104 (46.2%) and 71/104 (68.3%), respectively. In the AA-97 study, the response rates at 3 and 6 months were 49/103 (47.6%) and 59/104 (56.7%), respectively. The overall 10-year survival rates in AA-92 and AA-97 were 82.7% and 93.6%, respectively. In VSAA patients, the response rate at 6 months in AA-92 was significantly higher than in AA-97 (69.8% vs 46.5%, p=0.029). However, the overall 10-year survival rates for patients with VSAA in AA-92 and AA-97 were 81.4% and 90.4%, respectively. The failure-free 7-year survival rates for patients with VSAA in AA-92 and AA-97 were 55.5% and 61.5%, respectively. The cumulative incidence of clonal evolution between studies did not differ. Conclusions: Our results showed that the response rate of VSAA patients at 6 months in the danazol group was significantly higher than in those not receiving danazol, but overall survival and failure-free survival were not different. There is a possibility that a number of cases with androgen-responsive congenital bone marrow failure syndrome, such as dyskeratosis congenita, were hidden in our series of AA patients, which may explain the higher response rate with danazol in AA-92. Disclosures: No relevant conflicts of interest to declare.

Long-term sequelae of bone marrow transplantation (BMT) are a major concern among long-term survivors since the procedure has been considerably developed over the past decade. In this study, linear growth and growth hormone (GH) secretion were evaluated in 25 children (14 males and 11 females) with various neoplastic or non-neoplastic hematological disorders who had survived for more than 3 years after BMT. Impaired linear growth after BMT, as defined by a change in height standard deviation score (SDS) by more than − 1.0 SD, was observed in 14 patients (56%). Four children showed severe growth suppression with a decrease in SD score by more than 2.0, and 10 exhibited a moderate reduction by between 1.0 and 2.0 SD. A recovery of normal height velocity was observed in those who had received BMT at a younger age. The type of disease, a difference in preconditioning regimen, the presence of chronic graft-versus-host disease or a GH secretory capacity 1 year after BMT were not contributing factors for impaired growth. A serial examination of GH secretion with insulin-induced hypoglycemia demonstrated that poor GH secretion was not necessarily a prerequisite for impaired growth. These results indicate that the secretory status of GH does not predict the future growth pattern of children who received BMT.

The remarkable SME is induced above glass transition temperature (Tg) by the transition volume change on Zr-5at%Ni-9at%Al-30at%Cu glassy alloy. The shape memory metallic glass is a new concept of the actuator applicable for hard-irradiated environment such as in fusion reactor.

In order to develop new shape memory materials operated by temperature, magnetic field, electrical current and pressure, the shape memory effect of the high Tc YBa2Cu3O7-y superconductor was studied at different preparation methods using thermal expansion on softening. The sintering YBa2Cu3O7-y with 30 mass% Ag has a prominent shape memory effect.