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Various prospective trials have been performed to assess the roles of allogeneic hematopoietic cell transplantation (allo-HCT) and chemotherapy in patients with acute myeloid leukemia (AML) in first complete remission (CR1). However, the results have not always been consistent, and there has been a limited evaluation of quality of life (QOL) in these postremission strategies. We performed a Markov decision analysis that enabled us to compare survival outcomes with a QOL evaluation using a database of 2029 adult AML patients who achieved CR1. The Markov decision model compared 2 strategies: allo-HCT or chemotherapy in CR1. Patients who had intermediate- or unfavorable-risk AML had a longer life expectancy when they received allo-HCT in CR1 than patients treated with chemotherapy alone. Likewise, patients who had a suitable related donor who received allo-HCT in CR1 had a longer life expectancy. The life expectancy was shortened to a greater degree by adjustment for QOL in the allo-HCT group. Nevertheless, QOL-adjusted life expectancies in most of the subgroups remained longer in the allo-HCT group than in the chemotherapy group. Our results showed that older patients with a related donor and younger patients with unfavorable cytogenetics benefited the most from allo-HCT in CR1.

Background It is of great importance to know the impact in quality of life (QOL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) according to types and severity of chronic graft-versus-host disease (GVHD), to care for physical, mental and social aspects of transplant survivors. We conducted a cross-sectional questionnaire study to examine the relationship between patient-reported QOL and chronic GVHD defined by National Institute of Health (NIH) criteria. We also investigated the degree of agreement between visual analogue scales provided by patients (VASpt) and physicians (VASdoc). Methods The protocol was approved by the Institutional Review Board at each of the participating centers, and all subjects provided informed consent in accordance with the Declaration of Helsinki. Patients enrolled in the cohort were identified in the national transplant registry database registered from 47 centers which participated this study. Eligibility criteria included recipients of allo-HSCT for hematological diseases between 1995 to 2009, who were aged 16 years or above at transplant and 20 years or above at survey, and were relapse-free at survey. A total of 3301 eligible patients were registered in the database. SF-36, FACT-BMT, and VAS were administered to assess patient-reported QOL. Physicians evaluated the types and overall and organ-specific severity grades of chronic GVHD defined by NIH criteria (skin, mouth, eyes, gastrointestinal tract, liver, lung symptom, pulmonary function tests [PFT], joint and fascia, and genital tract), oral administration of immunosuppressant (IS), and VAS of respective patients at survey. Multivariable models were constructed to examine the relationship between QOL scores and types and severity of chronic GVHD after controlling for background covariates. Adjusted mean scores for the SF-36 summary scores were obtained as norm-based scores (mean=50, SD=10 based on general population). Interclass correlation coefficient (ICC) was obtained to evaluate the degree of agreement between VASpt and VASdoc. Data were analyzed with SPSS statistical software. Results In 1250 patients who were informed of the study, consent was obtained from 1216, and 1149 patients returned the questionnaires. Nine patients were excluded because of a time lag (>4 months) that patient/physician completed reports, consequently, 1140 pairs of patient's and physician's questionnaires were included in the analysis. Males accounted for 52%, the median age at survey was 51 (range, 20-77), and the median time after allo-HSCT was 7.1 years (3.3-18.9). By the global severity score, 34% of patients had no GVHD, 29% mild, 25% moderate, and 9% had severe chronic GVHD. Frequently affected organs were eye (31%), skin (25%) and oral cavity (21%). The median scores were 49.3 for physical component summary (PCS), 52.4 for mental component summary (MCS), and 52.3 for role/social component summary (RCS). Overall, VASdoc were higher than VASpt (median, 91.0 vs 75.6). By the NIH global severity, PCS, FACT-BMT total score, VASpt and VASdoc were significantly (p Conclusions In long-term survivors after allo-HSCT, physical, role/social, and general QOL was impaired in patients with higher grades of chronic GVHD global scoring. Even mild chronic GVHD impaired patients' physical and general QOL in most types of GVHD. Physicians tended to underestimate changes in patients' QOL, especially for those with no or mild GVHD. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

Introduction: Donor cell-derived leukemia/lymphoma (DCL) is an extremely rare complication after allogeneic hematopoietic stem cell transplantation (HSCT). Due to the rarity of DCL, most of the available data have been limited to case reports or small case series, and the number of the patients was still insufficient to understand the clinical features of DCL and to assess the risk factors for its development. In this study, we aimed to obtain the clinical perspectives and identify possible risk factors for DCL by conducting a survey based on data from the nationwide registry of the Japan Society for Hematopoietic Cell Transplantation (JSHCT). Patients and Methods: In this study, DCL was defined as hematologic malignancy including leukemia, lymphoma, and myelodysplastic syndrome (MDS) which were confirmed as donor origin based on short tandem repeat analysis or fluorescence in situ hybridization (FISH) for sex chromosomes. Our survey identified 40 DCL from 36,870 allogeneic HSCT performed between 1974 and 2012 which achieved engraftment. Results: The median interval from HSCT to DCL diagnosis was 22 months (range, 3-190 months). Incidence of DCL was estimated as 0.12 ± 0.02% at 5 years, 0.13 ± 0.02% at 10 years, and 0.16 ± 0.03% at 15 years from HSCT. The incidence was correlated with types of stem cell sources, 0.09 ± 0.02% with bone marrow (n = 23,431), 0.02 ± 0.02% with PBSC (n = 7,210), no DCL with combined BM and PB (n = 196), while 0.35 ± 0.09% with CB (n = 6,012) with statistical significance (Figure A, p = 0.0047). When limited to HSCT performed after 2004 (n = 20,346), the incidence of DCL after CB transplantation (n = 4,966, 0.29 ± 0.09%) was significantly higher than that of non-CB transplantation (n = 15,380, 0.09 ± 0.03%, p = 0.0013). Excluding CB, older age was associated with higher incidence of DCL, 0.05 ± 0.05% with donor ≤ 20 years old, 0.06 ± 0.03% with donor of 21-40 years old, and 0.20 ± 0.07% with donor > 40 years old (Figure B, p = 0.045). On the other hand, patient age did not show statistical significance with incidence of DCL. No significant difference in the incidence of DCL was noted between other factors. The incidence was not different between gender match/mismatch (0.10 ± 0.03% with gender match and 0.17 ± 0.04% with gender mismatch, p = 0.56). G-CSF usage also did not show correlation with incidence of DCL (0.14 ± 0.03% for HSCT with G-CSF, 0.10 ± 0.07% for HSCT without G-CSF, p = 0.47). Underlying disease of patients, conditioning regimen (with or without TBI), and GVHD prophylaxis did not correlated with incidence of DCL. Of the 40 DCL, 7 were lymphoid malignancy (2 ALL and 5 B-cell lymphoma) and the rest were myeloid malignancy (10 AML and 23 myelodysplastic syndrome). In the seven patients with lymphoid DCL, two B-cell lymphoma had alteration affecting chromosome 8q24, and one ALL case had t(4;11). In the 33 patients with myeloid DCL, -7 (n = 5), +8 (n = 3) and +21 (n = 2) were recurrently observed. Of note, +8 and +21 were mainly detected in AML, whereas all of -7 patients was MDS. Overall survival probability was estimated as 36.4 ± 8.1% at 4 years from diagnosis of DCL. Our survey obtained information regarding donor health condition from 11 related donors. Only one donor developed MDS with gain of chromosome 8, which was the same feature with DCL, but the rest of the donors did not develop hematological malignant diseases afterwards. Conclusion: CB was a risk factor for DCL development compared to other stem cell sources, and it also should be noted that donor age affected the incidence of DCL. Our study revealed the frequency and risk factors for DCL. Given the results, especially the high frequency of CB-derived DCL, dominance of myeloid phenotype, and distribution of cytogenetic abnormalities, we are convinced that DCL is not a natural occurrence of hematological malignancy. Further molecular and immunological investigation would clarify the pathogenesis of DCL, and may provide additional clues for the understanding of the underlying mechanism of typical hematological malignancies. Figure 1. Figure 1. Disclosures Nakaseko: Otsuka: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Introduction Secondary cancer is one of the life-threatening late complications among long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several studies have reported that survivors of allo-HSCT had a 2-3-fold increased risk of developing new malignancies compared to the general population, although results were inconsistent among the studies in types, incidence, and risk factors of secondary cancers. We conducted a retrospective single-center study, in order to assess the incidence, risks, and risk factors of developing secondary cancers. Methods We retrospectively evaluated data on patients who received a first allo-HSCT for hematological disorders between 1982 and 2012. Cumulative incidences of secondary cancers were estimated, with death without developing secondary cancers treated as a competing risk. Standardized incidence ratios (SIRs) of secondary cancers were calculated using the incident rate in the general population. Multivariate analyses were used to identify risk factors of developing secondary cancers. Variables considered in multivariate analyses were patient age at HSCT ( Results A total of 1060 patients were included in the analysis, with the median age of 46 years (1-69) and the median follow-up of 4.2 years. 60% of patients were males. 43% of patients had peripheral blood transplantation from a related donor, 22% had bone marrow transplantation from a related donor, 31% had bone marrow transplantation from an unrelated donor, and the remaining 4% had others including cord blood transplantation or haplo-identical transplantation. Approximately half (49%) of the patients received reduced-intensity conditioning, and in those who received myeloablative regimens, two-thirds had total body irradiation (>10Gy). Overall, 42 secondary cancers were identified: the sites of cancers with >2 patients were esophagus (8), stomach (5), colon (4), oral (4), lung (4) and breast (3). The cumulative incidence rate of developing any secondary cancers at 5, 10, and 15 years after allo-HSCT were 2.5% (95% CI 1.6-3.8%), 5.9% (95% CI 4.1-8.3%), and 8.5% (95% CI 5.6-12.1%), respectively. Allo-HSCT recipients had a 3.4-fold higher risk of developing cancers compared with the general population. SIR was particularly higher for the oral (SIR = 15.3) and esophagus (SIR = 23.4). The development of oral or esophageal cancer was detected at ≥3 years after allo-HSCT. Multivariate analysis showed that patient age ≥50 years, CML/MPD, and chronic GVHD were associated with onset of secondary cancers. As for the site of chronic GVHD, patients who developed oral or intestinal GVHD had a higher incidence of secondary cancers compared with those who did not. The overall survival rate was 62% at 3 years after the diagnosis of a secondary cancer. In 18 of the 42 patients who developed secondary cancers, cancers were diagnosed by routine medical checkups or follow-up screenings at outpatient clinic. Conclusions Recipients of allo-HSCT have a significantly higher risk of developing secondary cancers than the general population. SIRs were especially higher in oral and esophageal cancers. Lifelong screening is important for patients who have risk factors such as older age and oral or intestinal chronic GVHD. Disclosures No relevant conflicts of interest to declare.

Background: Steroid-refractory acute graft vs. host disease (SR-aGVHD) remains a significant complication of allogenic hematopoietic stem cell transplantation (allo-HSCT). In this phase II-III multicenter clinical study we evaluated the efficacy and safety of MSCs(JR-031; JCR Pharmaceuticals Co., Ltd., Japan) for SR-aGVHD. Method: 25 patients (age: 5-66 years, median 33years; male 15, female 10) who developed SR-aGVHD (grade III 22, grade IV 3) after allo-HSCT (Nov. 2011-Sept. 2012) were enrolled and given 8 biweekly infusions of 2x106 cells/kg of JR-031 for 4 weeks, with an additional 4 infusions weekly after 28 days in patients with partial response (PR). They were followed up to 24 weeks. Results: At 4 weeks after the first dose, 6 (24%) patients showed complete response (CR), 9 (36%) patients showed PR, 4 (16%) patients showed mixed response (MR) and 1(4%)patient showed no change (NC). During 24 weeks of observation period, 12 (48%) patients achieved durable CR (CR >=28days). As for response by organ, 80% (16/20) of GI, 66.7% (8/12) of skin and 66.7%(4/6) of liver GVHD completely responded (stage 0). 15 (60%) patients survived up to 24 weeks after the first dose.All patients experienced at least one adverse event(AE). Common AEs were leukopenia (12 patients), thrombopenia (9 patients), sepsis, anemia, TMA and hepatic dysfunction (6 patients). Among 10 death, causal relationship with JR-031 were not completely ruled out in 4 cases (TTP, pneumonia, sepsis and relapse of underlying malignancy), however there was no case in which the causality was strongly suggested. Conclusion: It was suggested that JR-031 is a safe and effective therapy in the treatment of patients with SR-aGVHD. Disclosures Miyamura: Novartis: Honoraria, Speakers Bureau.

Background Allogeneic hematopoietic cell transplantation (HCT) is one of the most curative therapeutic modalities for hematological malignancies. Recent advances in availability of stem cell sources, conditioning regimens, managements of graft-versus-host disease (GVHD) and supportive care have improved the outcomes of HCT. But even now, relapse is still the leading cause of treatment failure and some long-term survivors after HCT suffer late relapse of the original disease. To better understand the risk and risk factors of late relapse in HCT recipients, we conducted a nationwide retrospective study of the patients who received first HCT for hematological malignancies in Japan. Patients and Methods The study population included HCT recipients reported to the Japan Society for Hematopoietic Cell Transplantation. From this database, we extracted the data of patients with hematological malignancies who received first HCT between 1974 and 2011. There were 29,479 recipients selected according to this criterion. Then, we excluded 1,192 (4.0%) cases from the study because of missing key variables. Results A total of 28,287 recipients were evaluated in this study. Median age at transplant was 37 years old (range, 0-88), and 41.0% (n=11,605) were female. Underlying diseases were acute lymphoblastic leukemia (ALL) (n=7,300, 25.8%), acute myeloid leukemia (AML) (n=11,526, 40.7%), chronic myelogenous leukemia (CML) (n=3,038, 10.7%), myelodysplastic syndrome (MDS) (n=3,235, 11.4%), malignant lymphoma (ML) (n=2,956, 10.5%) and plasma cell disorder (PCD) (n=232, 0.8%). Type of transplant included bone marrow transplantation (BMT) from HLA-matched or 1 locus serological mismatched (“matched”) related donor (n=8,002, 28.3%), BMT from more than 1 locus-mismatched (“mismatched”) related donor (n=261, 0.9%), BMT from HLA-matched unrelated donor (n=9,074, 32.1%), BMT from HLA-mismatched unrelated donor (n=1,112, 3.9%), peripheral blood stem cell transplantation (PBSCT) from “matched” related donor (n=4,385, 15.5%), PBSCT from “mismatched” related donor (n=467, 1.7%), cord blood transplantation (CBT) from “matched” unrelated donor (n=2,326, 8.2%) and CBT from “mismatched” unrelated donor (n=2,556, 9.0%). Myeloablative conditioning regimens were applied to 77.0% (n=21,773) of recipients and reduced-intensity conditioning regimens to 22.1% (n=6,247). Median follow-up of survivors was 1,934 days (range, 18-11,123). Event-free survival of all cases was 41.8% and cumulative incidence of relapse (RI) of them was 33.1% at 5 years. Disease-free survival (DFS) and RI at 7 years of recipients who had been in remission for 2 years since HCT (“DF2”, n=11,500) were 83.2% and 10.2%. DFS and RI at 10 years of recipients who had been disease-free for 5 years (“DF5”, n=7,093) were 91.5% and 2.9%. In multivariate analysis, disease, disease risk at transplant and patients’ age were powerful (p Adjusted for patients’ age, disease risk at transplant, year of transplant, donor-recipient sex match, ABO disparity, type of transplant and intensity of conditioning regimen, acute and chronic GVHD were included as time-dependent covariates in Cox model for relapse. In DF2, grade II-IV acute GVHD was associated with a reduced risk of relapse for patients with ALL (Hazard Ratio 0.75, 95% confidence interval 0.57-0.99, p=0.043) and AML (0.74, 0.57-0.97, p=0.029), and chronic GVHD for those with CML (0.65, 0.47-0.89, p=0.0067) and ML (0.37, 0.20-0.60, p=0.00067). In DF5, grade II-IV acute GVHD significantly reduced risk of relapse for recipients with AML (0.40, 0.18-0.85, p=0.018), and chronic GVHD for those with CML (0.56, 0.34-0.92, p=0.021). Conclusion Recipients of HCT for hematological malignancies who remain in remission for more than 2 or 5 years have favorable long-term survival. Our study demonstrates there are relatively small but persistent risks of relapse and underlying disease and disease risk at transplant are the major risk factors of late relapse. We also show acute and chronic GVHD are associated with a reduced risk of late relapse but the strength of this association differs between underlying diseases. Disclosures: No relevant conflicts of interest to declare.

Abstract 3048 Background: In solid organ transplantation, lifelong immunosuppression is required to preserve graft function, and medication nonadherence is a major risk factor for graft failure. Tacrolimus (Tac) was first developed as an oral twice-daily formulation (Tac BID) and has been widely used in hematopoietic stem cell and solid transplantation, but long-term adherence remains a concern. In renal transplant patients, morning dosing is associated with significantly higher adherence than evening dosing. In response to this potential adherence problem, a once-daily modified release formulation (Tac QD) has been developed with a morning dosing regimen that maximizes the potential for adherence. However, several investigators have recently reported a sustained decrease in Tac exposure in kidney transplant recipients after conversion from Tac BID to Tac QD. In this study, we measured Tac exposure after switching from Tac intravenous infusion (Tac iv) to Tac QD and analyzed the pharmacokinetics (PK) of Tac QD to investigate the correlation between area-under-curve (AUC) and trough in patients who received allogeneic hematopoietic stem cell transplantation (HSCT). This is the first report of the PK study of Tac QD in patients who received allogeneic HSCT. Methods: Patients who were 15–65 years of age and received HSCT from unrelated donors were eligible. They received Tac iv 0.03mg/kg by continuous infusion beginning one day before transplantation, and administration was converted to Tac QD at a 1:4 ratio when the patients engrafted and could tolerate oral medication. Doses were modified to maintain whole-blood trough concentration of 8–12 ng/ml. To analyze PK of Tac QD, plasma samples were obtained at baseline and at 0, 1, 2, 3, 6, 12, and 24 hours after the once-daily administration. Plasma concentration of Tac was determined by an ELISA method. Results: A total of 10 patients with hematological malignancies (AML 6, ALL 1, MDS 2, NHL 1) were enrolled in the PK study. Median age was 45 (23–65) years. Five patients received myeloablative preparative regimens, and 5 patients received reduced intensity regimens, and stem cell sources were bone marrow (BM) from HLA-matched unrelated donor (n=4), BM from HLA DRB1 mismatched unrelated donor (n=4), or cord blood (n=2). After conversion from Tac iv to Tac QD, six out of 10 patients (60%) showed a sustained decrease in Tac exposure and required an increase in their Tac QD daily dose. One patient experienced a quick decrease of more than 78% in trough level of Tac QD, and he developed grade II acute GVHD after the conversion. No other patients developed grade II-IV acute GVHD. None of the patients had to discontinue the agent because of adverse effects, and none developed treatment-related mortality within 100 days after HSCT. In PK analysis, median area-under-curve (AUC) was 246 ng·h/ml. There was a strong correlation between AUC and trough level (Figure 1). Obtaining over 240 ng•h/ml of AUC required 7.5 ng/ml of whole-blood trough levels of tacrolimus. Conclusions: Despite initial reports showing the bioequivalence of Tac QD with Tac BID, we found that 60% of patients experienced a sustained decrease in Tac exposure. Therefore, the conversion from Tac iv to Tac QD should be performed under close medical supervision. Our study demonstrated that AUC and trough concentration level curves showed a strong correlation in patients who underwent allogeneic HSCT. The whole-blood trough should be maintained above 7.5ng/ml to provide an adequate level of AUC. If the trough level of Tac QD can be maintained above 7.5 ng/ml, Tac QD can be as effective as Tac iv and stable administration can be maintained for the patients with reduced stress because of the easier administration schedule. Our findings indicate that the use of Tac QD instead of Tac BID for GVHD prophylaxis is beneficial for patients undergoing allogeneic HSCT without moderate toxicities. Disclosures: No relevant conflicts of interest to declare.

Abstract 1945 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from female donor to male recipient (F to M) has been reported to be a risk factor of poor prognosis. Although immune responses to male specific minor histocompatibility antigens (H-Y) are suggested to be involved, this hypothesis has not yet been well validated. To clarify the significance of exposure to H-Y, we retrospectively surveyed the medical records of 292 patients with hematological malignancies who underwent allo-HSCT from a related donor at National Cancer Center Hospital from 2001 to 2010. Data about children's sex and pregnancies of female donors were collected by chart review. The median follow-up of survivors was 69 months (range; 3–128) after HSCT. The median age of donors and recipients were 47 years (range; 12–69 years) and 51 years (range; 18–69 years), respectively. The distribution of sex combination of donors and recipients were as follows: 94 male to male, 57 female to female, 70 female to male and 71 male to female. About a half of female donors had pregnancy history (79 of 127; 62.2%, including abortion history). According to F to M sex-mismatch pattern and children's sex, patients were divided into three groups: 31 female donor with male child to male recipient (F to M with MC), 39 female donor without male child to male recipient (F to M without MC) and 222 non-F to M sex combination (non-F to M). The F to M sex-mismatch pattern did not significantly affect OS regardless of children's sex (5-year OS, F to M with MC; 52%, F to M without MC 40%; non-FtoM; 43%). In multivariate analysis, only disease status before HSCT significantly affected OS (hazard ratio [HR]; 1.64, 95% confidential interval [CI]; 1.17 to 2.28, P Disclosures: No relevant conflicts of interest to declare.

Abstract 1922 In allogeneic hematopoietic stem cell transplantation (HSCT) for recipients with acute myeloid leukemia (AML), cyclophosphamide (Cy) combined with total body irradiation (TBI) (Cy+TBI) is the most common myeloablative conditioning (MAC) regimen, but busulfan (Bu) in combination with Cy (Bu+Cy) has been an alternative to Cy+TBI since early 1980s. But as oral Bu has a problem of interpatient variation in intestinal absorption, intravenous Bu (ivBu) has been developed and substituted for Bu in conditioning regimens for HSCT. For the last decade, fludarabine (Flu)-based regimens with the addition of cytotoxic agents such as Bu or melphalan (L-PAM) have been developed as reduced-intensity conditioning (RIC) regimens. After the introduction of ivBu, Flu+ivBu has become one of the common RIC regimens. In Japan, ivBu was introduced in 2006 and have been widely used as a part of conditioning regimens. In this nationwide retrospective study, we evaluated the clinical outcomes of allogeneic HSCT for AML, especially focusing on ivBu-based conditioning regimens. The study population included HSCT recipients reported to the Japan Society for Hematopoietic Cell Transplantation. From this database, we extracted the data of adult patients with AML who received first allogeneic HSCT between 1975 and 2010. There were 9,396 recipients selected according to this criterion. Then, we excluded 345 (3.7%) cases from the study because of missing key variables. A total of 9,051 recipients were evaluated in this study. Median age at transplant was 43 years (range, 16–82), and 41.8% (n=3,785) were female. Types of transplant included bone marrow transplantation from sibling donor (RBMT) (n=1,978, 21.9%), peripheral blood stem cell transplantation from sibling donor (RPBSCT) (n=1,411, 15.6%), bone marrow transplantation from unrelated donor (UBMT) (n=3,321, 36.7%) and cord blood transplantation from unrelated donor (CBT) (n=1,728, 19.1%). MAC regimens were applied to 80.2% (n=7,259) of recipients and RIC regimens to 19.8% (n=1,792), according to the definitions proposed by the NMDP and the CIBMTR in 2007. These MAC regimens included Bu+Cy-based (12.4% of all MAC regimens), Cy+TBI-based (50.0%) and ivBu+Cy-based (5.6%) regimens. RIC regimens consisted mainly of Flu+Bu-based (27.6% of all RIC regimens), Flu+L-PAM-based (24.1%) and Flu+ivBu-based (19.5%) regimens. Median follow-up of survivors was 1,437 days (range, 26–8,344). In MAC setting, overall survival (OS) of HSCT recipients with ivBu+Cy-based regimens did not show the significant difference between that with Bu+Cy or Cy+TBI-based ones in RBMT (p=0.168), RPBSCT (p=0.236) and UBMT (p=0.604). But in CBT, Cy+TBI was significantly superior to Bu+Cy (p=0.004). Though the cumulative incidences of relapse (RI) were similar among recipients with these three regimens, the cumulative incidence of non-relapse mortality (NRM) with Bu+Cy was significantly higher than with Cy+TBI in CBT (p=0.049). In RIC setting, OS of recipients with Flu+ivBu-based regimens was comparable to that with Flu+Bu or Flu+L-PAM-based ones regardless of the type of transplant. RIs with these three regimens were almost equivalent, but NRM with Flu+ivBu-based was significantly lower than that with Flu+L-PAM-based in UBMT (p=0.023). In the multivariate analysis for OS, ivBu+Cy-based regimens did not have significant impacts regardless of the type of transplant, but Flu+ivBu-based regimen had a significantly favorable impact in RBMT (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.23–0.99). In the multivariate analysis for NRM, Flu+ivBu-based regimen had a significantly reduced risk compared with Flu+L-PAM in RBMT (HR 0.32, 95%CI 0.11–0.95) and UBMT (HR 0.46, 95%CI 0.25–0.83). These data indicates that ivBu+Cy-based and Cy+TBI-based MAC regimens have almost equivalent efficacy profiles for OS, RI and NRM, and Flu+ivBu-based RIC regimens can reduce the risk of NRM compared with Flu+Bu and Flu+L-PAM-based ones in allogeneic HSCT for recipients with AML. Disclosures: No relevant conflicts of interest to declare.

Abstract 4542 Background: Norovirus-gastroenteritis (NV-GE) is considered as a highly transmittable disease that can lead to fatal outcomes in vulnerable populations. Therefore, prompt detection of norovirus in stool specimens is important for patients who undergo hematopoietic stem cell transplantation (HSCT). The commercially available immunochromatography kit (Denka Seiken, Tokyo, Japan) is a diagnostic tool that can easily and rapidly detect norovirus antigens with high specificity and relatively less sensitivity compared with reverse transcription polymerase chain reaction (RT-PCR). Although previous studies used RT-PCR to detect norovirus in stool, this method is not necessarily a standardized technique for the clinical use, and only limited information is available about clinical significance of norovirus infection among the HSCT recipients. Here, we report an analysis of patients with NV-GE in our HSCT unit using the immunochromatography method. Patients and Methods: We prospectively examined stool specimens to detect norovirus antigens in patients who developed diarrhea in our HSCT unit between December 2008 and June 2011. We also retrospectively examined stool specimens which had been collected for Clostridium difficile (CD) toxin test and frozen at –40°C between January 2007 and November 2008. During the study period, a total of 468 patients underwent HSCT (autologous 83, allogeneic 385) at our center and we tested stool specimens from 355 patients who developed diarrhea. Results: Norovirus was detected by the immunochromatography method in 11 patients among the HSCT recipients, and in 1 patient who died before HSCT because of disease progression. Among the 12 patients with NV-GE, 3 were retrospectively diagnosed using the frozen specimens. The CD toxin test was also positive in 1 of the 12 patients with NV-GE. The median age of the 12 patients was 56 years (range, 29–66). The median duration of symptoms was 30 days (2–134). Among the 11 patients who developed NV-GE after HSCT, primary disease included lymphoma (6 patients), acute leukemia (4 patients), and multiple myeloma (1 patient), and 9 of them were not in remission at HSCT. One patient developed NV-GE after autologous HSCT, and 10 patients after allogeneic HSCT. Among the 10 allo-HSCT recipients, 6 received grafts from unrelated bone marrow donor and 4 received grafts from related donor. Five patients received myeloablative conditioning and 5 received reduced-intensity conditioning before allo-HSCT. The median time from HSCT to the onset of symptoms was 36 days (4–93). The median time from HSCT to diagnosis of NV-GE was 37 days (11–101). At diagnosis of NV-GE, all allo-HSCT recipients were given immunosuppressive agents, and 2 of them received corticosteroids for intestinal graft-versus host disease (GVHD). The volume of diarrhea was more than 500 ml per day in 4 patients. Among 4 patients who underwent endoscopy of the lower gastrointestinal tract, intestinal GVHD was diagnosed in 2 patients by histopathology findings, whereas the other 2 patients had no evidence of intestinal GVHD, which resulted in no need for an intensification of immunosuppression. Of the 12 patients with NV-GE, 6 were alive with a median follow-up of 826 days (17–1168) after the diagnosis of NV-GE. No patients died of NV-GE, and 6 died of other causes (disease progression, 4; GVHD, 1; multiple organ failure, 1). There was no outbreak of NV-GE as we promptly implemented isolation of infected patients and enhanced hygiene strategy within an hour of collection of stool specimens in patients with diarrhea. Conclusions: In this study, we detected 11 patients who developed NV-GE after HSCT using the immunochromatography method. Our results suggested that this method is helpful in the differential diagnosis of patients with diarrhea after HSCT and enable us to take an appropriate and prompt preventive measure. In the future study, validation with RT-PCR and immunochromatography method is warranted among the immune-compromised populations. Disclosures: No relevant conflicts of interest to declare.

Abstract 4508 Long-term follow-up data of the patients who underwent HSCT more than 2 years ago at a single institution in Japan was presented. The patients who received first allogeneic hematopoietic stem cell transplantation (HSCT) at Tokyo Metropolitan Komagome Hospital between January, 1990 and December, 2007 under hematology division were included. Follow-up data were obtained annually from the medical records if the patients visited our institution regularly. If the patients were not followed in our institution, follow-up data were requested to the hospitals where the patients had been followed or questionnaires were sent directly to the patients unless their addresses are not known. These letters were sent annually. The most recent laboratory data and any kind of complications under treatment including hypertension, hyperlipidemia, diabetes including usage of insulin, renal failure, dialysis, and any kind of malignancies were requested to be reported. Survival was the most primitive data and the reason of death was defined by one of the authors, HA. Chronic GVHD was excluded from the independent etiology of death. Progression of the disease or complications of the treatment for the progressive disease were considered to be due to relapse. The incidence of each complication was calculated using the number of the patients whose data are available. In total, 622 patients had received transplantation and 370 patients survived more than 2 years. During last two years, 211 patients had been followed in our institution while 74 patients by the institutions outside. Letters were sent directly to rest of surviving patients. As the result, 6 patients could not be reached by any method. Letters had been received without response in 15 patients. 72 patients died later than 2 years after transplantation. Relapse was the most important reason of death even more than 2 years after the transplantation. Although the incidence declined annually, the latest relapse was observed in the patient with CML almost 15 years after the transplantation. Pulmonary complications including bronchiolitis obliterans and infections followed. Secondary malignancy was the reason of death in 7 patients. Chronic kidney disease was already observed in 27 % of the patients who survived 2 years after transplantation and one of the devastating complications. In total of 7 patients needed to start regular dialysis or kidney transplantation and another 2 patients showed eGFR level of less than 15 ml/min/m2. Nephrotic syndrome was another renal complication observed in 4 patients. Hypertension was reported on 46/244 (19%) of the patients. Diabetes was reported on 27/241 (11.2%) and 13 of them were on regular insulin treatment. Definitive diagnostic criteria of diabetes were not indicated on this analysis suggesting higher incidence of glucose intolerance in these patients. There were 14 patients developed secondary malignancies diagnosed later than 2 years after transplantation and oral mucosa, tongue, esophagus and colon were the main organs involved. Physicians taking care of those patients were recommended to check kidney function and gastrointestinal tract including head/neck, esophagus and colon for secondary malignancy, as well as hematological status. Disclosures: No relevant conflicts of interest to declare.

Abstract 3463 Introduction: Chronic kidney disease (CKD) is common in survivors of hematopoietic stem cell transplantation (SCT). However, evolution over time of kidney dysfunction and its association with post-SCT acute kidney injury (AKI) are unclear. Methods: A retrospective cohort study was performed in 86 myeloablative allogenic SCT patients who received SCT between 1990 and 1999 and lived without relapse for 10 years or more. CKD was defined as a sustained decrease in estimated GFR less than 60 ml/min/1.73 m2 at least for a period more than 3 months. Post-SCT AKI was classified into three stages according to the acute kidney injury network (AKIN) criteria within 100 days after SCT. Incidence of new-onset CKD was studied by 1-year interval along the course of follow-up. Cumulative CKD incidence was evaluated by the Kaplan-Meier analysis. The factors associated with CKD at the time of 10 years after SCT were examined using Cox regression analysis. Results: The incident of new CKD was the highest (10.5%) at the first year after SCT and then remained almost constant (2.3 to 3.5%) (Figure 1). The prevalence of CKD increased along the follow-up time (Table 1). The cumulative incidence of CKD increased according to increasing AKI stages with significant difference between stages ≥1 and no AKI (Figure 2). Cox regression showed that each AKIN stage was a significant predictor of CKD: stage 3: hazard ratio (HR) 12.7, 95% confidence interval (CI) 2.42–97.6; stage 2: HR 7.75, 95% CI 1.83–53.6; and stage 1: HR 4.36, 95% CI 1.06–29.5. Other predictors included total body irradiation (TBI) (HR, 4.00; 95% CI, 1.63–10.5) and age on SCT (HR, 1.08; 95% CI, 1.03–1.13). Conclusions: CKD accumulated among long-term survivors receiving myeloablative allogenic SCT. Post-SCT AKI, regardless of the AKIN stages, is the most significant risk of CKD in such SCT population. Disclosures: No relevant conflicts of interest to declare.

Abstract 1150 Poster Board I-172 Introduction ABO-incompatibility is not generally considered to be a risk factor of hematopoietic stem cell transplantation (HSCT). However, in our single-institute study of 568 patients, the incidence of acute GVHD was higher in minor-ABO incompatible HSCT than others (45.3% vs 35.2%, p=0.019). We made a hypothesis that there is a potential association between donor-derived isohemagglutinin (IH) and the outcomes of minor-ABO incompatible HSCT. Patients and method There were 1052 patients undergone HSCT between 1988 and 2009 at Komagome hospital. We analyzed 130 of 1052 patients (12.4%), who had received minor- ABO incompatible HSCT. Blood type and anti-A/B antibody titers were evaluated at least weekly in first one month after HSCT, and were repeated monthly until blood type had completely changed to the donor type. Our analysis was especially focused on the impact of IH on the outcome of minor-ABO incompatible HSCT. Result Minor ABO-incompatible HSCT were 130 cases that included AML (n=40), ALL (n=28), CML (n=27), MDS (n=15), SAA (n=9), NHL (n=7), MM (n=2) and ATL (n=2). Median age was 37 (range: 16-67) years old. Seventy-seven patients were male, 53 were female. Stem cell sources were bone marrow (n=96), peripheral blood (n=16) and umbilical cord blood (n=18). Eleven cases were HLA-matched and 9 were HLA-mismatched transplants. Anti-host IgG and IgM IH had been detected in 20 of 130 transplants undergoing minor ABO-incompatible HSCT (15.4%). Median time to IH detection was 13 days after HSCT (12-39days). There was a higher incidence of IH production in the HLA-mismatched group than in the HLA-matched group (p=0.007).There was also a higher incidence of IH production in the unrelated transplants group than in the related transplants group. (p=0.021). None of 18 patients receiving umbilical cord blood transplantation showed evidence of IH production. The incidence of grade II-IV acute GVHD was significantly higher (90% vs 60%, p Discussion and Conclusion Our study showed that IH production had association with HLA-mismatched and unrelated transplants in minor-ABO incompatible HSCT. We also showed that early detection of IH was related with the onset of grade II-IV acute GVHD. These findings indicate that strong allo-immunity induces not only severe acute GVHD caused by T lymphocytes but also antibody-production by B lymphocytes. In conclusion, we suggest that early detection of IH has impact on severity of acute GVHD. Disclosures No relevant conflicts of interest to declare.

Abstract 2281 Poster Board II-258 Background: A decision analysis using the Markov process is a flexible and convenient analytical method that tracks the clinical events that occur after a certain decision with different probabilities and utilities over time. To address the role of allogeneic hematopoietic cell transplantation (allo-HCT) for acute myeloid leukemia (AML) in CR1, we performed a Markov decision analysis using newly collected clinical data from 2029 patients. Methods: Probabilities and other outcome data were derived from a database of adult AML patients that was constructed from case report files collected for this study. We included patients who were diagnosed with AML other than M3 between 1999 and 2006, aged 16 to 70 years, and who had achieved CR1 after 1 or 2 courses of induction chemotherapy. Using the software package TreeAge Pro 2009, we constructed a Markov decision model that compared 2 strategies: allo-HCT in CR1 (HCT group) and no allo-HCT in CR1 (CTx group). Possible health states considered in each decision included, for the HCT group, 1) no relapse without chronic GVHD, 2) no relapse with chronic GVHD, 3) relapse, and 4) dead, and, for the CTx group, 1) no relapse, 2) relapse, 3) second remission, 4) after salvage allo-HCT, and 5) dead. Quality-of-life (QOL) adjustments were made by incorporating time trade-off utilities that were derived from a questionnaire to 12 physicians who were familiar with the treatment of AML. The cycle length between state transitions was set at 3 months. Results: A total of 2029 patients were eligible for this analysis. The median age was 50 years, and the median follow-up of the surviving patients was 4.10 years. The proportions of patients with favorable, intermediate, unfavorable and unknown cytogenetic risk by SWOG criteria were 20%, 54%, 17% and 9%, respectively. Therapies performed at CR1 were allo-HCT in 494 patients (24%) and chemotherapy in 1535 patients (76%). Among 1076 patients whose HLA typing was performed for allo-HCT in CR1, 431 had HLA-matched or 1-antigen-mismatched related donors. Life expectancy and quality-adjusted life expectancy for the HCT and CTx groups in each risk category are summarized in Table 1. Life expectancy of the HCT group was longer than that of the CTx group (4.96 years vs. 4.44 years). However, quality-adjusted life expectancy of the HCT group was comparable to that of the CTx group (4.06 years vs. 3.98 years) due to a larger reduction of expected life length in the HCT group after QOL adjustment. In a subset analysis of the CTx group, patients with more favorable cytogenetic risk had a longer life expectancy. Whereas allo-HCT in CR1 was associated with a shorter life expectancy in patients with favorable-risk AML, allo-HCT in CR1 was associated with a longer life expectancy in those with intermediate-risk or unfavorable-risk AML. Adjustment for QOL did not change the preferred decision in the intermediate- and unfavorable-risk groups, although the survival advantages for allo-HCT in CR1 were less than those without QOL adjustment. In a subset of patients who had related donors, both life expectancy and quality-adjusted life expectancy were longer in the HCT group. Conclusion: The results of our decision analysis using the Markov process indicated that patients with intermediate- or unfavorable-risk AML have a longer life expectancy and quality-adjusted life expectancy with a decision of allo-HCT in CR1. Our results also showed that a Markov decision analysis that incorporates QOL may be useful as a decision-making tool for patients who might be candidates for allo-HCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 524 Background: The benefits of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1) have mostly been evaluated in related younger donor/patient pairs by allocating treatment options based on donor availability. However, the benefits of allo-HCT in elderly patients have not been fully elucidated. To overcome an increased risk of non-relapse mortality (NRM) in elderly patients, reduced-intensity conditioning (RIC) regimens have been developed. We performed a nationwide retrospective survey to address recent optimal post-remission strategies for elderly AML patients stratified according to risk factors such as cytogenetic risks. Methods: We collected data from adult patients aged 50 to 70 years who were diagnosed with AML between 1999 and 2006, and who achieved CR1 after 1 or 2 courses of induction chemotherapy. Results: After we excluded patients with M3 or those who received autologous HCT during CR1, a total of 1,036 patients from 67 centers were eligible for this analysis. The median follow-up of the surviving patients was 1,323 days. The proportions of patients with favorable, intermediate, unfavorable and unknown cytogenetic risks by SWOG criteria were 16%, 60%, 16% and 9%, respectively. Therapies performed at CR1 were allo-HCT in 152 patients (HCT-group, 15%) and chemotherapy in 884 patients (CTx group, 85%). Of the 884 patients who did not receive allo-HCT, 46 relapsed or died within 2 months after achieving CR1; they were excluded from the landmark analysis. Donor sources for HCT in CR1 were HLA-matched related (42%), mismatched related (9%), unrelated bone marrow (34%), or unrelated cord blood (15%). The median ages of patients conditioned with myeloablative (38%) and reduced-intensity (62%) conditioning regimens were 52 (range, 50-59) and 58 (range, 50-70) years, respectively. In the landmark analysis, the relapse rate (RR) in the HCT group was significantly lower than that in the CTx group (27% vs. 68% at 3 years, p Conclusion: Our data suggest that allo-HCT is effective for reducing the incidence of relapse after CR1 in elderly patients with AML. This benefit was observed not only in RFS but also in OS, especially in patients with AML other than favorable risk, which may be explained by recent improvements in peri-transplant supportive procedures and the introduction of RIC. Disclosures: No relevant conflicts of interest to declare.

The pain during bone marrow aspiration (BMA) can be best explained by negative pressure inside the bone marrow cavity. Although most standard textbooks recommend rapid suctioning with high negative pressure to minimize peripheral blood contamination, this technique might be associated with more pain. To date, there is no evidence that rapid suctioning can reduce peripheral blood contamination. To find a technique that reduces pain without loss of specimen quality, we conducted two trials. The first was a randomized, crossover trial comparing slow aspiration with low negative pressure (L method) and rapid aspiration with high negative pressure (H method). To evaluate pain during the procedure, 49 patients with hematological malignancy who required BMA more than once were randomly assigned to receive either the first aspiration by the L method and the second by the H method or vice versa. Under local anesthesia, a 16-gauge BMA needle was inserted into the BM cavity. A 1-mL syringe (L method) or a 30-mL syringe (H method) was used to aspirate 0.5 mL of BM fluid. To ensure accuracy of aspiration volume in the H method, an extension tube was connected between the 30-mL syringe and needle, and clamped by forceps when the aspirated volume reached 0.5 mL. Pain during each procedure was evaluated using a visual analog scale (VAS), verbal descriptor scale (VDS), and McGill pain questionnaire (MPQ). In the first trial, repeated measures one-way analysis of variance design was used for serial measurement of pain, and the one-tailed Wilcoxon’s test was used to compare pain between the two groups. The second trial compared aspirate quality between the L and H methods. Sixteen allogeneic transplantation donors (median age, 33.5 years; range, 22 to 62 years), underwent the first puncture of the harvest procedure under general anesthesia. BMA was drawn simultaneously from the right and left posterior iliac crest with a 1-mL and a 30-mL syringe; the aspiration side and syringe size were randomized. Nucleated cell counts (NCC) of the BM specimens were determined by automated hematology analyses. The non-inferiority margin was defined as less than 25% on the basis of the absolute difference of NCC between the L and H methods. In the first trial, 34 of the 49 patients (67%; 21 men and 13 women; median age, 49 years; age range, 17 to 77 years) completed the study and provided VAS, VDS and MPQ score data after two consecutive BMA. Present pain intensity (PPI) score of the MPQ was significantly decreased with L method when compared with H method (median absolute difference 0, P=0.037) (Table 1). VAS score and total pain rating index (PRI) of the MPQ were also lower with the L method (median absolute differences −0.6 and −0.5), although these results did not reach statistical significance. There was no significant ordinal interaction in repeated measurement of any scores except the affective-PRI of the MPQ, which was significantly higher at the first aspiration, regardless of the negative pressure intensity (P=0.024). In the second trial, the geometric mean of NCC with the L method was non-inferior to the mean with the H method (P=0.025) (Table 2). These findings indicated that BMA with low negative pressure tended to be less painful, while maintaining specimen quality. There remains difficulty in evaluating the impact of psychological factors on the results. Nonetheless, on the basis of our results we recommend suctioning slowly with low negative pressure using a small syringe in order to reduce pain during BMA. Table 1 L method H method P-value median (range) median (range) VDS 1 (0 to 3) 1 (0 to 3) 0.212 VAS 2.2 (0 to 8.4) 3.2 (0 to 9.0) 0.055 MPQ PRI-S 3 (0 to 16) 4 (0 to 30) 0.080 PRI-A 0 (0 to 7) 0 (0 to 9) 0.192 PRI-E 0 (0 to 4) 0 (0 to 4) 0.414 F’RI-M 2 (0 to 11) 3 (0 to 11) 0.093 PRI-T 6 (0 to 32) 7.5 (0 to 53) 0.063 PPI 1 (0 to 4) 1 (0 to 5) 0.037 Table 2 L method H method P-value Genomic mean of NCC (×104/μL) (95%IC) 6.6 (4.6–9.5) 7.8 (5.9– 10.4) 0.025

Hematopoietic stem cell transplantation (HSCT) recipients have an increased risk of acute kidney injury (AKI) or chronic kidney disease (CKD). However, serum creatinine level may underestimate the prevalence of these renal complications because of decreased lean body mass or concurrent liver disease, which was frequently observed in a HSCT setting. Cystatin C measurement may be more sensitive for detecting impaired kidney function. We retrospectively reviewed the medical records of 70 HSCT (54 allogeneic and 16 autologous) recipients who had at least one chance to monitor serum cystatin C level during last 2 years in our institution, and evaluated cystatin C as a possible new marker which can predict subsequent renal dysfunction. The occurrence of AKI was defined by the RIFLE classification and CKD staging was based on KDOQI criteria. Of 70 transplant recipients, 20 patients developed AKI after median 50.5 days (range 0–283 days) after HSCT, while worsening CKD stage was observed in 21 patients during observational periods. Cystatin C level was not influenced by pretransplant disease status (P=0.153) or autologous transplant (P=0.311), but significantly elevated after allogeneic transplantation (P0.90mg/l) and the episode of AKI after transplantation were a great risk for substantially worsening CKD stage (Hazard ratio 4.21 and 16.0, P=0.042 and P

In allogeneic bone marrow transplantation (BMT) from unrelated donor of Japan Marrow Donor Program (JMDP), the standard bone marrow nucleated cell dose for transplantation is regulated as 3.0×10E8 total nucleated cells (TNC)/recipient’s body weight (RBW) (kg). RBW are also used to estimate the target harvest volume of bone marrow from the donor. So RBW determine the dose of harvested TNC, and these factors will influence the outcomes of BMT. We retrospectively analyzed the clinical data of 3,114 adult transplant patients (median age 33, range 16–70) from extracted the database of JMDP. The diagnosis of these patients were AML (n=1257), ALL (n=927) and CML (n=930). Five years overall survival (OAS) of all cases was estimated as 47.6%. Possible factors that could influence on survival and hematological recovery were analyzed by using proportional hazards analysis. In univariate analysis, TNC>=3.0×10E8/RBW was one of the significant factors to improve OAS (p=0.022). TNC/recipients’ ideal body weight (IBW) whose body mass index (BMI) was over 22 could be also a significant favorable factor for OAS (p=0.014). In multivariate analysis, variables correlated with improving OAS were TNC>=2.0×10E8/IBW (p=0.011), using tacrolimus for GVHD prophylaxis (p=0.011), younger recipient’s age (p=0.013). TNC>=2.0×10E8/IBW were also powerful variables correlated with the recovery of neutrophils, reticulocytes and platelets. These findings suggest that TNC/IBW can substitute for TNC/RBW to evaluate infused cell dose. And in our data set, use of IBW to estimate the harvest volume from the donor brought 10.7% reduction of target bone marrow volume compared with use of RBW. JMDP sets up the upper limit of harvested bone marrow volume based on the donor’s BW, but heavyweight recipients often require larger volume of bone marrow from the donors. Appropriate evaluation of TNC for transplantation and recipients’ BW by using BMI may be one of the useful methods to improve outcomes of unrelated BMT and avoid excess risk and stress of unrelated donors.

Although expression of the genes ERG (ETS-related gene) and BAALC (brain and acute leukemia, cytoplasmic) predicts outcome in acute leukemia, there is little information about their utility as markers of minimal residual disease (MRD). A real-time quantitative reverse transcriptase-polymerase chain reaction (RQ-PCR) was used to examine relative levels of ERG and BAALC gene expression in 11 patients with acute leukemia. Pretreatment and post-chemotherapy bone marrow (BM) samples were analyzed to quantify these transcripts. Peripheral blood (PB) samples were also obtained to evaluate the correlation of ERG and BAALC expression levels in BM and PB samples. Significant levels of ERG gene were expressed in all patients. In contrast with ERG, the levels of BAALC gene expression were significantly lower in some patients. Continuous monitoring of the ERG mRNA was performed and assessed a correlation between MRD levels and subsequent clinical courses. In patients with relative high expression of BAALC transcripts (>7x10exp-3/GAPDH), high levels of ERG gene expressions were consistently observed whether they were in remission status or not. In 2 patients with acute promyelocytic leukemia (APL), MRD was simultaneously monitored by RQ-PCR using primers for PML/RAR alpha. Changes in expression levels of PML/RAR alpha and ERG presented poor correlation. While, in other patients with relative low expression of BAALC transcripts (

Background: Although it has been reported that the incidence of acute GVHD (aGVHD) and early non-relapse mortality (NRM) after HLA-identical sibling BMT are different between Japanese and other ethnicities, including white American, African American and Irish populations (Oh, Blood.2005), there has been no previous comparison among Asian countries. Patients and Methods: We retrospectively surveyed the data of 1933 patients (pts) (996 Korean and 937 Japanese) who underwent allo-Tx for leukemia or MDS between Jan, 2000 and Dec, 2005. The median age of the pts was 37 yrs (range, 16–70; 34 yrs vs 43 yrs, respectively) and the median follow-up of surviving pts was 1046 days (11–2435). Unexpectedly, the pts’ backgrounds, including age, underlying disease, disease status at Tx, stem cell source, donor type, No. of HLA-mismatched (MM) antigen/allele, conditioning regimen, in vivo T-cell depletion with ATG or Campath-1H and GVHD prophylaxis were significantly different between the two groups. Results: (Table) In a multivariate analysis, Tx from a serologically HLA-1-antigen MM donor, Tx from an unrelated donor (URD), pts with high-risk disease at Tx, no in vivo T-cell depletion and a conditioning regimen that included TBI ≥ 10 Gy were associated with an increased risk of grade II–IV aGVHD. Overall, race was not a risk factor for grade II–IV (P=0.19) or III–IV (P=0.98) aGVHD. The incidence of chronic GVHD (cGVHD) in Japanese was significantly lower than that in Korean (P=0.016). In a multivariate analysis, Tx from a genetically HLA-allele MM donor, Tx from an URD, pts with performance status 2–4 at Tx, pts with high-risk disease at Tx, pts with ALL, female to male Tx and pts’ age ≥ 40 yrs were associated with poor OS. Race was not a risk factor for OS. The incidence of relapse adjusted for the underlying disease status was associated with grade II–IV aGVHD (RR 0.75, 95% CI 0.61–0.94, P=0.010), but not cGVHD (P=0.63). Conclusions: Despite their different medical backgrounds, our data confirmed that the biology of GVHD is very similar between these two Asian populations, and this provides a uniform foundation for large-scale clinical studies in the region. Korean (n=996) Japanese (n=937) Grade II–IV/III–IV aGVHD 37%/15% 44%/19% Median onset of aGVHD day 28 day 21 cGVHD 60% 47% 3-yr OS in standard/high risk 70%/42% 65%/41% NRM 25% 30% Relapse 25% 24%

Although imatinib mesylate has a highly inhibitory effect against BCR-ABL kinase, primary and secondary refractoriness have been observed. Point mutation within the kinase domain of BCR-ABL is one of the most important drug-resistant mechanisms. Of 25 reported point mutations, T315I BCR-ABL mutation might be dismal in clinical settings because it mediates clinical resistance to imatinib, nilotinib, and dasatinib, and the only established therapeutic option is hematopoietic stem cell transplantation at this moment. However, there is no information about the kinetics of this mutated clone. Here we developed quantitative Invader assay to monitor T315I BCR-ABL transcript. By using fluorescent resonance energy transfer system, the amount of released 5′ flap is measured as signal intensity, which enables us to calculate the percentage of T315I products with standard curve. Using this assay, we serially monitored T315I BCR-ABL transcript in a CML patient whose BCR-ABL transcript was still detectable (more than 100 copies/microgram RNA) 3 months after starting imatinib therapy. Although we have continued to monitor T315I BCR-ABL transcripts in 13 patients (chronic phase) up to 10 months, there was no patients who appear to be apparently resistant to imatinib due to a given T315I mutant, so far. In contrast, in a case of Ph+ ALL was being treated with chemotherapy including imatinib, we serially monitored both wild type and T315I BCR-ABL transcripts and observed the increased level of T315I transcript during relapse (0%at the time of diagnosis and 54.8% at relapse). Thus, our new strategy could be a useful tool to study the kinetics of the mutant clone and the pharmacokinetics of the drug resistant to T315I mutation.

In allogeneic bone marrow transplantation from unrelated donor of Japan Marrow Donor Program (JMDP), the standard nucleated cell dose for transplantation is regulated as 3.0x10E8 bone marrow nucleated cells/recipient’s body weight. But if a recipient is heavyweight, it it often diffecult to get enough bone marrow from the donor for transplantation. Infused cell number and recipients’ body weight may infuence the engraftment and outcome of transplantation. We retrospectively analysed the clinical data of 4065 adult transplant recipients (median age 35, range 16–70) from extracted the database of JMDP. Based on the previous studies, the possible factors which could influence on engraftment were collected. The correlations of these factors with engraftment and neutrophil recovery after transplantation were analysed by using multiple logistic regression. Variables correlated with an increased possibility of engraftment were: incrased recipient’s body weight (p500 were: use of G-CSF after transplantation (p500 significantly earlier than other group (p

Hepatic veno-occlusive disease (VOD) is one of the most serious complication of hematopoietic stem cell transplantation (HSCT). Various factors have been identified as increasing the risk of hepatic VOD, but few of them have been associated with a significantly increased risk. We retrospectively analyzed the clinical data of 5024 transplant recipients (median age28, range 0–68) which extracted from the Japan Marrow Donar Program. The diagnosis of VOD was made according to the McDonald’s criteria, and 324 out of 4833 patients (6.7%) were eventually diagnosed with VOD. The possible risk factors based on the previous studies were counted on an initial univariate analysis, and cumulated significant factors were further analyzed for their potential value for VOD development in multivariate analysis. Variables correlated with an increased risk of VOD were: time of transplant >2 times (relative risk (RR) 2.7; p=0.006), pretransplant disease status (RR 2.3; p=0.000), prior liver disease (RR 2.1; p=0.017), ABO blood type mismatch (RR1.7; p=0.000). In patients receiving either busulfan or melphalan for conditioning increased VOD risk (RR 1.5 and 1.8; p=0.007 and 0.002, respectively). In our multivariate analysis, stem cell source, and prophylactic use of heparin and Ursodiol had no significant effect on VOD development. This analysis might contribute to revise the previously reported risk factors for VOD and the data could be used to know which patients might be suitable subjects for new trials for VOD prevention.

Although encouraging survival statistics are now reported after hematopoietic stem cell transplantation (HSCT), pulmonary complications occur in up-to half of patients after HSCT and are major causes of morbidity and mortality. In this study, we describe cryptogenic organizing pneumonia (COP) after allogeneic HSCT in our institution between January 1986 and December 2005. Charts and chest radiographs of 601 transplant recipients were retrospectively reviewed for COP. Total 12 cases of COP were observed (2.0%) at a median interval of 148 days after HSCT (range, 53–475 days). They presented low-grade fever, non-productive cough and dyspnea at the onset of COP. The initial antibiotics treatment did not ameliorate these symptoms, but all patients well responded to 0.5–1mg/kg of prednisolone. However, in 9 out of 12 patients, COP eventually flared-up after the tapering-off of steroid, but responded to the retreatment. Although 3 patients died, there was no death due to pulmonary failure and 5-year survival was 74.1%. In remaining 9 patients, there was no relapse of primary disease for which the patient underwent HSCT. The clinical features of 12 patients were similar in that they all received an irradiation containing conditioning and most patients had a history of acute graft-versus-host disease (GVHD). Furthermore, 8 patients had active chronic GVHD (6 extensive and 2 limited) at the onset of COP. These findings suggest that both the irradiation and allogeneic immune reaction may play a crucial role in the development of COP after HSCT. Moreover, the patients with COP might enjoy a relatively good prognosis due to low rate of relapse of primary disease through graft-versus-leukemia reaction, even though facing multiple episodes of disease exacerbation of COP.

Background: The outcome of patients who suffer from GF after allogeneic transplantation is poor, primarily due to an increased risk of infectious complications and toxicities. We evaluated whether rescue with RICBT could improve survival after GF. Patients and Methods: We retrospectively surveyed the data of 63 patients (median age, 51 years: range, 17–68 years) with hematological disorders who received RICBT within 3 months of GF between Jan, 2000, and Apr, 2006. The diagnosis included AML (n=28), MDS (12), CML (2), ALL (13), lymphoma (4), and AA (4), and 28 patients were not in remission before the preceding allogeneic HCT, which had been performed with either myeloablative (29) or reduced-intensity conditioning regimens (34). Twelve patients (19%) had received unrelated BM, while 46 (73%) received CB. Fifty-one patients had developed primary GF (failure of the ANC to surpass 500/mm3 or Results: The median time interval between the preceding HCT to salvage RICBT was 47 days (27–162), and that between the diagnosis of GF to salvage RICBT was 16 days (5–61). Prior to RICBT, 21 patients (33%) were in PS 3–4, 8 (13%) had grade 3 organ toxicities according to CTCAE v3.0, and 53 (84%) had documented infections or febrile neutropenia. All patients were conditioned with fludarabine-based regimens with L-PAM (n=20), BU (15), CY (12) or thiotepa (2), with or without additional 2–4 Gy TBI. GVHD prophylaxis included CyA/FK alone (37) and a combination of MTX plus CyA/FK (10). The median number of infused TNC was 2.3 (1.0–4.3) x107/kg. Among the 46 evaluable patients who survived more than 28 days after RICBT, 33 (72%) engrafted, but 10 (22%) again experienced GF. Multivariate analysis disclosed that infusion of TNC ≥2.0x107/kg and a fludarabine/L-PAM-based regimen were associated with a higher probability of engraftment. The cumulative incidence of grade II–IV acute GVHD was 28%. The median follow-up of surviving patients was 236 days (39–937) after rescue RICBT. The 1-year overall and progression-free survival rates were 27% and 20%, respectively. Forty-five patients (70%) died at a median of 37 days (2–485) after RICBT, with a day-100 TRM of 54%. The cause of death included bacterial (14), fungal (10) and viral infections (7), and relapse (6). Multivariate analysis showed that high-risk disease, grade 3 organ toxicity before RICBT, and the use of MTX were associated with an increased risk of mortality. Conclusions: Our data support the feasibility of RICBT for patients suffering from GF, with an engraftment rate of >70%, when they receive a graft containing ≥2.0x107/kg cells. The earlier application of RICBT while patients still have better PS without infections or organ toxicities will be the subject of continued clinical research.

Purpose We report the outcomes of allogeneic stem cell transplantation (SCT) for the patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in a single center. Patients and Methods Between August 1993 and March 2005, 36 patients with Ph+ALL received SCT at Tokyo Metropolitan Komagome Hospital. The median age was 41 years (range; 17 to 60 years). All patients received myeloablative conditioning regimen (cytosine arabinoside, cyclophosphamide and fractionated 12Gy total-body irradiation). Stem cell source of SCT was 14 related donors (bone marrow [n=9] and peripheral blood stem cell [n=5]) and 22 unrelated donors (bone marrow [n=13] and cord blood [n=9]). Results Seventeen (47%) of 36 patients are alive at a median of 2.16 years (range; 1.0 to 3.3 years) after transplantation. Three years overall survival (OS) and disease free survival (DFS) for all patients are 42.3% and 35.4%, respectively. Three years OS and DFS are 55.4% and 46.4% for the 24 patients in complete remission (CR) at transplantation, while 36.4% (p Conclusion This analysis suggests that shorter duration between diagnosis and transplantation improve the clinical outcomes of SCT for Ph+ALL, especially performed in CR.

Hepatic veno-occlusive disease (VOD) is one of the most serious complications of hematopoietic stem cell transplantation (HSCT). Various factors have been identified as increasing the risk of hepatic VOD; history of liver dysfunction, elevated AST level, transplant from an HLA-mismatched or unrelated donor, and abdominal irradiation, but few of them have been associated with a significantly increased risk. A recent study showed a newly association between the use of granulocyte colony-stimulating factor (G-CSF) and subsequent higher incidence of VOD. The present analysis was performed to elucidate the clinical effects of G-CSF on the incidence of hepatic VOD and survival after HSCT in a large group of patients at a single institution. We retrospectively reviewed 440 patients (264 males, 176 females; median age 35, range 0–67) with hematological diseases who underwent allogeneic transplantation between September 1986 and December 2003. G-CSF was given basically according to the primary diseases and type of transplant, and a total of 230 patients with lymphoid malignancy received G-CSF shortly after transplantation, while G-CSF was not administered in remaining 210 patients with myeloid malignancy. A diagnosis of VOD was made according to the McDonald’s criteria and 47 patients (11.0%) were eventually diagnosed with VOD. Hepatic VOD occurred in 33 of 230 patients (14%) in the patients with G-CSF versus 14 of 210 patients (6%) in the non G-CSF group. Several possible risk factors based on the previous studies, including the use of G-CSF, were counted on an initial univariate analysis and cumulated significant factors further analyzed for their potential value for VOD development in multivariate analysis. By univariate analysis, the HLA disparity, performance status before transplantation, febrile episode during conditioning therapy and the use of G-CSF were significantly related to the incidence of VOD. A multivariate analysis with logistic regression again identified the use of G-CSF as the factor that significantly influenced the occurrence of VOD, in addition to the former three independent variables. Our analysis of risk factors in this series confirmed some other published studies but differed for other factors. Surprisingly,the administration of G-CSF may have an adverse impact on the subsequent survival after transplantation. Patient survival probability was statistically different (p=0.0063) between two groups, as analyzed by the Kaplan-Meier plot: the ten year survival rate was 50±4% in the G-CSF group and 64±4% in the non G-CSF group (p=0.0063). There were a total of 98 deaths in the G-CSF group compared with 70 deaths in the non G-CSF group. Although relapse and GVHD were the most common cause of death in both groups, death due to hepatic failure/VOD/TMA was observed 10% in the G-CSF group versus 4% in the non G-CSF group. Our data based on retrospective analysis should be interpreted with some caution, but they have suggested that G-CSF might be involved in VOD development and also adversely affected the outcome. Although underlying mechanism how G-CSF adversely effect on survival should be multifactorial, it is possible that G-CSF could activate the coagulation system and therefore induce thrombotic events including VOD. Thus, this putative mechanism of G-CSF towards a prothrombotic tendency warrants a further clarification, and the use of G-CSF should be carefully assessed in transplant recipients.

[Introduction] Blastic mantle cell leukemia is defined as CD5-positive, CD23-negative, cyclin D1-positive mature B-lymphoid tumor characterized by leukemic presentation, blastic blood and bone marrow features with aggressive clinical behavior. Its prognosis is usually dismal and overall survival was reported to be 3 months. We present the case of blastic mantle cell leukemia treated with rituximab, enjoying complete remission for 3 years. [Case presentation] A 68 year-old man was admitted because of leukocytosis. His CBC revealed WBC 31.0 x 10E9/L with 64% of blast. Hemoglobin level was 5.3 g/dl, and 78% of medium-sized blasts that were positive for CD5, CD19, CD20, and HLA-DR. Chromosomal study revealed normal karyotype. He was treated with adriamycin, vincristine, cyclophosphamide, and predonisone as for acute lymphoblastic leukemia, and then, with another two cycles of intensive chemotherapy including hyper-CVAD without any significant response. He was transferred to our hospital for further treatment. The blastic cells showed bcl1/IgH re-arrangement on FISH analysis and bone marrow biopsy revealed CD23-negative and cyclin D-positive that confirmed the diagnosis of mantle cell lymphoma/leukemia. CT scan of the body showed no significant lymphadenopathy. He was treated with fludarabine and idarubicin without any effect and then was treated with rituximab 375 mg/m2. After the initiation of rituximab treatment, blasts disappeared from peripheral blood within 24 hours completely and after 4 times of rituximab once per every week, CBC returned to normal and bone marrow examination revealed complete remission. He was treated with another 2 injection of rituximab and then followed without any further treatment. He has been in complete-remission status for 3 years since then. [Discussion] Blastic mantle cell leukemia is usually chemotherapy-resistant as our case is and its prognosis is dismal. Our case represent the possibility that even in those patients, one may enjoy prolonged complete remission after the simple treatment with rituximab. This is, of course, only a single case experience and it is necessary to proceed for further investigation.