ALBERT

Description: In acute-type leukemia, no method for the prediction of relapse following allogeneic stem cell transplantation based on minimal residual disease (MRD) levels is established yet. In the present study, MRD in 72 cases of allogeneic transplantation for acute myeloid leukemia, acute lymphoid leukemia, and chronic myeloid leukemia (accelerated phase or blast crisis) was monitored frequently by quantitating the transcript of WT1 gene, a “panleukemic MRD marker,” using reverse transcriptase–polymerase chain reaction. Based on the negativity of expression of chimeric genes, the background level of WT1 transcripts in bone marrow following allogeneic transplantation was significantly decreased compared with the level in healthy volunteers. The probability of relapse occurring within 40 days significantly increased step-by-step according to the increase in WT1 expression level (100% for 1.0 × 10−2-5.0 × 10−2, 44.4% for 4.0 × 10−3-1.0 × 10−2, 10.2% for 4.0 × 10−4-4.0 × 10−3, and 0.8% for 〈 4.0 × 10−4) when WT1 level in K562 was defined as 1.0). WT1 levels in patients having relapse increased exponentially with a constant doubling time. The doubling time of theWT1 level in patients for whom the discontinuation of immunosuppressive agents or donor leukocyte infusion was effective was significantly longer than that for patients in whom it was not (P 〈 .05). No patients with a short doubling time of WT1 transcripts (〈 13 days) responded to these immunomodulation therapies. These findings strongly suggest that the WT1 assay is very useful for the prediction and management of relapse following allogeneic stem cell transplantation regardless of the presence of chimeric gene markers.

Description: Abstract 4707 Reduced-intensity stem cell transplantation (RIST) has come to be generally accepted as a method of allogeneic stem cell transplantation (SCT) for patients considered ineligible for myeloablative preparative regimens because of advanced age or comorbidities. We have recently reported unmanipulated nonmyeloablative HLA-haploidentical SCT using a conditioning treatment consisting of fludarabine, busulfan and anti-T-lymphocyte globulin and graft-versus-host disease (GVHD) prophylaxis consisting of tacrolimus and methylprednisolone (1 mg/kg) (Biol Blood Marrow Transplant 2006; 12:1073). In that study, the incidence of severe GVHD was only 10%. One of the mechanisms for such a low incidence of GVHD may have been caused by a reduced intensity of conditioning. Less intensive regimens should be associated with lower toxicity, a lower release of inflammatory cytokines, and potentially less GVHD; however, the mechanisms remain to be determined. Thus, using a murine MHC-haploidentical BMT model, BDF1(H-2b/d)®B6C3F1 (H-2b/k), that we established, we examined the influence of an intensity of conditioning treatment on GVHD. Recipient mice received T-cell-depleted bone marrow (5×106) and spleen cells (2×107) after total body irradiation (TBI) 13 Gy (myeloablative group) or 5 Gy (RIST group). Both groups of mice rapidly achieved donor engraftment. Recipients in the RIST group showed significantly fewer GVHD signs than those in the myeloablatve group. Histopathological examination of the myeloablative group on day 14 revealed various pathological changes in intestine (in particular large intestine) compatible to GVHD. In contrast, intestine samples from the RIST group showed few pathological changes with much less infiltration of donor T cells. Consequently, all recipients in the myeloablative group had died of GVHD by day 60, while all recipients survived for more than 3 months. These results clearly showed that the intensity of conditioning treatment influenced on the severity of GVHD and survival of recipients. Next, we investigated the mechanisms by which reduced intensity of conditioning ameliorated GVHD. Transplantation was performed using spleen cells that were labeled with the fluorescent cytoplasmic dye, carboxyfluorescein diacetate succinimidyl ester (CFSE), and cells in secondary lymphoid organs were analyzed by flow cytometry. The number of donor T cells in mesenteric lymph nodes on day 7 of the RIST group was significantly lower than that of the myeloablative group. In addition, a significantly increased number of host CD4+ T cells were recruited to secondary lymphoid organs on day 4 in the RIST group compared with the myeloablative group. An increased number of donor or host regulatory (Foxp3+CD4+) T cells were also observed in the RIST group. The levels of IFN gamma or IL-4 in lymphoid organs of the RIST group were higher than those of the myeloablative group. These results strongly suggest that host immune cells that survived conditioning treatment or cytokine milieu in secondary lymphoid organs contributed to the suppression of donor T cells during the initiation of GVHD. In addition, the expression of Th1 chemokine receptor, CXCR3, on donor T cells in secondary lymphoid organs and the expression levels of CXCL9, CXCL10, and CXCL11, ligands for CXCR3, in the large intestines were relatively lower in the RIST group, suggesting that the migration ability of donor T cells into GVHD target organs was negatively influenced by the intensity of conditioning. In conclusion, we showed that reduced intensity of conditioning improved the severity of GVHD, and that recipient immune cells, including regulatory T cells, together with reduced expression of inflammatory cytokines or chemokines, contributed to the improvement of GVHD in RIST. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3648 Background: Radioimmunotherapy (RIT) with 90Y-ibritumomab tiuxetan has been used for the treatment of relapsed or refractory indolent B-cell lymphoma. Early prediction of response to the therapy may offer the potential to identify patients who will benefit this therapy. We evaluated the efficacy of fluorine 18 fluorodeoxyglucose (FDG) combined positron emission tomographic-computed tomographic (FDG-PET/CT) imaging for assessment of therapy and predicting outcome in 90Y-ibritumomab tiuxetan radioimmunotherapy. Methods: Radioimmunotherapy with 90Y-ibritumomab tiuxetan was preformed in 52 patients with relapsed or refractory indolent B cell lymphoma (follicular lymphoma, 45; mucosa-associated lymphoid tissue lymphoma, 5; lymphoplasmacytic lymphoma, 2) at Hyogo College of Medicine Hospital from June 2009 through August 2012. FDG-PET/CT scanning was performed at two weeks and the later after 90Y-ibritumomab tiuxetan therapy. Results: In FDG-PET at 2 weeks after 90Y-ibritumomab therapy, 26 (50%) showed complete response (defined as early CR), 20 (38%) showed partial response (PR-2W) and 6 (12%) showed non response (NR-2W). Further follow-up revealed 10 later CR (8 CR out of 20 PR-2W and 2 CR out of 6 NR-2W), showing 69 %(36) of overall CR rate. Relapse was occurred in 4(17%) of 26 early CR and in 6 (60%) of 10 later CR, indicating significantly low relapse late in early CR (P= 0.0074, by Chi-square test). Patients with early CR (CR in 2 weeks after the RIT) showed significantly better progression free survival than those with later CR (P=0.0046, by Logrank test). In contrast, analysis at six weeks after the RIT showed 36 CR patients (10 of which eventually relapse), but failed to discriminate patients who had high risk of relapse. Conclusion: Our results suggest that CR assessed by FDG-PET/CT at 2 weeks after 90Y-ibritumomab tiuxetan therapy discriminates good responder to the RIT and predicts better progression free survival in relapsed or refractory indolent B cell lymphoma. Disclosures: No relevant conflicts of interest to declare.

Description: Allogeneic hematopoietic cell transplantation (HCT) is the only treatment modality that can either cure or prolong life of patients with primary myelofibrosis (PMF). However, the issues of the choice of stem cell source, the choice of conditioning regimen, and the timing of HCT are currently under debate. To determine whether a difference in stem cell source affects the outcome of HCT for PMF patients, a retrospective study was conducted using the national registry data on 224 patients who received first allogeneic HCT in Japan with bone marrow (BM), peripheral blood stem cells (PBSC) or umbilical cord blood (UCB). This study was approved by the Data Management Committee of the Japan Society for Hematopoietic Cell Transplantation and by the ethics committee of the Nagoya University School of Medicine. One hundred fifty-two male and 72 female, with a median age of 55 years (range, 21-79 years), were treated with a myeloablative (48%) or non-myeloablative (52%) preconditioning and GVHD prophylaxis such as calcineurin inhibitor with methotrexate (78%) between 1993 and 2016. Stem cell sources were HLA-A, -B and -DR 6/6 matched related BM (Rtd-BM) (n = 22), HLA-A, -B and -DR 6/6 matched related PBSC (Rtd-PBSC) (n = 48), HLA-A, -B, -C and -DRB1 alleles 8/8 or 7/8 matched unrelated BM (UR-BM) (n = 91), unrelated UCB (UR-UCB) (n = 29) and others (n = 34) including HLA 5/6 or 4/6 matched related BM and PBSC, HLA-haploidentical related BM and PBSC, HLA alleles 6/8 or 5/8 matched unrelated BM, and HLA alleles 8/8 or 7/8 matched unrelated PBSC. All UR-UCB transplantation was performed with a single unit. The median follow-up term for living patients was 48 (0.3-202) months. Cumulative incidences of neutrophil recovery (≥0.5 × 109/L) on day 60 were 100% in Rtd-BM (median days to recovery, 21 days), 94% in Rtd-PBSC (16 days), 86% in UR-BM (21 days), 79% in UR-UCB (25 days) and 91% in other transplantation (23 days). Cumulative incidences of grade II-IV and III-IV acute GVHD on day 100 were 23% and 5% in Rtd-BM, 27% and 19% in Rtd-PBSC, 27% and 10% in UR-BM, 31% and 10% in UR-UCB, and 26% and 15% in other transplantation, respectively. Cumulative incidences of chronic GVHD at 2 years after HCT were 35% in Rtd-BM, 41% in Rtd-PBSC, 34% in UR-BM, 19% in UR-UCB and 13% in other transplantation. Non-relapse mortality (NRM) at 2 years after HCT were 22% in Rtd-BM, 41% in Rtd-PBSC, 39% in UR-BM, 47% in UR-UCB and 48% in other transplantation. Multivariate analysis demonstrated that RBC transfusion ≥20 times before HCT (HR, 2.05; 95% CI, 1.06-3.98), PLT transfusion 10-19 times before HCT (3.56, 1.57-8.05), UR-UCB transplantation (4.70, 1.13-19.6) and other transplantation (4.38, 1.05-18.3) were predictive factors for higher NRM. Although performance status ≥2 at HCT was significant for higher NRM in univariate analysis, it was not significant in multivariate analysis. Relapse rates at 2 years after HCT were 14% in Rtd-BM, 17% in Rtd-PBSC, 13% in UR-BM, 24% in UR-UCB and 15% in other transplantation. Multivariate analysis demonstrated that no factor was associated with the incidence of relapse, although high-risk group of chromosome karyotype was significant for higher relapse rate in univariate analysis. Neither stem cell source groups nor DIPSS was not significant in univariate analysis. Overall survival (OS) rates at 2 and 5 years after HCT were 71% and 71% in Rtd-BM, 52% and 52% in Rtd-PBSC, 54% and 46% in UR-BM, 43% and 27% in UR-UCB, and 48% and 33% in other transplantation, respectively. Multivariate analysis demonstrated that age of 46-55 years (HR, 2.14; 95% CI, 1.00-4.56) and ≥56 years (2.69, 1.32-5.48), RBC transfusion ≥20 times before HCT (1.91, 1.13-3.25) and PLT transfusion 10-19 times before HCT (3.51, 1.64-7.52) predicted lower OS rate. Although performance status ≥2 at HCT, DIPSS intermediate-2 or high at HCT, high-risk group of chromosome karyotype, UR-UCB transplantation and other transplantation were significant for lower OS in univariate analysis, they were not significant in multivariate analysis. The present study could not find an advantage of use of JAK1/2 inhibitor before HCT, use of anti-thymoglobulin as a preconditioning, and non-myeloablative preconditioning regimen in terms of decreasing NRM or increasing OS rate. Our results suggest that allogeneic HCT provide a curative treatment for PMF patients, however careful management is required in HCT with other than Rtd-BM, Rtd-PB and UR-BM. Further analysis in a large cohort is required. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 4117 Related haploidentical donors, as cord blood, can be alternative donor sources in stem cell transplantation (SCT). Severe GVHD, however, has interfered the progress of haploidentical SCT (haploSCT). To deal with this strong GVHD, T cell depletion has usually been used in US and European countries. In order to pursue the controllable GVL effect by T cells, we have performed unmanipulated haploSCT using myeloablative or reduced intensity preconditioning regimen accompanied with intensified GVHD prophylaxis, including steroids. In this meeting, we will summarize our experience of haploSCT for more than ten years. From August 1998 to September 2010, we have performed 351 cases of haploSCT (all cases were HLA 2–3 antigen mismatched in GVH direction). Patients' characteristics are sex: male 186, female 168, age: 16–65 years old (median 39), disease: AML/MDS 149, ALL 81, ML 67, others 54. Eighty-three percent of cases underwent SCT in non-complete remission (non-CR) status. Patients under 45 years old underwent myeloablative preconditioning regimen consisting of FLU/CA/CY/TBI 8Gy (haplo-full, n=100), and patients over 45 years old or with comorbidities or repetitive SCT (including second to fifth SCT) underwent reduced intensity preconditioning regimen consisting of FLU/(CA)/BU/ATG or FLU/(CA)/MEL/ATG (haplo-mini, n=251). High dose Ara-C (CA) was optional to reduce tumor burden. As ATG, ATG (Fresenius) 8mg/kg, or thymoglubulin (genzyme) 2–4mg/kg were integrated into conditioning treatments mainly for reduced-intensity transplantation. GVHD prophylaxis consisted of taclolimus (TAC), methylprednisolone (mPSL) 2mg/kg/day, short term MTX, and mycophenolate mofetil (MMF) 15mg/kg/day in haplo-full, and TAC, and mPSL 1mg/kg/day in haplo-mini, respectively. For elderly patients over 50 years old in haplo-mini, MMF was added. Hematopoietic engraftment in haploSCT was as rapid as that in HLA-identical SCT, except 10 cases of graft rejection. The median time to reach a neutrophil account of 〉0.5 × 109/l was 10 days for haplo-mini and 13 days for haplo-full. Platelet recovery was achieved in 66 % and 60% of patients undergoing haplo-mini and haplo-full, respectively. The median time to reach a nontransfused platelet count of 3 20 × 109/l was 22 days for haplo-mini and 33 days for haplo-full. Sixty percent of haplo-mini patients and 54 % of haplo-full patients did not develop acute GVHD. Acute GVHD (grade II-IV) was observed in 20% for haplo-mini and 36 % for haplo-full. Overall survival at five years was 30% for haplo-full and 40% for haplo-mini, respectively. If limited to CR cases, overall survival reached over 60% in haplo-mini. There is no difference in survival rate among patients' diseases. In multivariate analysis on survival using variables, including disease status before transplantation, haplo-full vs haplo-mini, mismatches in GVH direction, mismatches in HVG direction, patients' age, and the number of transplantation times, the disease status (CR) was found to be only a significantly favorable factor (P= 0.0026). Unmanipulated haploSCT is feasible and effective for refractory diseases. ATG dose used in haplo-mini is critical, and rather low compared with that of European cases reported so far. Although it should be too early to refer long term outcome, unmanipulated haploSCT could be considered as an option to control refractory diseases. Disclosures: No relevant conflicts of interest to declare.

Description: [Background] We previously demonstrated that allogeneic hematopoietic stem cell transplantation (HSCT) in the first complete remission (CR1) was recommended for adult patients wih Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) who have a human leukocyte antigen (HLA)-matched related (Leukemia 2011;25:259-265) or unrelated donor (Bone Marrow Transplant 2013;48:1077-1083). However, pediatric-inspired high-intensity chemotherapy dramatically improved the prognosis of adult patients with Ph-negative ALL. Therefore, the optimal treatment strategy for Ph-negative ALL in CR1 has not been established in the era of high-intensity chemotherapy. [Methods] Outcomes of patients with Ph-negative ALL who underwent HSCT from HLA-matched related or unrelated donor in CR1 performed between 2002 and 2011 (HSCT-MRD group and HSCT-MUD group, respectively) were obtained from the Transplant Registry Unified Management Program (TRUMP), which is the registry database of the Japanese Society for Hematopoietic Cell Transplantation (JSHCT). Patients aged between 16 and 24 and between 25 and 65 were analyzed separately, and their outcomes were compared with those of patients who did not receive HSCT in CR1 in clinical studies by Japan Adult Leukemia Study Group (JALSG), ALL-202U study in which patients received chemotherapy designed for pediatric patients (Blood Cancer J 2014;4:e252)(202U group) and ALL-202O study in which patients were randomly assigned to receive adult-type chemotherapy with high-dose or intermediate-dose methotrexate (MTX) therapy (Leukemia 2018;32:626-632)(202O group), respectively. Median durations between diagnosis to HSCT were obtained from the TRUMP data, and only patients who were disease-free more than each median duration were included from the JALSG studies. Risk stratifications were performed based on the white blood cell (WBC) count and cytogenetics. [Results] In patients aged less than 25 who underwent HSCT from related donor, the median duration between diagnosis to HSCT was 188 days. Overall survival (OS) in 202U group (N = 93) was significantly superior compared with OS in HSCT-MRD group (N = 102) (OS at 5 years: 81.8% vs 67.8%, P = 0.016) (Figure 1(A)), and which was attributed to the higher non-relapse mortality in HSCT-MRD group (NRM at 5 years: 1.4% vs 9.5%, P = 0.015). Disease-free survival (DFS) and relapse rate (RR) were similar between two groups (DFS at 5 years: 70.2% vs 62.5%, P = 0.115, and RR at 5 years: 28.4% vs 28.4%, P = 0.689). Higher OS was preserved in younger (

Description: For patients with malignant hematological diseases that relapse after allogeneic hematopoietic stem cell transplantation (HSCT), a second HSCT is thought to be a curative option. A second donor is usually searched for due to HLA discrepancy between the graft and the host. However, it is unclear whether HLA discrepancy between the graft and the first donor has an impact on the outcome of second HSCT. To address this issue, we focused on second HSCT patients who had received first HSCT from an HLA-mismatched (MM) donor and compared the effects of HLA discrepancy between graft and first donor with those between graft and host. We retrospectively analyzed 646 patients receiving second HSCT between 1994 and 2016 after an initial HLA-MM transplantation. With regard to the graft versus host results, the one-allele mismatch (1 MM) group (relative risk [RR], 1.88; 95% confidence interval [CI], 0.79-4.45; p=0.163) and more than one-allele mismatch group (≥ 2 MM) (RR, 1.84; 95% CI, 0.75-4.51; p=0.182) had higher risks of grade III-IV acute GVHD compared to the HLA-matched (0 MM) group, although the results were not significant. In contrast, almost no difference in risk of acute GVHD was found among the 0, 1, and ≥ 2 MM group with respect to graft vs. first donor. Furthermore, with regard to graft vs. host, the ≥ 2 MM group showed a significantly higher risk of treatment-related mortality (TRM) (RR, 1.90; 95% CI, 1.04-3.50; p=0.038) compared to the 0 MM group. In contrast, the risk of relapse was slightly lower in the ≥ 2 MM group (RR, 068; 95% CI, 0.44-1.06; p=0.086). Consequently, no significant difference in OS was found among the three groups. In the analysis of each HLA allele MM, B allele MM between graft and host was associated with an increased risk of grade III-IV acute GVHD (RR 2.87; 95% CI, 1.42-5.79; p=0.003) and DR allele MM between graft and host was associated with a lower risk of relapse (RR, 0.75; 95% CI, 0.58-0.95; p=0.018) and higher risk of TRM (RR, 1.44; 95% CI, 1.03-2.00; p=0.033). In contrast, with regard to graft vs. first donor, there were no significant differences in relapse, TRM, or OS among the three groups, and also analysis of each HLA allele MM indicated no associations with relapse, TRM, or OS. These findings suggested that HLA discrepancy between graft and host, rather than between graft and first donor may induce transplant-related immunological responses in second HSCT leading to an increase in TRM. In conclusion, HLA-MM donor is an option after initial HLA-MM transplantation, however, TRM remains a challenge, particularly with a ≥ 2 MM donor regarding to graft versus host. In this study, the biological effects of HLA discrepancy between the graft and the first donor on the outcome appeared negligible, and our findings shed light on the role of nonhematopoietic APCs on transplant-related immunological responses. Figure. Figure. Disclosures Nakamae: Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding. Ichinohe:Mundipharma: Honoraria; Eisai Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Zenyaku Kogyo Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; CSL Behring: Research Funding; Novartis.: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Chugai Pharmaceutical Co.: Research Funding; Astellas Pharma: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding. Kanda:Ono: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Pfizer: Research Funding; Taisho-Toyama: Research Funding; MSD: Research Funding; Novartis: Research Funding; Tanabe-Mitsubishi: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; CSL Behring: Research Funding; Asahi-Kasei: Research Funding; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria.

Description: The origin of macrophage in HPS after SCT was also very interesting to be examined. Material and Method The characteristics of the patients and the information of infections were summarized in Table 1. 1. IL6, MCP|1, VCAM-1, TNF-a, RANTES, sE-selectin and HMGB1were measured by immunosorbent assay of cryopreserved blood samples. 2. In situ hybridization was performed to paraffin sections of aspirated bone marrow cells whose sex chromosome were dyed in different colors to detect the Y chromosome in macrophages. Result yperferritinemia and high levels of serum soluble interleukin-2 receptor were recognized. On day14, initial neutrophil engraftment and complete chimerism were successfully achieved. High dose mPSL 1000mg/day was administered several times but phagocytosis was little better and finally peripheral bloods were completely deprived (secondary graft failure). About sex chromosome, mononuclear cells had XX (donor type) but the phagocytes held original chromosome XY (recipient type). MCP-1 and VCAM-1 were rising up steadily but another adhesion molecule E-selectin or cytokines were not elevated (Fig1.). The same movement of MCP-1 and VCAM-1 was recognized in the case of patient#4 EBV-associated HPS who had immunological dysfunction with Bechet disease. The following two cases, patient #2 and #3 who received haplo-mini-SCT showed completely different cytokine movement. Patient #3 who was 75y.o.female with AM/MDS was infected with multiple candida species after haplo-mini-transplantation. MPC-1 inversely decreased less than 400 pg/ml. Patient#2 who was 60y.o. female with AML(M1) de Montréal (CHUM) between June 1, 2012 and May 31, 2013. Date was collected through medical and pharmaceutical patient records. Our local ethics board approved this study. Results A total of 45 patients received bortezomib for MM or amyloidosis with a median age of 68 years (SD ± 9.3) and 53.3 % were male. Patients received bortezomib in various protocols including Vel-Dex (42.2%), VMP (44.4%) and CyBorD (13.3%). The median starting dose of bortezomib was 1.3 mg/m2 (SD ± 0.13). Patients received SC only bortezomib injections (71.1%) or IV only (15.6%) or were switched from IV to SC (13.3%) for a total of 157 cycles (786 doses). A total of 444 BP values before and 425 BP values after SC bortezomib were analysed. No significant difference was detected between the average systolic BP (125 vs 125; p=0.76), diastolic BP (70 vs 71; p=0.77) or heart rate (79 vs 78; p=0.89) between the 2 measurements. Hypotension, defined as a drop of 20 mmHg of systolic BP, occurred 18 times (4.2%) but systolic BP was never below 90 mmHg. One patient had a severe dysautomia, possibly related to bortezomib that required the discontinuation of the treatment. At our center, CBC are performed prior to each bortezomib dose. Neutropenia occurred in 10 % of the total doses received. Risk factors influencing neutropenia were the use of oral alkylating agent (melphalan and cyclophosphamide) in the regimen and baseline neutrophil count less than 2.0 x 109. Many patients also received bortezomib for a relapsed / refractory disease and were previously exposed to many lines of therapy. Thrombocytopenia occurred in 7,2% of doses received. Cutaneous toxicity occurred mostly with the first patients treated with the SC technique. With time, nursing changed their technique and further skin reactions were less reported. Neuropathy occurred in 21 patients (13 SC, 4 IV, 4 IV to SC), caused dose reductions in 7 patients (2 SC, 2 IV, 3 IV to SC) and treatment discontinuation in 2 patients (SC). Conclusion Our results demonstrate SC bortezomib was well tolerated. The rates of hypotension was quite low. Also rates and intensity of neutropenia and thrombocytopenia varied among different bortezomib containing regimens. Because of the low rate of profound neutropenia, Vel-Dex and VMP protocols can be modified to decrease the number of CBC to once weekly during the cycle rather than before every injection. More data are needed with CyBorD protocol before drawing any conclusions. Disclosures: Adam: Jansen Ortho: Honoraria. Lemieux-Blanchard: Celgene: Honoraria. Lemieux: Jansen Ortho: Honoraria.

Description: Introduction: Philadelphia chromosome-positive acute myeloid leukemia (Ph+AML) is a rare form of AML and confers a dismal prognosis when treated with chemotherapy, with limited data available on the outcome when treated with allogeneic transplantation (allo-HCT). Methods: Patients were selected from the Japanese nationwide transplantation registry database based on the following criteria: AML patients aged ≥16 years; first allo-HCT conducted between 1995 and 2016; complete remission at transplantation; and intermediate- or poor-risk cytogenetics. Patients with secondary AML or chronic myeloid leukemia in blast phase were not included. Ph+AML was defined as AML, including mixed phenotype acute leukemia (MPAL), that presented with t(9;22)(q34.1;q11.2) or BCR-ABL1 fusion transcripts at diagnosis. The primary endpoint was overall survival (OS) and secondary endpoints were relapse and non-relapse mortality (NRM). The probability of OS was estimated based on the Kaplan-Meier method and compared between the groups with log-rank test. The incidences of relapse and NRM were estimated using cumulative incidence analysis and compared between the groups with Gray's test. Multivariate analysis was performed using the Cox proportional hazards model. A matched-pair analysis was also performed based on the propensity score to minimize the confounding effect of baseline patient characteristics. Sex, age at HCT (20,000/µL), GVHD prophylaxis (cyclosporine- or tacrolimus-based), disease status at HCT (CR1/CR2 or CR〉2), conditioning regimen (RIC or MAC), donor type (HLA-matched related/unrelated donor or alternative donor), MPAL or not, and performance status at HCT (0-1 or 2-4) were used to calculate the propensity score. Results: Of 5,304 eligible patients, 4,372 (82.4%), 882 (16.6%), and 50 (1.0%) were classified into cytogenetically intermediate-risk AML, cytogenetically poor-risk AML (excluding Ph+AML), and Ph+AML groups, respectively. Their median age was 47, 47, and 43.5 (range: 16-76, 16-74, and 16-85) years, respectively. The median follow-up for surviving patients was 2.3 (range, 0.0-22.4) years. MPAL accounted for 1.7% of the whole cohort, and its distribution was different among groups: 1.3%, intermediate-risk AML; 2.4%, poor-risk AML; and 26.0%, Ph+AML (p 〈 0.001). No significant difference was noted in OS between patients with and without MPAL (p = 0.22). OS at 3 years after allo-HCT was 62.8% for intermediate-risk AML, 51.1% for poor-risk AML, and 70.2% for Ph+AML (p 〈 0.001) (Fig 1A). The 3-year incidences of relapse and NRM were 19.6% and 22.2% for intermediate-risk AML, 32.6% and 21.7% for poor-risk AML, and 6.3% and 27.9% for Ph+AML, respectively (Fig 1B and 1C). Multivariate analysis revealed that the Ph+AML and intermediate-risk AML groups had comparable risk in terms of OS [hazard ratio (HR), 0.75; 95% confidence interval (CI), 0.45-1.28; p = 0.29]; for these groups, the risk of Ph+AML was significantly lower than the poor-risk AML (HR, 0.54; 95% CI, 0.31-0.91; p 〈 0.001). Ph+AML had significantly lower risk of relapse than poor-risk AML (HR, 0.16; 95% CI, 0.05-0.51; p 〈 0.001) and intermediate-risk AML (HR, 0.31; 95% CI, 0.10-0.94; p = 0.04). There was no significant difference in the risk of NRM (HR, 1.45; 95% CI, 0.86-2.45; p = 0.17 for Ph+AML vs. intermediate-risk AML; HR, 1.50; 95% CI, 0.87-2.57; p = 0.14 for Ph+AML vs. poor-risk AML). The matched-pair analysis extracted 39 and 38 patients from each group based on the propensity score using optimum matching (intermediate-risk AML vs. Ph+AML and poor-risk AML vs. Ph+AML). OS in the Ph+AML group was comparable with that in the intermediate-risk AML group (p = 0.81), whereas it was significantly better than that in the poor-risk AML group (p = 0.012). Conclusion: Our data show that post-transplant outcomes were better for Ph+AML patients than those with other poor-risk cytogenetics and were comparable with those for patients with intermediate-risk cytogenetics, suggesting that allo-HCT overcomes the poor prognosis of Ph+AML. Although our registry did not secure information on the use of tyrosine kinase inhibitors, their use may partly contribute to improvements in post-transplant outcomes. Disclosures Mizuno: Celgene Corporation: Honoraria; Bristol-Myers Squibb Corporation: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Kanda:Eisai: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Tanabe Mitsubishi: Research Funding; Otsuka: Research Funding; Celgene: Consultancy, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Alexion: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Nippon-Shinyaku: Research Funding; Alexion: Consultancy, Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Mochida: Consultancy, Honoraria; Sanofi: Research Funding; Takara-bio: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Nippon-Shinyaku: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Tanabe Mitsubishi: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; CSL Behring: Research Funding; Pfizer: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Novartis: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; CSL Behring: Research Funding; MSD: Research Funding; Taiho: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria; Taisho-Toyama: Research Funding; Taiho: Research Funding. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria.

Description: Purpose It is difficult to decide whether children with leukemia who could not achieve complete remission (CR) after relapse or primary induction failure should undergo transplantation. Nonetheless, allogeneic hematopoietic stem cell transplantation (HSCT) is a possible approach for refractory acute myeloid leukemia (AML). Despite being refractory to conventional chemotherapy, a graft versus leukemia (GVL) effect could be expected to some extent. This approach is considered to be experimental because the mortality rate of HSCT is extremely high. A previously conducted large-scale study demonstrated that age less than 10 years was a factor of good prognosis; however, the details in children remain unclear. The purpose of this retrospective analysis was to describe the outcomes and risk factors of HSCT for children with refractory AML. Patients and Methods The data was collected through the Transplant Registry Unified Management Program (TRUMP) system, the registry of The Japan Society for Hematopoietic Cell Transplantation. A total of 417 patients with AML younger than 21 years old at the time of HSCT between January 2001 and December 2015 who had blasts in peripheral blood and/or bone marrow were analyzed. Both myeloablative and reduced-intensity conditioning regimens were analyzed. Patients with AML were classified according to a previous report, which was based on the Eastern Cooperative Oncology Group/Southwest Oncology Group classification as good (inv16, t[8;21], t[15;17]), poor (5/del[5q], 7/del[7q], inv[3q], abn11q, 20q or 21q, del[9q], t[6;9], t[9;22], abn17p, and complex karyotype defined as 3 or more abnormalities), or intermediate (other and normal karyotypes) risk. Myeloablative conditioning was defined as total body irradiation (TBI) of 〉8 Gy and the administration of 8 mg/kg of busulfan (BU), 〉140 mg/m2 of melphalan, or 〉10 mg/kg of thiotepa. All other regimens were analyzed as reduced-intensity conditioning HSCT, including low-dose TBI (≤8 Gy) and low-dose BU (≤8 mg/kg). The graft included bone marrow, peripheral blood stem cells, or cord blood. Overall survival (OS) was used as a primary outcome because for HSCT during relapse, post-HSCT CR was not always achieved or reliably documented. Results The median follow-up time of survivors was 1052 days (range 60-4399). The median age was 13 years. Twenty-three percent of patients had a pre-HSCT performance status (PS) of 0, which corresponds to a Karnofsky PS ≥90. The rate of pre-HSCT fungal infection was 12%. Fifty-two percent of patients had more than 25% marrow blasts at the time of HSCT. At the time of HSCT, 36%, 47%, and 17% of patients exhibited primary induction failure, first relapse, and second or additional relapse, respectively. Eighty-nine percent of patients had neutrophils and 70% exhibited platelet recovery by day 100. Three hundred and fourteen patients died. The causes of death were leukemia progression (58%), followed by graft-versus-host disease (GVHD) (11%) and graft failure (10%). The 3-year OS rate was 23% (95% confidence interval (CI) 19-28). Grade ≥2 acute GVHD did not affect OS. Patients with chronic GVHD had better 3-year OS (47%, 95% CI 36-57%) compared to that in patients without chronic GVHD (22%, 95% CI 16-28%) (p = 0.001) (Figure 1). Low PS, greater than 25% marrow blasts, the presence of blasts in blood at the time of transplantation, French-American-British subgroup other than M1 or M2, transplant from a male donor, and a history of transplantation were adverse pre-HSCT variables (Table 1). Patients with 0 (n = 24), 1-2 (n = 175), 3-4 (n = 188), and 5-6 (n = 30) variables had 52% (95% CI 30-71%), 30% (95% CI 23-37%), 17% (95% CI 12-23%), and 0% 3-year OS, respectively (p 〈 0.001) (Figure 2). Discussion Some patients with refractory pediatric AML achieved relatively long survival following HSCT in the relapsed period, especially when a GVL effect was obtained. A scoring system using pre-HSCT variables should help decide whether HSCT should be performed or not. HSCT is worth considering for children who have undergone ≤2 pre-HSCTs. Disclosures No relevant conflicts of interest to declare.