ALBERT

Description: Point mutations in the kinase domain of c-Kit are frequently associated with t(8;21)-acute myeloid leukemia (AML). In our study, eleven (26 %) of 43 patients had mutations: six Asp816Val, two Asp816Tyr, one Asp816Ala, one Asp816His, and one Asn822Lys. Here, we provide evidences that proliferation of leukemia cells expressing both the AML1-ETO chimera and a c-Kit mutation heavily depends on signals originating from mutated c-Kit, and this mutation is a possible therapeutic target for imatinib mesylate. We initially investigated effects of imatinib on the growth of the Kasumi-1 cell line, which harbors both t(8;21) and a c-Kit kinase domain mutation (Asn822Lys). Imatinib inhibited autophosphorylation of c-Kit at the standard concentration (0.1 μM), and induced cell cycle arrest and apoptosis in an even faster time course than Ph1-positive cell lines treated with this drug. By contrast, growth of SKNO-1, another t(8;21)-positive leukemia cells without c-Kit mutation was not affected by imatinib. To test whether imatinib is effective for Asp816 c-Kit mutants, we isolated t(8;21)-positive fresh leukemia cells from untreated patients. Numbers of cells with an Asp816 mutant from four patients after short-term cultures in the presence of imatinib (0.1 μM, 4 days) were 20–30 % of those in the absence of imatinib, while no significant difference was observed for cells isolated from four patients without c-Kit mutation. (Viability of fresh leukemia cells without imatinib was maintained over 80% during this short-term culture.) Moreover, autophosphorylation of mutated c-Kit in leukemia cells from one patient with an Asp816 mutant was inhibited by imatinib. Our results disagree with those of previous studies, which indicated that cells with c-Kit mutations in the kinase domain are resistant to imatinib in murine IL-3-dependent cells and human mast cell leukemia cells. This discrepancy could be explained by high expression levels of c-Kit mutants in IL-3-dependent cells by powerful ectopic promoters, since overexpression of Bcr-Abl kinase is one of the major causes of resistance to imatinib in the treatment of CML patients. In addition, drug metabolism may be different between human t(8;21)-positive leukemia cells and in murine IL-3-dependent cells or mast cell leukemia cells. Although t(8;21) in AML represents a favorable prognostic indicator for achievement of cure, a substantial number of these patients relapse and eventually die of their disease. Indeed, of five patients harboring both t(8;21) and c-Kit mutations who we identified and followed up for more than five years, four relapsed. Therefore, our results suggest that imatinib would be useful for eliminating minimal residual disease in these patients after achievement of complete remission.

Description: Abstract 3527 With modern intensive chemotherapy, about 90% of adult patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) achieve complete remission. However, the overall survival rate drops due to the high rate of relapse. Therefore, the establishment of optimal post-remission therapy is important, and the efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-matched sibling in first remission (CR1) has been demonstrated through clinical studies using genetic randomization. However, the efficacy of unrelated HSCT for adult patients with Ph-negative ALL in CR1 who lack an HLA-matched sibling remains unclear. Decision analysis is a statistical technique that aids the clinical decision-making process under uncertainty, especially in situations where a well-designed clinical trial is practically difficult to perform. We previously demonstrated through a decision analysis that HSCT is superior to chemotherapy (CTx) alone in CR1 for adult patients with Ph-negative ALL who have an HLA-matched sibling, even after an adjustment for quality of life (QOL) (Kako S et al, BMT 45 supp. p414, 2010). In a similar manner, we performed a decision analysis based on the decision tree (Figure 1) to evaluate the efficacy of unrelated HSCT for adult patients with Ph-negative ALL in CR1 who lack an HLA-matched sibling. The transition probabilities and utilities were estimated from studies of the Japan Adult Leukemia Study Group (JALSG) (ALL93; n=122, ALL97; n=119), the database of the Japan Marrow Donor Program (JMDP) (HSCT in CR1: n=231), and the literature. The primary outcome measure was the 10-year survival probability with or without a QOL adjustment, in which we especially consider the presence of chronic graft-versus-host disease (GVHD). Subgroup analyses were performed according to risk stratification based on the white blood cell count and cytogenetics, and according to age stratification with a cutoff of 35 years. In the whole population, the superiority of unrelated HSCT in CR1 was demonstrated in analyses both with and without a QOL adjustment (40.6% vs. 31.1% and 43.6% vs. 31.9%, respectively). A probabilistic sensitivity analysis using a Monte Carlo simulation supported these results. A similar tendency was observed in all subgroups (Table 1). The decision model was sensitive to the probability of disease-free survival following CTx and the probability of overall survival following HSCT in CR1 in standard-risk and higher-aged patients. In conclusion, to improve the probability of long-term survival, unrelated HSCT in CR1 is recommended for patients who lack an HLA-matched sibling donor. However, improvement of CTx in the future may change the result. Table 1. Expected 10-year survival probabilities with and without adjusting for quality of life (QOL) Expected survival probability without a QOL adjustment Expected survival probability With a QOL adjustment HSCT Chemotherapy HSCT Chemotherapy All patients 43.6% 31.8% 40.6% 31.0% Standard-risk patients 44.0% 36.7% 40.9% 36.0% High-risk patients 43.7% 23.8% 40.6% 23.1% Lower-aged patients 44.3% 30.0% 41.2% 29.2% Higher-aged patients 42.1% 33.1% 39.1% 32.6% Abbreviations: HSCT, hematopoietic stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2934 Background: Since MDS is more prevalent in the elderly, use of intensive chemotherapy is considered to be difficult. However, granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF), use of clean room and development of promising antifungal agents have resulted in dramatically enhanced safety of post-chemotherapy control of elderly patients. Thus, we attempted to use intensive chemotherapy in HR-MDS and MDS-AML patients. Objectives: To evaluate, in HR-MDS and MDS-AML patients, the efficacy and safety of remission induction therapy and post-remission therapy that are standard treatment for de-novo AML in our department.This study enrolled 213 consecutive patients initially treated at our department between 2000 and 2010 who suffered MDS-related disease and whose survival was expected to be less than several months with supportive therapy alone. Almost all of the patients had ≥20% myeloblasts. The age of the patients ranged from 16 to 93 years (median: 70 years). They comprised 2 with good prognosis, 107 with intermediate prognosis and 104 with poor prognosis based on chromosomal findings. Methods: Remission induction therapy consisted of behenoyl-ara-C (BHAC) 350 mg/m2 (300 mg/m2 for patients aged ≥70 years) over 10 days and idarubicin (IDA) 12 mg/m2 (10 mg/m2 for patients aged ≥70 years) over 4 days. Additional etoposide 100 mg/m2 over 4 days was given if bone-marrow examination on Day 15 revealed residual myeloblasts of ≥5%. The efficacy of the therapy was evaluated after the first course. Patients showing maintained remission received 8 courses of post-remission therapy over 11 months. This post-remission therapy included high-dose cytarabine (2 g/m2, or 1g/m2 for patients aged ≥60 years) (HDAC) × 10 and mitoxantrone (MIT) 7mg/m2 × 3 given initially after remission. Maintenance/intensification therapy mainly consisted of BHAC 350 mg/m2 × 4 plus aclarubicin (ACR) 20 mg/body × 6 or IDA 10 mg × 1 alternately every 5 weeks. Outpatient maintenance therapy consisted of M-CSF over 7 days after the end of chemotherapy, followed by administration of G-CSF until neutrophil recovery. Patients were admitted to a clean room if WBC became

Description: There is little evidence to support the efficacy of dosage exceeding conventional high dose chemotherapy (HDC), referred to as super-HDC (SHDC) for Acute Leukemia (AL). However our hospital has been successfully conducting an original SHDC and has realized the highest complete remission rate and 10 years event free survival ratio for all generations with no selection bias. For example, de novo AML except M3 results are 91%, 59% for under 70 years old and 75%, 32% for over 70 years old respectively (51st ASH #1052, until 2010). The treatment of complications is the key to SHDC success, with fungal infection one of the major complications. With our unique preemptive approach, we have successfully eliminated fungal mortalities on all AML patients with no selection bias (53st ASH #1544). In this group using ITCZ as prophylaxis, pulmonary invasive aspergillosis (PIA) morbidity rate was still high, so we had to switch from ITCZ to VRCZ. Thus we theorized that VRCZ is more effective as prophylaxis. As there is little supporting data, we scheduled this prospective randomized study commencing 2011/4/23. This is the interim analysis of the first 100 of 200 patients as of 2012/9/26. All AL patients without a history of PIA who received induction chemotherapy were included. The patient number was dictated by our previous GM positive rate (30%). Either VRCZ or ITCZ were randomly assigned at admission and commenced from day 5. VRCZ as tablet at 400-600 mg/day, ITCZ as capsule at 150-200 mg/day. The primary end point is PIA morbidity rate and the secondary end points are all cause mortality, fungal infection mortality, non-PIA fungal infection, non-assigned antifungal drug use and PIA treatment efficiency using GM. This study is unique as diagnostic and treatment strategies are completely unified for all. We conducted GM twice a week with CT at the time of admission and weekly. Additional CT was conducted within 24 hours when pyrexia of ≥38.0°C occurred, without improvement CT was repeated every 3 days. Our concept is original preemptive therapy, we assumed PIA when GM ≥0.5, and VRCZ was automatically started. Combination therapy using Micafungin (MCFG) was routinely conducted when PIA continued to worsen. Per contra we assumed candida infection, and conducted MCFG treatment, when the results met our original twice weekly surveillance culture and ß-D glucan criteria. Table 1 shows patient characteristics. Excluding ALL and M3, all other characteristics were almost identical. Regarding PIA morbidity, Probable PIA rate was the same 22%, with no proven cases (EORTC/MSG criteria). However this result does not actually reflect the strength of these prophylactic drugs. As, in many cases, PIA existed from hospitalization (fig1). With our unique diagnostic strategy of regular CT and GM regardless of pyrexia from admission, we traced the onset more precisely to a much earlier stage than the theory that PIA appears from the latest phase of neutropenia. All cause mortality rate was identical, 6%. In VRCZ group (gp) AL progression was the sole cause. In addition to AL progression, 1 fungal infection caused by Cunninghamella was proved in ITCZ gp. Non-PIA fungal infections were only seen in ITCZ gp, Trichosporonemia, Candidemia or Cunninghamella pneumoniae were proved in three different patients. For non-assigned antifungal drug use, MCFG was comparable. VRCZ 60% (30/50), 17days (2-62), versus (vs) ITCZ 64% (32/50), 15 days (2-154). L-AmB was prescribed less in VRCZ gp (4% vs 8%) and VRCZ was prescribed to 18 ITCZ gp patients. The ITCZ gp required more drugs. Regarding PIA treatment efficacy using GM, was evaluated by max GM, number of days at max GM and final GM. All data median plus range. VRCZ was superior in every aspect, with 0.8 (0.5-3.1), 15 (9-53), 0.2 (0.1-1.5) results vs 2.35 (0.5-5.1), 28 (2-44), 0.65 (0.2-1.3) for ITCZ. Using our peerless fugal strategies, satisfactory results were realized for both gp. PIA onset was found to be much earlier, so morbidity appears comparable. However, VRCZ superior results including better PIA control appears to be achieved due to early PIA onset, and supports VRCZ prophylactic use. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Imatinib (IMA), a first-generation tyrosine kinase inhibitor (TKI), has enabled safer, more successful treatment of chronic myeloid leukemia (CML). Moreover, second-generation TKIs such as nilotinib (NIL) and dasatinib (DAS) have enabled achievement of deeper molecular responses than IM. TKIs have improved prognosis for CML patients, but lifelong continuation of TKIs lowers quality of life and places an economic burden on patients. Whether administration of TKIs can be stopped is thus an important question. Trials including the STIM trial have suggested that IMA can be stopped in CML patients who maintain complete molecular response (CMR) for 〉24 months, but little data is available regarding second-generation TKIs. Methods: Among adult CML patients in the chronic phase diagnosed at Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital from May 1995 to September 2010, we analyzed patients who achieved and maintained CMR for 〉1 year on TKIs, and then stopped TKIs. We started TKI treatment with IMA in all patients and changed to NIL or DAS after March 2009, when second-generation TKIs became available in Japan. We continued each TKI for ³6 months, and for 〉12 months in most cases. Molecular monitoring was performed with BCR-ABL1 real-time quantitative PCR (RQ-PCR) using bone marrow or peripheral blood samples. Sensitivity of this RQ-PCR was 0.004%, corresponding to MR4.4. Relapse was defined as a loss of CMR. We provided TKI therapy for relapsed patients. RQ-PCR was performed every three months after relapse. Results: Stopping TKI was possible in 51 patients (32 males, 19 females). Observations were continued until June 2015, and the median duration of observation was 147 months (range, 59-257 months). Interferon (IFN)-α was administered to 18 patients. Median age at diagnosis was 44 years (range, 22-83 years). Two deaths were observed, with neither due to CML. Median duration of TKI treatment was 91 months (range, 29-160 months). Median interval from starting TKIs until achieving CMR was 41 months (range, 6-144 months), and that from achieving CMR to stopping TKIs was 20 months (range, 10-91 months). Median duration of observation from stopping TKIs was 42 months (range, 4-135 months). TKI treatment comprised IMA alone in 10 patients, IMA → NIL in 8, and IMA →NIL → DAS in 33. Relapse after stopping TKIs was observed in 14 cases. The period from stopping TKIs to relapse was 3 months in 12 patients, and 6 months and 18 months in 1 patient each. We treated all relapse patients with TKIs as patients chose, and all achieved 2nd CMR. Median period from relapse to 2nd CMR was 20.5 months (range, 6-40 months). In univariate analysis by Fisher's exact test, no correlation was seen between relapse rate and sex (male, n=32 vs. female, n=19; p=0.106), history of IFN-α therapy (yes, n=18 vs. no, n=33; p=0.525), duration from achieving CMR to stopping TKI (³24 months, n=34 vs,

Description: Abstract 1052 Poster Board I-74 Background: Until recently, intensive chemotherapy for acute myeloid leukemia (AML) did not necessarily lead to high success rates, partly because of deaths from infections due to the associated long-term neutropenic phase. However, the advent of effective antifungal agents or the use of granulocyte colony-stimulating factor (G-CSF) or macrophage colony-stimulating factor (M-CSF) has definitely reduced deaths from chemotherapy and has improved the results of treatment with intensive chemotherapy also in elderly patients. Objectives: The complete remission rate after remission induction therapy and the event-free survival (EFS) after postremission therapy were investigated in 165 patients (99 men and 66 women) with untreated de novo AML (excluding subtype M3) who were consecutively registered in a single institution between March 2001 and March 2009. The patients' ages ranged from 16 to 94 years (median: 59 years). There were 3 patients with M0, 18 patients with M1, 25 patients with M2, 25 patients with t(8;21), 35 patients with M4, 12 patients with M4Eo, 35 patients with M5, 10 patients with M6, and 2 patients with M7. Methods: Remission induction therapy consisted of 10 days of behenoyl-ara-C (BHAC) at 350 mg/m2 (300 mg/m2 for patients 70 years or older) and 4 days of idarubicin (IDA) at 12 mg/m2 (10 mg/m2 for 70 years or older). Further, if bone marrow examination revealed 5% or more residual blast cells on day 15, etoposide was additionally administered at a dose of 100 mg/m2 for 4 days. The efficacy of the remission induction therapy was evaluated after 1 course of treatment. The patients who had achieved remission underwent 9 courses of postremission therapy, which lasted 11 months. The details are omitted, but therapy with high-dose (2 g/m2 [1 g/m2 for patients 60 years or older]) cytarabine (HDAC)×10 plus 7 mg/m2 of mitoxantrone (MIT) ×3 was performed during the 1st and 9th courses. No HDAC was performed on the elderly aged above 75 years old. The intensive therapy with Aclarubicin (ACR) of 20 mg/body for 14 days and the maintenance therapy with a combination of BHAC 350 mg/m2×4 with ACR or IDA were repeated alternately every 6 weeks. Chemotherapies other than remission induction therapy and HDAC were performed in an outpatient clinic, and if the patients with the WBC decreasing to 1000/mm3 were hospitalized in the biological clean room. M-CS was administered for 7 days after the day following the end of chemotherapy, and subsequently G-CSF was administered until the WBC becomes to be 1000/mm3. Results: Complete remission (CR) was achieved in 143 of the 165 patients overall (86.7%), 113 of the 123 patients 69 years or younger (92.7%), and 29 of the 42 patients 70 years or older (69.1%). During the remission induction therapy, death occurred in 6 of the 165 patients overall (3.6%), 2 of the 123 patients 69 years or younger (1.6%), and 4 of the 42 patients 70 years or older (9.5%). The EFS in patients with CR was 61.5% at 8 years in patients 69 years or younger, while it was 26.9% at 5 years in patients 70 years or older. There was only a case of death due to chemotherapy during postremission therapy. Seven patients underwent bone marrow transplantation during the first remission, and 6 of these patients have been enjoying EFS. Conclusion: Improvement in supportive care has enabled safe intensive chemotherapy. The patients with good or intermediate prognosis were clearly improved by the present preliminary treatment at a single institution, but the patients with poor prognosis still highly require bone marrow transplantation in the future. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Patients with AML-MRC are almost older and highly resistant to chemotherapy, so that they are thought to be not eligible for intensive chemotherapy (IC) compared with de novo AML. Reduced intensity chemotherapy, such as low-dose cytarabine and azacitidine (AZA), are used for AML-MRC therapy, but their overall survival (OS) is not satisfactory. Although chemotherapies for AML (except for M3) have not improved for 30 years, several supportive cares for IC have shown a great progress. In this background, we have used IC as induction, consolidation, and maintenance therapies, including AZA, for elderly AML-MRC to avoid relapses and obtain longer survivals. For patients, whose age are under 65 years, hematopoietic stem cell transplantations (HSCT) were mainly considered after IC treatments. Methods Between March 2012 and April 2015, 62 newly diagnosed AML-MRC were treated with idarubicin (IDR) 12 mg/m2 on days 1, 3, 5, 8, and enocitabine (BH-AC) 350mg/m2 on days 1-10 as an induction chemotherapy (IDR+BH-AC). Over 70 years patients, IDR and BH-AC were reduced to 10 mg/m2 and 300 mg/m2, respectively. On day 15, if bone marrow blasts were over 5%, etoposide 100 mg/m2 was additionally treated on days 16-19. Some fit patients, who reached complete remission (CR), were received cytarabine (Ara-C) 1 g/m2 on days 1-5 (bid) and mitoxantrone (MIT) 7 mg/m2 on days 2-4, as a consolidation therapy (Ara-C+MIT). As a maintenance therapy, AZA 75mg/m2 days 1-5 (i.v.) and IDR day1 + BH-AC days 1-4 (or aclarubicine 14 mg/m2 days 1-6 + BH-AC days 1-4) were sequentially treated for one year. If a relapse was observed, mainly AZA was treated to keep a good quality of life. Results Total number of patients was 62 (44 were male) and median age at diagnosis was 71 years (range 36-86). Median WBC was 3,800 x 109/L (600-129,200), median peripheral blast count was 16% (0-96), and median bone marrow blast count was 57% (22-95). Thirty-five patients had intermediate cytogenetics and 27 adverse. Twenty-nine patients, who had 〉5% bone marrow blasts on day 15, were additionally treated with etoposide. Median follow-up time was 25 months. After the induction therapy, 54 patients (87%) achieved CR, 5 (8%) partial remission, 2 (3%) were refractory, and 1 (2%) died. The CR rate of male was 82% (36/44) and female 100% (18/18). The CR rate of patients with intermediate cytogenetics was 86% (30/35), adverse 89% (24/27),

Description: Background: Thrombotic microangiopathy (TMA) and sinusoidal obstruction syndrome (SOS) as well as acute GVHD are major complications after allogeneic hematopoietic stem cell transplantation (alloHSCT) to overcome to achieve better overall survival. These complications are closely relevant to inflammation and coagulation involving endothelium, which are named as transplantation-associated coagulopathy (TAC). Recombinant thrombomodulin (rTM) is a new drug for treating DIC approved by Japanese Ministry of Health, Labour and Welfare in 2008. Membranous TM has many aspects to inhibit inflammation via activated Protein C (APC), lectin-like domain, and activated thrombin-activatable fibrinolysis inhibitor as well as to inhibit coagulation by binding factor IXa and Xa through APC. Biomarkers such as inflammatory cytokines and endothelial molecules are expected to be clue in elucidating TAC. We established SIGHT study group to explore above complications following alloHSCT. In the present study, we investigated the effects of rTM on levels of the biomarkers and whether we could prevent TAC using rTM among registered patients in the SIGHT study group. Patients and methods: SIGHT study group covered nationwide institutes more than 70 in Japan. Patients whoever were eligible for alloHSCT to treat hematopoietic disorders by physicians decision were permitted and written informed consent was requested to register in the study. Blood samples were collected from the patients before and after transplantation through day 28. Levels of cytokines (IL-6, TNF-α, HMGB1, MCP-1, RANTES) and soluble molecules (VCAM-1, E-selectin, PAI-1, PDMP) were measured by ELISA. rTM was administered as a prophylactic therapy for TAC in day 4-14 after alloHSCT. Control group was received heparin or no anti-coagulation therapy as prophylaxis during same schedule as rTM group. Patients were not randomized to these three arms but allowed to select one by their physicians decision. The primary endpoint was a comparison of fluctuation of these biomarkers in three arms. Secondary endopoint was a comparison of the rate of developing TAC. Results: The subjects were 293 patients who underwent alloHSCT in SIGHT study group between June 2010 and February 2014. 271 patients out of them were analyzed to measure level of these biomarkers. There was no significant difference in all characteristics but GVHD prophylaxis between two groups. rTM group received more cyclosporine than control group (p=0.05). MCP-1 and IL-6 exhibited more significant elevations on day 7 after alloHSCT, while HMGB-1 did on the day of alloHSCT. In contrast, the levels of TNF-α, E-selectin, VCAM-1, PAI-1 and PDMP exhibited increment since around day 7 after alloHSCT. Significant improvements in TNF-α, E-selectin, VCAM-1, HMGB-1, PAI-1 and PDMP was shown after rTM-treatment, but not shown in control group. Regarding complications following alloHSCT, the rate of developing acute GVHD and SOS was significantly lower in rTM group than without it (36.5% vs 62.2%, p=0.000; 12.5% vs 24.5%, p=0.032, respectively), while TMA did not differ (8.4% vs 10.2%, p=0.961). Stepwise multivariate logistic regression analyses revealed that anti-coagulation therapy without rTM and the level of PAI-1 on day 28 after HSCT were independent risk factor for acute GVHD (p=0.000, odds ratio=3.006; p=0.000, odds ratio=1.068, respectively). Also anti-coagulation therapy without rTM and the level of HMGB-1 on day 28 after HSCT were significantly predictive for risk of SOS (p=0.015, odds ratio=2.650; p=0.001, odds ratio=1.433, respectively). Tacrolimus was significantly good risk of SOS (p=0.022, odds ratio=0.404). The level of VCAM-1 on day 28 after HSCT was significantly associated with risk of TMA (p=0.040, odds ratio=1.001). Conclusions: We identified predictive biomarkers for TAC following alloHSCT, which were PAI-1 for acute GVHD, HMGB-1 for SOS, and VCAM-1 for TMA, respectively in this study. The present findings suggest that rTM has the possibility to play a therapeutic role for acute GVHD and SOS induced by suppression on these biomarkers. Endothelial and pro-coagulant biomarkers were released delayed compared with inflammatory biomarkers. TMA is reported to develop around day 44 in median after alloHSCT. Further studies are needed whether rTM should administer later or longer to improve TMA than the present duration after alloHSCT. Disclosures No relevant conflicts of interest to declare.

Description: Background Azacitidine (AZA) and intensive chemotherapy (IC) are respectively effective for MDS-MRC to some extent. However, their median overall survivals (OS) are within 1 year in the previous reports. Aims The remission induction therapy is performed with AZA for patients with the bone marrow (BM) blast of 30% to improve CR rate. The patients who reached CR with AZA or IC, maintenance therapy by sequential AZA and IC were performed to prolong the OS. Patients and methods Sixty-six patients,who were diagnosed as AML-MRC from December, 2011 to March, 2014 in our institution were included. AZA was administered by drip infusion at a dose of 75 mg/m2 for 5 days every 26 day. As the IC, IBMP (idarubicin,behenoyl-ara-C (enocitabine), mercaptopurine, and prednisolone) was administered for 10 days. The patients ,who reached CR with AZA or IBMP, then sequential therapy of AZA for 5 days and mini-IBMP for 5 days/or BAMP (A; acularubicin) for 6 days were treated by establishing the withdrawal period for 21 to 35 days. When possible, the high-dose ara-C (HDAC) for 5 days was included. Among the patients with the BMblast of 〉30%, 4 patients underwent allogeneic stem cell transplantation (allo-SCT). OS was evaluated using Kaplan-Meier estimates. Results Twenty four patients, whose BM blast30% (32-95%, median 56%) treated with the remission induction therapy by IBMP. One secondary AML was included. Thirty patients were male (73%), the median age was 73-years (36-86), the cytogenetic risk was good in 8 patients (19%), intermediate in 14 (33%) and poor in 20 (48%). CR was achieved by 34 patients (81%), PR by 4 (10%) and failure by 4 (10%). The median follow up was 13 M in the BM blast30% group. The median OS in the BM blast30% group have not reached and 1year survival was 67%, 2 years survival 51% on the basis of Kaplan-Meier estimates. In both groups, there were 51 patients with CR+PR, 9 of which were treated with AZA only after CR, and 42 (82%) of which received sequential AZA treatment and IC. HDAC was included in chemotherapy by 24 patients (57%). Thirty eight patients, other than 4 patients who underwent Allo-SCT, have not reached the median OS, and 2 years survival was 55%. As concerns cytogenetic risk, the median OS in 33 patients with poor risk was 17 M, and 33 patients with good + intermediate risk have not reached the median OS, and 2years survival was 55%. Summary/Conclusion There was only one death of chemotherapy and AZA and IC for AML-MRC is very safe and good remission induction therapy. We have not described this time, but the measures for infection by such as fungi have contributed largely. In spite of the interim analysis of small sample size as 66 patients and short observation period, the median OS is approximately 2 years, so that the sequential therapy of AZA and IC is a feasible and useful therapy which realizes prolongation of OS. Particularly, the median OS of 17 M in the cytogenetic poor risk group can be mentioned as great progress. Because before introduction of AZA, when we treated more than 200 patients with AML-MRC only by almost similar chemotherapy, the median OS in the poor risk group was only 6M. Currently, we are following up 6 patients, who stopped the treatment,alive more than 6 M without any treatments. SinceAML-MRC is a disease in elderly people, it is important to devise therapeutic methods to prolong the untreatment period with CR in many patients in the future. Disclosures No relevant conflicts of interest to declare.

Description: Background Levels of cytokines, chemokines and soluble molecules fluctuate after allogeneic hematopoietic stem cell transplantation (HSCT). These biomarkers are possible to be a diagnostic and prognostic value for transplantation-associated coagulopathy (TAC). In the present study, we investigated the effects of recombinant thrombomodulin (rTM) on levels of the cytokines, chemokines, and soluble factors registered in the ‘SIGHT’ research. SIGHT comprises the capital letters of five complications after HSCT, namely sinusoidal obstruction syndrome (SOS same as VOD), infection, GVHD, hemophagocytic syndrome and thrombotic microangiopathy. Methods The subjects were 159 patients who underwent allogeneic HSCT (bone marrow = 83, peripheral blood stem cells = 31, cord blood = 45). Blood samples were collected before and after transplantation. Levels of cytokines (interleukin-6, tumor necrosis factor-α, high-mobility group box (HMGB) 1), chemokines (monocyte chemotactic protein (MCP)-1, RANTES), and soluble molecules (soluble vascular cell adhesion molecule (VCAM)-1, soluble E-selectin, plasminogen activator inhibitor-1, platelet-derived microparticles (PDMP)) were measured by enzyme-linked immunosorbent assay. The rTM was administered as a therapy for transplantation-associated coagulopathy (TAC). This protocol was completed in day 4-14 after HSCT and consisted of day doses of 380 unit/kg with every days. Control group was also used heparin or no anti-coagulation therapy. Results MCP-1, IL-6, and TNF-a exhibited more significant elevations on days 7–14 after HSCT. In contrast, the levels of HMGB1, sE-selectin, sVCAM-1, PAI-1 and PDMP exhibited significant changes on days 14–28. There were significant improvements in TNF-a, sE-selectin, sVCAM-1, HMGB1, PAI-1 and PDMP after rTM-treatment (n=73), but not after rTM-untreatment patients (n=86). Conclusion We believe one of causes for TAC is pro-inflammatory cytokine including HMGB1. For this reason, it is thought that the direct anti-inflammatory effect of rTM’s lectin domein plays an important role in therapeutic mechanism for TAC. The present findings suggest the possibility that rTM can play a therapeutic role for TAC after allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.