Abstract: The introduction of all-trans-retinoic acid (ATRA) has significantly improved outcomes for acute promyelocytic leukemia (APL), although a subset of patients still suffer relapse. The purpose of this study was to evaluate the role of maintenance therapy with the synthetic retinoid tamibarotene in APL. Patients and Methods Patients with newly diagnosed APL in molecular remission at the end of consolidation therapy were randomly assigned to receive ATRA or tamibarotene, both orally, for 14 days every 3 months for up to 2 years. Results A total of 347 patients were enrolled. Of the 344 eligible patients, 319 (93%) achieved complete remission. After completing three courses of consolidation therapy, 269 patients underwent maintenance random assignment. The relapse-free survival (RFS) rate at 4 years was 84% for the ATRA arm and 91% for the tamibarotene arm (hazard ratio [HR], 0.54; 95% CI, 0.26 to 1.13). When the analysis was restricted to 52 high-risk patients with an initial WBC count ≥ 10.0 × 10 9 /L, the intergroup difference was statistically significant, with 4-year RFS rates of 58% for the ATRA arm and 87% for the tamibarotene arm (HR, 0.26; 95% CI, 0.07 to 0.95). For patients with non–high-risk disease, the HR was 0.82 (95% CI, 0.32 to 2.01). The test for interaction between treatment effects and these subgroups resulted in P = .075. Both treatments were generally well tolerated. Conclusion In this trial, no difference was detected between ATRA and tamibarotene for maintenance therapy. In an exploratory analysis, there was a suggestion of improved efficacy of tamibarotene in high-risk patients, but this requires further study.

Abstract: DNA hypermethylation has long been implicated in the pathogenesis of myelodysplastic syndromes (MDS) and also highlighted by the frequent efficacy of demethylating agents to this disease. Meanwhile, recent genetic studies in MDS have revealed high frequency of somatic mutations involving epigenetic regulators, suggesting a causative link between gene mutations and epigenetic alterations in MDS. The accumulation of genetic and epigenetic alterations promotes tumorigenesis, hypomethylating agents such as Azacitidine exert their therapeutic effect through inhibition of DNA methylation. However, the relationship between patterns of epigenetic phenotypes and mutations, as well as their impact on therapy, has not been clarified. To address this issue, we performed genome-wide DNA methylation profiling (Infinium 450K) in combination with targeted-deep sequencing of 104 genes for somatic mutations in 291 patients with MDS. Beta-mixture quantile normalization was performed for correcting probe design bias in Illumina Infinium 450k DNA methylation data. Of the 〉 480,000 probes on the methylation chip, we selected probes using the following steps: (i) probes annotated with "Promotor_Associated" or "Promoter_Associated_Cell_type_specific; (ii) probes designed in "Island", "N_Shore" or "S_Shore"; (iii) removing probes designed on the X and Y chormosomes; (iv) removing probes with 〉 10% of missing value. Consensus clustering was performed utilizing the hierarchical clustering based on Ward and Pearson correlation algorithms with 1000 iterations on the top 0.5% (2,000) of probes showing high variation by median absolute deviation across the dataset using Bioconductor package Consensus cluster plus. The number of cluster was determined by relative change in area under cumulative distribution function curve by consensus clustering. Unsupervised clustering analysis of DNA methylation revealed 3 subtypes of MDS, M1-M3, showing discrete methylation profiles with characteristic gene mutations and cytogenetics. The M1 subtype (n=121) showed a high frequency of SF3B1 mutations, exhibiting the best clinical outcome, whereas the M2 subtype (n=106), characterized by frequent ASXL1, TP53 mutations and high-risk cytogenetics, showed the shortest overall survival with the hazard ratios of 3.4 (95% CI:1.9-6.0) and 2.2 (95% CI:1.2-4.0) compared to M1 and M3, respectively. Finally, the M3 subtype (n=64) was highly enriched (70% of cases) for biallelic alterations of TET2 and showed the highest level of CpG island methylation and showed an intermediate survival. In the current cohort, we had 47 patients who were treated with demethylating agents, including 11 responders and 36 non-responders. When DNA methylation status at diagnosis was evaluated in terms of response to demethylating agents, we identified 54 differentiated methylated genes showing 〉 20% difference in mean methylation levels between responders and non-responders (q 〈 0.1). Twenty-five genes more methylated in responders were enriched in functional pathways such as chemokine receptor and genes with EGF-like domain, whereas 29 less methylated gene in responders were in the gene set related to regulation of cell proliferation. Genetic alterations were also assessed how they affected treatment responses. In responders, TET2 mutated patients tended to more frequently respond (45% vs 34%), whereas patients with IDH1/2 and DNMT3A mutations were less frequently altered (0% vs 14%, 9% vs 14%) in responders, compared in non-responders. In conclusion, our combined genetic and methylation analysis unmasked previously unrecognized associations between gene mutations and DNA methylation, suggesting a causative link in between. We identified correlations between genetic/epigenetic profiles and the response to demethylating agents, which however, needs further investigation to clarify the mechanism of and predict response to demethylation agents in MDS. Disclosures Alpermann: MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kiyoi:Taisho Toyama Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma K.k.: Research Funding; Pfizer Inc.: Research Funding; Takeda Pharmaceutical Co.,Ltd.: Research Funding; MSD K.K.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Alexion Pharmaceuticals.: Research Funding; Teijin Ltd.: Research Funding; Zenyaku Kogyo Company,Ltd.: Research Funding; FUJIFILM RI Pharma Co.,Ltd.: Patents & Royalties, Research Funding; Nippon Shinyaku Co.,Ltd.: Research Funding; Japan Blood Products Organization.: Research Funding; Eisai Co.,Ltd.: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Consultancy, Research Funding; Fujifilm Corporation.: Patents & Royalties, Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Bristol-Myers Squibb.: Research Funding; Chugai Pharmaceutical Co.,LTD.: Research Funding; Mochida Pharmaceutical Co.,Ltd.: Research Funding. Kobayashi:Gilead Sciences: Research Funding. Naoe:Toyama Chemical CO., LTD.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Patents & Royalties, Research Funding; Pfizer Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Celgene K.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Patents & Royalties. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Miyazaki:Chugai: Honoraria, Research Funding; Shin-bio: Honoraria; Sumitomo Dainippon: Honoraria; Celgene Japan: Honoraria; Kyowa-Kirin: Honoraria, Research Funding.

Abstract: Background: Tamibarotene, a new synthetic retinoid, displays (i) approximately 10-fold increased potency over ATRA at inducing in vitro differentiation of NB-4 cells (ii) enhanced chemical stability compared with ATRA (iii) low affinity for cellular RA-binding protein. The clinical efficacy of tamibarotene for the treatment of acute promyelocytic leukemia (APL) has also been reported. A prospective randomized controlled study to evaluate tamibarotene by comparison to ATRA was carried out for maintenance therapy of APL in JALSG APL204 (Shinagawa et al, 2014). The 4-year-relapse free survival (RFS) did not differ between patients treated with ATRA or tamibarotene. However, an improved efficacy of tamibarotene in high-risk patients was suggested, which warrants further investigation. Here, we evaluate the long-term outcome of the study. Patients and Methods: Patients enrolled in this study were newly diagnosed with APL and documented cytogenetic and/or molecular evidence of t(15;17)/ PML-RARA . The age of the patients ranged between 15 and 70 years and the ECOG performance status was between 0 and 3. For remission induction therapy, ATRA was administered to all patients at a daily dose of 45 mg/m2 until complete remission (CR). The chemotherapy protocol varied depending on the initial leukocyte count and blast count in the peripheral blood. In brief, patient groups were defined as: leukocytes & lt; 3,000/µl (Group A: ATRA alone), 3,000/µl ≤ leukocytes & lt; 10,000/µl (Group B: ATRA plus IDA/Ara-C: 2+5), and leukocytes ≥ 10,000/µl (Group C: ATRA plus IDA/Ara-C: 3+5). Those patients who experienced leukocytosis received additional chemotherapy (Group D). Patients who achieved molecular remission after consolidation chemotherapy were randomly assigned to 2 groups of maintenance therapy, and administered tamibarotene at a daily dose of 6 mg/m2 divided into 2 doses for 14 days or ATRA at a daily dose of 45 mg/m2 divided into 3 doses for 14 days. Each cycle of treatment was repeated every 3 months for 2 years. The primary endpoint was hematological or molecular relapse-free survival (RFS) during the maintenance and follow up period. This study is registered at the University Hospital Medical Information Network Clinical Trials Registry as C000000154. Results: A total of 347 patients were enrolled in the study. Of the 344 eligible patients, 319 (93%) achieved CR. After completing three courses of consolidation therapy, 269 patients underwent maintenance random assignment; 135 patients were assigned to ATRA, and 134 patients were assigned to tamibarotene. The mean follow-up of patients alive and relapse-free at the date of last contact was 7 years. The 7-year RFS rate was 84% for the ATRA arm and 93% for the tamibarotene arm (p=0.031) (Fig.1). When the analysis was restricted to 52 high-risk patients with an initial leukocyte count ≥ 10,000/µl, the difference was more prominent (62% vs 89%, p=0.034) (Fig.2). The 7-year RFS of induction treatment for Group A (92 cases) was 91%, Group B (38 cases) 92%, Group C (52 cases) 75% and Group D (87 cases) 91% (p=0.005). Both treatments were generally well tolerated. Secondary hematopoietic disorders were observed in 12 cases, malignancies in 9 cases, late cardiac complications (grade 3 or more) in 5 cases. However, there was no significant difference in terms of these complications between the two treatment groups. Conclusions: Maintenance therapy with tamibarotene was effective at decreasing the relapse rate in APL patients by comparison to ATRA at the 7-year observation point. In particular, tamibarotene was significantly more effective than ATRA for high risk patients with leukocytes ≧10,000/μl. These results could lead to a new strategy for the treatment of high risk patients, which is one of the recent priority issues in the treatment of APL. Disclosures Takeshita: Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Phizer Japan Inc.: Research Funding; Takeda Pharmaceutical Co Ltd: Research Funding. Asou: Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding. Ueda: KAINOS LABORATORIES INC: Membership on an entity's Board of Directors or advisory committees; Abrynx nv: Membership on an entity's Board of Directors or advisory committees; Elli LiLLY Japan KK: Other: Clinical Trial; Takeda PharmaceuticalCompany Limited: Other: Clinical TRial; Otsuka Pharmaceutical Co Ltd: Other: Clinical Trial; Celgene KK: Other: Clinical Trial; Symbio Pharmaceutical Limited: Other: Clinical Trial; AstellasPharma Inc: Other: Clinical Trial; Eisai Co. Ltd: Other: Clinical Trial. Fujita: Chugai Pharmaceutical: Honoraria. Usui: Nippon Shinyaku Pharmaceutical Co: Research Funding. Kobayashi: Pfizer, Ohtsuka, Astellas, Ariad: Research Funding. Kiyoi: Kyowa Hakko Kirin Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; ONO Pharmaceutical Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Meiji Seika Pharma Co.,Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Eisai Co., Ltd.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Phizer Japan Inc.: Honoraria, Research Funding; MSD K.K.: Research Funding; Novartis Pharma K.K.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; JCR Pharmaceuticals Co.,Ltd.: Research Funding. Atsuta: Otsuka Pharmaceutical Co., Ltd.: Honoraria. Naoe: Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Nippon Boehringer Ingelheim Co.: Honoraria, Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Dainippon Sumitomo Pharma Co.,LTD.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding. Miyazaki: Nippon Shinyaku: Honoraria.

Abstract: This phase I trial conducted in Japanese patients with acute myeloid leukemia evaluated the safety, maximum tolerated dose and pharmacokinetics of volasertib (BI 6727), a selective Polo‐like kinase inhibitor. The primary endpoints were the maximum tolerated dose of volasertib and the incidence of dose‐limiting toxicities. Secondary endpoints were best response and remission duration. Other endpoints included safety and pharmacokinetics. Patients who were ineligible for standard induction therapy or with relapsed or refractory disease received volasertib monotherapy as a 2‐h infusion on days 1 and 15 of a 28‐day cycle, with dose escalation following a 3 + 3 design. A total of 19 patients were treated with three volasertib doses: 350, 400 and 450 mg. One patient receiving volasertib 450 mg reported a dose‐limiting toxicity of grade 4 abnormal liver function test and 450 mg was determined as the maximum tolerated dose. The most frequently reported adverse events were febrile neutropenia (78.9%), decreased appetite (42.1%), nausea and rash (36.8% each), and sepsis, fatigue, hypokalemia, stomatitis and epistaxis (26.3% each). Best responses were complete remission ( n = 3), complete remission with incomplete blood count recovery ( n = 3) and partial remission ( n = 1). The median remission duration of the six patients with complete remission or complete remission with incomplete blood count recovery was 85 days (range 56–358). Volasertib exhibited multi‐compartmental pharmacokinetic behavior with a fast distribution after the end of infusion followed by slower elimination phases. Volasertib monotherapy was clinically manageable with acceptable adverse events and anti‐leukemic activity.

Abstract: The management of myelodysplastic syndrome ( MDS ) remains challenging. We performed a phase I/ II study to evaluate the safety and efficacy of decitabine in patients with MDS in Japan. Patients with MDS with red cell transfusion dependence or 5–30% blasts in marrow and with an I nternational P rognostic S coring S ystem score of intermediate‐1 or higher were eligible. Patients received intravenous decitabine at 15 or 20 mg/m 2 daily for 5 days every 4 weeks. A total of 37 patients were enrolled. Three patients received 15 mg/m 2 and experienced no dose limiting toxicity during the first cycle. Thirty‐four patients received 20 mg/m 2 . Grade 3 or greater non‐hematologic toxicities included cerebral infarction ( n  = 1), subdural hematoma ( n  = 1), elevated blood glucose ( n  = 1), and pulmonary hypertension ( n  = 1). At 20 mg/m 2 , complete response, partial response, and hematologic improvement were observed in 7 (20.6%), 2 (5.9%), and 7 (20.6%) patients, respectively. Complete cytogenetic response was observed in 30% of evaluable 20 patients. The median number of cycles to clinical response was 4 (range 4–8), and duration of remission was 474+ days (range 294–598+). The 2‐year rate of acute myeloid leukemia‐free survival was 52%. Correlative studies revealed hypomethylation in multiple genes in peripheral blood cells after treatment. Hypomethylation was generally more profound in CD 15 + peripheral blood cells, which reflects myeloid cells, than in peripheral blood mononuclear cells. In summary, decitabine was safe and demonstrated efficacy in Japanese patients with high‐risk MDS . This trial was registered at C linical T rials.gov ( NCT 00796003).

Abstract: While unrelated bone marrow transplantation ( UBMT ) has been widely used as alternative donor transplantation, the use of umbilical cord blood transplantation ( UCBT ) is increasing recently. Methods We conducted a decision analysis to address which transplantation procedure should be prioritized for younger patients with acute myeloid leukemia ( AML ) harboring high‐ or intermediate‐risk cytogenetics in first complete remission ( CR 1), when they lack a matched related donor but have immediate access to a suitable umbilical cord blood unit. Main sources for our analysis comprised the data from three phase III trials for a chemotherapy cohort ( n = 907) and the registry data for a transplantation cohort ( n = 752). Results The baseline analysis showed that when the 8/8 match was considered for UBMT , the expected 5‐year survival rate was higher for UBMT than for UCBT (58.1% vs. 51.8%). This ranking did not change even when the 7/8 match was considered for UBMT . Sensitivity analysis showed consistent superiority of UBMT over UCBT when the time elapsed between CR 1 and UBMT was varied within a plausible range of 3–9 months. Conclusions These results suggest that 8/8 or 7/8 UBMT is a better transplantation option than UCBT even after allowing time required for donor coordination.