FLT3-ITD and FLT3-TKD mutations were observed in approximately 20 and 10% of acute myeloid leukemia (AML) cases, respectively. FLT3 inhibitors such as midostaurin, gilteritinib and quizartinib show excellent response rates in patients with FLT3-mutated AML, but its duration of response may not be sufficient yet. The majority of cases gain secondary resistance either by on-target and off-target abnormalities. On-target mutations (i.e., FLT3-TKD) such as D835Y keep the TK domain in its active form, abrogating pharmacodynamics of type II FLT3 inhibitors (e.g., midostaurin and quizartinib). Second generation type I inhibitors such as gilteritinib are consistently active against FLT3-TKD as well as FLT3-ITD. However, a “gatekeeper” mutation F691L shows universal resistance to all currently available FLT3 inhibitors. Off-target abnormalities are consisted with a variety of somatic mutations such as NRAS, AXL and PIM1 that bypass or reinforce FLT3 signaling. Off-target mutations can occur just in the primary FLT3-mutated clone or be gained by the evolution of other clones. A small number of cases show primary resistance by an FL-dependent, FGF2-dependent, and stromal CYP3A4-mediated manner. To overcome these mechanisms, the development of novel agents such as covalently-coupling FLT3 inhibitor FF-10101 and the investigation of combination therapy with different class agents are now ongoing. Along with novel agents, gene sequencing may improve clinical approaches by detecting additional targetable mutations and determining individual patterns of clonal evolution.

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients. Bi-/tri-specific antibodies (e.g., bispecific T-cell engager (BiTE) and dual-affinity retargeting (DART)) exhibited 11–67% CR rates with 13–78% risk of cytokine-releasing syndrome (CRS). Conventional chemotherapy in combination with anti-PD-1/anti-CTLA4 antibody for relapsed/refractory AML showed 10–36% CR rates with 7–24 month-long median survival. The current advantages of IO therapy in the field of AML are summarized herein. However, although cancer vaccination should be included in the concept of IO therapy, it is not mentioned in this review because of the paucity of relevant evidence.

From 2001 to 2012, 71 individuals with hematological diseases received HSCT in our institution. Of these, 41 developed disseminated intravascular coagulation (DIC) in association with various underlying conditions. The patients who developed DIC after 2008 (n = 23) were treated by recombinant human soluble thrombomodulin (rTM), and the others (n = 11) were treated by either heparin and/or antithrombin III concentrate. Seven patients did not receive any anticoagulant therapy. Of note, treatment for coagulopathy by rTM significantly improved clinical outcomes of patients at day 100 and dramatically prolonged their overall survival (P = 0.044). Taken together, rTM is useful to improve clinical outcomes of transplant recipients with coagulopathy.

Tumor cells use immune-checkpoint pathways to evade the host immune system and suppress immune cell function. These cells express programmed cell-death protein 1 ligand 1 (PD-L1)/PD-L2, which bind to the programmed cell-death protein 1 (PD-1) present on cytotoxic T cells, trigger inhibitory signaling, and reduce cytotoxicity and T-cell exhaustion. Immune-checkpoint blockade can inhibit this signal and may serve as an effective therapeutic strategy in patients with solid tumors. Several trials have been conducted on immune-checkpoint inhibitor therapy in patients with malignant lymphoma and their efficacy has been reported. For example, in Hodgkin lymphoma, immune-checkpoint blockade has resulted in response rates of 65% to 75%. However, in non-Hodgkin lymphoma, the response rate to immune-checkpoint blockade was lower. In this review, we evaluate the biology of immune-checkpoint inhibition and the current data on its efficacy in malignant lymphoma, and identify the cases in which the treatment was more effective.

The present study analyzed the incidence and clinical features of disseminated intravascular coagulation (DIC) developed in association with non-Hodgkin lymphoma (NHL). Two hundred thirty-six patients with newly diagnosed NHL were admitted to our institute since Jul. 2008 to Dec. 2014. Coagulation markers were evaluated in 161 of 236 patients at the time of diagnosis. DIC was diagnosed in 18 patients (11.2 %) based on the criteria established by Ministry of Health, Labor, and Welfare of Japan. All of the 18 patients had Ann-Arbor Stage IV advanced disease, and 17 patients were in poor performance status. Liver function panels, such as bilirubin, aminotransferases, serum choline esterase, and albumin levels, were worse in patients with DIC than those without DIC, indicating impaired production of coagulation factors. Importantly, DIC exerts significantly negative impact on prognosis of NHL; median survival of both groups was 176 versus 2430 days. The difference remains significant after statistically adjusting for age, performance status, Ann-Arbor stage, international prognostic index, and liver function panels. Nine of 18 patients with DIC received anti-coagulants, which failed to improve clinical outcome. Nevertheless, early recognition and intervention to DIC state may contribute to improve prognosis of NHL.

Background: Recently, whole exome sequencing has been used for the next-generation sequencing of acute myeloid leukemia (AML), and certain gene mutations have been identified in patients with AML. The treatment strategies for leukemia have undergone drastic changes with the rapid development of new drugs. However, the proper use of newly developed agents poses a major challenge in AML treatment. Genome profiling analysis can be used to select the optimal treatment for patients with newly diagnosed AML. Methods and Results: Hematologic malignancies (HM)-SCREEN-Japan 01 is an actionable mutation profiling multicenter study of patients with newly diagnosed AML who cannot be treated with first standard treatment or patients who have relapsed/refractory AML (R/R-AML). The objective of this study was to evaluate the frequency and characteristics of cancer-related genomic alterations in patients with AML using a comprehensive genome profiling assay (FoundationOne®Heme (F1H)) and determine the quality of specimens used in gene analysis. Before participant recruitment, approval was obtained from the institutional review board at each participating institution. The trial was registered in the UMIN Clinical Trials Registry (UMIN000035233). This study was conducted at 17 participating institutions and had a sample size of 200. The eligibility criteria were as follows: 1) histological diagnosis of AML through bone marrow aspiration; 2) fulfillment of either of the following conditions: i) newly diagnosed AML unfit for standard treatment (ND-unfit AML) or ii) R/R-AML; 3) sufficient sample collection via bone marrow aspiration; 4) Age of participants 20 years or above during registration; 5) provision of written informed consent by participants. The primary outcome was the frequency of each genomic alteration, as determined using F1H, which is a comprehensive genome profiling test based on next-generation sequencing, in the AML specimens. The secondary outcome was the association between each genomic alteration and the clinicopathological characteristics, prognosis, and quality of specimens used in the genetic analysis. Serial genome profiling analyses were performed to evaluate the time-dependent changes in the genome profiles of patients administered FLT3 inhibitors, gilteritinib, and quizartinib for treating AML. One hundred and eighty-two patients were recruited, and the F1H report was successfully obtained for 177 patients (97.3%). The median age of the 66 patients with ND-unfit AML was 73 years (63-79 years), and that of the 105 patients with R/R-AML was 50 years (41-68 years). The median turnaround time was 13 days (minimum 8 days). Recurrent alterations were observed in FLT3 (28.7%), TP53 (21.6%), RUNX1 (20.5%), DNMT3A (18.7%), NPM1 (18.7%), ASXL1 (15.2%), TET2 (14.0%), KMT2A-rearrangement (13.5%), and NRAS (13.5%). IDH1 and/or IDH2 mutations were identified in specimens collected from 30 patients (17.5%). Compared with the prevalence in 2247 patients with AML in the US and Europe who underwent F1H analysis, the frequencies of mutations in FLT3 (28.7% vs. 20.5%) and TP53 (21.6% vs. 17.0%) were higher in this Japanese cohort. Mutations in IDH2, PTPN11, and SF3B1 were observed along with KMT2A rearrangement. Mutations in TP53 tended to be exclusive to the FLT3 mutation. In comparison between the ND-unfit AML and R/R-AML, mutations in TET2 and ASXL1 tended to be more frequnt in ND-unfit AML (17.9% vs. 7.0%, p=0.038, 18.9% vs. 8.5%, p=0.055, respectively). The median expression level of WT1 mRNA at the time of sample collection was 4,490 copies/μgRNA (n=158), and WT1 mutation was frequently found in the WT1-high expression group (13.9% vs. 3.8%, p=0.03), suggesting that the mutation of WT1 may cause overexpression of WT1 as an oncogene. Conclusions: In our evaluation of the suitability of F1H for HM-SCREEN-Japan 01, we successfully identified leukemia-associated genes that can be used as therapeutic targets in AML, which have rarely been identified thus far. Figure 1 Figure 1. Disclosures Yamauchi: Astellas: Research Funding; Abbie: Research Funding; Chugai: Honoraria; Pfizer: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Otsuka: Research Funding; Daiichi Sankyo: Research Funding; Solasia Pharma: Research Funding. Shibayama: Celgene: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Avvie: Honoraria, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Essentia Pharma Japan: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Fujimoto: Honoraria; Nippon Shinyaku: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Otsuka: Honoraria; Mundi Pharma: Honoraria. Kondo: Astellas Pharma Inc.: Consultancy, Honoraria; Otsuka Pharmaceutical: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho: Consultancy. Yamamoto: Eisai: Honoraria, Research Funding; IQIVA/Incyte: Research Funding; IQIVA/HUYA: Honoraria; HUYA: Consultancy; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; MSD: Honoraria; Mundipharma: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; SymBio: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Micron: Honoraria; IQIVA/Genmab: Research Funding; ADC Therapeutics: Honoraria; Daiichi Sankyo: Honoraria; Chugai: Honoraria, Research Funding; Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Kuroda: Sanofi: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Abbvie: Consultancy, Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Sysmex: Research Funding; Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Shionogi: Research Funding; Asahi Kasei: Research Funding; Taiho Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Nippon Boehringer Ingelheim: Research Funding; Takeda: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Janssen: Research Funding; Ono: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Symbio: Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Astellas: Research Funding, Speakers Bureau; Astellas-Amgen-Biopharma: Research Funding; Nippon shinyaku: Research Funding, Speakers Bureau; Kyowa Kirin: Research Funding, Speakers Bureau; Pfizer: Research Funding; Alexion: Speakers Bureau; Eisai: Speakers Bureau; MSD: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Speakers Bureau; Mundipharma: Research Funding. Yoshimitsu: Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Ishitsuka: Eli Lilly: Research Funding; Mochida: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Pfizer: Other: Personal fees; Novartis: Other: Personal fees; Janssen Pharmaceuticals: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Takeda: Other: Personal fees, Research Funding; BMS: Other; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Huya Japan: Other: Personal fees. Ono: DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Takeda Pharmaceutical Company Limited.: Honoraria; Astellas Pharma Inc.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Takahashi: Kyowahakko-Kirin: Research Funding; Ono: Research Funding; Asahikasei: Research Funding; Toyamakagaku: Research Funding; Eizai: Research Funding; Chugai: Research Funding; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Iyama: Otsuka: Honoraria, Research Funding; Novartis: Honoraria; Nippon Shinyaku: Honoraria; MSD: Research Funding; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Daiichi Sankyo: Honoraria; CSL Behring: Honoraria; Astellas: Honoraria; Alexion Pharmaceuticals: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; SymBio Pharmaceuticals: Research Funding. Izutsu: Yakult: Research Funding; Takeda: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Genmab: Honoraria, Research Funding; Huya Biosciences: Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Solasia: Research Funding; Symbio: Honoraria; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding.

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