ALBERT

Beschreibung: Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy associated with the human T-cell leukemia virus type I (HTLV-1). Classification of ATL into clinical subtypes acute, lymphoma, chronic and smoldering types was proposed based on prognostic factors, clinical features and natural history of the disease. Although HTLV-1 infection alone is not sufficient to cause ATL and only about 5% of HTLV-1 carriers progress to ATL, the prognosis is generally poor especially for patients with aggressive ATL (i.e., acute, lymphoma or unfavorable chronic types), with a median survival time at around 1 year, even after chemotherapy. Currently, biomarkers to predict ATL onset and progression are limited, making early diagnosis and treatment for ATL challenging. To develop early diagnostic biomarkers for ATL, we performed, for the first time, an extensive proteomic profiling of HTLV-1 carriers and ATL patients as a foundation for establishing a blood-based biomarker panel for ATL. Expression levels of 1305 plasma proteins in HTLV-1 carriers (n=40), untreated ATL patients (n=40, 28 acute; 4 lymphoma; 5 chronic; 3 smoldering), and remission status (n=5) were measured by SOMAscan assay (SomaLogic Inc, Boulder, CO). ATL diagnosis was based on criteria proposed by the Japan Clinical Oncology Group (JCOG) and identification of monoclonal integration of HTLV-1 proviral DNA using Southern blot hybridization method. Deregulated proteins in HTLV-1 versus ATL versus remission states were ranked by significance (Welch's t-test) and discrimination capacity (area under the curve [AUC]). In addition, machine learning algorithms were used to set discrimination boundaries for HTLV-1, ATL, and remission states using some of the top deregulated proteins. Statistical analyses were performed using Python 3.6.2 software. To elucidate on ATL pathogenesis, we further analyzed our proteomic data using Gene Set Enrichment Analysis (GSEA 3.0 hallmarks, curated gene sets) and Gene Ontology (GO Panther Pathways) and determined pathway deregulation among disease states as well as among ATL subtypes. Overrepresented pathways in ATL versus HTLV-1 included inflammation mediated by cytokine and chemokine signaling, angiogenesis, notch signaling, and IL6/JAK/STAT3, among others. Among a total of 176 proteins which were categorized as extremely significant (p

Beschreibung: Background: Since FLT3-ITD is a poor prognostic factor for acute myeloid leukemia (AML), allogeneic hematopoietic stem cell transplantation (allo-HSCT) is practically performed. However, clinical usefulness of allo-HSCT at the first remission (CR1) has not been fully evaluated by the prospective study. To prospectively elucidate the role of allo-HSCT at CR1 in younger adult patients with FLT3-ITD positive AML and explore the prognostic impacts of clinical and genetic features, we conducted a phase II multicenter study (JALSG AML209-FLT3-SCT, UMIN Clinical Trials Registry UMIN000003433, http://www.umin.ac.jp/ctr/). Methods: A total of 49 patients 16 to 49 years of age with newly diagnosed de novo AML were enrolled in this study if they had a FLT3-ITD mutation and achieved complete remission within 2 courses of the standard induction therapies consisting of cytarabine and either daunorubicin or idarubicin. All patients were to be received allo-HSCT as soon as possible while continuing 4 courses of consolidation therapy combining cytarabine plus mitoxantrone, daunorubicin, aclarubicin or etoposide, vincristine, and vindesine. Patients received no further chemotherapy until allo-HSCT or relapse. Conditioning was selected according to each institutional standard from myeloablative regimens except for reduced intensity conditioning only in patients older than 40 years old or with higher HCT-CI than 1 point. GvHD prophylaxis was according to each institutional standard based on cyclosporine A or tacrolimus combined with short-term MTX. Targeted sequencing of 57 genes frequently identified in myeloid malignancies were analyzed using the preserved DNA extracted from AML cells at diagnosis. FLT3-ITD allelic ratio (AR) was quantified using DNA fragment analysis. Primary endpoint was 3-year disease-free survival (DFS). Results: Among 48 eligible patients with the median age of 38.5 (range, 17-49) years, 36 (75%) maintained CR1 to receive allo-HSCT at the median of 108 (range, 54-228) days after the achievement of CR1. Median follow-up was 1,726 (range, 983-2,974) days. The 3-year DFS rate was 43.8% (95% confidence interval [CI], 30-57%, Figure 1). The lower limit of 95% CI exceeded threshold response rate of 20%, concluding the treatment was effective. The 3-year overall survival, post-transplant DFS and non-relapse mortality rates were 54.2% (95%CI, 39-67%), 58.3 % (95%CI, 41-72%) and 25.0% (95%CI, 12-40%), respectively. There was no significant difference in DFS post allo-HSCT according to donor sources (related BM 64.6% vs. related PB 50.0% vs. unrelated BM 63.6% vs. UCB 60.0% at 3 years, P= .881). Neutrophil recovery was achieved in 94.3%. Cumulative incidences of grade II to IV and III to IV acute GvHD at day 100 were 21.2% (95%CI, 9-37%) and 9.1% (95%CI, 2-22%), respectively. Cumulative incidence of chronic GvHD at 1 year was 25.0% (95%CI, 12-40%). Mutations in NPM1 gene (65%) and genes associated with DNA methylation were frequently identified including DNMT3A (36%), IDH1 (6%), IDH2 (17%) and TET2 (17%, Figure 2). Median ITD AR was 0.344 (range, 0.006-4.099). There was no significant overlap of genetic alterations with high ITD-AR (≥ 0.5). No significant impact on DFS was observed by high ITD AR (≥0.5) (Hazard ratio [HR], 1.53; 95%CI, 0.58-4.06; P= .39) or other co-occurring genetic alterations including NPM1 mutations (HR, 0.78; 95%CI, 0.28-2.20; P= .64). Conclusions: This prospective study demonstrated the efficacy and safety of proceeding faster to allo-HSCT in CR1 for younger adult patients with FLT3-ITD positive AML, whose graft sources were not limited to HLA identical donors and the first available donor should be considered. Beyond FLT3-ITD mutations, no significant prognostic factor was identified in their genetic background or high ITD AR. Further study is required to improve the prognosis of AML patients with FLT3-ITD by establishment of an adequate therapeutic strategy using FLT3 inhibitors and allo-HSCT. Disclosures Atsuta: Kyowa Kirin Co., Ltd: Honoraria; Mochida Pharmaceutical Co. Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Sawa:Asahi-Kasei: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Honoraria; Mochida: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Kyowa-Hakko Kirin: Honoraria; Nippon Shinyaku: Honoraria; Pfizer Japan Inc.: Honoraria; Novartis: Honoraria; Eisai: Honoraria; Otsuka Pharmaceutical: Honoraria; Shire: Honoraria; Mundi Pharma: Honoraria. Ozawa:Kyowa-Hakko Kirin: Honoraria; Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Astellas Pharma Inc.: Honoraria. Tomita:Taiho Pharma: Research Funding; Kyowa Kirin: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding. Maeda:Nippon Shinyaku Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K..: Honoraria. Usuki:Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Astellas Pharma Inc: Research Funding, Speakers Bureau. Matsuoka:Takeda Pharmaceutical: Research Funding; Novartis: Research Funding; Astellas Amgen Biopharma: Consultancy. Asou:SRL Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharm Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Asahi Kasei Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd: Research Funding; Novartis Pharmaceuticals: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding. Matsumura:Otsuka Pharmaceutical: Consultancy, Research Funding; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Miyazaki:Kyowa-Kirin: Honoraria; Dainippon-Sumitomo: Honoraria; Chugai: Research Funding; Nippon-Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria. Kiyoi:Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Zenyaku Kogyo Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Perseus Proteomics Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding.

Beschreibung: Background and objectives: Although intravenous (IV) FAMP in combination with Rituximab was reported to be effective against indolent B-NHL (JCO2005; 23:694), IV administration of FAMP for 3 to 5 consecutive days is inconvenient in an outpatient setting. We conducted a multicenter phase 2 study to evaluate the efficacy and safety of oral FAMP with Rituximab for relapsed or refractory indolent B-NHL. Patients and treatment: Eligible patients were: aged 20 to 74 years, with indolent B-NHL, with measurable lesions (the greatest transverse diameter 〉 1.5 cm by CT), performance status 0 or 1, with no major organ dysfunctions. Mantle cell lymphoma was excluded. Prior chemotherapies were limited to 〈 = 2 regimens, and prior rituximab treatments up to 16 times were allowed. Patients who received nucleoside analogs or stem cell transplant were excluded. Patients who had progressive disease within 6 months of receiving rituximab therapy were also excluded. Based on the results of the preceding phase 2 study (JCO2006; 24:174), oral FAMP 40 mg/m2 was administered on day 1 to 5, with rituximab 375 mg/m2 on day 1, repeated every 4 weeks, for up to 6 cycles. Results: Forty-one patients were enrolled and received oral FAMP with rituximab. Thirty-eight patients (93%) were follicular lymphoma, two with MALT lymphoma, and one with small lymphocytic lymphoma. Thirty-four patients (83%) received rituximab with or without chemotherapy prior to enrollment. Median treatment cycles were 6 cycles (range: 2 to 6, 66% of patients completed 6 cycles of treatment). Investigator-assessed overall response rate and complete response rate were 83% (34/41; CI: 68 to 93%) and 76% (31/41; CI: 60 to 83%), respectively. Central evaluation is pending. With median follow-up period of 9 months, median progression-free survival was not reached, and 28 patients (68%) were still alive without disease progression. Toxicity was primary hematologic, transient and manageable. Most common grade 4 hematologic toxicities included lymphopenia (98%), neutropenia (66%), and leukopenia (42%). Grade 3 or greater non-hematologic toxicities were observed in 29% of patients including one each of grade 4 stomatitis and hyperuricemia. Dose reduction of oral FAMP (from 40 to 30 mg/m2) was necessary in 44% of patients at some points of treatment courses. One patient died from Pneumocystis jiroveci pneumonia and other 2 from disease progression after the end of the study. Conclusion: Oral FAMP combined with rituximab is highly effective with acceptable toxicities for patients with relapsed or refractory indolent B-NHL who have been mostly pretreated with rituximab, and more convenient than the combination with IV FAMP. Prolonged prophylactic therapy against Pneumocystis jiroveci pneumonia would be recommended.