ALBERT

Description: Abstract 2641 INTRODUCTION: Since the introduction of the anti-CD20 monoclonal antibody rituximab, the outcomes of B-cell non-Hodgkin lymphoma (B-NHL) have improved markedly. However, fulminant hepatitis due to reactivation of hepatitis B virus (HBV) infection has emerged as a serious problem. Recently, rituximab plus corticosteroid containing chemotherapy (R-chemo) has been identified as a risk factor for HBV reactivation in hepatitis B surface antigen (HBsAg)-negative B-NHL patients. Currently, there is no standard management to prevent HBV reactivation in HBV-resolved patients without HBsAg, but with antibodies against hepatitis B core antigen (anti-HBc) and/or HBsAg (anti-HBs). PATIENTS AND METHODS: We conducted a multicenter prospective observational study to estimate the incidence of HBV reactivation by serial monthly monitoring of HBV DNA in HBV-resolved patients with B-NHL during and just after R-chemo, and to establish preemptive antiviral therapy guided by this monitoring. The major eligibility criteria included previously untreated CD20-positive B-NHL with prior HBV-resolved infection, and planned treatment with 6 to 8 cycles of R-chemo defined by protocol. The baseline HBV status was evaluated on enrollment at each institute, comprising HBsAg, anti-HBc, and anti-HBs serology. Patients were excluded if they were seropositive for hepatitis C virus or human immunodeficiency virus. Plasma HBV DNA levels were measured independently at a central laboratory, using an automated real-time TaqMan polymerase chain reaction assay after enrollment. The primary end point was the incidence of HBV reactivation defined as HBV DNA levels of 1.8 log copies per mL or more. If HBV DNA levels of less than 1.8 log copies per mL were confirmed at baseline, the serial monitoring of HBV DNA (without prophylaxis of antiviral drugs) was performed with assessments every 4 weeks after enrollment for 1.5 years. Prompt antiviral treatment with an anti-HBV nucleoside analogue (entecavir, 0.5 mg per day) was highly recommended in patients with confirmed HBV reactivation. An ancillary study was conducted to identify risk factors for HBV reactivation using the preserved specimens. The protocol was approved by the Institutional Review Board of each participating institution. All patients gave written informed consent. The planned interim analysis was performed after the enrollment of 200 patients, using data available up to June 30, 2011. RESULTS: Between Sept. 2008 and Sept. 2010, a total of 187 patients (50.8% male) with a median age of 63 years (range, 26 to 79) from 45 institutes were analyzed. Histologic subtypes of B-NHL were diffuse large B-cell lymphoma (n=121, 64.7%), follicular lymphoma (n=57, 30.5%), MALT lymphoma (n=5, 2.7%) and other types (n=4, 2.0%). The number (%) of patients positive for both anti-HBc and anti-HBs was 132 (70.6%), 35 (18.7%) were positive for anti-HBc but negative for anti-HBs, and 19 (10.2%) were negative for anti-HBc but positive for anti-HBs. One patient was positive for anti-HBc but lacked anti-HBs measurement. 168 (89.8%) patients received 6 to 8 cycles of R-CHOP (n=151) or other R-chemo (n=17). With a median follow-up of 549 days (range, 35 to 939), HBV reactivation was observed in 16 out of 187 analyzed patients. The incidence of HBV reactivation at 1 year was 7.7% (95% confidence interval [CI], 4.7 to 12.7). HBV reactivation was diagnosed at a median time of 158 days (range, 33 to 490) after enrollment. No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were 1.8 to 3.1 log copies per mL. Multivariate analysis of the ancillary study showed that an anti-HBs baseline titer less than 10 mIU per mL was an independent risk factor for HBV reactivation, compared to a titer of 100 mIU per mL or more (adjusted hazard ratio, 5.3; 95% CI, 1.3 to 21.8; p=0.02). HBV mutations of precore (G1896A) or basal core promoter (A1762T/G1764A) that enhanced HBV replication were identified in 4 patients, two of whom had both mutations. Our strategy could inhibit such highly replicative clones and prevent hepatitis. CONCLUSIONS: Monthly monitoring of HBV DNA is highly effective for preventing hepatitis due to HBV reactivation in HBV-resolved B-NHL patients treated with R-chemo. (UMIN-CTR 000001299) (This study was supported by the Ministry of Health, Labour and Welfare of Japan.) Disclosures: Kusumoto: Bristol-Myers Squibb: Honoraria; Zenyaku Kogyo: Honoraria; Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Abbott: Honoraria. Tanaka:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Abbott: Honoraria. Tanaka:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Kinoshita:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria. Ogura:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria, Research Funding. Mizokami:Chugai Pharmaceutical Co., LTD.: Honoraria; Abbott laboratories: Honoraria. Ueda:Chugai Pharmaceutical Co., LTD.: Research Funding.

Description: Chronic graft versus host disease (cGVHD) is the most common cause of poor outcomes after hematopoietic stem cell transplantation (HSCT), while the pathophysiology of cGVHD remains poorly understood. We have revealed the association Fc receptor-like protein 3 (FCRL3) gene -169C/T single nucleotide polymorphism (SNP) and developing cGVHD. This gene is a member of Fc receptor-like protein gene family which contains 5 genes and well known as autoimmune disease associated gene. These 5 genes make cluster lesion on chromosome 1q21 to 23. In this current study, to investigate the relationship with another Fc receptor-like protein genes and cGVHD, we used 4 microsatellite polymorphisms belong to FCRL1, 2, 3 and 4 as a linkage analysis genetic marker. And we also investigated FCRL3 -169C/T SNP and another 3 SNPs to explore haplotype and the incidence of cGVHD. We analyzed 123 case of Japanese HLA-matched sibling recipients and their donor who underwent HSCT in the Japanese Red-Cross Nagoya First hospital. Before day 100, 11 patients died from severe acute GVHD, infection, thrombotic microangiopathy or disease relapse. Therefore, we analyzed 112 recipients and 108 donors for the relationship between gene polymorphisms and chronic GVHD. We analyzed microsatellite polymorphisms and SNPs by using TaqMan® assay. Chronic GVHD occurred in 54 out of 112 (48.2%) patients in this cohort. The nearest microsatellite marker from FCRL3 gene had significant different allele frequency between cGVHD and non-GVHD recipient (p=0.0034). There were no association with another microsatellites allele and developing cGVHD. FCRL3 gene haplotypes with frequency 〉0.01 were -TGGG-, -CACA- and -CGCA-. Chronic GVHD patients significantly less the frequency of -CACA- or -CGCA- allele than non GVHD patients (p=0.0040). There were no significant difference in donor allele frequency and incidence of cGVHD. In conclusion, our studies show FCRL3, which is autoimmune disease associated gene, is also the candidate of cGVHD associated gene and its protective haplotype may prevent from occurring cGVHD but not homologous another FCRL proteins.

Description: Background: MEDI-551 is an affinity-optimized and afucosylated humanized IgG kappa anti-CD19 monoclonal antibody enhanced for antibody-dependent cellular cytotoxicity. In a previous multicenter, phase 1/2 trial conducted in the United States and Europe, an overall disease control (objective response + stable disease) rate of 73.5% was achieved with MEDI-551 in patients (N=83) with relapsed or refractory B-cell malignancies, and median progression-free survival was 9.4 months (95% CI, 3.9–18.6 months) (Forero-Torres A, et al. 2013, ASH meeting). Objective: We conducted an open-label, multicenter, phase 1 dose escalation study of MEDI-551 in Japan in patients with relapsed or refractory B-cell lymphoma and myeloma to determine the safety profile, maximum tolerated dose (MTD) or optimal biologic dose (OBD), and the preliminary antitumor activity of MEDI-551. Methods: Patients aged 20 years or older with relapsed or refractory chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or multiple myeloma (MM) were enrolled at 3 institutes in Japan. All patients received MEDI-551 (at 2, 4, or 8 mg/kg) intravenously on days 1 and 8 of the first 28-day cycle, then once every 28 days, with an additional dose cohort of 12 mg/kg added. Dose escalation continued to the maximum dose of 12 mg/kg or until MTD was reached. Therapy continued for 2 cycles after the achievement of complete response (CR) or until unacceptable toxicity or disease progression. Dose-limiting toxicity (DLT) was defined as a MEDI-551–related adverse event (AE) that inhibited completion of a full first cycle of MEDI-551, or as a grade ≥3 toxicity that could not be attributed to another cause. Results: From April 2011 through June 30, 2014, a total of 20 patients, including 6 with DLBCL, 11 with FL, 2 with CLL, and 1 with MM, received study treatment across 4 dose levels (2-mg/kg cohort; n=3; 4-mg/kg cohort, n=7; 8-mg/kg cohort, n=4; 12-mg/kg cohort, n=6). Two DLTs, including one infusion-related reaction and one case of neutropenia/leukopenia, were observed at the 12-mg/kg dose; thus, the MTD was determined to be 8 mg/kg. The AEs most commonly reported (in ≥15% of patients) were infusion-related reaction, hypertriglyceridemia, leukopenia, nasopharyngitis, decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, and rash. A serious AE of epiglottitis (not treatment-related) was observed on day 64 after 4 cycles of MEDI-551 12-mg/kg. No treatment-related deaths were reported. Two patients with 12-mg/kg were discontinued due to treatment-related AEs (infusion-related reaction, decreased neutrophil count). Among 20 patients evaluable for response, 2 and 10 patients achieved CR and partial response, respectively, with an overall response rate of 60%. Six patients (30%) had stable disease. Response was obtained in 3/6 patients with DLBCL, 0/2 with CLL, 9/11 with FL, and 0/1 with MM, and in 2/3 at the MEDI-551 2-mg/kg dose, 3/7 at 4 mg/kg, 3/4 at 8 mg/kg, and 4/6 at 12 mg/kg. Data from this phase I study are being finalized. Conclusions: This phase I study demonstrated acceptable toxicity and preliminary but promising antitumor activity of MEDI-551, with an MTD of 8 mg/kg, in Japanese patients with relapsed or refractory DLBCL or FL. Disclosures Ogura: AstraZeneca: Research Funding; Pfizer: Research Funding; GSK: Research Funding; Eizai: Research Funding; Symbio: Research Funding; Kyowahakko-Kirin: Research Funding; Chugai: Research Funding; Zenyaku: Research Funding; Otsuka: Research Funding; Dainippon Sumitomo: Research Funding; Jansen: Research Funding; Soraisia: Research Funding; Mundi: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Ando:Kyowahakko-Kirin: Research Funding. Yagawa:AstraZeneca: Employment; AstraZeneca: Stock ownership, Stock ownership Other. Yokoi:AstraZeneca: Employment; AstraZeneca: Stock ownership, Stock ownership Other.

Description: The Dickkopf-1 (DKK-1) gene product is an extracellular Wnt inhibitor. Hypermethylation of the DKK-1 promoter results in transcriptional silencing and may play an important role in cancer development. Here, we investigated hypermethylation of the DKK-1 promoter in patients with acute myeloid leukaemia (AML), especially core-binding factor (CBF) leukaemia. The methylation status of DKK-1 was analyzed by methylation-specific polymerase chain reaction in 47 patients with AML. DKK-1 methylation was found in 14 (29.8%) of the patients, and more frequently in those with CBF leukaemia (6 of 12 patients), than in those with acute promyelocytic leukaemia (0 of 6 patients) (P = .03). In contrast, Wnt inhibitory factor-1 methylation was found in acute promyelocytic leukaemia (4 of 6 patients) but not in CBF leukaemia (0 of 12 patients) (P = .001). Multivariate analyses suggested that DKK-1 methylation was a risk factor for poorer overall survival. Sequential analysis using 4 paired samples obtained at diagnosis and relapse suggested that DKK-1 methylation was involved in the progression of leukaemia. DKK-1 methylation may therefore be involved in leukaemogenesis, especially in CBF leukaemia, and may be a useful prognostic marker in AML.

Description: Abstract 2700 Poster Board II-676 Background: Hepatitis B virus reactivation after systemic chemotherapy including rituximab is a well-documented complication. However, no studies have investigated the influence of hepatitis C virus (HCV) infection for hepatic toxicity of diffuse large B-cell lymphoma (DLBCL) patients treated by rituximab containing chemotherapy. The prognostic value of HCV infection in DLBCL in the era of rituximab was also unclear. Herein we conducted a multicenter retrospective analysis to compare the outcome and hepatic toxicity of DLBCL patients with and without HCV infection treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) as an initial therapy. Methods: We analyzed 548 patients: HCV-positive (n=126) or -negative (n=422) patients with CD20-positive DLBCL receiving RCHOP between January 2004 and March 2008. HCV-negative patients treated during same period with HCV-positive patients in each institute were enrolled. Hepatitis B surface antigen positive patients were excluded in this study. For survival analysis, event-free survival (EFS) and overall survival (OS) were compared according to HCV infection. The definition of severe hepatic toxicity was more than Grade 3 transaminases increase according to National Cancer Institute of Canada criteria. The change of serum HCV-RNA levels was examined in 33 HCV-positive patients. Results: Before the treatment, HCV-positive patients had higher age (P

Description: Introduction Multiple myeloma (MM) is an incurable plasma cell neoplasm developing through long-term multistep genetic events. Biological and clinical features of the MM are known to be associated in part with relatively early genetic aberrations such as chromosomal translocations involving IGH. The t(14;16)(q32;q23) involving c-MAF oncogene locus is an important chromosomal aberration observed in approximately 5 percent of newly diagnosed MM. Various studies have suggested that MM carrying t(14;16) is associated with specific clinical characteristics. However, these studies were not definitive, since the number of the patients analyzed was relatively small. The aim of this study is to clarify the clinical features of patients with newly diagnosed MM harboring t(14;16) detected by double-color fluorescence in situ hybridization (FISH) in Japan. Methods Clinical and laboratory features of t(14;16)-positive MM diagnosed between 2002 and 2013 were collected retrospectively as a nationwide study in Japan after approval by each institutional ethical committee. The t(14;16) translocation was detected by FISH analysis using bone marrow or peripheral blood samples from all patients. Expression of surface antigens such as CD56 and CD20 was detected by flow cytometric analysis (FCM) and defined as positive when more than 20% of the CD38-positive plasma cells were positive. To compare t(14;16)-positive and t(14;16)-negative MM, we also assessed 132 patients with newly diagnosed symptomatic MM and without c-MAF mRNA expression, as confirmed by global RQ/RT-PCR using purified plasma cells (Tajima E, et al.:Haematologica 2005; 90: 559, Inagaki A et al.: Leuk Res 2013; 37: 1648) at Nagoya City University Hospital. Results In total, 37 patients carrying t(14;16)-positive MM were enrolled from 19 institutions. Median ages of the MM patients with or without t(14;16) at diagnosis were 62 and 68, respectively. Regarding the cell surface phenotype, none of the t(14;16)-positive MM cells was positive for CD56 (Fig. 1), whereas 82 of 118 (69%) t(14;16)-negative ones were positive. Positivity for CD20 antigen was more common in t(14;16)-positive MM cells (11/23, 48%) than in t(14;16)-negative ones (16/115, 14%)(p= 0.001). The proportion of patients with additional chromosome aberrations other than t(14;16), determined by G-banded karyotyping, was higher in patients with t(14;16) (16/30, 53%) than in those without (19/131 cases, 15%) (p〈 0.001). Moreover, MM patients with t(14;16) showed higher frequencies of IgG subtype M protein, leukocytosis (p= 0.001), thrombocytopenia (p〈 0.001) and hyperproteinemia (p= 0.001), and a lower frequency of hypercalcemia (p= 0.001), compared to those without t(14;16). Overall survival (OS) of the patients with t(14;16) was significantly shorter than that of those without t(14;16) even though the patients received one or more lines of treatment containing novel drugs such as bortezomib, thalidomide and lenalidomide (p= 0.014) (Fig. 2). Poor PS (PS ≥ 2-4), low PLT count (1.0N) were significantly unfavorable prognostic factors for OS in patients with t(14;16)-positive MM, whereas they were not in those without t(14;16). Progression-free survival (PFS) of the patients with t(14;16) was also significantly shorter than those without t(14;16) (p= 0.002) Conclusion The t(14;16)-positive MM comprises a specific category in MM, which is featured by negativity for CD56, higher positivity for CD20 and unfavorable outcome, even in the novel drug era. Unraveling biological characteristics of this specific disease category will lead us to establish novel treatment strategies. Disclosures No relevant conflicts of interest to declare.

Description: The influence of hepatitis C virus (HCV) infection on prognosis and hepatic toxicity in patients with diffuse large B-cell lymphoma in the rituximab era is unclear. Thus, we analyzed 553 patients, 131 of whom were HCV-positive and 422 of whom were HCV-negative, with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)–like chemotherapy. Survival outcomes and hepatic toxicity were compared according to HCV infection. The median follow-up was 31 and 32 months for patients who were HCV-positive and HCV-negative, respectively. HCV infection was not a significant risk factor for prognosis (3-year progression-free survival, 69% vs 77%, P = .22; overall survival, 75% vs 84%, P = .07). Of 131 patients who were HCV-positive, 36 (27%) had severe hepatic toxicity (grade 3-4), compared with 13 of 422 (3%) patients who were HCV-negative. Multivariate analysis revealed that HCV infection was a significant risk factor for severe hepatic toxicity (hazard ratio: 14.72; 95% confidence interval, 6.37-34.03; P 〈 .001). An exploratory analysis revealed that pretreatment transaminase was predictive of severe hepatic toxicity. HCV-RNA levels significantly increased during immunochemotherapy (P = .006). These results suggest that careful monitoring of hepatic function and viral load is indicated during immunochemotherapy for HCV-positive patients.