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Optically active γ-cyanoallylic alcohols were synthesized by using asymmetric hydrocyanation of α,β-alkenyl aldehydes catalyzed by peptide-titanium complex to give α-cyanoallylic alcohols (cyanohydrins) with high optical yields followed by palladium complex catalyzed [3.3]sigmatropic chirality transfer of the corresponding acetates.

Background:Diffuse large B-cell lymphomas (DLBCLs) with MYC-rearrangement (MYC-R) or double protein expression (DE) of the MYC and BCL2 are associated with poor prognosis. MYC-R reportedly occurs in approximately 5-14% of DLBCL cases. While the pathological and genetic prognostic factors for DLBCL with MYC-R have been reported, the clinical prognostic factors, including the extranodal sites involved, have not been fully elucidated. In the updated National Comprehensive Cancer Network guidelines for non-Hodgkin lymphomas, the presence of pleural effusion is a poor prognostic criterion for low-grade B-cell lymphomas; however, its prognostic significance in high-grade B-cell lymphomas is unclear. Therefore, we aimed to investigate the association between the presence of pleural effusion at diagnosis and outcomes in DLBCL with MYC-R or DE.

Mishima: Chugai Pharmaceutical CO., LTD.: Consultancy. Nishimura:Chugai Pharmaceutical CO., LTD.: Consultancy. Yokoyama:Chugai Pharmaceutical CO., LTD.: Consultancy. Hatake:Chugai Pharmaceutical CO., LTD.: Other: lecture speaking.

Nishimura: Chugai Pharmaceutical CO., LTD.: Consultancy. Mishima:Chugai Pharmaceutical CO., LTD.: Consultancy. Yokoyama:Chugai Pharmaceutical CO., LTD.: Consultancy. Hatake:Chugai Pharmaceutical CO., LTD.: Other: lecture speaking.

Nishimura: Chugai Pharmaceutical CO., LTD.: Consultancy. Mishima:Chugai Pharmaceutical CO., LTD.: Consultancy. Yokoyama:Chugai Pharmaceutical CO., LTD.: Consultancy. Hatake:Chugai Pharmaceutical CO., LTD.: Other: lecture speaking.

Yokoyama: Chugai Pharmaceutical CO., LTD.: Consultancy. Mishima:Chugai Pharmaceutical CO., LTD.: Consultancy. Nishimura:Chugai Pharmaceutical CO., LTD.: Consultancy. Hatake:Chugai Pharmaceutical CO., LTD.: Other: lecture speaking.

Introduction: R-CHOP therapy is standard chemotherapy for DLBCL. In the LNH98-5 study, CR was 75% and 5-year EFS was 63% in low-risk patients and 41% in high-risk patients. Five-year OS was 80% in the low-risk group, and 48% in the high-risk group. R-CHOP is tolerable and commonly applied to outpatients. However, almost 20% of patients with DLBCL were very elderly, 75 years of age or more. Chemotherapy for very-elderly patients often causes many troubles, and thus the prognosis is worse than those of younger patients. The dose of R-CHOP therapy for the elderly patients varies among institutions because there are no suitable guidelines for it. Therefore, the optimal dose of R-CHOP therapy is needed to be determined to improve the outcome of the elderly patients with DLBCL.

Backgrounds

Introduction

Introduction: There are various poor prognosis factors in diffuse large B cell lymphoma (DLBCL). CD5 positive (CD5+) is estimated as one of the poor prognosis markers in DLBCL. CD5+DLBCL is completely distinguished from CLL or Mantle cell lymphoma, and de Novo CD5+DLBCL is related to a high incidence of cytogenetic abnormalities of 8p21 and 11q13. In many cases, CD5+DLBCL is associated with an aggressive clinical status and advanced stages. Several chromosomal studies have demonstrated the gene expression was similar to non-GCB type of DLBCL. In the clinical phase, it is easy to express chemo-resistance and CNS invasion. However, the clear characterization and mechanisms of chemo-resistance have not been demonstrated yet. In this study, we examined our previous CD5+DLBCL patients in our institute, then evaluated the prognosis and clinical characteristics regarding GCB or non GCB type.

Background

[Background]The therapeutic outcomes in patients with peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) are correlated with positivity of Epstein-Barr virus (EBV) -encoded small RNA in situ hybridization. EBV nuclear antigen 1 (EBNA), the only viral protein consistently expressed by EBV, itself positivity has been the mainstay evidence to diagnose the latent EBV infection to date. However, it has been unknown whether the difference value of EBNA titer has another clinical implication, to say nothing of hematological malignancies field.

Introduction

Mishima: Chugai Pharmaceutical CO., LTD.: Consultancy. Yokoyama:Chugai Pharmaceutical CO., LTD.: Consultancy. Nishimura:Chugai Pharmaceutical CO., LTD.: Consultancy. Hatake:Chugai Pharmaceutical CO., LTD.: Other: lecture speaking.

Mishima: Chugai Pharmaceutical CO., LTD.: Consultancy. Nishimura:Chugai Pharmaceutical CO., LTD.: Consultancy. Yokoyama:Chugai Pharmaceutical CO., LTD.: Consultancy. Hatake:Chugai Pharmaceutical CO., LTD.: Other: lecture speaking.

Yokoyama: Chugai Pharmaceutical CO., LTD.: Consultancy. Nishimura:Chugai Pharmaceutical CO., LTD.: Consultancy. Mishima:Chugai Pharmaceutical CO., LTD.: Consultancy. Hatake:Chugai Pharmaceutical CO., LTD.: Other: lecture speaking.

No relevant conflicts of interest to declare.

Masahiro: Chugai Pharmaceutical co.,LTD: Consultancy. Nishimura:Chugai Pharmaceutical Co., LTD: Consultancy.

No relevant conflicts of interest to declare.

Background and Purpose

Introduction: Radiation therapy (RT) for localized- refractory or relapsed diffuse large B cell lymphoma (DLBCL) after chemotherapy is a standard therapy. Though some cases achieve complete remission (CR) after RT for local residual disease, others reveal disease progression after RT.

Extranodal natural killer (NK) /T cell lymphoma, nasal type is much common in East Asia than in Western countries. CHOP therapy is not effective for NK/T cell lymphoma because of the drug resistance induced by P glycoprotein. Yamaguchi et al reported the effectiveness of concurrent radiotherapy and DeVIC (RT-DeVIC) therapy for localized nasal NK/T cell lymphoma. Nowadays, RT-DeVIC therapy is recognized as a standard treatment. So far, we have limited information about this treatment because NK/T cell lymphoma is rare phenotype.

Ocular adnexal lymphomas (OALs) are relatively rare, accounting for 2% of all lymphomas and 5% of non-Hodgkin lymphomas. OALs often represent as isolated and require only radiation therapy (RT). However, some of them are systematic and need intensive chemotherapy.

In the rituximab era, there are several studies that have reported the risk factors for central nervous system (CNS) involvement in non-Hodgkin lymphoma, but the same factors emerge, such as high international prognostic index (IPI) score, >1 extranodal site, elevated lactate dehydrogenase (LDH) level, poor performance status (PS), advanced stage, bone marrow involvement. Macrophages are an important component of the tumor microenvironment and the immune response to malignancy. Recently, elevated peripheral blood monocyte counts have been shown to be an independent marker associated with poor prognosis in patients with both non-Hodgkin and Hodgkin lymphoma.We reviewed data from a total of 1238 lymphoma patients(1185 non-Hodgkin lymphoma, 53 Hodgkin lymphoma) at our institution between February 2005 and May 2013. Of these, 42 patients (3.4%) developed CNS complications during the clinical course. Thirty patients out of these 42 (71.4%) were diagnosed with diffuse large B-cell lymphoma (DLBCL). Therefore, we focused on DLBCL. In this study, we retrospectively analyzed data from a total of 557 DLBCL patients, 30 patients (5.4%) who developed CNS involvement and 527 patients with DLBCL but without CNS involvement. This study was approved by the Institutional Review Board of the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. The clinical features of all 557 DLBCL patients, including 30 patients with CNS involvement, are summarized in Table 1. CNS involvement was defined by the presence of at least one histologically confirmed CNS involvement; neuroimaging findings compatible with CNS involvement with lymphoma, in conjunction with consistent clinical presentation; and the absence of other clinically feasible diagnosis or positive cerebrospinal fluid (CSF) (lymphoma cells detected by cytology). The absolute monocyte counts (AMC) and monocyte ratio were derived from pre-treatment complete blood counts.Immunohistochemical analysis was carried out using mAbs against CD68 at our institution.The incidence of CNS involvement was 5.4%, 1.3% having CNS involvement at diagnosis with DLBCL. Intriguingly, absolute monocyte counts (AMC) ≥0.6 (×109/L) at diagnosis were significantly frequent in 30 DLBCL patients (p=0.0420) with CNS involvement, compared with in 527 DLBCL patients without CNS involvement. Furthermore, the monocyte ratio ≥8% in peripheral blood at diagnosis was significantly frequent in 30 DLBCL patients (p=0.0325) with CNS involvement, compared with in 527 DLBCL patients without CNS involvement. DLBCL patients with CNS involvement showed age ≤60 years, stage III-IV, IPI score ≥3, and PS ≥2, elevated soluble IL-2 receptor levels was significantly frequent, compared with in DLBCL patients without CNS involvement. Neither gender, elevated LDH level, white blood cell counts (WBC) differed significantly in the two groups. With regard to pathological immunohistochemistry, the numbers of CD68 positive cells in or around lymphoma samples did not differ in the 14 DLBCL patients with CNS involvement that we were able to analyze, compared with DLBCL patients without CNS involvement. CNS involvement free survival rate in DLBCL patients was significantly lower in AMC ≥0.6 (×109/L) and/or the monocyte ratio ≥8% (Log-rank test, P=0.0102) in peripheral blood at diagnosis, compared with in AMC less than 0.6 (×109/L) and the monocyte ratio less than 8%.These results suggest that in DLBCL patients, AMC and monocyte ratios in peripheral blood at diagnosis are closely correlated with the risk of eventual CNS involvement. AMC and monocyte ratios in peripheral blood at diagnosis in DLBCL patients could be a useful prognostic marker for the risk of CNS involvement during the clinical course.Yokoyama: Chugai Pharmaceutical CO., LTD.: Consultancy. Nishimura:Chugai Pharmaceutical CO., LTD.: Consultancy.

Ocular adnexal lymphomas (OALs) are relatively rare, accounting for 2% of all lymphomas and 5% of non-Hodgkin lymphomas. OALs often represent as isolated and require only radiation therapy (RT). However, some of them are systematic and need intensive chemotherapy.We analyzed newly diagnosed OALs at Cancer Institute Hospital from January 2006 to May 2013. All patients (pts.)’ samples were performed biopsy by expert oncology-ophthalmologists and all the histopathology samples were reviewed by expert hematopathologists, according to the WHO classification. Positron emission tomography-computed tomography and bone marrow assessment were required for initial evaluation.A total of 83 pts. were included in this study. Baseline pts.’ characteristics were a median age of 64.48 years (range, 29.46-85.26 years), 39 male and 44 female, 62 pts. (74.7%) with stage I (according to Ann Arbor staging system), and 21(25.3%) with over stage II. Sixty-five pts. (78.3%) had unilateral OAL, and 18 (21.7%) bilateral. None had central nervous system involvement. Sixty pts. (72.3%) had extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type, in which 9 pts. with over stage II, 9 pts. (10.9%) diffuse large B cell lymphoma (DLBCL), 3 pts.(3.6%) follicular lymphoma, 2 pts.(2.4%) mantle cell lymphoma, and 9 pts. (10.8%) others. Fifty-five pts.(66.3 %) have received only RT, 19 pts.(22.9%) only chemotherapy, 5 pts.(6.0%) both RT and chemotherapy, and 4 pts. (4.8%) haven’t received any therapy at the hospital. Nineteen pts. have received rituximab with or without other chemotherapy. At a median follow-up of 26.8 months (range 1.3-88.7), the 2-year progression free survival (PFS) and overall survival (OS) rates were 84.0% and 91.6%, respectively. In MALT, PFS and OS were 96.2% and 95.0%, respectively. In DLBCL, PFS and OS were 37.5% and 66.7%, respectively. The sites were orbit (38, 45.8%), conjunctiva (32, 38.6%), lachrymal gland (7, 8.4%), eyelid (5, 6.0%), and dacryocyst (1, 1.2%). None demonstrated disease progression at conjunctiva. Three pts. (60.0%) at eyelid were progressive, 3 pts. (42.9%) at lachrymal gland, and 6 pts. (15.7%) at orbit. Over stage II contained 13 pts. at orbit, 3 pts. at conjunctiva and eyelid, and 2 pts. at lachrymal gland. DLBCL were 6 pts. at orbit, 1 pt. at conjunctiva, eyelid, dacryocyst, and lachrymal gland.MALT demonstrated good prognosis. DLBCL as OALs might indicate poorer prognosis than those at other parts. At the standpoint of site, conjunctiva represented remarkably good prognosis. Conjunctiva may be independent from other OALs. Eyelid and lachrymal gland represented high rate of progressive disease. For ophthalmologists, especially the back side of bulbar is hard to distinguish between conjunctiva and eyelid. The separation of both at biopsy is important because the prognoses of them are different. Since the sample of biopsy is small at OALs, careful collection of sample by ophthalmologists and choice of examination by hematopathologists are important. OALs require cross-sectional cooperation for diagnosis and treatment.Yokoyama: Chugai Pharmaceutical CO., LTD.: Consultancy. Nishimura:Chugai Pharmaceutical CO., LTD.: Consultancy.

In the rituximab era, there are several studies that have reported the risk factors for central nervous system (CNS) involvement in non-Hodgkin lymphoma, but the same factors emerge, such as high international prognostic index (IPI) score, >1 extranodal site, elevated lactate dehydrogenase (LDH) level, poor performance status (PS), advanced stage, bone marrow involvement. Macrophages are an important component of the tumor microenvironment and the immune response to malignancy. Recently, elevated peripheral blood monocyte counts have been shown to be an independent marker associated with poor prognosis in patients with both non-Hodgkin and Hodgkin lymphoma.

No relevant conflicts of interest to declare.

Abstract 1337

Interleukin-2 receptor (IL2R) is usually expressed on activated T cells by antigen stimulation and on pre-B cells during B cell differentiation. Soluble IL-2R (sIL-2R) in serum is a truncated form of the 55-kDa chain of IL-2R, which is believed to be produced by cleavage by proteases. The concentration of sIL-2R in serum has been an index of tumor burden in adult T cell leukemia/lymphoma (ATL), in which CD4-positive T cells express IL-2R (CD25) on the cell surface. Subsequently, analysis of serum sIL-2R concentration has also been useful in predicting disease activity and response to treatment in B cell lymphoma. However, it is still unclear whether B cell lymphoma cells express IL-2R (CD25) or whether serum sIL-2R concentration is due to IL-2R on B cell lymphoma cells. Furthermore, it is unclear how sIL-2R is released from IL-2R in ATL. First, we examined whether serum sIL-2R concentration is a prognostic factor in previously untreated patients with DLBCL (n = 105, median age 67.0 (18–91 years)) or FL (n = 30, median age 60.0 (40–82 years)) diagnosed between January 2001 and December 2005, and who received six cycles of R + CHOP or R + THP-COP therapy. Patients who relapsed or had disease progression after R + CHOP or R + THP-COP received R + EDAP or R + ICE for DLBCL, and R + FND for FL. The 5-year OS rates for patients with sIL-2R levels of < 1500 U/ml and ⊠ 1500 U/ml were 76% and 62%, respectively (p < 0.05) in DLBCL, and 100% and 79.3%, respectively (p = 0.19) in FL. Next, we analyzed IL-2R (CD25) expression on lymphoma cells by flow cytometry. Nine of 25 patients with DLBCL and 4 of 11 patients with FL showed CD25 expression. Some T cells (CD3-positive cells) expressed CD25 in both lymphomas. On the other hand, 7 of 7 patients with MCL expressed CD25. There was no significant relationship between serum sIL-2R concentrations and CD25 expression on lymphoma cells or clinical stage in either DLBCL or FL. Metalloproteinase-9 (MMP-9) is reported to be an important protease for releasing sIL-2R from IL-2R. However, there was no significant relationship between MMP-9 and sIL-2R levels in sera from patients with DLBCL or FL. On the other hand, 7 of 7 patients with ATL showed high concentration of MMP-9 (> 128 ng/ml) irrespective of sIL-2R levels. We then confirmed MMP-9 expression in 3 ATL cell lines by Western blotting, and addition of MMP-9 inhibitor to culture media of these cell lines significantly decreased sIL-2R levels in supernatants. On immunohistochemical staining (IHC) using anti-MMP-9 antibody, macrophages not lymphoma cells or T cells were positive for MMP-9 in DLBCL and FL. These findings suggest that high serum sIL-2R concentrations in ATL are due to the cleavage of IL-2R by MMP-9 produced by ATL cells. On the other hand, the main source of sIL-2R may be due to release from activated T cells in DLBCL and FL. Therefore, serum sIL-2R levels may indicate activity of neoplastic cells in ATL; however, its levels may reflex the activity of microenviromental non-neoplastic cells in DLBCL and FL.

Interleukin-2 receptor (IL2R) is usually expressed on activated T cells by antigen stimulation and on pre-B cells during B cell differentiation. Soluble IL-2R (sIL-2R) in serum is a truncated form of the 55-kDa chain of IL-2R, which is believed to be produced by cleavage by proteases. The concentration of sIL-2R in serum has been an index of tumor burden in adult T cell leukemia/lymphoma (ATL), in which CD4-positive T cells express IL-2R (CD25) on the cell surface. Subsequently, analysis of serum sIL-2R concentration has also been useful in predicting disease activity and response to treatment in B cell lymphoma. However, it is still unclear whether B cell lymphoma cells express IL-2R (CD25) or whether serum sIL-2R concentration is due to IL-2R on B cell lymphoma cells. Furthermore, it is unclear how sIL-2R is released from IL-2R in ATL. First, we examined whether serum sIL-2R concentration is a prognostic factor in previously untreated patients with DLBCL (n = 105, median age 67.0 (18–91 years)) or FL (n = 30, median age 60.0 (40–82 years)) diagnosed between January 2001 and December 2005, and who received six cycles of R + CHOP or R + THP-COP therapy. Patients who relapsed or had disease progression after R + CHOP or R + THP-COP received R + EDAP or R + ICE for DLBCL, and R + FND for FL. The 5-year OS rates for patients with sIL-2R levels of < 1500 U/ml and ⊠ 1500 U/ml were 76% and 62%, respectively (p < 0.05) in DLBCL, and 100% and 79.3%, respectively (p = 0.19) in FL. Next, we analyzed IL-2R (CD25) expression on lymphoma cells by flow cytometry. Nine of 25 patients with DLBCL and 4 of 11 patients with FL showed CD25 expression. Some T cells (CD3-positive cells) expressed CD25 in both lymphomas. On the other hand, 7 of 7 patients with MCL expressed CD25. There was no significant relationship between serum sIL-2R concentrations and CD25 expression on lymphoma cells or clinical stage in either DLBCL or FL. Metalloproteinase-9 (MMP-9) is reported to be an important protease for releasing sIL-2R from IL-2R. However, there was no significant relationship between MMP-9 and sIL-2R levels in sera from patients with DLBCL or FL. On the other hand, 7 of 7 patients with ATL showed high concentration of MMP-9 (> 128 ng/ml) irrespective of sIL-2R levels. We then confirmed MMP-9 expression in 3 ATL cell lines by Western blotting, and addition of MMP-9 inhibitor to culture media of these cell lines significantly decreased sIL-2R levels in supernatants. On immunohistochemical staining (IHC) using anti-MMP-9 antibody, macrophages not lymphoma cells or T cells were positive for MMP-9 in DLBCL and FL. These findings suggest that high serum sIL-2R concentrations in ATL are due to the cleavage of IL-2R by MMP-9 produced by ATL cells. On the other hand, the main source of sIL-2R may be due to release from activated T cells in DLBCL and FL. Therefore, serum sIL-2R levels may indicate activity of neoplastic cells in ATL; however, its levels may reflex the activity of microenviromental non-neoplastic cells in DLBCL and FL.