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Background: Some studies evaluating differences in clinical features and outcome between supra-diaphragmatic (SpD) and infra-diaphragmatic (InD) primary lesions in Hodgkin lymphoma (HL) have been reported (Cancer 1991;68:1476-1481: Haematologica 2006;91:32-39). In regard to non-Hodgkin's lymphoma, there exist some previous studies that report on outcomes of patients with gastrointestinal (GI) involvement (J Clin Oncol 2005;23:2797-2804; Cancer 2003;97:2462-73). However, no studies comparing outcome between SpD and InD primary lesions have been conducted for patients with diffuse large B cell lymphoma (DLBCL). Thus, we retrospectively evaluated outcome differences between SpD and InD lesions, and the prognostic impact of GI involvement in limited-stage DLBCL. Patients and Methods: We analyzed data from 178 patients with limited-stage DLBCL who were treated with rituximab plus cyclophosphamide (CPA), doxorubicin (DXR), vincristine (VCR), and prednisone (PSL; R-CHOP) therapy at 7 institutions of the Yokohama City University Hematology Group between 2003 and 2009. Patients who needed a dose reduction of more than 20% per cycle of R-CHOP therapy were excluded from the study. We classified the patients into SpD lesions group or InD lesions group according to the location of lesions. The patients in the InD lesions group were subsequently classified into InD with GI involvement group or InD without GI involvement group according to the presence of GI lesions. The impact of primary site location on patient outcome was evaluated using univariate and multivariate analyses. Results: The study cohort included 104 men and 74 women with a median age of 63 years (range, 18-80 years). All patients were categorized as Ann Arbor stage I (n = 66) or II (n = 112). The primary sites were SpD in 109 patients and InD in 69 patients. There were no significant differences in distribution between the SpD lesions group and the InD lesions group with respect to age, sex, Ann Arbor stage, the IPI score, ECOG performance status, and the presence of a bulky mass. Significantly more patients in the InD group presented with B symptoms (P = 0.003). Comparing patients in the InD lesions group presenting with (n = 35) or without (n = 34) GI involvement, resulted in similar findings with respect to clinical characteristics. The group with GI involvement consisted of 20 patients with stomach lesions (57%), 7 with small intestine lesions (20%), 7 with colon lesions (20%), and 1 with both colon and rectum lesions (3%). The median observation period for all surviving patients was 52 months (range, 3 – 94 months). The 4-year progression-free survival (PFS) and overall survival (OS) rates of all 178 patients were 84% and 91%, respectively. Twenty-six patients presented with disease progression after R-CHOP therapy. In total, 16 patients died: 14 of recurrent lymphoma, 1 of secondary malignancy (acute lymphoblastic leukemia), and 1 as a result of an accident. No statistical differences in PFS or OS were observed between patients with SpD lesions and those with InD lesions (4-year PFS rate: 87% and 81%, respectively; P = 0.31; Fig 1; 4-year OS rates: 92% and 86%, respectively; P = 0.31). When patients were classified and assessed according to primary site location, and their GI involvement status, which were SpD group, InD with GI involvement group, or InD without GI involvement group, the PFS rate was higher in SpD group (4-year PFS rates 86%), and InD with GI involvement group (4-year PFS rates 97%) than InD without GI involvement group (4-year PFS rates 67%; P = 0.036, and P = 0.003, respectively; Fig 2). However, no significant differences in regard to OS were observed among 3 groups (4-year OS rates: 93%, 97%, and 78%, respectively; P = 0.09). The multivariate analysis revealed that SpD or InD localization had no independent effect on PFS or OS. In addition, primary sites according to the presence of GI lesions were incorporated into the multivariate analysis, whereas SpD, and InD were excluded as overlapping variable. The multivariate analysis revealed that the presence of GI involvement in patients with InD lesions was an independent prognostic factor in predicting favorable PFS (P = 0.024, HR 0.09). Conclusion: No outcome differences were observed between SpD and InD lesions in limited-stage DLBCL. However, the presence of GI lesions was associated with a favorable prognosis. Disclosures No relevant conflicts of interest to declare.

Background Peripheral T-cell lymphoma (PTCL) is known to have an aggressive clinical course and be associated with poor survival. The International Prognostic Index (IPI) score and the Prognostic Index for T-cell lymphoma (PIT) have been suggested as methods to predict the prognosis of PTCL. Ferritin, the iron storage protein, is associated with chronic inflammation. Although higher levels of serum ferritin are detected in many cancer patients, the significance of elevated serum ferritin as a prognostic factor for lymphoma has yet to be established. Thus, our retrospective study aimed to examine the prognostic value of serum ferritin levels in PTCL. Patients and Methods Serum ferritin levels were evaluated in 78 patients with PTCL, who were treated with anthracycline-containing regimens in 8 institutions affiliated to the Yokohama City University Hematology Group between 1998 and 2011. Fourteen patients received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); 44 receivedpirarubicin, cyclophosphamide, vincristine, and prednisone (THP-COP); 3 received THP-COP followed by radiotherapy; 3 received up-front autologous peripheral blood stem cell transplantation; and 14 received THP-COP at 2-week intervals in a clinical trial. Results The study population comprised 50 male and 28 female patients with a median age of 64 years at the time of diagnosis (range, 16–83 years). With regard to the PTCL subtype, 39 patients had PTCL, not otherwise specified, and 39 had angioimmunoblastic T-cell lymphoma. Twelve patients had localized disease and 66 patients had advanced Ann Arbor stage lymphoma. Twenty-three patients had a poor Eastern Cooperative Oncology Group performance status (PS) of 2–4. B symptoms were present in 34 patients. Risk stratification according to the IPI was as follows: low risk, 9 patients; low–intermediate risk, 20 patients; high–intermediate (HI) risk, 30 patients; and high (H) risk, 19 patients. According to the PIT, 4 patients were categorized into group 1, 25 into, group 2 , 28 into, group 3, 21 into, as group 4. The median observation period for the surviving patients was 50 months. The median serum ferritin level was 183 ng/ml (range, 5–14,622 ng/ml). Factors associated with a poor overall survival (OS) in univariate analysis were HI and H risk status with regard to IPI (P = 0.024), assignment to group 3 or 4 with regard to PIT (P = 0.017), poor performance status (P< 0.001), and ferritin levels ≥ 300 ng/ml (P< 0.001). The 4-year OS rate of all 78 patients was 54%. The 4-year OS rate was poorer in patients with serum ferritin levels ≥300 ng/ml (n = 21) than in those with serum ferritin levels< 300ng/ml (n = 57; 22% vs. 65%; P< 0.001) (Figure). Multivariate analysis including each factor comprising the IPI (age, lactate dehydrogenase level, PS, Ann Arbor stage, and number of extranodal lesions), gender, bone marrow involvement, and serum ferritin level showed that poor PS (P = 0.002, relative risk [RR] 3.6) and a serum ferritin level ≥300 ng/ml (P = 0.014, RR 2.7) were independent risk factors for poor OS. Conclusion The serum ferritin level is a useful prognostic marker for PTCL. Disclosures: No relevant conflicts of interest to declare.

Background The prognosis of diffuse large B-cell lymphoma (DLBCL) has considerably improved during the last decade, mainly due to the addition of rituximab to chemotherapy. However, a significant proportion of patients still experience relapses after achieving first complete remission (CR), leading to poor survival. Although a specific predictor of relapse of non-Hodgkin’s lymphoma has not been identified thus far, recently, the peripheral blood lymphocyte/monocyte ratio (LMR) at diagnosis, which reflects the host’s immune status, was reported to predict clinical outcomes in DLBCL patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, the significance of LMR as a predictor of relapse in DLBCL patients in remission is not clear. The aim of this study was to assess whether LMR at 6 months after remission is a predictor of relapse after R-CHOP therapy in DLBCL patients. Methods From 2003 to 2009, 357 consecutive DLBCL patients were diagnosed, treated with R-CHOP, and followed up at 1 of the 7 participating hospitals in Japan. Of these, 315 DLBCL patients achieved CR after 6–8 cycles of R-CHOP therapy. Among the 315, those who were in remission for more than 6 months (n = 280) were enrolled in this study. The cumulative incidence of relapse was calculated from 6 months after CR to the first subsequent relapse or last follow-up. The effects of risk factors of relapse were assessed in univariate and multivariate Cox regression analyses. In multivariate analysis, risk factors tested at the time of diagnosis, confirmed remission and 6 months after remission included gender, International Prognostic Index at diagnosis (age > 60 years, elevated lactate dehydrogenase level, poor Eastern Cooperative Oncology Group performance status [ECOG PS], the presence of 2 or more extranodal involvement sites, and advanced clinical stage), and LMR ≤ 3.3. Results The study included 161 men and 119 women, with a median age of 64 years at diagnosis (range, 18–80 years). The median LMR at 6 months after remission was 3.7 (range, 0.5–18.0). The median observation period for surviving patients was 63 months. In all, 35 (12.5%) patients had confirmed relapse after achieving first CR, with a median time to relapse of 23 months (range, 6–61 months). The estimated 5-year cumulative incidence rate of relapse for the entire cohort was 14.7%. According to the LMR at 6 months after remission, the 5-year cumulative incidence rate for LMR ≤ 3.3 was 17.0% compared to 12.7% for LMR > 3.3 (P = 0.188). In the univariate analysis, advanced clinical stage at diagnosis (hazard ratio [HR] = 2.61, 95% confidence interval [CI], 1.33–5.13, P = 0.005) and poor ECOG PS at diagnosis (HR = 2.62, 95% CI, 1.19–5.77, P = 0.017) were associated with the occurrence of relapse. Multivariate analysis identified advanced clinical stage at diagnosis (HR = 2.42, 95% CI, 1.11–5.27, P = 0.026) and LMR ≤ 3.3 at 6 months after remission (HR = 2.10, 95% CI, 1.01–4.35, P = 0.047) as the risk factors for relapse. Conclusions The LMR at 6 months after remission is an independent predictor of relapse in first CR in DLBCL patients treated with R-CHOP. Disclosures: No relevant conflicts of interest to declare.

Background Serum beta-2 microglobulin (β2MG) is an HLA class I protein. Its concentration is determined mainly from lymphoid tissue. Previous reports demonstrated that serum β2MG levels tend to increase with the stage of Hodgkin lymphoma (HL; Eur. J. Cancer. 1979; 15: 791-796: Cancer. 1980; 45: 318-326). Thus, this retrospective study aimed to examine the prognostic value of serum β2MG levels in HL. Patients and Methods We analyzed the data of 67 patients with previously untreated HL whose serum β2MG levels had been evaluated at diagnosis and who were treated at 7 institutions of the Yokohama City University Hematology Group between 1998 and 2011. We assessed the associations between survival and serum β2MG levels, all factors comprising the international prognostic index (sex, age, Ann Arbor stage, albumin levels, hemoglobin levels, white blood cell counts and lymphocyte counts at diagnosis), performance status, lactate dehydrogenase levels, and number of extra-nodular lesions, using univariate and multivariate analyses. Results The patients included 40 men and 27 women with a median age of 41 years (range, 16- 81 years). The HL subtype was nodular sclerosis classical HL in 37 patients, mixed cellular classical HL in 23 patients, lymphocyte-rich classical HL in 6 patients, and nodular lymphocyte-predominant HL in 1 patient. The Ann Arbor stage of HL was stage I in 9 patients, stage II in 30 patients, stage III in 19 patients, and stage IV in 9 patients. All the patients were treated with doxorubicin, bleomycin, vinbrastine, and dacarbazine (ABVD) therapy alone (n = 37) or ABVD therapy plus involved-field radiation therapy (IFRT; n = 30). The clinical stage of HL in the patients treated with ABVD therapy alone was stage II in 11 patients, stage III in 17, and stage IV in 9. The clinical stage of HL in the patients who received ABVD plus IFRT was stage I in 9 patients, stage II in 19, and stage III in 2. The median observation period in the surviving patients was 53 months (range, 5- 123 months). The 4-year progression-free survival (PFS) and overall survival (OS) rates of all 67 patients were 76% and 89%, respectively. Thirteen patients had disease progression after treatment of HL. In total, 9 patients died: 3 of recurrent lymphoma, 2 of infection, 1 of acute circulatory failure during chemotherapy for HL, 1 of secondary malignancy, 1 of brain hemorrhage, and 1 of pulmonary chronic graft versus host disease. The patients with serum β2MG levels ³2.5 µg/mL showed inferior PFS (n = 18; 4-year PFS rate, 42%) compared to those with serum β2MG levels below Conclusion Therefore serum β2MG level at diagnosis is a useful prognostic marker for patients with HL. Disclosures: No relevant conflicts of interest to declare.

Abstract 1574 Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma (NHL), with a highly variable natural history ranging from an indolent disease to a rapidly progressive one such as its transformation to aggressive NHL. We have used the Follicular Lymphoma International Prognostic Index (FLIPI) that uses patient- or tumor-specific characteristics for the risk-stratification of patients with FL at the time of diagnosis. The tumor microenvironment, including variable monocyte-derived cell infiltration, has recently shown to play an important role in the clinical course of FL patients. Wilcox et al. showed that an elevated absolute monocyte count (AMC) is associated with inferior overall survival of FL patients receiving varying treatment strategies (Wilcox RA, et al. Leuk Lymphoma 2012). We retrospectively evaluated the prognostic changes in AMC at diagnosis in FL patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy alone. This study included 157 consecutive FL patients treated with the R-CHOP therapy at 1 of the 7 participating hospitals between 2001 and 2009. Since 2001, the Yokohama City University Hematology Group in Japan uniformly and curatively treated patients with FL, except for those with stage 1 FL; the patients were treated with 6 cycles of standard R-CHOP therapy for 21 days. Patients who showed partial response (PR) after the initial 4 cycles were administered a total of 8 R-CHOP cycles, and those who did not show PR after the initial 4 cycles or patients in whom the disease progressed at any given time received salvage therapy. Patients who had bulky masses at diagnosis received involved field radiation following 6—8 cycles of R-CHOP therapy. Patients for whom the doses had to be reduced by more than 20% were excluded from the study. The study included 80 men and 77 women, with a median age of 63 years at diagnosis (range, 18—80 years). The FL of the 157 patients were classified as grade 1 (n = 65), grade 2 (n = 60), grade 3a (n = 20), and grade 3b (n = 12) according to the World Health Organization (WHO) scheme. The median AMC at diagnosis was 349 cells/μL (range, 10—1110 cells/μL). The median observation period for surviving patients was 45 months. The 5-year progression-free survival (PFS) estimated for the entire cohort was at 71.3%. The differences in the PFS when patients were stratified according to their AMCs were not significant. The effect of the following variables on PFS were assessed: (1) AMC > 390 cells/μL; (2) age > 60 years; (3) hemoglobin level < 120 g/L; (4) elevation of serum lactate dehydrogenase levels; (5) nodal areas > 4; and (6) advancement of clinical stage. In the univariate analysis, the presence of more than 4 nodal areas (hazard ratio [HR] = 2.65, 95% CI, 1.58—4.47, P < 0.001) and advanced clinical stage (HR = 2.75, 95% CI, 1.26—6.03, P= 0.01) were associated with inferior PFS. However, in the multivariate analysis, the association between the presence of more than 4 nodal areas and survival was found to be significant (HR = 2.33, 95% CI, 1.28—4.24, P = 0.006). Therefore, both univariate and multivariate analyses indicate that AMC was not a prognostic factor for PFS. There was no statistically significant correlation between AMC and FL patients' clinical outcome. AMC is not a prognostic factor in FL patients treated by R-CHOP. Disclosures: No relevant conflicts of interest to declare.

Abstract 3948 Background: The central nervous system (CNS) is considered a sanctuary because drugs at standard doses rarely reach it. CNS event is defined as disease recurrence in the CNS during complete systemic remission or CNS progression as concurrent disease in the CNS during active systemic disease. These CNS events are associated with extremely poor patient prognosis. To evaluate the risk of CNS events in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab (R) era, we performed a retrospective study with a large cohort in Japan. Materials and Methods: All patients were diagnosed as having DLBCL and underwent primary therapy from September 2003 to December 2006. Patients with distinct forms of DLBCL, such as intravascular lymphoma, primary effusion lymphoma, and pyothorax-associated lymphoma were excluded. Those who had received any prophylactic CNS treatment; and those with CNS involvement at the beginning of therapy were also excluded. Primary therapy comprised standard R-CHOP therapy or R-THP-COP therapy (pirarubicin instead of doxorubicin hydrochloride). CNS involvement was considered when malignant cells were detected in cytocentrifuged preparations of cerebrospinal fluid (leptomeningeal type) and/or when an intracranial or spinal mass was detected by radiologic imaging such as computed tomography or magnetic resonance imaging (parenchymal type). Results: (1) Baseline characteristics. Clinical data from 1,492 patients were collected from 48 institutions. The median age was 67 years (range, 15–93 years). R-CHOP therapy was administered in 1,227 patients (82.2%) and R-THP-COP therapy, in 265 patients (17.8%). Therapy for 6–8 cycles was administered to 1099 patients (73.7%). Local irradiation was included for 344 patients (23.1%). The 5-year overall survival (OS) rate in the entire cohort was 72.8%, and the median observation period for the surviving patients was 47.6 months. (2) Incidence of CNS events. In total, 94 CNS events (6.3%) were recorded. More than half were of the parenchymal type (57.4%); the rest were mostly of the leptomeningeal type (29.8%), and some were of both types (12.8%). The events occurred during the first complete remission (CR) in 40 patients (42.6%) and in the second or later CR in 11 patients (11.6%). Death from any cause was recorded in 64 of the 94 patients (68.1%) during the observation period, and most deaths were due to lymphoma. The cumulative 5-year probability of CNS events was 8.0%. (3) Risk factors for CNS events. Multivariate Cox regression analysis identified involvement of the breast (relative risk (RR), 7.9), adrenal gland (RR, 3.3), paranasal sinus (RR, 2.9), and bone (RR, 2.3). as risk factors for CNS events. Time to CNS event curves differed significantly between patients with and without CNS risk sites (P < 0.001). (4) Survival after CNS events. Patients with CNS events demonstrated significantly poorer OS (P < 0.001). The 2-year OS rate after a CNS event was 25.7%, and the 50% survival duration was 4.6 months. No significant differences were observed between any 2 of the 3 types of CNS events. Depending on the systemic lymphoma status at the time of the CNS events, patients in first CR showed better survival than the others (P = 0.019). Patients in any CR also showed superior survival than those not in CR (P = 0.015). Conclusions: We concluded that DLBCL patients in the R era with any of these risk factors (breast, adrenal gland, paranasal sinus, or bone involvement), in addition to patients with testicular involvement in whom CNS prophylaxis has been already justified, are at high risk for CNS events. The efficacy and manner of CNS prophylaxis for each involvement sites should be evaluated further. Disclosures: No relevant conflicts of interest to declare.