ALBERT

Description: The outcome of patients with non-Hodgkin’s lymphoma has been improved by current approaches to treatment. Nevertheless, many patients either do not have a complete remission or ultimately relapse. To identify such patients, it is important to be able to predict the outcome. We previously found that the differentiation inhibitory factor/nm23 was correlated with the prognosis of acute myeloid leukemia. To examine the prognostic effect of nm23 on non-Hodgkin’s lymphoma, we established an enzyme-linked immunosorbent assay procedure to determine nm23-H1 protein levels in plasma and assessed the association of this protein level with the response to chemotherapy, overall survival, and progression-free survival in patients with aggressive non-Hodgkin’s lymphoma. The plasma concentration of nm23-H1 was significantly higher in patients with malignant lymphoma than in normal controls, especially in aggressive non-Hodgkin’s lymphoma. The complete remission rate in patients with higher nm23-H1 levels was significantly worse than that in patients with lower nm23-H1 levels. Overall survival and progression-free survival were also lower in patients with higher nm23-H1 levels than in those with lower levels. The 3-year survival rates in patients with low and high nm23-H1levels were 79.5% and 6.7% (P = .0001). A multivariate analysis of prognostic factors showed that the plasma nm23-H1level was independently associated with the survival and progression-free survival. An elevated plasma nm23-H1concentration predicts a poor outcome of advanced non-Hodgkin’s lymphoma. Therefore, nm23-H1 in plasma may be useful for identifying a distinct group of patients at very high risk.

Description: 2′-Deoxycoformycin (dCF) as a single agent has been reported to be less effective against myeloid than against lymphoid malignancies in clinical trials. However, previous studies have shown that in the presence of 2′-deoxyadenosine (dAd), human monocytoid leukemia cell lines are much more sensitive to dCF with regard to the inhibition of cell proliferation. Thus, dCF might be useful for treating monocytoid leukemia with the aid of dAd analogs. The antiproliferative effects of dCF in combination with dAd or its derivatives were examined on normal and malignant blood and bone marrow cells. In the presence of 10 μmol/L dAd, the concentration of dCF required to inhibit the viability of primary monocytoid leukemia cells was much lower than that required to inhibit normal or non-monocytoid leukemic cells. Among the dAd analogs, 9-β-d-arabinofuranosyladenine (AraA) was also effective in combination with dCF. Athymic nude mice were inoculated with human monocytoid leukemia U937 cells and treated with dCF or a dAd analog or both. Although dCF alone slightly but significantly prolonged the survival of mice inoculated with U937 cells, combined treatment with dCF and AraA markedly prolonged their survival. These data suggest that the combination of dCF and AraA may be useful for the clinical treatment of acute monocytic leukemia.

Description: Background and Objective Primary mediastinal large B-cell lymphoma (PMBL) accounts for 2 to 4% of non-Hodgkin lymphomas and is characterized by distinct clinical, pathological and genetic features. Although the utility of DA-EPOCH-R without radiotherapy (RT) and a PET-guided RT approach were recently reported, a standard therapy has not yet been established, mostly due to the lack of data from prospective randomized studies. In addition, the prognosis for patients (pts) with relapsed PMBL is not well understood. Therefore, we conducted a multicenter, cooperative retrospective study to evaluate the clinical outcome of pts with PMBL. Patients and Methods We analyzed a total of 345 pts with newly diagnosed PMBL from 65 institutes between May 1986 and September 2012 in Japan. Pts were treated according to each institutional protocol or physicians' decisions. In pts treated with R-CHOP, the role of PET before RT was analyzed. In addition, we analyzed prognostic factors for PMBL pts and constructed a novel prognostic model using data from patients treated with R-CHOP. Results The median age was 32 (range, 17-83) years, and female pts were predominant (58%) among the patient population. Median tumor diameter was 10 cm. Stage I/II, low-risk by IPI, and PS 0/1 were also predominant (68%, 52% and 75%, respectively). The presence of pleural or pericardial effusion, elevated lactate dehydrogenase level and extra-nodal lesions were observed in 46%, 80% and 44% of pts, respectively. With a median follow-up of 48 months in surviving pts, overall survival (OS) and progression-free survival (PFS) at 4 years were 87% and 70%, respectively. The OS and PFS were improved in pts treated with rituximab(R)-containing chemotherapy (n = 267) (4-year OS: 91% vs. 77%, P 〈 0.001; 4-year PFS: 75% vs. 54%, P 〈 0.001, respectively). The OS at 4 years for patients treated with CHOP (n = 44), R-CHOP (n = 187), DA-EPOCH-R (n = 9), second- or third-generation regimens (n = 45; 28 with R and 17 without R), and chemotherapy followed by ASCT (n = 57; 43 with R and 14 without R) were 67%, 90%, 100%, 91% and 92%, respectively (P 〈 0.001). The PFS at 4 years were 40%, 71%, 100%, 83% and 76%, respectively (P 〈 0.001) (Figure 1). Consolidative RT was given to 42% of the patient population. A total of 119 of 187 pts treated with R-CHOP were assessed by PET/CT after the completion of R-CHOP, and 64 pts received consolidative RT after R-CHOP. In pts with negative PET after R-CHOP (n = 84), the OS (100% vs. 100%, P 〉 0.99) and PFS (92% vs. 72%, P = 0.36) at 4 years were similar when comparing pts treated with (n =25) or without RT (n =59). However, in pts with positive PET after R-CHOP (n = 28), both OS (100% vs. 60%, P = 0.010) and PFS (80% vs. 17%, P 〈 0.001) at 4 years were superior in pts who received RT (n = 21) than in pts who did not receive RT (n = 7). A total of 97 pts (28%) relapsed or progressed after first-line therapy. Of these, 67 (19%) and 11 pts (3%) relapsed in the mediastinum and CNS, respectively. Median time from initial diagnosis to relapse or progression was 9 months. Median OS after relapse or progression was 16 months and was higher in patients treated with stem-cell transplantation (SCT) (n = 58; 44 ASCT, 14 allogeneic SCT) than in patients who did not undergo SCT (4-year OS: 67% vs. 31%, P 〈 0.001). The IPI was predictive for OS (P = 0.002) and PFS (P 〈 0.001) in pts with PMBL treated with R-CHOP. Moreover, multivariate analysis showed that the presence of pleural or pericardial effusion was a significant and independent prognostic factor for PFS. We constructed a novel prognostic model (PMBL prognostic index; PMBIPI) and classified pts treated with R-CHOP into three different risk groups using these two factors (the presence of pleural or pericardial effusion, and IPI high/intermediate-risk or high-risk). For 93 pts (51%) classified as the low-risk group (0 factor), OS and PFS at 4 years were 97% and 89%, respectively. For 61 pts (34%) classified as the intermediate-risk group (1 factor), OS and PFS at 4 years were 85% and 59%, respectively. For 27 pts (15%) classified as the high-risk group (2 factors), OS and PFS at 4 years were 72% (P = 0.001) and 44% (P 〈 0.001), respectively (Figure 2). Conclusions The combination of R and chemotherapy improved outcomes for patients with PMBL. In addition, PET could predict the necessity for RT in pts with PMBL treated with R-CHOP. PMBIPI is a promising tool for risk-stratification of pts with PMBL. These findings require further validation in prospective studies. Disclosures: No relevant conflicts of interest to declare.

Description: Standard treatment for relapsed or refractory follicular lymphoma has not been established. Doxorubicin (DXR) is often administered during the initial treatment. The dosage or drugs chosen for salvage therapy are limited by DXR-induced cardiomyopathy. Pirarubicine (THP) was developed in Japan as a less cardiotoxic and highly effective anti-neoplastic drug. We previously reported that the THP-COPBLM regimen, in which THP was used instead of DXR, showed the same degree of efficacy as the COP-BLAM regimen and that cardiac sympathetic dysfunction and cardiac mitochondrial damage were less common with THP than with DXR (Leukemia12:1457, 1998). The R-EPOCT (rituximab with etoposide, vincristine, THP, cyclophosphamide, and prednisone) regimen, in which less cardiotoxic THP is used instead of DXR, with G-CSF was administered to 20 patients with relapsed or refractory follicular lymphoma. The safety (especially cardiotoxicity) and efficacy of this regimen were studied. As markers of cardiotoxicity, serum troponin T and plasma B-type natriuretic peptide (BNP) levels were measured. Adverse reactions occurred in 14 of the 20 patients, and mainly consisted of grade 3/4 hematological toxicity. In the evaluation of cardiotoxicity, the BNP level was slightly elevated in 2 patients before the treatment (22.4 pg/ml and 25.6 pg/ml; normal, less than 20 pg/ml). After 4 cycles of treatment, the BNP level in these two patients increased to 26.8 pg/ml and 28.8 pg/ml, respectively, but it returned to approximately the previous level one month after completion of treatment. The troponin T level was undetectable before and after the treatment in all patients. The response rate was 100%, with complete remission in 16 patients (80%). G-CSF administration increased both FcγRI expression on neutrophils and ADCC activity. Upon G-CSF administration during the second cycle of treatment, the level of FcγR1 (CD64) expression on neutrophils increased from 60.1 ± 3.6 (MFI) before G-CSF administration to 324.7 ± 33.2 (p = 0.0005) after 9 days of administration of 2 μg/kg G-CSF. After 11 days of G-CSF administration, the level of FcγR1 expression was 346.2 ± 24.2. The expression of FcαRI (CD89) on neutrophils was examined in a similar fashion. There was no remarkable change in the level of FcαRI expression before and after G-CSF administration. We conclude that the combination of R-EPOCT and G-CSF is well-tolerated. This regimen was not cardiotoxic. We are planning a randomized trial to compare the efficacy between R-EPOCT and a combination of R-EPOCT with G-CSF.

Description: A previous study reported that a nondifferentiating myeloid leukemia cell line produced differentiation-inhibiting factors. One of the factors was purified as a homologue of the nm23 genes. Thenm23 genes were overexpressed in acute myelogenous leukemia (AML) cells, and a higher level of nm23 gene expression was correlated with a poor prognosis in AML. The present study determined the plasma levels of nm23-H1 protein by enzyme-linked immunosorbent assay and assessed the association between this level and the clinical outcome in 102 patients with AML. The plasma concentration of nm23-H1 was higher in patients with AML than in normal controls (P = .0001). Plasma nm23-H1 levels were correlated with the product of the intracellular nm23 messenger RNA (mRNA) level and the white blood cell count, but not with the mRNA level alone. Therefore, nm23-H1 plasma levels probably depend on the total mass of leukemic cells overexpressing the nm23-H1 gene. Overall survival was lower in patients with higher plasma nm23-H1 levels than in those with lower levels. Multivariate analysis using the Cox proportional hazard model showed that elevated plasma nm23-H1 levels significantly contributed to the prognosis of AML patients. Furthermore, the plasma nm23-H1 levels were investigated in 70 patients with other hematologic neoplasms, including 6 with acute lymphoblastic leukemia, 13 with chronic myelogenous leukemia, and 12 with myelodysplastic syndrome. Plasma nm23-H1 levels were significantly higher in all of these hematologic neoplasms than in normal controls. Increased plasma levels of nm23-H1 may have prognostic value in these hematologic malignancies as well as in AML.

Description: The adenosine deaminase (ADA) inhibitor 2′-deoxycoformycin (dCF) significantly inhibits the proliferation of leukemia and lymphoma cell lines. When cells were incubated in the presence of both dCF and 2′-deoxyadenosine (dAd), the concentration of dCF required to induce apoptosis of monocytoid leukemia cells was much lower than that required for myeloid, erythroid, or lymphoma cell lines. Among the cell lines tested, U937 cells were the most sensitive to this treatment. The concentration of dCF that effectively inhibited the proliferation of U937 cells was 1/1,000 of that required for lymphoma cell lines, on a molar basis. However, the uptake of dCF or dAd in U937 cells was comparable with that in other leukemia and lymphoma cell lines. The intracellular accumulation of dATP in U937 cells was only slightly higher than that in other leukemia cells in dCF-treated culture. Treatment with dCF plus dAd induced apoptosis in U937 cells at low concentrations, and this apoptosis was reduced by treatment with caspase inhibitors. Induction of caspase-3 (CPP32) activity accompanied the apoptosis induced by dCF plus dAd. No activation of CPP32 was observed in cytosol prepared from exponentially growing leukemia and lymphoma cells. However, dATP effectively induced CPP32 activation in cytosol from monocytoid cells, but not in that from nonmonocytoid cells, suggesting that dATP-dependent CPP32 activation is at least partly involved in the preferential induction of apoptosis in monocytoid leukemia cells. The combination of dCF and dAd may be useful for the clinical treatment of acute monocytic leukemia. © 1998 by The American Society of Hematology.

Description: Abstract 2725 Poster Board II-701 Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma, accounting for approximately 30% of all new patients. The addition of rituximab to CHOP regimen has been found to improve the outcome of DLBCL. However, it dose not provide a satisfactory treatment outcome in the high-risk group according to the international prognostic index (IPI). More recent study, however, suggested that intensified regimens may indeed yield superior results to CHOP. We administered the CyclOBEAP (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) regimen to patients with DLBCL, and previously reported its safety and efficacy. The CyclOBEAP regimen was administered over a total period of 12 weeks, in which the dose intensities of cyclophosphamide, doxorubicin, and vincristine are equal to or higher than those in the CHOP regimen, and bleomycin were added to the CHOP regimen. The results showed that 106 (80%) of the 121 patients achieved complete response (CR), the 5-year overall survival (OS) rate was 72%, and the 5-year progression-free survival (PFS) rate was 62%. Here, we report the results of a multicenter phase II study of the R-CyclOBEAP regimen. This was a prospective, single-arm phase II trial in the Adult Lymphoma Treatment Study Group (ALTSG) in Japan. Patients were enrolled in the study between April 2004 and March 2008. Patients aged between 15 and 60 years who were in the low-intermediate, high-intermediate, or high risk groups, were eligible for this study. The CyclOBEAP regimen was administered over a total period of 12 weeks. Rituximab 375mg/m2 was given every 2 weeks. There were 101 eligible patients and the median age was 51 years. A CR was achieved in 96 patients (95%). The 5-year OS rate was 85% and PFS rate was 76%. When the patients were divided according to the IPI or revised IPI, the 5-year OS and PFS rates did not significantly differ among the risk groups. We next examined survival curve of the patients with DLBCL in whom soluble interleukin-2 receptor data were available. The 5-year survival rates for the high (≧2000 IU/ml) and low soluble interleukin-2 receptor groups (

Description: Introduction: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of diseases in terms of morphology, immunohistochemistry and molecular features. The prognostic factors of DLBCL in the rituximab era are different from previously reported prognostic factors. Hans, et al. reported that patients with non-germinal center B-cell like (GCB)-type DLBCL had a significantly poorer prognosis than those with GCB-type DLBCL in the pre-rituximab era. In patients who received rituximab combination chemotherapy, there is a report that did not find a difference in survival ratio between those with GCB DLBCL or non-GCB DLBCL. On the other hand, there was a report that found a difference in survival ratio between patients with GCB DLBCL and those with non-GCB DLBCL. In addition, the previously reported that patients with Epstein-Barr virus (EBV)-positive DLBCL had a significantly poorer prognosis than those with EBV-negative DLBCL in the pre-rituximab era. In the present study, we considered the prognostic factors of DLBCL patients who received rituximab combined chemotherapy. Patients and Methods: The subjects were 209 DLBCL patients in whom immunohistochemical markers (CD20, CD5, CD10, BCL-2, BCL-6, MUM-1) could be analyzed. In addition, 86 patients were examined EBV-encoded RNA (EBER) in situ hybridization. Pathologic evaluation of the materials from each patient was performedat several central review meetings by six hematopathologists in the ALTSG pathology review board. Patients were treated with cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, and prednisolone (CyclOBEAP) regimen or CHOP regimen. Rituximab was administered to all patients. One hundred forty-six DLBCL patients who underwent CHOP-like therapy were assumed as historical controls. The median follow-up period was 69 months (range, 46-88months). Results: In the R-chemotherapy and CHOP-like groups, patients with stage III or IV disease comprised 57% and 67%, respectively, patients with performance status≧2 comprised 32% and 23%, respectively, and patients with serum LDH 〉normal comprised 61% and 69%, respectively. There were no significant differences in clinical characteristics between the R-chemotherapy group and CHOP-like group. BCL2 was positive in 72 (55%) of the 131 patients who received the R-chemotherapy and in 71 (50%) of the 142 patients who received the CHOP-like regimen. When the 209 patients who received the R- chemotherapy group were divided into the GCB group and the non-GCB group, the GCB group consisted of 74 patients (35%) and the non-GCB group consisted of 135 patients. The relationships between immunohistological markers and outcome among the patients with DLBCL who received CHOP-like therapy were studied. CD5, CD10, and BCL6 had no prognostic impact on 5-year overall survival (OS) and progression-free survival (PFS) rates. When the patients were divided into the GCB DLBCL and non-GCB DLBCL groups, the 5-year PFS of the GCB group was 78% and that of the non-GCB group was 48% (p=0.0008). Next, the effect of rituximab with chemotherapy was examined. CD5, CD10, BCL2, BCL6, and MUM-1 had no prognostic impact on 5-year OS and PFS rates. When the patients were divided into the GCB DLBCL (n=74) and non-GCB DLBCL (n=135) groups, the 4-year PFS of the GCB group was 79% and that of the non-GCB group was 73%, showing no significant difference. We also evaluated the significance of EBER expression among patients by incorporating the EBV-positive DLBCL (n=14) and EBV-negative DLBCL (n=72).There were no significant differences in immunophenotyping analysis between the EBV-positive DLBCL and EBV-negative DLBCL. As for EBER expression in DLBCL, the 4-year PFS of the EBER-positive group was 37% and that of the EBER-negative group was 75% (P=0.007), indicating that the EBER-positive group showed significantly poorer prognosis. The 4-year OS of the EBER-positive group was 50% and the EBER-negative group was 86% (P=0.0005). Conclusions: The EBER may be an important prognostic factor in patients with DLBCL who underwent R-chemotherapy therapy. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of diseases in terms of morphology, immunohistochemistry and molecular features. The t(14;18)(q32;q21) translocation juxtaposes the BCL2 gene, normally located at 18q21, with the IGH locus on 14q32. The t(14;18)(q32;q21) occurs in about 80-90% of follicular lymphomas and about 25-30% of de novo DLBCLs. On the other hand, the t(8;14)(q24;q32) translocation juxtaposes the c-MYC protooncogene, which is located at 8q24, to the immunoglobulin heavy chain (IGH) gene, located at 14q32, resulting in deregulated expression of c-MYC. t(8;14)(q24;q32) has been found in 80-90% of Burkitt lymphoma cases and in 5-15% of DLBCL cases. B-cell lymphoma having both t(14;18) and 8q24, so called double hit lymphoma (DHL), is rare. The pathological diagnosis in most cases of DHL is B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BCLU). Patients with DHL have elevated serum LDH levels, advanced stage, bone marrow involvement, extranodal involvement and the presence of B symptoms. In the present study, we evaluated the clinicopathological characteristics and prognoses of patients with BCLU with DHL. Patients and Methods: A total of 368 patients with DLBCL and BCLU were treated from 2007 to 2013. Chromosomal data were available in 195 of the 368 patients. Pathologic evaluation of the materials from each patient was performedat several central review meetings by six hematopathologists in the ALTSG pathology review board. Patients were treated with cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, and prednisolone (CyclOBEAP) regimen or CHOP regimen. Rituximab was administered to all patients. The median follow-up period was 44 months (range, 12-61 months). Results: t(14;18) + 8q24 dual translocation was seen in 18 (9.2 %) of the 195 patients with DLBCL and BCLU. There were 12 males and 6 females, with a median age of 62 (range, 47-76) years. Stage III/IV was found in 56%, bone marrow infiltration was found in 39％, central nervous system (CNS) infiltration was found in 17％, and high risk of international prognostic index (IPI) was found in 67％. Among the 18 patients with the DHL, extranodal sites of disease were bone marrow (7 patients), CNS (3 patients), pleural effusion (5 patients), and gastrointestinal tract (3 patients). Furthermore, 8 patients had at least two extranodal localizations. Immunophenotyping analysis (CD20, CD5, CD10, BCL2, BCL6, MUM1, Ki-67) was performed and showed BCLU with a germinal center type in all cases. Ki-67 staining ranged from 30-90%. All lymphoma cells were positive for CD20 and negative for CD5. CD10, BCL2, BCL6, and MUM1 were positive in 89%, 75%, 88%, and 19%, respectively. The 4-year overall survival (OS) rate was 72% among the patients with dual translocation (n=18) and 75% among the patients in the other chromosomal abnormalities group (n=177). The 4-year progression-free survival (PFS) rate was 52% among the patients with the dual translocation and 71% among the patients in the other chromosomal abnormalities group. The 4-year OS rate of the stage I/II and stage III/IV groups was 100% and 47%, respectively (P=0.016). We next examined the survival curve of patients in whom data on serum LDH levels were available. The 4-year OS rates of the high (〉2N) and low LDH groups (

Description: The adenosine deaminase (ADA) inhibitor 2′-deoxycoformycin (dCF) significantly inhibits the proliferation of leukemia and lymphoma cell lines. When cells were incubated in the presence of both dCF and 2′-deoxyadenosine (dAd), the concentration of dCF required to induce apoptosis of monocytoid leukemia cells was much lower than that required for myeloid, erythroid, or lymphoma cell lines. Among the cell lines tested, U937 cells were the most sensitive to this treatment. The concentration of dCF that effectively inhibited the proliferation of U937 cells was 1/1,000 of that required for lymphoma cell lines, on a molar basis. However, the uptake of dCF or dAd in U937 cells was comparable with that in other leukemia and lymphoma cell lines. The intracellular accumulation of dATP in U937 cells was only slightly higher than that in other leukemia cells in dCF-treated culture. Treatment with dCF plus dAd induced apoptosis in U937 cells at low concentrations, and this apoptosis was reduced by treatment with caspase inhibitors. Induction of caspase-3 (CPP32) activity accompanied the apoptosis induced by dCF plus dAd. No activation of CPP32 was observed in cytosol prepared from exponentially growing leukemia and lymphoma cells. However, dATP effectively induced CPP32 activation in cytosol from monocytoid cells, but not in that from nonmonocytoid cells, suggesting that dATP-dependent CPP32 activation is at least partly involved in the preferential induction of apoptosis in monocytoid leukemia cells. The combination of dCF and dAd may be useful for the clinical treatment of acute monocytic leukemia. © 1998 by The American Society of Hematology.