Masami Hirano

Effect of granulocyte colony-stimulating factor after intensive induction therapy in relapsed or refractory acute leukemia.

Background. Although colony-stimulating factors have been shown to accelerate recovery from severe neutropenia after intensive chemotherapy or bone marrow transplantation, their use in acute leukemia has been controversial because in vitro they stimulate leukemic colonies as well as normal granulocyte colonies. Methods. We conducted a prospective, randomized, controlled study to determine the safety and efficacy of recombinant human granulocyte colony-stimulating factor (CSF) after a standard course of intensive therapy in 108 patients with relapsed or refractory acute leukemia (67 with acute myelogenous leukemia, 30 with acute lymphocytic leukemia, 9 in blast crisis from chronic myelogenous leukemia, and 2 with acute leukemia arising from myelodysplastic syndromes). Treatment with granulocyte CSF (200 micrograms per square meter of body-surface area per day in a 30-minute infusion) was begun two days after the end of the chemotherapy and continued until the neutrophil count rose above 1500 per cubic millimeter. Results. Treatment with granulocyte CSF accelerated the recovery of neutrophils significantly (P less than 0.01), shortening it by about a week, but it had no effect on platelet recovery. Although the incidence of febrile episodes was almost the same, documented infections were significantly less frequent in the group treated with granulocyte CSF (P = 0.028). There was no evidence that granulocyte CSF accelerated the regrowth of leukemic cells. Fifty percent of 48 patients in the CSF group who could be evaluated and 36 percent of 50 controls had complete remission. The rate of relapse was almost the same in the two groups. Conclusions. It appears that recombinant human granulocyte CSF is safe in acute leukemia, accelerating neutrophil recovery and thereby reducing the incidence of documented infection without affecting the regrowth of leukemic cells. It should be used with caution, however, pending further confirmation of these early results.

Clinical features and prognosis of de novo diffuse large B-cell lymphoma with t(14;18) and 8q24 /c-MYC translocations

Diffuse large B-cell lymphoma (DLBCL) having both t(14;18) and 8q24 translocations is rare. We evaluated the clinical characteristics and prognoses of patients with DLBCL carrying both t(14;18) and 8q24 translocations. A total of 1972 patients with non-Hodgkins lymphoma were treated in the Adult Lymphoma Treatment Study Group (ALTSG) from 1998 to 2007. Nineteen cases of de novo DLBCL with the dual translocation were identified. The dual translocation was observed in 19 of 394 patients with DLBCL (10 males and 9 females, with a median age of 61 years). The dual translocation was observed significantly more frequently among patients with high lactate dehydrogenase levels, B symptoms, bone marrow involvement and advanced stage. Immunophenotyping was performed and showed DLBCL with a germinal center type in the majority of cases. Progression-free survival and overall survival rates were significantly lower in patients with the dual translocation than in those with other translocation. DLBCL patients with concurrent t(14;18) and 8q24 translocations have very poor prognosis. Even if patients had a complete response to chemotherapy, they subsequently suffered early relapse. In this study, only a few patients received rituximab, and its usefulness could not be assessed. Future studies with larger numbers of patients are required.

De novo CD5+ diffuse large B-cell lymphoma: results of a detailed clinicopathological review in 120 patients

Diffuse large B-cell lymphoma (DLBCL) constitutes the largest category of aggressive lymphomas, and is considered to have heterogeneous biological properties. De novo CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a distinct entity. This study reveals the morphological spectrum of CD5+ DLBCL, shows that the incidence of central nervous system recurrence in this form of lymphoma in high, and confirms that CD5+ DLBCL frequently expresses BCL2 protein. Background De novo CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is clinicopathologically and genetically distinct from CD5-negative (CD5−) DLBCL and mantle cell lymphoma. The aim of this retrospective study was to clarify the histopathological spectrum and obtain new information on the therapeutic implications of CD5+ DLBCL. Design and Method From 1984 to 2002, 120 patients with CD5+ DLBCL were selected from 13 collaborating institutes. We analyzed the relationship between their morphological features and long-term survival. The current series includes 101 patients described in our previous study. Results Four morphological variants were identified: common (monomorphic) (n=91), giant cell-rich (n=13), polymorphic (n=14), and immunoblastic (n=2). Intravascular or sinusoidal infiltration was seen in 38% of the cases. BCL2 protein expression in CD5+ DLBCL was more frequent than in CD5− DLBCL (p=0.0003). Immunohistochemical analysis in 44 consecutive cases of CD5+ DLBCL revealed that 82% of these cases (36/44) were non-germinal center B-cell type DLBCL. The 5-year overall survival rate of the patients with CD5+ DLBCL was 38% after a median observation time of 81 months. Patients with the common variant showed a better prognosis than those with the other three variants (p=0.011), and this was confirmed on multivariate analysis. Overall, 16 patients (13%) developed central nervous system recurrence. Conclusions Our study revealed the morphological spectrum of CD5+ DLBCL, found that the incidence of central nervous system recurrence in this form of lymphoma in high, confirmed that CD5+ DLBCL frequently expresses BCL2 protein and showed that it is mainly included in the non-germinal center B-cell type of DLBCL.

Simultaneous elevation of the serum concentrations of vascular endothelial growth factor and interleukin‐6 as independent predictors of prognosis in aggressive non‐Hodgkin's lymphoma

Abstract: Therapeutic approaches for non‐Hodgkins lymphoma (NHL) are currently based on the International Prognostic Index (IPI). Research on biological prognostic factors has been actively pursued in recent years, with serum vascular endothelial growth factor (VEGF) and interleukin‐6 (IL‐6) being identified as prognostic factors for NHL. Here, we determined that serum VEGF and IL‐6 levels are independent prognostic factors for aggressive lymphoma. Compared with normal controls, serum VEGF and IL‐6 levels were significantly higher in patients with aggressive lymphoma or adult T‐cell leukemia/lymphoma. Furthermore, overall and disease‐free survival rates for patients with high levels of VEGF or IL‐6 were significantly poorer than for patients with low levels. In addition, the prognosis for patients with high levels of both serum VEGF and IL‐6 was significantly poorer than that for patients with high levels of either VEGF or IL‐6 or with low levels of both VEGF and IL‐6. Multivariate analyses of a variety of prognostic factors, including the five IPI factors, revealed that serum VEGF and IL‐6 were both independent prognostic factors for overall survival of aggressive lymphoma. Therefore, a combination of VEGF and IL‐6 represents a useful prognostic factor for aggressive lymphoma.

Clinical significance of 8q24/c‐MYC translocation in diffuse large B‐cell lymphoma

Diffuse large B‐cell lymphoma (DLBCL) has heterogeneous clinical, histological, and molecular features. We evaluated the clinical characteristics and prognoses of patients with DLBCL carrying 8q24 translocations. A total of 1864 consecutive patients with non‐Hodgkins lymphoma were treated in the Adult Lymphoma Treatment Study Group from 1998 to 2005. Of the 252 patients with DLBCL with abnormal karyotypes, 28 patients with DLBCL with the 8q24 translocation were identified. There were 14 men and 14 women, with a median age of 61 years. The 8q24 translocation was observed significantly more frequently among patients with poor performance status, among patients with high lactate dehydrogenase level, and among patients with bone marrow involvement. The 5‐year overall survival was 43.9% among the patients with 8q24 translocation, and 67% among the patients with other chromosomal abnormalities. The 8q24 translocation group showed significantly poorer prognosis than the group with other translocations. In addition, patients with t(14;18) and 8q24 translocation showed significantly poorer prognosis than those with 8q24 translocation alone. It will be necessary to study whether more aggressive chemotherapy or rituximab combination chemotherapy is effective in 8q24 translocation cases. (Cancer Sci 2009; 100: 233–237)

Clinicopathologic correlations of diffuse large B-cell lymphoma in rheumatoid arthritis patients treated with methotrexate

Among methotrexate (MTX)‐related lymphoproliferative disorders (MTX‐LPD), diffuse large B‐cell lymphoma (DLBCL) accounts for about half. We studied the clinicopathological characteristics and prognosis of patients with DLBCL in MTX‐LPD. This study included 29 patients who developed DLBCL after receiving MTX for rheumatoid arthritis. MTX was discontinued in all patients. Their median age was 62 years. Elevated lactate dehydrogenase (LDH) level was observed in 97% of the patients, bone marrow involvement in 17%, and involvement of extranodal sites in 41%. As for the cellular immunophenotype, CD20 was positive in 93%, CD5 in 3%, CD10 in 31%, BCL2 in 21%, BCL6 in 69%, and Epstein–Barr virus (EBV)‐encoded small non‐polyadenylated RNA (EBER) in 24%. Chemotherapy was started within 2 months after MTX withdrawal in 23 patients, of whom 12 patients received combination with rituximab. Spontaneous remission occurred in the remaining six patients. The EEBV‐positive rate was 67% (4/6), and the four EBV‐positive patients achieved complete response. Among the 23 DLBCL patients treated with chemotherapy, 20 patients achieved complete response. The 5‐year overall survival was 74% and the 5‐year progression‐free survival was 65%. After the development of DLBCL, withdrawal of MTX was the first choice of treatment. Germinal center B‐cell type and EBER‐positive patients tended to show spontaneous remission. The utility of rituximab should be examined in future studies.

Treatment of adult T‐cell leukemia/lymphoma with MST‐16, a new oral antitumor drug and a derivative of bis(2,6‐dioxopiperazine)

Background. MST‐16, a new orally administered bis(2,6‐dioxopiperazine) analogue and an inhibitor of topoisomerase II, was given to 24 patients with adult T‐cell leukemia‐lymphoma (ATLL) in a Phase I‐II multiinstitutional cooperative study.

The HOX complex neighbored by the EVX gene, as well as two other homeobox-containing genes, the GBX-class and the EN-class, are located on the same chromosomes 2 and 7 in humans

Two newly identified human homeobox‐containing genes, GBX1 and GBX2, are closely related genes, as are members of the other homeobox genes, EN‐1 and EN‐2. GBX1 and EN‐2 have been mapped to chromosome 7q36. The present study shows that GBX2 was mapped to chromosome 2q37. EN‐1 was mapped to chromosome 2q14. Moreover, two HOX complexes neighbored by the EVX gene, HOXA and HOXD, are located at chromosome 7p15‐p14 and 2q31‐q37, respectively. Thus, it is possible that these homeobox genes were linked to each other on an ancestral genome and that the ancestral chromosome segment was duplicated during evolution.

Phase I Study of Rituximab-CHOP Regimen in Combination with Granulocyte Colony-Stimulating Factor in Patients with Follicular Lymphoma

Purpose: Rituximab is an anti-CD20 monoclonal antibody, and it is used to treat B-cell lymphomas. Antibody-dependent cellular cytotoxicity (ADCC) is considered one of the mechanisms through which rituximab exerts its effects. Granulocyte colony-stimulating factor (G-CSF) enhances the cytotoxicity of neutrophils through ADCC, and it can be speculated that a combination of rituximab and G-CSF may augment the treatment efficacy of rituximab. Experimental Design: We administered rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) treatment with G-CSF to 15 patients with follicular lymphoma, and we investigated the safety and efficacy of this regimen. We investigated ADCC activity in neutrophils and the expression of cell surface antigens including Fcγ receptor type I [FcγRI (CD64)] on neutrophils to determine the optimal dose of G-CSF. Results: Adverse reactions occurred in 14 of 15 patients and consisted mainly of grade 3/4 hematological toxicity. The response rate was 100%, with complete remission in 12 patients (80%) and partial remission in 3 patients (20%). At 14 months, the median length of the observation period, 2 of 12 patients had relapsed. G-CSF administration increased both FcγRI expression and ADCC activity. There were no significant differences in the levels of FcγRI expression or ADCC activity between the 2 μg/kg G-CSF and 5 μg/kg G-CSF groups, indicating that the optimal dose of G-CSF was 2 μg/kg. Conclusions: We conclude that the combination of rituximab-CHOP and G-CSF is well tolerated. We plan to carry out a randomized trial to compare efficacy between rituximab-CHOP treatment and treatment with a combination of rituximab-CHOP and G-CSF.

Clinicopathologic characteristics and treatment outcome of the addition of rituximab to chemotherapy for CD5-positive in comparison with CD5-negative diffuse large B-cell lymphoma

BACKGROUND CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) comprises ∼10% of DLBCLs, and it is associated with poor prognosis. The clinicopathologic characteristics and prognosis of CD5-negative (CD5-) DLBCL and CD5+ DLBCL were compared. PATIENTS AND METHODS The subjects were 607 DLBCL patients in whom cell surface markers could be analyzed, among 930 consecutive patients registered in the Adult Lymphoma Treatment Study Group between 1998 and 2008. RESULTS In all, 102 patients (16.8%) had CD5+ DLBCL. Compared with CD5- DLBCL, CD5+ DLBCL was more closely associated with elevated serum lactate dehydrogenase level, advanced stage, poor performance status, extranodal sites, CD10-, BCL-2+, MUM1+, and nongerminal center B-cell type. The 5-year overall survival (OS) rates of CD5+ DLBCL (n = 102) and CD5- DLBCL (n = 505) were 55% and 65%, respectively (P = 0.032), with 5-year progression-free survival (PFS) rates of 52% and 61%, respectively (P = 0.041). In the CD5+ DLBCL patients, the addition of rituximab to chemotherapy significantly improved PFS (4-year PFS, 47.4% versus 62.5%), but not OS (4-year OS, 57.8% versus 63.5%). CONCLUSIONS For CD5+ DLBCL, the addition of rituximab to chemotherapy significantly improved the PFS, but not OS. Therefore, it is thought that a new treatment strategy is necessary for CD5+ DLBCL.