The standard international prognostic index for predicting the risk of CNS involvement in DLBCL without specific prophylaxis.

Central nervous system (CNS) involvement is a serious complication in patients with diffuse large B-cell lymphoma (DLBCL) and evaluating CNS risk is an important issue. Using the standard international prognostic index (IPI) and CNS-IPI, a recently proposed model including IPI risk factors and adrenal/kidney involvement, we assessed CNS risk in 1220 untreated DLBCL patients who received R-CHOP without prophylaxis. According to the standard IPI, the cumulative incidences of CNS involvement at 2 years were 1.3, 4.6, 8.8, and 12.7% in the low-, low-intermediate-, high-intermediate-, and high-risk groups, respectively (p <.001). This result is comparable with that of the CNS-IPI. Patients with breast involvement tended to have lower risk according to the standard IPI but showed frequent CNS involvement, similar to patients with testis involvement. The standard IPI is also a useful predictor of CNS involvement. Patients with breast/testis involvement would be candidates for prophylaxis regardless of the standard IPI risk.

Central nervous system event in patients with diffuse large B-cell lymphoma in the rituximab era.

Central nervous system (CNS) events, including CNS relapse and progression to CNS, are known to be serious complications in the clinical course of patients with lymphoma. This study aimed to evaluate the risk of CNS events in patients with diffuse large B-cell lymphoma in the rituximab era. We performed a retrospective survey of Japanese patients diagnosed with diffuse large B-cell lymphoma who underwent primary therapy with R-CHOP chemoimmunotherapy between September 2003 and December 2006. Patients who had received any prophylactic CNS treatment were excluded. Clinical data from 1221 patients were collected from 47 institutions. The median age of patients was 64 years (range, 15-91 years). We noted 82 CNS events (6.7%) and the cumulative 5-year probability of CNS events was 8.4%. Patients with a CNS event demonstrated significantly worse overall survival (P < 0.001). The 2-year overall survival rate after a CNS event was 27.1%. In a multivariate analysis, involvement of breast (relative risk [RR] 10.5), adrenal gland (RR 4.6) and bone (RR 2.0) were identified as independent risk factors for CNS events. We conclude that patients with these risk factors, in addition to patients with testicular involvement in whom CNS prophylaxis has been already justified, are at high risk for CNS events in the rituximab era. The efficacy and manner of CNS prophylaxis in patients for each involvement site should be evaluated further.

Central nervous system involvement in intravascular large B-cell lymphoma: a retrospective analysis of 109 patients.

Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity with a high incidence of central nervous system (CNS) involvement at diagnosis. To evaluate CNS involvement, particularly recurrence including progression on therapy and relapse of IVLBCL, we retrospectively analyzed 109 patients with IVLBCL receiving chemotherapies with or without rituximab. In 82 patients (75%) without CNS involvement at initial diagnosis, risk of CNS recurrence at 3 years was 25% with a median follow-up in survivors of 39 months (range, 2-158 months). In 27 patients (25%) with CNS involvement at initial diagnosis, risk of CNS recurrence at 1 year was 25% with a median follow-up in survivors of 18 months (range, 10-77 months). Duration from diagnosis to CNS recurrence tended to be short in patients with CNS involvement at diagnosis. No significant difference in risk of CNS recurrence was found between patients receiving chemotherapies with or without rituximab. On multivariate analysis skin involvement at initial diagnosis was identified as a predictive factor for CNS recurrence in patients without CNS involvement at diagnosis (hazard ratio, 5.27; 95% confidence interval, 1.59-17.4; P = 0.007). Survival rate after CNS recurrence at 2 years was 12% in patients without CNS involvement at diagnosis. Central nervous system recurrence is a serious complication in IVLBCL patients and optimal strategies for CNS involvement should be established to obtain further improvements to clinical outcomes in the rituximab era.

Clinicopathological features of lymphoma/leukemia patients carrying both BCL2 and MYC translocations.

BACKGROUND: Lymphoid neoplasm with 18q21.3/BCL2 and 8q24/MYC translocation to immunoglobulin (IG) genes as dual-hit lymphoma/leukemia is very rare and known to have a poor clinical outcome. DESIGN AND METHODS: To clarify the clinicopathological characteristics of this malignancy, we analyzed 27 cases of cytogenetically proven dual-hit lymphoma/leukemia. RESULTS: Dual-hit lymphoma/leukemia was diagnosed at presentation in 22 cases and at relapse or disease progression in 5 cases. At the time of diagnosis of dual-hit lymphoma/leukemia, extranodal involvement was found in 25 cases (93%) and central nervous system involvement occurred in 15 cases (56%). The median survival and 1-year survival rate of the 27 cases were only 6 months and 22%, respectively, after diagnosis of the dual-hit lymphoma/leukemia. Seven cases of triple-hit lymphoma/leukemia (dual-hit lymphoma/leukemia with 3q27/BCL6 translocation) were included; the median survival of these patients was only 4 months from the diagnosis of the dual-hit lymphoma/leukemia. The duration of survival of the patients with a triple-hit malignancy was shorter than that of the other 20 cases of dual-hit lymphoma/leukemia (p=0.02). The translocation partner of MYC subdivided the dual-hit cases into two groups; 14 cases of IGH and 13 cases of IGK/L. The MIB-1 index was investigated in 14 cases with aggressive B-cell lymphoma, and was higher in the group with MYC-IGH translocation (n=7) than in the MYC-IGK/L group (n=7) (p=0.02). Overall survival was not different between the MYC-IGH translocation group (n=14) and the MYC-IGK or MYC-IGL translocation group (n=13). CONCLUSIONS: Dual-hit lymphoma/leukemia is a rare but distinct mature B-cell neoplasm with an extremely poor prognosis characterized by frequent extranodal involvement and central nervous system progression with either of the translocation partners of MYC.

A case of acquired aplastic anemia with repeated cerebral infarctions at the beginning of immunosuppressive therapy.

Acquired aplastic anemia is a rare hematopoietic stem-cell disorder that results in pancytopenia and hypocellular bone marrow. The pathophysiology is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated. Acquired aplastic anemia can now be cured or ameliorated by stem-cell transplantation or immunosuppressive drug therapy such as antithymocyte globulin or cyclosporine. We present a rare case report of a 68-year old patient with acquired severe aplastic anemia with repeated cerebral infarctions at the beginning of immunosuppressive therapy. He started immunosuppressive drug therapy with antithymocyte globulin and cyclosporine. During follow-up, magnetic resonance imaging revealed high signals at right thalamus and right pons by diffusion-weighted image. He was diagnosed with repeated cerebral infarctions of right thalamus and right pons. We successfully managed cerebral infarctions by frequent transfusions, edaravone administration, keeping the trough of serum cyclosporine (CsA) concentration around lower limit. This is the first report of successful management of acquired aplastic anemia with repeated cerebral infarctions.

Characterization of de novo diffuse large B-cell lymphoma with a translocation of c-myc and immunoglobulin genes.

The characteristics of de novo diffuse large B-cell lymphoma (DLBCL) with translocation of c-myc and immunoglobulin (Ig) genes (c-myc/Ig DLBCL), were investigated in 13 cases of c-myc/Ig DLBCL. Immunohistochemistry revealed five cases were positive for CD10 and BCL6 expression (CD10(+)/BCL6(+)), five cases of CD10(-)/BCL6(+)/MUM1(-), one case of CD10(-)/BCL6(+)/MUM1(+) and two cases of CD10(-)/BCL6(-)/MUM1(+) expression, indicating 10 cases of germinal center B-cell DLBCL and three cases of non-germinal center B-cell DLBCL. Ongoing mutation of the Ig heavy chain gene variable region (IgH-V) was found in two cases with CD10 and BCL6 expression and one case showing CD10(-)/BCL6(+)/MUM1(-) expression. These three cases of ongoing mutation of the IgH-V gene did not express BCL2, unlike those without ongoing mutation. These results suggest a heterogeneous immunophenotype and genotype for c-myc/Ig DLBCL, with CD10(-)/BCL6(+)/MUM1(-) cases the most frequent.

Retrospective analysis of intravascular large B-cell lymphoma treated with rituximab-containing chemotherapy as reported by the IVL study group in Japan.

PURPOSE: To evaluate the safety and efficacy of rituximab-containing chemotherapies for intravascular large B-cell lymphoma (IVLBCL). PATIENTS AND METHODS: We retrospectively analyzed 106 patients (59 men, 47 women) with IVLBCL who received chemotherapy either with rituximab (R-chemotherapy, n = 49) or without rituximab (chemotherapy, n = 57) between 1994 and 2007 in Japan. The median patient age was 67 years (range, 34 to 84 years). The International Prognostic Index was high-intermediate/high in 97% of patients. RESULTS: The complete response rate was higher for patients in the R-chemotherapy group (82%) than for those in the chemotherapy group (51%; P = .001). The median duration of follow-up for surviving patients was 18 months (range, 1 to 95 months). Progression-free survival (PFS) and overall survival (OS) rates at 2 years after diagnosis were significantly higher for patients in the R-chemotherapy group (PFS, 56%; OS, 66%) than for patients in the chemotherapy group (PFS, 27% with P = .001; OS, 46% with P = 0.01). Multivariate analysis revealed that the use of rituximab was favorably associated with PFS (hazard ratio [HR], 0.45; 95% CI, 0.25 to 0.80; P = .006) and OS (HR, 0.42; 95% CI, 0.21 to 0.85; P = .016). Treatment-related death was observed in three patients (6%) who received R-chemotherapy and in five patients (9%) who received chemotherapy. CONCLUSION: Our data suggest improved clinical outcomes for patients with IVLBCL in the rituximab era. Future prospective studies of rituximab-containing chemotherapies are warranted.

Phase II study of a salvage regimen using cyclophosphamide, high-dose cytarabine, dexamethasone, etoposide, and rituximab in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.

The management of relapsed or refractory B-cell non-Hodgkin's lymphoma (B-NHL) remains challenging. We investigated the efficacy and safety of salvage chemoimmunotherapy (CHASER) in patients with relapsed or refractory B-NHL who had radiographically measurable disease and adequate major organ function. The CHASER treatment consisted of: rituximab 375 mg/m(2), day 1; cyclophosphamide 1200 mg/m(2), day 3; cytarabine 2 g/m(2), days 4 and 5; etoposide 100 mg/m(2), days 3-5; and dexamethasone 40 mg, days 3-5. The treatment was repeated every 3 weeks up to a total of four courses in the absence of disease progression. Thirty-two patients were enrolled and received a median of four courses of treatment (range 1-4 courses) per patient. Twenty patients (63%) were previously treated with rituximab-containing regimens. The median age was 54 years (range 28-67 years). The treatment was generally well tolerated, with major toxicities being grade 4 neutropenia (n = 32), thrombocytopenia requiring transfusion (n = 28), and grade 3 transaminase elevation (n = 2). Overall response rates in the entire group, and in patients with indolent (n = 17) and aggressive (n = 15) diseases were 84%, 100% and 67%, respectively. Responses were observed similarly in patients with (n = 20) and without (n = 12) previous rituximab exposure (85% and 83%, respectively). Stem cell harvest was successful in 19 of 22 patients. The median time to treatment failure for the entire group was 24.5 months. This promising result of high activity and favorable toxicity profile warrants further investigation in large-scale multicenter trials.

Prognostic significance of FLT3 internal tandem duplication and NPM1 mutations in acute myeloid leukemia in an unselected patient population.

Mutations in the fms-like tyrosine kinase 3 (FLT3) gene containing an internal tandem duplication (FLT3/ITD) or mutations in the nucleophosmin 1 gene (NPM1) are thought to be prognostic indicators in acute myeloid leukemia (AML). Previous studies suggested that FLT3/ITD mutation indicates a poor prognosis and that NPM1 mutation indicates a more favorable one, but these studies were often performed with selected patient populations. We investigated the clinical significance of these mutations at our institution with an unselected group of patients with newly diagnosed AML. This group included patients > or =60 years old and those with a poor performance status. Using polymerase chain reaction and sequencing analyses, we detected FLT3/ITD mutations in 12 patients (20.0%) and NPM1 mutations in 7 patients (11.7%) among a group of 60 patients. There was a nonsignificant trend for FLT3/ITD mutation to be associated with a poorer predicted overall survival (OS) probability in this population. In contrast, OS was significantly higher in patients with wild-type NPM1 than in patients with NPM1 mutation, both for all AML patients and for AML patients with a normal karyotype. In this general and unselected AML patient population, NPM1 mutation was not a prognostic indicator of a favorable outcome.

[Measurement of rituximab concentration in the cerebrospinal fluid in CNS lymphoma].

We measured rituximab concentrations in the cerebrospinal fluid (CSF) in 2 patients with diffuse large B-cell lymphoma in whom central nervous system (CNS) invasion had developed. They received rituximab intravenously following irradiation therapy (patient no.1) or along with chemotherapy (patient no.2). The rituximab concentrations in the CSF were considered to be very low (0.2-0.6 microg/ml), and could not be increased significantly by serial intravenous administrations of rituximab. The lymphoma relapsed in patient no.1, and the combined therapy was not effective in patient no.2. An alternative approach such as intrathecal administration of rituximab could be anticipated as a new therapeutic strategy for CNS lymphoma.