Marta Bruno‐Ventre

PURPOSE: Treatment of secondary CNS dissemination in patients with aggressive lymphomas remains an important, unmet clinical need. Herein, we report the final results of a multicenter phase II trial addressing a new treatment for secondary CNS lymphoma based on encouraging experiences with high doses of antimetabolites in primary CNS lymphoma and with rituximab plus high-dose sequential chemoimmunotherapy (R-HDS) in relapsed aggressive lymphoma. PATIENTS AND METHODS: HIV-negative patients with aggressive B-cell lymphoma and secondary CNS involvement at diagnosis or relapse, age 18 to 70 years, and Eastern Cooperative Oncology Group performance status ≤ 3 were enrolled and treated with high-doses of methotrexate and cytarabine, followed by R-HDS (cyclophosphamide, cytarabine, and etoposide) supported by autologous stem-cell transplantation (ASCT). Treatment included eight doses of rituximab and four doses of intrathecal liposomal cytarabine. The primary end point was 2-year event-free survival; the planned accrual was 38 patients. RESULTS: Thirty-eight patients were enrolled; CNS disease was detected at presentation in 16 patients. Toxicity was usually hematologic and manageable, with grade 4 febrile neutropenia in 3% of delivered courses and grade 4 nonhematologic toxicity in 2% of delivered courses. Four patients died because of toxicity. Autologous stem cells were successfully collected in 24 (89%) of 27 patients (median, 10 × 10(6)/kg); 20 patients underwent ASCT. Complete response was achieved in 24 patients (complete response rate, 63%; 95% CI, 48% to 78%). At a median follow-up of 48 months, 17 patients remained relapse free, with a 2-year event-free survival rate of 50% ± 8%. At 5 years, 16 patients were alive, with a 5-year overall survival rate of 41% ± 8% for the whole series and 68% ± 11% for patients who received transplantation. Systemic (extra-CNS) and/or meningeal disease did not affect outcome. CONCLUSION: The combination of high doses of antimetabolites, R-HDS, and ASCT is feasible and effective in patients age 18 to 70 years old with secondary CNS lymphoma, and we propose it as a new standard therapeutic option.

The most effective strategy to prevent central nervous system (CNS) dissemination in diffuse large B-cell lymphoma (DLBCL) remains an important, unmet clinical need. Herein, we report a retrospective analysis of risk-tailored CNS prophylaxis in 200 human immunodeficiency virus-negative adults with DLBCL treated with rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or similar. High risk of CNS relapse was defined by involvement of specific extranodal organs, or simultaneous presence of advanced stage and high serum lactate dehydrogenase level; CNS prophylaxis with high-dose methotrexate ± intrathecal chemotherapy (IT) was routinely used in high-risk patients diagnosed after 2007. CNS relapse risk was low in 93 patients and high in 107; 40 high-risk patients received prophylaxis, which consisted of IT alone in 7. At a median follow-up of 60 months, one low-risk and nine high-risk patients (1% vs. 8%; P = 0·01) experienced CNS relapse. In the high-risk group, CNS relapses occurred in 8/67 (12%) patients who did not receive prophylaxis and in 1/40 (2·5%) patients who did; the latter occurred in a patient managed with IT alone. CNS relapse rate was 12% (9/74) for patients treated with "inadequate" prophylaxis (none or IT only) and 0% (0/33) for patients managed with intravenous prophylaxis (P = 0·03). In conclusion, high-dose methotrexate-based prophylaxis significantly reduces CNS failures in high-risk patients stratified by involvement of specific extranodal sites and International Prognostic Index.

'Multifocal bone lymphoma' or 'polyostotic lymphoma' is a neoplasm with exclusive multifocal involvement of the skeleton, without affecting lymph nodes or other soft tissues. Knowledge on this uncommon condition is limited because the related literature is sparse and fragmentary. We reviewed cases of multifocal bone diffuse large B-cell lymphoma (MB-DLBCL) registered in a clinico-pathological database of the International Extranodal Lymphoma Study Group that includes 499 cases of bone lymphoma. Clinical features, management and prognosis of 37 MB-DLBCL patients and 63 'controls' (stage-IV DLBCL and skeletal involvement) were analysed. Presentation and treatment of MB-DLBCL and controls were identical. At a median follow-up of 52 months (10-189), MB-DLBCL patients exhibited a significantly better response rate (92% vs. 65%; P = 0·002), progression-free survival (5-year: 56 ± 9% vs. 34 ± 6%; P = 0·003) and overall survival (5-year: 74 ± 8% vs. 36 ± 7%; P = 0·002). Among MB-DLBCL patients, the use of post-chemo radiotherapy was associated with better overall survival (5-year: 83 ± 12% vs. 55 ± 16%; P = 0·003). Two MB-DLBCL patients (5·4%) with spine and skull involvement experienced central nervous system (CNS) relapse. Thus, MB-DLBCL patients exhibit a significantly better prognosis compared to patients with advanced-stage DLBCL, and should be treated with conventional anthracycline-based chemotherapy, keeping intensified treatment for relapsing cases, considering involved-field radiotherapy, and CNS prophylaxis in high-risk patients.

The management of Hodgkin's lymphoma (HL) recurring after allogeneic stem cell transplantation is challenging. We retrospectively describe 18 adults treated with bendamustine followed by escalated donor lymphocyte infusion. Hematological toxicity was manageable (39% grade III to IV neutropenia and 28% grade III to IV thrombocytopenia). The overall response rate was 55%, with 3 complete and 7 partial responses. Median overall and progression-free survival were 11 (range, 1 to 52) and 6 (range, 1 to 28) months, respectively. One-year overall survival of responders (complete or partial) was 70% (95% confidence interval, 42% to 98%), although it was only 16% for nonresponders (n = 8). Our data show that bendamustine followed by donor lymphocyte infusion is feasible and can be efficacious as salvage treatment in HL relapsing after an allograft.

Indolent lymphomas primarily involving the skeleton (iPBL) represent < 1% of all primary bone lymphomas. The management and prognosis have not been previously described. Patients with primary and secondary iPBL were selected from an international database of 499 patients with a histopathological diagnosis of non-Hodgkin lymphoma and skeleton involvement, and clinical features, management and prognosis were analyzed. Twenty-six (5%) patients had an iPBL. Ten patients had small lymphocytic lymphoma, 10 had follicular lymphoma and six had lymphoplasmacytic lymphoma. Eleven patients had limited stage and 15 had advanced disease. The overall response rate was 73% (95% confidence interval [CI] = 57-89%). Median follow-up was 58 months, and the 5- and 10-year progression-free survival (PFS) rates were 37 ± 10% and 25 ± 12%, respectively. Nine patients are alive, with 5- and 10-year overall survival (OS) rates of 46 ± 10% and 29 ± 11%, respectively. Patients with small lymphocytic lymphoma showed significantly better outcome than patients with follicular lymphoma. Performance status and stage of disease were independently associated with OS. The prognosis of patients with primary bone lymphoplasmacytic or follicular lymphoma was less favorable.