Marco Foppoli

High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial

BACKGROUND Chemotherapy with high-dose methotrexate is the conventional approach to treat primary CNS lymphomas, but superiority of polychemotherapy compared with high-dose methotrexate alone is unproven. We assessed the effect of adding high-dose cytarabine to methotrexate in patients with newly diagnosed primary CNS lymphoma. METHODS This open, randomised, phase 2 trial was undertaken in 24 centres in six countries. 79 patients with non-Hodgkin lymphoma exclusively localised into the CNS, cranial nerves, or eyes, aged 18-75 years, and with Eastern Cooperative Oncology Group performance status of 3 or lower and measurable disease were centrally randomly assigned by computer to receive four courses of either methotrexate 3.5 g/m(2) on day 1 (n=40) or methotrexate 3.5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice a day on days 2-3 (n=39). Both regimens were administered every 3 weeks and were followed by whole-brain irradiation. The primary endpoint was complete remission rate after chemotherapy. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00210314. FINDINGS All randomly assigned participants were analysed. After chemotherapy, seven patients given methotrexate and 18 given methotrexate plus cytarabine achieved a complete remission, with a complete remission rate of 18% (95% CI 6-30) and 46% (31-61), respectively, (p=0.006). Nine patients receiving methotrexate and nine receiving methotrexate plus cytarabine achieved a partial response, with an overall response rate of 40% (25-55) and 69% (55-83), respectively, (p=0.009). Grade 3-4 haematological toxicity was more common in the methotrexate plus cytarabine group than in the methotrexate group (36 [92%] vs six [15%]). Four patients died of toxic effects (three vs one). INTERPRETATION In patients aged 75 years and younger with primary CNS lymphoma, the addition of high-dose cytarabine to high-dose methotrexate provides improved outcome with acceptable toxicity compared with high-dose methotrexate alone. FUNDING Swiss Cancer League.

Increased interleukin-10 serum levels in patients with solid tumours

In 40 out of 99 patients (40.4%) with solid tumours of different tissue, but the same stage (IV), elevated serum levels of interleukin-10 were observed. The mean levels of the cytokine in patients with malignant melanoma (24.3 ng/ml), pancreatic (6.8 ng/ml) or gastric (6.3 ng/ml) adenocarcinoma were significantly higher than in healthy subjects (3.4 ng/ml) or in patients with uterine fibroma (1.7 ng/ml). Patients with colon (6.8 ng/ml) and renal (5.7 ng/ml) carcinoma had similar values of interleukin-10 but did not significantly differ from controls. Interleukin-10 is known to suppress the functions of both T lymphocytes and macrophages, working as a general dampener of the immune and inflammatory responses. The observation of increased circulating levels of interleukin-10 in cancer patients may have important implications for future investigations, immunological monitoring and therapeutic intervention on neoplastic patients, and suggests a mechanism for tumour cells escaping from immune surveillance.

MATILDE regimen followed by radiotherapy is an active strategy against primary CNS lymphomas

The authors assessed MATILDE chemotherapy followed by response-tailored radiation therapy in 41 patients aged 70 years or younger with primary CNS lymphoma in a Phase II trial. With response rates of 76% after MATILDE and 83% after chemotherapy with or without radiation therapy, this was an active strategy, particularly in low- to intermediate-risk patients (International Extranodal Lymphoma Study Group [IELSG] score). Myelosuppression was the dose-limiting toxicity, with 9.5% of lethal complications. After a median follow-up of 49 months, a plateau in the survival curve (5-year overall survival: 41 ± 7%) was obtained.

Aberrant methylation in the promoter region of the reduced folate carrier gene is a potential mechanism of resistance to methotrexate in primary central nervous system lymphomas

We investigated the prevalence and prognostic role of CpG island methylation of the reduced folate carrier (RFC) gene promoter region in primary central nervous system lymphoma (PCNSL) in immunocompetent patients. Genomic DNA from 40 PCNSL was used for methylation‐specific polymerase chain reaction and bisulphite genomic sequencing of the RFC promoter region. Human immunodeficiency virus‐negative systemic diffuse large B‐cell lymphomas (DLBCL) were used as controls (n = 50). The impact on outcome of RFC promoter methylation was assessed in 37 PCNSL patients treated with high‐dose methotrexate (HD‐MTX)‐based chemotherapy ± radiotherapy. RFC promoter methylation occurred in 12 of 40 (30%) PCNSL and in four of 50 (8%) DLBCL (P = 0·01). Of 37 PCNSL treated with HD‐MTX‐based chemotherapy, methylation occurred in nine cases (24%, M‐PCNSL), while 28 cases (76%, U‐PCNSL) were negative. Three M‐PCNSL (33%) and 15 U‐PCNSL (54%) achieved complete remission (CR) after primary chemotherapy. Logistic regression confirmed the independent association between CR rate and International Extranodal Lymphoma Study Group score (P = 0·03), RFC promoter methylation (P = 0·07) and use of cytarabine (P = 0·08). The 3‐year failure‐free survival (FFS) and overall survival for M‐PCNSL and U‐PCNSL was 0% vs. 31 ± 9% (P = 0·34) and 0% vs. 31 ± 9% (P = 0·35) respectively. This is the first study to assess the methylation status of the RFC promoter in human tumour samples. RFC methylation is more common in PCNSL compared with systemic DLBCL, and is associated with a lower CR rate to HD‐MTX‐based chemotherapy. If confirmed in prospective trials on PCNSL treated with HD‐MTX alone, these data may suggest the necessity for alternative strategies in M‐PCNSL considering the increased risk of MTX resistance by tumour cells.

High Doses of Antimetabolites Followed by High-Dose Sequential Chemoimmunotherapy and Autologous Stem-Cell Transplantation in Patients With Systemic B-Cell Lymphoma and Secondary CNS Involvement: Final Results of a Multicenter Phase II Trial

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.

Risk-tailored CNS prophylaxis in a mono-institutional series of 200 patients with diffuse large B-cell lymphoma treated in the rituximab era.

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.

Salvage chemoimmunotherapy with rituximab, ifosfamide and etoposide (R‐IE regimen) in patients with primary CNS lymphoma relapsed or refractory to high‐dose methotrexate‐based chemotherapy

Despite a high proportion of patients with primary CNS lymphoma (PCNSL) experiences failure after/during first‐line treatment, a few studies focused on salvage therapy are available, often with disappointing results. Herein, we report feasibility and activity of a combination of rituximab, ifosfamide and etoposide (R‐IE regimen) in a multicentre series of patients with PCNSL relapsed or refractory to high‐dose methotrexate‐based chemotherapy. We considered consecutive HIV‐negative patients ≤75 years old with failed PCNSL treated with R‐IE regimen (rituximab 375 mg/m2, day 0; ifosfamide 2 g/m2/day, days1–3; etoposide 250 mg/m2, day 1; four courses). Twenty‐two patients (median age 60 years; range 39–72; male/female ratio: 1:4) received R‐IE as second‐line (n = 18) or third‐line (n = 4) treatment. Eleven patients had refractory PCNSL, and 11 had relapsing disease. Twelve patients had been previously irradiated. Sixty (68%) of the 88 planned courses were actually delivered; only one patient interrupted R‐IE because of toxicity. Grade 4 hematological toxicity was manageable; a single case of grade 4 non‐hematological toxicity (transient hepatotoxicity) was recorded. Response was complete in six patients and partial in three (overall response rate = 41%; 95%CI: 21–61%). Seven patients were successfully referred to autologous peripheral blood stem cell collection; four responders were consolidated with high‐dose chemotherapy supported by autologous stem cell transplant. At a median follow‐up of 24 months, eight responders did not experience relapse, two of them died of neurological impairment while in remission. Six patients are alive, with a 2‐year survival after relapse of 25 ± 9%. We concluded that R‐IE is a feasible and active combination for patients with relapsed/refractory PCNSL. This regimen allows stem cell collection and successful consolidation with high‐dose chemotherapy and autologous transplant. Copyright

Clinical relevance of the dose of cytarabine in the upfront treatment of primary CNS lymphomas with methotrexate-cytarabine combination

BACKGROUND The combination of high doses of methotrexate (MTX) and cytarabine (araC) is the standard chemotherapy for patients with primary CNS lymphoma (PCNSL). The addition of an alkylating agent could improve MTX-araC efficacy because it is active against quiescent G0 cells and increases antimetabolites cytotoxicity. A pilot experience with high doses of MTX, araC, and thiotepa (MAT regimen) was performed to investigate feasibility and efficacy of adding an alkylating agent. With respect to MTX-araC combination, araC dose was halved to minimize toxicity. Herein, we report tolerability, activity, and efficacy of MAT regimen and compare these results to those previously reported with MTX/ara-C combination. METHODS Twenty HIV-negative patients with PCNSL treated with MAT regimen and whole-brain irradiation and selected according to eligibility criteria of the International Extranodal Lymphoma Study Group (IELSG) #20 trial were analyzed. RESULTS Patient characteristics of MAT and MTX-araC series were similar. G4 hematologic toxicity was common after MAT chemotherapy, with dose reductions in 60% of patients, infections in 20%, G4 non-hematologic toxicity in 15%, and one (5%) toxic death. Response after chemotherapy was complete in four patients (clinical response rate, 20%; 95% confidence interval, 3%-37%) and partial in three (overall response rate, 35%; 95% confidence interval, 15%-55%). Fifteen patients experienced failure and 16 died (median follow-up, 26 months), with a 2-year overall survival of 24% ± 9%. CONCLUSIONS MAT and MTX-araC combinations showed similar tolerability, whereas araC dose reduction was associated with a remarkably lower efficacy, hiding any potential benefit of thiotepa. Four doses of araC 2 g/m(2) per course are recommended in patients with PCNSL.

Gamma-delta t-cell lymphomas

Gamma‐delta T‐cell lymphomas are aggressive and rare diseases originating from gamma‐delta lymphocytes. These cells, which naturally play a role in the innate, non‐specific immune response, develop from thymic precursor in the bone marrow, lack the major histocompatibility complex restrictions and can be divided into two subpopulations: Vdelta1, mostly represented in the intestine, and Vdelta2, prevalently located in the skin, tonsils and lymph nodes. Chronic immunosuppression such as in solid organ transplanted subjects and prolonged antigenic exposure are probably the strongest risk factors for the triggering of lymphomagenesis. Two entities are recognised by the 2008 WHO Classification: hepatosplenic gamma‐delta T‐cell lymphoma (HSGDTL) and primary cutaneous gamma‐delta T‐cell lymphoma (PCGDTL). The former is more common among young males, presenting with B symptoms, splenomegaly and thrombocytopenia, usually with the absence of nodal involvement. Natural behaviour of HSGDTL is characterised by low response rates, poor treatment tolerability, common early progression of disease and disappointing survival figures. PCGDTL accounts for <1% of all primary cutaneous lymphomas, occurring in adults with relevant comorbidities. Cutaneous lesions may vary, but its clinical behaviour is usually aggressive and long‐term survival is anecdotal. Available literature on gamma‐delta T‐cell lymphomas is fractioned, mostly consisting of case reports or small cumulative series. Therefore, clinical suspicion and diagnosis are usually delayed, and therapeutic management remains to be established. This review critically analyses available evidence on diagnosis, staging and behaviour of gamma‐delta T‐cell lymphomas, provides recommendations for therapeutic management in routine practice and discusses relevant unmet clinical needs for future studies.

Treatment approaches for primary CNS lymphomas

Importance of the field: Primary central nervous system lymphomas (PCNSL) are rare but potentially curable tumours. The overall outcome for PCNSL patients is unsatisfactory and several therapeutic questions remain open. Modest progress in outcome reflects difficulties in conducting randomized trials and scarce molecular and biological knowledge. Areas covered in this review: This review describes conventional and investigational treatments for PCNSL and focuses on the main questions for future clinical trials. PubMed and the authors’ own files were utilized for references search. The terms ‘PCNSL’, ‘primary AND CNS lymphoma’, and ‘CNS AND lymphoma’ were used for PubMed queries. All papers published in English before November 2009 were considered. What the reader will gain: This review illustrates how the paradigm for PCNSL treatment changed during the 1990s from radiotherapy alone to the establishment of high-dose methotrexate–cytarabine combination as standard approach. We present promising data from Phase II studies and discuss questions for randomized trials. Finally, we offer a 5-year scenario for the management of PCNSL. Take-home message: The methotrexate–cytarabine combination should currently be considered as the reference treatment for PCNSL. Well-designed randomized trials and biological studies deriving from the use of novel technologies will be crucial to further improve outcome in these patients.