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

Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan, Italy.
The Lancet (Impact Factor: 39.21). 09/2009; 374(9700):1512-20. DOI: 10.1016/S0140-6736(09)61416-1
Source: PubMed

ABSTRACT 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.
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, number NCT00210314.
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).
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.
Swiss Cancer League.

  • [Show abstract] [Hide abstract]
    ABSTRACT: High-dose methotrexate-based chemotherapy is the mainstay of treatment for primary central nervous system lymphoma (PCNSL), but relapses remain frequent. High-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) may provide an alternative to address chemoresistance and overcome the blood-brain barrier. In this single-center phase II study, newly-diagnosed PCNSL patients received 5-7 cycles of chemotherapy with rituximab, methotrexate (3.5g/m(2)), procarbazine and vincristine (R-MPV). Those with a complete or partial response proceeded with consolidation HDC with thiotepa, cyclophosphamide and busulfan (TBC), followed by ASCT and no radiotherapy. Primary endpoint was 1-year progression-free survival (PFS), N=32. The median age was 57; median KPS was 80. Following R-MPV, objective response rate was 97% and 26 (81%) patients proceeded with HDC-ASCT. Among all patients, median PFS and overall survival (OS) were not reached (median follow-up: 45 months). The 2-year PFS was 79% (95%CI 58-90), with no events observed beyond two years. The 2y-OS was 81% (95%CI 63-91). In transplanted patients, the 2-year PFS and OS were 81%. There were three treatment-related deaths. Prospective neuropsychological evaluations suggested relatively stable cognitive functions post-transplant. In conclusion, this treatment was associated with excellent disease control and survival, with an acceptable toxicity profile and no evidence of neurotoxicity thus far. This trial is registered to as NCT00596154. Copyright © 2015 American Society of Hematology.
    Blood 01/2015; DOI:10.1182/blood-2014-10-604561 · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Nordic Lymphoma Group has conducted a phase ll trial in primary central nervous system lymphoma patients applying age-adjusted multi-agent immunochemotherapy regimen, which in elderly patients included temozolomide maintenance treatment. Design and Methods: Patients with newly diagnosed PCNSL aged 18-75 years were eligible. Sixty-six patients (median age 64 years) were enrolled. Two age groups were predefined as those of 18-65 and 66-75 years of age. Results: The overall response rate was 90.8 %. With a median follow-up of 22 months, the 2-year overall survival probability was 60.7 % in patients < 65 years and 55.6% in patients > 65 years (p= 0.40). The estimated progression-free survival at 2 years was 33.1% (CI: 19.1%-47.9%) in patients < 65 years and 44.4% (CI: 25.6%-61.8%) in the elderly subgroup (p=0.74). Median duration of response was 10 months in the younger, not reached in the elderly patients (p=0.33). Four patients aged 64-75 years (6 %) died from treatment related complications. Conclusion: Survival in the two age groups was similar despite a de-escalation of induction treatment in patients > 65 years. Duration of response in elderly patients receiving maintenance temozolomide was longer than in the younger age subgroup. While toxicity during induction is still of concern especially in the elderly patients we conclude from these data that de-escalation of induction therapy in elderly PCNSL patients followed by maintenance treatment seems to be a promising treatment strategy. Trial registration: number NCT01458730. Copyright © 2014, Ferrata Storti Foundation.
    Haematologica 12/2014; DOI:10.3324/haematol.2014.108472 · 5.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Adult T-cell leukemia/lymphoma (ATLL) is a T-cell neoplasm, associated with infection by the retrovirus human T-lymphotropic virus type 1 (HTLV-1). Central nervous system (CNS) involved by ATLL is often occurred in advanced disease, such as acute and lymphomatous variants. On the other hand, isolated CNS lymphoma is rare. We repot a 50-year-old woman who presented with multiple infiltrative brain lesions on the magnetic resonance (MR) imaging. Results of initial biopsy of brain tumor indicated CNS vasculitis. The patient received one course of high-dose methotrexate and MR imaging of brain revealed remission of infiltrative lesions. Two years later, new brain lesions were detected. Histopathologic examination of specimens via craniotomy revealed T-cell lymphoma. The patient responded poorly to subsequent chemotherapy, and salvage whole-brain irradiation was performed. Six months later, the patient had hepatosplenomegaly, hypercalcemia, and multiple lymphocytes with a cloverleaf appearance in circulation. Results of flow cytometry analysis of peripheral blood indicated ATLL and antibodies to human T-lymphotropic virus type 1 (HTLV-1) were detected. Clinicians should screen HTLV-1 infection when patients are diagnosed with peripheral T-cell lymphoma. Combined antiviral therapy and intensive chemotherapy may improve the outcomes of ATLL.