New approaches in primary central nervous system lymphoma

Abstract

Primary central nervous system lymphoma (PCNSL) has long been associated with an inferior prognosis compared to other aggressive non-Hodgkin's lymphomas (NHLs). However, during the past 10 years an accumulation of clinical experience has demonstrated that long-term progression-free survival (PFS) can be attained in a major proportion of PCNSL patients who receive dose-intensive consolidation chemotherapy and avoid whole brain radiotherapy. One recent approach that has reproducibly demonstrated efficacy for newly diagnosed PCNSL patients is an immunochemotherapy combination regimen used during induction that consists of methotrexate, temozolomide, and rituximab followed by consolidative infusional etoposide plus high-dose cytarabine (EA), administered in first complete remission (CR). Other high-dose chemotherapy-based consolidative regimens have shown efficacy as well. Our goal in this review is to update principles of diagnosis and management as well as data regarding the molecular pathogenesis of PCNSL, information that may constitute a basis for development of more effective therapies required to make additional advances in this phenotype of aggressive NHL.

Keywords: Non-Hodgkin’s lymphoma (NHL); brain tumors; immunotherapy.

Figure 1

BCL6 expression is associated with shorter progression-free and overall survival in PCNSL patients treated in the CALGB 50202 study. (A) Strong nuclear BCL6 expression in a PCNSL case from patient treated on study (40× magnification); (B) high BCL6 expression (60% of lymphoma nuclei) was associated with shorter progression-free survival (P<0.016). High BCL6 was also associated with shorter overall survival (P<0.009).

Figure 2

Oncogenic survival signaling components in PCNSL. Activation of the TLR/MYD88 pathway may directly contribute to pro-survival signaling directly via NFkB as well as via the enhanced production of IL-10 which itself contributes to survival signals via the JAK/STAT pathway. GPCR, G protein-coupled receptor.

Figure 3

Outcomes with intensive chemotherapy and immunotherapy in newly-diagnosed PCNSL, without WBRT: CALGB (Alliance) 50202. (A) Outcome for all 50,202 patients; y-axis refers to probability of event, PFS for all patients, the 2-year PFS was 59%; (B) PFS for patients who attained a complete response with MT-R induction and received EA consolidation (n=27); (C) PFS was similar for patients age >60 (n=23) and for younger patients (n=21; P=0.48); (D) there was a trend between shorter PFS and highest IELSG risk score of 4–5 (P=0.16). PFS, progression-free survival. Reprinted with permission from (12).

Figure 4

Treatment of lymphomatous meningitis with intraventricular rituximab. Example of brain parenchymal response in a patient with refractory CNS lymphoma who was treated with intraventricular rituximab at the 25 mg dose level in combination with intrathecal methotrexate (12 mg). (A) and (C) are baseline; (B) and (D) are after 4 weeks of intraventricular therapy. Reprinted with permission from (109).