Primary CNS Lymphoma - High-Dose-Chemotherapy with Autologous PBSCT and Hyperfractionated Radiotherapy as First-Line-Therapy - Results of a Multicenter Phase II Study.

Abstract

Primary NHL of the CNS (PCNSL) carries a poor prognosis despite initial response to steroids and radiotherapy (RT). Addition of methotrexate (MTX) to RT has improved the prognosis of patients (pts) with PCNSL, but a significant proportion of patients are still not cured. To improve relapse free survival and to reduce neurotoxicity we initiated a multicenter phase II study with early dose intensified chemotherapy (CT) and PBSCT followed by hyperfractionated whole-brain radiation (WBRT) for pts aged under 65yrs. The use of high-dose (HD) lipophilic blood-brain-barrier-penetrating agents (BCNU, Thiotepa) in addition to maximum doses of water-soluble agents (MTX, AraC) is a novel approach in the treatment of PCNSL. To reduce the risk of delayed neurotoxicity, intrathecal chemotherapy was completely avoided and CT was administered before RT. Induction treatment included 3 repetitive cycles of HD-MTX (8g/m2). AraC (2x 3g/m2) and thiotepa (40mg/m2) followed by rG-CSF were used for stem-cell-mobilisation. The conditioning regimen included BCNU (400mg/m2) and thiotepa (2x5mg/kgBW) prior PBSCT. Additional hyperfractionated WBRT (45 Gy, 2x1Gy/d) was administered as consolidation. From 1999 to 2003 thirty pts (age under 65y) have been enrolled in the study (median age 54, range 30–64y). 21 of 30 pts responded to HD-MTX (6 CR, 15 PR). 22/30 pts received high dose CT and autologous PBSCT according to the protocol. Four pts refractory to MTX proceeded to RT directly and 1 patient died from PD subsequently. One patient died because of treatment-related liver toxicity after High-Dose MTX. Beside cytopenia no severe acute toxicities [WHO Grade 3 or 4] were observed after high-dose chemotherapy. After intention-to-treat analysis the response-rate was 89%. All patients that completed the protocol obtained CR (22/22). Three of these pts died, two died during follow-up due to relapse after 1 or 5 years respectively, the third patient died after 25 mo due to progressive heart failure. With a median follow-up of 42 months (range 3–84 mo) the overall survival of all pts included and pts that fulfilled the protocol is 71,3% and 86,5%, respectively. We conclude that sequential systemic application of high-dose differential acting cytostatic agents with consolidating hyperfractionated radiotherapy is very effective and well tolerable. In a new multicenter phase II study, pts will be treated with more intensive high dose CT and PBSCT omitting consolidating radiotherapy.