Sequential High Dose Immuno-Chemotherapy Followed by Autologous Peripheral Blood Stem Cell Transplantation for Patients with Untreated Primary Central Nervous System Lymphoma - a Multicentre Study by the Collaborative PCNSL Study Group Freiburg

Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin′s lymphoma with poor prognosis. Addition of methotrexate (MTX) to whole brain radiotherapy (WBRT) has improved the prognosis of patients (pts) with PCNSL, but a significant proportion are still not cured. Preliminary reports suggested that dose-intensified chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) are highly effective in the treatment of newly-diagnosed PCNSL in younger pts. To strengthen the evidence of this approach, we initiated a prospective multicenter phase II study with early HDT and ASCT to investigate efficacy, safety and survival. This trial is registered at ClinicalTrials.gov (NCT 00647049).

Immunocompetent pts <65 years with untreated biopsy proven PCNSL were eligible. Induction treatment consisted of 4 repetitive cycles of MTX (8g/m²) and 2 cycles cytarabine (2×3g/m²) and thiotepa (TT, 40mg/m²). Rituximab (375mg/m²) was added by amendmend after 2 included patients; it was given on day −7 before induction treatment and before each chemotherapy cycle. After the 2nd cycle cytarabine/TT stem-cells were collected after mobilisation with rG-CSF. The HDT regimen included carmustine (400mg/m²) and TT (4×5mg/kgBW) prior ASCT. Primary endpoint was complete remission (CR) 30 days after ASCT. Secondary end-points were overall-survival (OS), duration of response and toxicity. Patients not in complete remission after HDT and ASCT received WBRT.

From 2007 to 2011 79 pts (44 female, 35 male) were enrolled from 18 German centers and evaluable for analysis (median age 55 years, range 20–66). Seventy eight pts had aggressive B-cell lymphomas and one T-cell-lymphoma. Median Karnofsky performance status at diagnosis was 90% (range 30–100). After induction treatment, 73 of 76 (96%) evaluable pts responded, (26,9% CR, 55,7 PR). Seventy-three pts (96%) received HDT and ASCT according to protocol. Six pts were treated off-protocol due to low performance status (n=1), progressive disease (n=1) and infectious complications (n=4). Regarding the primary endpoint, CR was achieved in 77% and partial remission (PR) in 14% of patients (overall response rate 91%) after HDT and ASCT. Ten pts in PR after HDT and ASCT received consolidating WBRT. After a median follow-up of 28.8 months (range 1–63 mo) 1 and 2 years OS was 92% and 87%, respectively. Myelotoxicity was the most frequent CTC grade 3–4 toxicity with grade 3–4 infections in 41/73 pts (56,2%) during the transplant-phase. Two patients had lethal infectious complications during induction treatment with cytarabine/TT, three further pts died after HDT and ASCT due to severe infection (n=1), renal failure (n=1) and pneumonitis (n=1). Further results will be presented.

Sequential MTX-based immuno-chemotherapy followed by carmustine/TT containing HDT and ASCT is highly effective and feasible in younger patients. Treatment related toxicity is of concern and comparable to non-high-dose protocols. Further randomised trials to compare HDT with conventional CT are needed.

Illerhaus:Riemser: Honoraria.