Autologous Stem Cell Transplantation (ASCT) As Upfront Treatment in Primary Central Nervous System Lymphoma (PCNSL): A Systematic Review and Comparative Analysis in Clinical Trials Setting
Authors: Kerbauy Mariana Nassif , de Moraes Fabio Ynoe , Kerbauy Lucila Nassif , Esteves Iracema , Perini Guilherme Fleury , Santos Fabio Pires de Souza , Ribeiro Andreza Alice Feitosa , Kerbauy Fabio Rodrigues , Hamerschlak Nelson 
Published: October 2019

Abstract
Purpose PCNSL standard treatment encompass 2 phases: induction and consolidation. Induction consists of high-dose methotrexate-based polychemotherapy for most patients and consolidation is still to be defined. ASCT is an effective treatment and despite the advancements in this technique for other disease sites, its role in PCNSL remains unclear. This systematic review aims to evaluate toxicity and outcomes of ASCT as upfront treatment in PNCSL.
Material and Methods In accordance to PRISMA guidelines, a systematic review of the literature was conducted on studies reporting ASCT in PCNSL. EMBASE, MEDLINE and Cochrane databases were systematically searched for relevant studies until May 2016. All clinical trials (CT) evaluating the role of ASCT as up front treatment for PCNSL (excluding recurrence or salvage) were included. Studies were classified into 2 groups for statistical analysis: (1) Regimens containing thiotepa (either on induction or intensification regimen or conditioning regimen; (2) Regimens without thiotepa. Dichotomous outcomes were summarized as risk ratios (RRs). The size effect of the intervention for time-to-event outcomes was calculated by the pooled hazard ratio (HR), followed by the confidence interval (CI) of 95%. For determining derivative of expected events, the Z-Score for two-tailed p-value was calculated based on relative risk of each study.
Results From 1803 references, 7 articles (6 phase 2; 1 pilot trial) from 2006 to 2016 were selected, comprising a total of 181 patients. For up front treatment of PCNSL with ASCT regimens containing thiotepa plus or minus WBRT: total of 128 patients were identified in 5 studies. Patient's median age was 54,5 (range, 54 to 57), KPS ranged from 70 to 90, WBRT was allowed in 3 studies and a median of 81% of the patients completes the ASCT protocol. Median complete response rate (CRR) was 69% (range, 54 to 81%), 2-years progression free survival (2PFS) 69% (range, 54 to 81%) and 2-years overall survival (2OS) 84% ranging from 83 to 91% in a median follow-up time of 15 to 63 months. Median neurotoxicity rates (NR) and treatment related mortality (TRM) were 3% (0 to 33%) and 3% (0 to 13%), respectively. (2) Up front ASCT regimens without thiotepa plus or minus WBRT: total of 53 patients were identified in 2 studies. Patient's median age was 52,5 (range, 52 to 53), KPS ranged from 70 to 80, WBRT was allowed in 1 study and a median of 59% of the patients completes the ASCT protocol. Median CRR was 31% (range, 18 to 44%), 2PFS 44% (range, 25 to 62%), 2OS of 65% ranging from 60 to 70% in a median follow-up time of 28 to 34 months. Median NR and TRM were 4% (0 to 8%) and 4%, respectively. Regimens containing thiotepa were associated with better 2OS (RR 0.46; IC95 0.27 to 0.80; P=0.006; Z=2.76) and increased 2PFS (RR 0.52; IC95 0.37 to 0.74; P=0.0002; Z=3.69). The addition of WBRT wasn't associated with better 2OS (RR 0.94; IC95 0.53 to 1.67; P=0.082; Z=0.22)
Conclusions Up front ASCT in the management of PCNSL is associated with high CRR and excellent 2OS and 2PFS when thiotepa is added to the regimen. Close to 200 patients treated in CT settings with up front ASCT for PCNSL were found in the literature and at least 4 different treatment scenarios were described. An important rate (>10%) of TRM was seen in two studies however ASCT was seem to be safe in most of the publications.

Disclosures
No relevant conflicts of interest to declare.