Thiotepa, Busulfan, and Cyclophosphamide and Busulfan, Cyclophosphamide, Etoposide As Autologous Stem Cell Transplantation Conditioning Regimen in Primary Central Nervous System Lymphoma

Introduction

Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma and standard treatment is yet to be established. Induction therapy with methotrexate-based chemotherapy regimen and consolidation with high-dose chemotherapy followed-by autologous stem cell transplantation (ASCT) is a good treatment option with promising outcomes, but only few studies are available. Asan Medical Center had previously used busulfan, cyclophosphamide, and etoposide regimen (BuCyE) as standard high-dose chemotherapy in consolidation therapy until thiotepa, busulfan, and cyclophosphamide regimen (TBC) was introduced in December, 2012. The purpose of this study is to compare outcomes and toxicity profile of BuCyE and TBC as conditioning regimens for ASCT in consolidation therapy of PCNSL patients.

Methods

The registry data set of PCNSL, collected from March 1993 to May 2017 at a single institute, Asan Medical Center, was retrospectively reviewed and patients who had BuCyE or TBC as conditioning regimens were enrolled in analyses. BuCyE group had busulfan with dose of 3.2 mg/kg IV in day-7 to day-5, etoposide 200 mg/ IV in day-5 to day-4 and cyclophosphamide 50 mg/kg IV in day-3 to day-2. TBC group had thiotepa with dose of 250 mg/ IV in day-9 to day-7, busulfan 3.2 mg/kg IV in day-6 to day-4 and cyclophosphamide 60 mg/kg IV in day-3 to day-2. OS was defined as from beginning of high-dose chemotherapy conditioning to any cause of death, and PFS as from beginning of ASCT to disease progression or any cause of death. Analyses with chi-square test or Fisher's exact test were done to compare variables between two groups. Survival curves were estimated by Kaplan-Meier methods with log-rank tests and multivariate analyses were done with known prognostic factors. All statistical analyses were performed using IBM SPSS version 21.0.

Results

Total 241 patients with diagnosis of PCNSL were identified and 73 patients who had ASCT as frontline or salvage setting with conditioning regimens of either TBC (45 patients) or BuCyE (28 patients) were enrolled in analyses. Median follow-up duration was 3.7 years [IQR 0.01-10.3], median OS was 6.1 years [95% CI 3.7-8.5], and median PFS was 6.5 [95% CI 1.4-11.7]. Median age was 54 years (range, 17-65), 27.4% of patients were 60 years or older and 54.8% of patients was male. Fifty three patients (72.6%) had upfront ASCT after induction therapy and 27.4% of patients had relapsed or refractory disease. ECOG performance status and infused dose of CD34 positive cells showed no statistical difference between two groups. Proportion of patient with refractory or relapsed disease was significantly higher in TBC group [TBC 37.8%, BuCyE 10.7%, p = 0.012]. Median OS of TBC group was not reached and median OS of BuCyE group was 4.5 years [95% CI 1.8-7.2] and TBC group showed better OS with log-rank test (p = 0.048). Median PFS of TBC group was not reached and median PFS of BuCyE group was 1.3 years [95% CI 0.00-2.7] and TBC group showed better PFS with log-rank test (p = 0.007). In multivariate analyses with age, ECOG performance status, CSF protein level, serum LD level, TBC group showed significantly better OS with HR of 0.20 [95% CI 0.04-0.97, p = 0.046] and better PFS with HR of 0.24 [95% CI 0.09-0.66, p = 0.006] compared to BuCyE group. Severe oral mucositis, nausea, vomiting (NCI CTC grade 3 or 4) was higher in TBC group. Median days to engraftment were 8 days (range, 3-19) in TBC group, and 9 days (range, 3-15) in BuCyE group. Median admission duration was 17 days (range, 4-42) in TBC group, and 18.5 days (range, 14-36) in BuCyE group. One case of treatment-related mortality was reported in TBC group due to septic shock.

Conclusion

TBC regimen showed better outcomes in both OS, PFS compared to BuCyE. Although TBC group showed more oral mucositis, nausea, vomiting, and diarrhea, it maybe tolerable regimen compared with BuCyE considering the fact that admission duration and days to engraftment was not inferior. Further long-term follow-up results with TBC regimen are warranted.