Thiotepa Containing Regimen As Conditioning Chemotherapy for Lymphoma Involving Central Nervous System Compared with BuCyE (Busulfan, Cyclophosphamide and Etoposide)
Authors: Kim Yi Rang , Yoon Dok Hyun , Kim Shin , Lee Kyoungmin , Kang Eun Hee , Park Jung Sun , Yoo Changhoon , Kim Jeong-eun , Jo Jae-Cheol , Huh Jooryung , Kim Jeong Hoon , Lee Sang-wook , Suh Cheolwon 
Published: October 2019

Abstract
Aims
Primary or secondary central nervous system (CNS) lymphoma is a rare entity which often leads to unsatisfactory outcome. Autologous stem cell transplantation (ASCT) using thiotepa containing regimen as conditioning chemotherapy showed improved outcomes in patients with CNS lymphoma. However, there are insufficient data on response to treatments and safety profile of thiotepa containing regimen in Asian population. We, therefore, aimed to evaluate clinical outcomes including safety profile and response to thiotepa, busulfan and cyclophosphamide (TBC) chemotherapy compared with busulfan, cyclophosphamide and etoposide (BuCyE) as conditioning regimens in patients with CNS lymphoma.
Methods
From November 2005 to April 2014, patients with primary and secondary CNS lymphoma who underwent one of the two conditioning regimens (TBC or BuCyE) followed by ASCT were included in this retrospective analysis. All patients were less than 66 years of age at the time of ASCT. TBC consists of thiotepa 250 mg/ m2 on day -9 to day -7, busulfan 3.2 mg/kg on day -6 to day-4 and cyclophosphamide 60 mg/kg on day -3 to day -2. BuCyE consists of busulfan 3.2 mg/kg on day -7 to day -5, etoposide 200 mg/m2 twice a day on day -5 to day-4 and cyclophosphamide 50 mg/kg on day -3 and day -2. Patient demographics, ECOG performance status, baseline and follow-up CBC profile, adverse events and radiologic response for 2 years after ASCT were retrospectively reviewed. Response to treatment was assessed by IELSG criteria. Event free survival (EFS), overall survival (OS) and date of engraftment were calculated by Kaplan-Meier method and compared by log-rank test. Adverse events were scored according to National Cancer Institute Common Terminology Criteria of Adverse Event version 4.0. Engraftment was defined as absolute neutrophil count (ANC) > 500 /mm3, and platelet count > 20,000 /mm3.
Results
Sixty one patients with primary or secondary CNS lymphoma underwent with TBC (n=26) or BuCyE (n=35) as conditioning regimen followed by ASCT. In TBC group, 17 patients (diffuse large B cell lymphoma: 17) had primary CNS lymphoma and 9 patients (diffuse large B cell lymphoma: 7, angioimmunoblastic lymphoma: 1 and T-lymphoblastic lymphoma: 1) had secondary CNS lymphoma. In BuCyE group, 28 patients (diffuse large B cell lymphoma: 27 and peripheral T-cell lymphoma: 1) had primary CNS lymphoma and 7 patients (diffuse large B cell lymphoma: 5, NK-T cell lymphoma: 1 and mantle cell lymphoma: 1) had secondary CNS lymphoma. Median age of TBC group and BuCyE group at ASCT was 52.5 years (range, 18-64 years) and 54 years (range, 26-64 years), respectively. Median ECOG performance status of TBC group and BuCyE group was 1 (range 0-2) and 1 (range 0-1), respectively. After the induction chemotherapy, 11 patients (42.3%) in TBC group and 21 patients (60%) in BuCyE group had already achieved complete remission (CR). In TBC and BuCyE group, CR had been induced in 9 (64.2%) and 11 (78.5%) among patients in partial remission (PR) after ASCT, respectively. With a median follow up period of 8.6 months (range, 0.2 to 18.5 months), 1-year OS rate did not significantly differ between two arms (76.4% in TBC group and 68.6% in BuCyE group, p=0.634). However, 1-year EFS rate was higher in TBC group (72.8%) compared with BuCyE group (45.7%, p=0.034). TBC group achieved ANC engraftment one day earlier compared to BuCyE group (day 8, range 7-12 days vs. day 9, range 7-12 days) (p= 0.011). However, there was no difference in time to engraftment of platelet between TBC group (median 8 days, range 6 to 34 days) and BuCyE group (median 8 days, range 6 to 22 days, p=0.582). Toxicity profiles are summarized in Table 1.
Table 1. Toxicity above grade 2 TBC BuCyE p-value Mucositis 92% 14.3% <0.001 Nausea 72% 34.3% 0.004 Vomiting 24% 2.9% 0.017 Diarrhea 84% 25.7% <0.001 AST,ALT elevation 15.4% 2.9% 0.154 Bilirubin elevation 30.8% 5.7% 0.014 Creatinine elevation 7.7% 0% 0.178 Veno-occlusive disease 7.7% 5.7% 1 Bleeding 3.8% 0% 0.426
Conclusions
TBC seems to be a feasible conditioning chemotherapy for Korean patients with acceptable toxicity and efficacy.

Disclosures
No relevant conflicts of interest to declare.