Consolidative High Dose Chemotherapy and Autologous Stem Cell Transplant for Patients with Primary Central Nervous System (CNS) Lymphoma or Non-Hodgkin Lymphoma with CNS Involvement Using Thiotepa, Busulfan, and Cyclophosphamide Conditioning Regimen
Authors: Young Patricia A. , Gaut Daria , Kimaiyo Davis A. , Grotts Jonathan A. , Chute John P , Schiller Gary J. , Timmerman John M. , de Vos Sven , Eradat Herbert A. 
Published: October 2019

Abstract
Background
Both primary central nervous system lymphoma (PCNSL) and non-Hodgkin lymphoma (NHL) with CNS involvement carry a poor prognosis. While there has been interest in intensification of treatment with high-dose chemotherapy and autologous stem cell transplant (ASCT), the side effect profile and long-term efficacy of consolidative transplant are not yet clear. Our aim was to investigate the efficacy and safety of a conditioning regimen of thiotepa, busulfan, and cyclophosphamide (TBC) (Soussain C., et al, J. Clin. Oncol., 19:742-749, 2001) followed by ASCT in patients with PCNSL or NHL with CNS involvement.
Methods
A retrospective analysis was performed among consecutive patients undergoing consolidative ASCT with TBC conditioning for PCNSL or NHL with CNS involvement between July 2006 and December 2017. For patients with PCNSL, a uniform induction therapy was given that consisted of rituximab and high dose methotrexate for 2-4 cycles followed by rituximab / cytarabine / thiotepa for 1-2 cycles based on published data (Illerhaus et al, Blood 120, no. 21 (2012): 302). For patients with secondary CNS lymphoma or relapsed disease, a variety of chemotherapy regimens were used at the discretion of the treating physician. Progression-free survival (PFS) was defined from the date of transplant to the date of relapse or any cause of death. Overall survival (OS) was calculated from the date of transplant to death.
Results
Forty-eight patients with NHL who underwent ASCT with TBC conditioning were identified: 27 patients with PCNSL, 12 patients with secondary CNSL, and 9 patients with relapsed disease with CNS involvement. Twenty-nine patients (60%) were in their first complete response (CR1) at the time of transplant. The median time from diagnosis to transplant was 7.1 months (range 3.7- 144.4). The median follow-up time after transplant was 23.9 months (range 8.6 - 59.6 months).
The median time to neutrophil recovery (absolute neutrophil count > 500/uL) and platelet recovery (>20,000 x 103/μL for > 2 consecutive days) were 9 days (range 7-12 days) and 7 days (range 1-40 days), respectively. Four patients were noted to have anemia (hemoglobin decrease >2 g/dL from baseline). Most patients (89.5%) experienced febrile neutropenia and 68.6% were found to have infection. Other common side effects included mucositis (89.5%, 35.4% with grade 3 or higher), electrolyte abnormalities (89.5%), dermatologic sequelae (31.3%), reversible neurotoxicity (18.8%), renal injury (16.7%), and hemorrhagic cystitis (8.3%). Four patients (8.3%) experienced treatment-related mortality, 3 of which had secondary CNSL. No evidence of pulmonary toxicity or veno-occlusive disease was noted.
The 1-year PFS was 78% (95% CI 63.3%-88.0%), and 1-year OS was 80.5% (95% CI 66%-89.8%). When analyzed according to primary diagnosis, 1-year PFS was 82.6% for PCNSL, 70% for secondary CNSL, and 75% for relapsed disease with CNS involvement (p = 0.69). According to diagnosis, 1-year OS was 87% for PCNSL, 70% for secondary CNSL, and 75% for relapsed disease with CNS involvement (p = 0.47).
Univariate analysis was performed to analyze gender, ethnicity, age > 60, Karnofsky score ≥ 80, diagnosis, cell of origin, and transplant in CR1 versus CR2 or partial response as independent predictors of PFS and OS. Only age (p = 0.001, 95% CI 1.9-42.6 for PFS; p = 0.030, 95% CI 0.99-23.42 for OS) and Karnofsky score ≥ 80 (p = 0.017, 95% CI 0.07-0.81 for PFS; p = 0.047, 95% CI 0.06-1.03 for OS) were found to be significant.
Conclusion
High dose chemotherapy and autologous stem cell transplant using TBC conditioning for PCNSL and secondary CNSL appears to have encouraging long term efficacy with manageable side effects. Future studies looking at longer follow-up periods and comparison with other conditioning regimens is warranted.

Disclosures
Schiller: Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding.