Outcomes of Autologous Stem Cell Transplant in Primary and Secondary Central Nervous System Lymphoma - a Multi Center Experience in Singapore
Authors: Tan Meredith W. , Tan Jing Yuan , Tan Melinda , Ang Chieh Hwee , Chen Yunxin , Quek Jeffrey , Tuy Tertius , Than Hein , Nagarajan Chandramouli , Lim Francesca , Goh Yeow Tee , Ho Aloysius Yew Leng , Linn Yeh Ching , Hwang William Ying Khee , Ling Victor , Koh Liang Piu , Tan Lip Kun , Lee Joanne Shu Xian , Chan Esther , De Mel Sanjay , Poon Michelle , Ng Lawrence Cheng Kiat 
Published: December 2024

Introduction
Central Nervous System Lymphoma, either primary (PCNSL) or secondary (SCNSL), is a rare and aggressive extranodal lymphoma with poor outcomes due to poor blood-brain barrier penetrance, treatment associated neurotoxicity, and heterogeneity of presentations. While thiotepa-based autologous stem cell transplant (ASCT) has shown effectiveness in treating CNSL, a proportion of patients relapse, highlighting the need to refine treatment strategies.
Aim/Methods
To evaluate survival outcomes of patients with primary and secondary CNSL who underwent thiotepa-based ASCT between 2013 and 2023 at Singapore's two largest national cancer centers, as either first-line consolidation or treatment for relapse or refractory (RR) disease.
Results
There were 61 patients included in this study, 34 patients with primary CNSL (cohort A) and 27 patients with secondary CNSL (cohort B). Non relapse mortality (NRM) were 8.1% for all patients.
For cohort A, median age at transplant was 59.5 years (27-75) evenly split between males and females (17 each). Among these patients, 30 (88.2%) had an ECOG Performance Status of 0-1, while 3 (8.8%) had an ECOG of 2-3. Of the 34 patients, 25 (73.5%) received ASCT as first-line consolidation, and 9 (26.5%) underwent ASCT for relapse or refractory disease. All but one patient received thiotepa-carmustine conditioning; the exception received thiotepa-busulfan. Disease status at transplant included Complete Response (CR) in 22 patients (64.7%), Partial Response (PR) in 8 patients (23.5%), and Stable Disease/Progressive Disease (SD/PD) in 4 patients (11.8%). RMVP was used as induction therapy in 25 of the 34 patients (74%). For relapsed primary CNSL, MATRix was used in 5 of the 9 cases (56%).
Cohort A had a median follow-up of 9 months. Both median PFS and OS were not reached. 25 patients who underwent ASCT as first-line consolidation had 100% PFS and OS but with caveat of relatively short follow-up duration as mentioned. In contrast, among the 9 patients who received ASCT for RR disease, 3 patients relapsed, and 3 patients died from NRM. This resulted in statistically significant difference in survival between first-line consolidation vs RR disease (PFS p=0.003; OS p=0.006). In addition, patients with SD/PD at transplant had a shorter median PFS compared to those with CR/PR (17 months vs. not reached, p=0.002), although no difference in OS. No significant survival differences were observed based on ECOG status (0-1 vs. 2-3) or induction therapy regimen (MATRix vs. RMVP).
Cohort B patients had median age of 58 years (28-70), comprising of 15 males (55.6%) and 12 females (44.4%). 23 (85.2%) patients were of ECOG 0-1 status, while 3 (11.1%) patients were ECOG 2-3. 4 (14.8%) patients underwent ASCT as first-line consolidation for synchronous disease, 14 patients (51.9%) had isolated relapsed SCNSL, and 9 patients (33.3%) had relapsed synchronous SCNSL. Conditioning was thiotepa-carmustine in 22 patients (85%), 1 with thiotepa-busulfan (4%) and 4 (14.8%) patients had incomplete data on conditioning regimen. Disease status at transplant was CR in 15 patients (55.6%), PR in 8 patients (29.6%), and SD/PD in 3 patients (11.1%). Anthracycline-based chemotherapy was used as first-line treatment in 25 of the 27 patients, while RDHAP (n=11) and MATRix (n=9) were more frequently used as subsequent lines of therapy.
With a median follow-up of 43 months, patients in Cohort B had a median PFS of 7 months and a median OS of 30 months. Median PFS varied by subtype of SCNSL: 17.5 months for those with synchronous disease receiving first-line ASCT consolidation, 11.5 months for isolated relapsed SCNSL, and 4 months for relapsed synchronous SCNSL. Notably, only one patient experienced a CNS relapse, while the rest had systemic relapses and subsequently received additional therapies, including CAR-T (n=2) and allogeneic transplant (n=1). Therefore, the median OS for above 3 subtypes were not-reached, 30 months, and not-reached, respectively, affected by post systemic-relapse treatment effectiveness. Disease status at transplant, ECOG status and number of prior salvage lines did not affect outcomes.
Conclusion
Early ASCT should be considered as an upfront treatment option for both PCNSL and SNCSL patients, particularly for those in CR/PR. We identified high risk patients including patients not in remission and relapsed synchronous CNSL who might benefit from novel therapies such as CAR-T.