Clinical outcomes associated with conditioning regimens in patients with primary central nervous system lymphoma undergoing consolidation autologous stem cell transplantation

Abstract Background: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive extra-nodal non-Hodgkin lymphoma confined to the central nervous system or eyes. While high-dose methotrexate (HD-MTX)-based induction therapy achieves high response rates, frequent relapses require consolidation treatment. Recent pivotal randomized controlled trials have established high-dose chemotherapy with autologous stem cell transplantation (HDC-ASCT) as the preferred consolidation strategy, demonstrating improved survival and reduced neurotoxicity compared to whole brain radiotherapy. Among conditioning regimens, thiotepa-based approaches have shown superior efficacy, but optimal regimen selection among those thiotepa-containing ones remains unclear. This study compared clinical outcomes of consolidation ASCT according to conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), busulfan/thiotepa (BuTT), and non-thiotepa regimens. Methods: This retrospective study included 160 newly diagnosed PCNSL patients treated at Asan Medical Center from 2004 to 2023 who responded to HD-MTX-based induction chemotherapy and proceeded to consolidation ASCT. Induction regimens included HD-MTX, HD-MTX/procarbazine/vincristine (MPV), or rituximab-MPV (R-MPV). Patients were categorized by conditioning regimen: non-thiotepa (busulfan/cytarabine/etoposide[BuCyE], busulfan/melphalan/etoposide[BuMelE], or BCNU/etoposide/cytarabine/melphalan[BEAM]; n=28), TBC (n=71), and BuTT (n=61). We evaluated progression-free survival (PFS), overall survival (OS), nonrelapse mortality (NRM), and treatment-related toxicities. PFS was defined as the time from the date of ASCT to the date of disease progression or death from any cause, whichever occurred first. OS was defined as the time from the date of ASCT to the date of death from any cause. Results: The median age at diagnosis was 57 years (range 17–68), and 84 (52.5%) were male. The BuTT group was older than the TBC and non-thiotepa groups (median age: 60 vs. 54 vs. 55 years, respectively; p<0.001). Induction chemotherapy regimens differed across groups: BuTT patients predominantly received R-MPV (98.4%), while TBC patients received R-MPV (39.4%), MPV (16.9%), or HD-MTX (43.7%), and all non-thiotepa patients received HD-MTX (p<0.001). With a median follow-up duration of 6.5 years, BuTT and TBC showed comparable outcomes (3-year PFS rate: 83.6% vs 80.3%, p=0.221; 3-year OS rate: 86.7% vs 83.1%, p=0.531), while non-thiotepa conditioning was significantly associated with worse survival outcomes with 3-year PFS rate of 46.4% (p<0.001) and 3-year OS rate of 64.3% (p=0.007) compared with BuTT. One-year NRM was higher in patients receiving thiotepa-based regimens (BuTT 9.8% vs. TBC 7.0% vs. non-thiotepa 0%). TBC was more frequently associated with infections: grade ≥3 infections (TBC 45.7% vs. BuTT 34.4% vs. non-thiotepa 28.6%), pneumonia (11.3% vs. 4.9% vs. 3.6%), bacteremia (21.1% vs. 13.1% vs. 3.6%), and septic shock (12.7% vs 6.6% vs 0%). Additionally, TBC was associated with prolonged hospitalization compared to BuTT (median admission duration: 19 vs 15 days, p=0.010). In the multivariate analysis adjusting for age, performance status, and induction regimen, there was no significant difference in survival outcomes of BuTT compared with TBC (PFS: hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.24–1.44, p=0.241; OS: HR 0.70, 95% CI 0.27–1.82, p=0.465), while non-thiotepa conditioning was associated with poor survival (PFS: HR 3.06, 95% CI 1.48–6.32, p=0.002; OS: HR 2.32, 95% CI 1.12–4.82, p=0.024). In the elderly subgroup (age ≥60 years; BuTT n=33, TBC n=23, non-thiotepa n=8), BuTT showed numerically higher survival rates compared with TBC (3-year PFS rate: 78.8% vs 65.2%, p=0.366; 3-year OS rate: 81.6% vs 69.6%, p=0.560) and significantly better outcomes than non-thiotepa (3-year PFS rate: 62.5%, p=0.028; 3-year OS rate: 62.5%, p=0.076). Conclusion: This study demonstrated that thiotepa-based conditioning regimens were associated with superior survival outcomes compared to non-thiotepa regimens for consolidation HDC-ASCT in PCNSL patients. Among thiotepa-based regimens, BuTT and TBC showed comparable survival outcomes, while BuTT demonstrated a more favorable safety profile with lower infection rates and shorter hospitalization duration. These findings suggest that BuTT may represent a more optimal conditioning regimen compared with TBC for patients with PCNSL undergoing consolidation HDC-ASCT.