The Survival Improvement of Transplant-Eligible Primary CNS Lymphoma Patients within Last 15 Years
Authors: Vodicka Prokop , Benesova Katerina , Janikova Andrea , Belada David , Hruskova Andrea , Mocikova Heidi , Duras Juraj , Steinerova Katerina , Sykorova Alice , Masar Michal , Dlouha Jitka , Blahovcova Petra , Trneny Marek 
Published: December 2024

Introduction
Primary CNS lymphomas (PCNSL) are rare hematologic malignancies. In contrast to systemic lymphomas, patients with PCNSL have poor prognosis and limited access to novel therapeutic modalities. Subsequent introduction of rituximab, intensive induction chemotherapy (CHT) including thiotepa (MATRix), and consolidation by autologous stem cell transplantation (ASCT) has been shown to improve outcomes of PCNSL patients. Rituximab was largely implemented into daily practice in our region for these patients since 2009 (used in &gt; 50% of patients), MATRix/ASCT since 2017 (MATRix used in &gt; 50% of transplant-eligible patients, T-elig.). We aimed to analyze how access to these modalities has changed outcomes of PCNSL patients in consecutive periods (regardless of their actual therapy): the pre-rituximab era (2007-2008), the pre-MATRix era (2009-2016), and the MATRix era (2017-2022).
Methods
Consecutive patients with PCNSL were prospectively collected in the NiHiL registry (NCT03199066) between 2007 and 2022. Individuals receiving systemic therapy were included in the analysis (n = 499). A subpopulation of T-elig. patients (≤ 65 years of age with PS ECOG ≤ 3) was analyzed separately (n = 231). In total, 43 PCNSL patients were diagnosed in the pre-rituximab era (2007-2008), 229 in the pre-MATRix era (2009-2016), and 227 in the MATRix era (2017-2022). All data were reviewed, cleaned and completed from patients' notes. Patients' survival was compared using log rank-test. Multivariate analysis was performed using Cox regression model.
Results
Median age at diagnosis was 65 years (64, 64, and 67 years, respectively, in the consecutive eras). PS ECOG 0-3 was observed in 409 (82%) patients (74%, 76%, and 83%, respectively, in the consecutive eras).
Across the entire inclusion period from 2007 to 2022, rituximab was used in 73% (9% in the pre-rituximab vs 79% in the rituximab era). Patients in the rituximab era (since 2009) had significantly improved progression-free survival (PFS) compared to those in the pre-rituximab era (n = 456 vs 43; 36% vs 26% at 3y, HR 0.71, P = 0.037). T-elig. subpopulation diagnosed in rituximab era had significantly improved both PFS (n = 206 vs 25; 53% vs 40% at 3y, HR 0.63, P = 0.036) and overall survival (OS; 66% vs 56% at 3y, HR 0.61, P = 0.036).
MATRix chemotherapy was used in 4%/8% of all/T-elig. patients in the pre-MATRix era (2009-2016) vs 35%/60% in 2017-2022 MATRix era (2017-2022). Any consolidation therapy (i.e., ASCT / WBRT) was administered in 41%/50% in the pre-MATRix era vs 41%/64% in the MATRix era, and in 56%/61% vs 57%/73% all/T-elig. patients who responded to induction chemotherapy. ASCT was provided to 11% vs 46% of T-elig. patients diagnosed in the pre-MATRix era vs the MATRix era, and to 12% vs 52% individuals who responded to induction chemotherapy.
T-elig. patients in the MATRix era (n = 94, 60% received MATRix CHT) had significantly improved PFS compared to pre-MATRix (n = 112, 8% received the MATRix CHT) with 59% vs 47% at 3y, resp., (HR 0.64, P = 0.016) and a trend towards improved OS was noted with 70% vs 62% at 3y, HR 0.73, P = 0.128). The improvement was especially significant in the patient population with PS ECOG 2-3 (n = 37 vs 48; PFS 55% vs 38% at 3y, HR 0.55, P = 0.028; OS 62% vs 42% at 3y, HR 0.48, P = 0.012). No significant survival changes were observed among patients ≤ 65 years of age with PS ECOG 0-1 (n = 57 vs 63).
Altogether 52% of patients diagnosed in the pre-MATRix era vs 50% in the MATRix era received treatment as initially planned. Reasons for treatment discontinuation included no response/progression in 24% vs 15%, toxicity in 10% vs 15%, infections 10% vs 16% (mainly due to the COVID-19 pandemic), and other/unknown reasons in 4% for both eras.
The multivariate analysis revealed that age at diagnosis, PS ECOG, and era of diagnosis were significant prognostic factors for PFS and OS in all as well as in T-elig. patients.
Conclusions
The survival of PCNSL patients is improving over time across the consecutive eras (2007-2008, 2009-2016, 2017-2022). This improvement is attributed to the implementation of rituximab since 2009 and the MATRix regimen with ASCT consolidation since 2017. In the current era, the real-world probability of 5-year PFS and OS for all PCNSL patients is 33% and 39%. For patients aged ≤ 65 years with PS ECOG ≤ 3, the 5-year probabilities are 51% for PFS and 62% for OS.
This work was supported by the Charles University Hem-Onco Cooperatio Program and grant NU21-03-00411.