Real-World Outcomes of Patients with Primary CNS Lymphoma (PCNSL): A Report from the Australasian Lymphoma Alliance (ALA)

Abstract

Aim: Primary Central Nervous System Lymphoma (PCNSL) [i.e. diffuse large B-cell lymphoma of the CNS] is a rare and poor-prognosis disease occurring predominantly in older patients (median age >60 years old). Prospective studies of two commonly used chemoimmunotherapy (CIT) protocols, MATRix and MPV/Ara-C (± rituximab), have reported 2-year PFS and OS of 57-61% and 69-81% respectively. Our aim was to evaluate registry-reported outcomes of frontline CIT strategies employed at Australasian sites. Method: A retrospective study of consecutive, immunocompetent, adult PCNSL patients (WHO criteria: 2017) treated with curative-intent CIT, from 10 sites (9 Australian, 1 Singaporean) between 1 st January 2009 and 31 st December 2018 (i.e. ten-year period). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier (log-rank) method. Univariate associations were derived using a Cox model with variables p<0.10 entered stepwise into a multivariate model. Results: Data was collected on 207 patients, 189 of whom met WHO diagnostic criteria for PCNSL (i.e. diffuse large B-cell lymphoma of the CNS). We excluded patients with insufficient data (6), non-DLBCL histology (6), secondary PCNSL (3) and post-transplant lymphoproliferative disorder (3). Of these, 176 (93%) received curative-intent CIT. The majority (66%) were over 65 years of age (median: 65, range: 25-87); ECOG performance status was ≥ 2 in 31% (data not available for 14% of patients). The majority were male (55%) and had deep structure involvement (64%). International Extranodal Lymphoma Study Group (IELSG) risk criteria could not be calculated in many patients due to missing data (predominantly LDH and CSF protein). CSF involvement was rare (n=23, 13%) but data was only available for 60% of patients. Of the 159 with documented renal function, 26% had renal impairment (defined as Cockroft-Gault creatinine clearance <60ml/min or eGFR <90ml/min). Five CIT regimens were used: MATRix (n=16), MPV/Ara-C + rituximab (Rtx) (n=94), MBVP+- Rtx (n=11), MTX +-Rtx (n=31) and MTX/Ara-C +- Rtx (n=24). Intrathecal chemotherapy was used in only 29 patients (16%), and almost exclusively in combination with R-MPV. Median cumulative MTX dose was 17,500mg/m 2 (range: 1,000-64,000mg/m 2) and 69% received Ara-C (median dose: 12,000mg/m 2 [range: 1,000-44,000mg/m 2]). Eighty percent of patients achieved an overall response at the end of MTX therapy, with 52% achieving a complete response [data unavailable in n=29, 16%]. Estimated 2-year PFS and OS for the entire cohort were 54% (95%CI: 0.46-0.62) and 77% (95%CI: 0.70-0.83) respectively at a median follow-up of 2 years. Older patients (>60yo) had shorter PFS but similar OS compared to their younger counterparts (2-year PFS: 47% vs 68%, p: 0.015, HR: 1.73, 95%CI: 1.11-2.70; 2-year OS: 74% vs 80%, p: 0.145, HR: 1.38, 95%CI: 0.81-2.33). R-MPV achieved superior PFS compared to MATRix although comparison was limited by low numbers in the MATRix cohort (n=16 vs n=94), likely reflective of the census period [2-year PFS: 74% vs 44% p: 0.025, HR 0.41, 95%CI 0.13-1.28]. Neither WBRT (n=57, 32%) nor ASCT (n=13, 7%) conferred a survival advantage but addition of rituximab (n=153, 87%) was associated with improved PFS (p: 0.007, HR: 0.47, 95%CI: 0.19-0.75). On multivariate analysis, type of induction CIT (p: 0.004, HR: 1.42, 95%CI: 1.23-1.42), cumulative MTX dose (p: 0.022, HR: 0.88, 95%CI: 0.83-0.94) and cumulative Ara-C dose (p: 0.016, HR: 0.76, 95%CI: 0.64-0.87) were associated with improved PFS. Cumulative MTX dose (p: 0.02, HR: 0.85, 95%CI: 0.78-0.92) and cumulative Ara-C dose (p: 0.007, HR: 0.67, 95%CI: 0.51-082) were also associated with improved OS. Conclusion: Registry-reported outcomes of contemporary CIT induction for PCNSL are favourable when compared to published trials and historical regimens. PCNSL with contemporary treatment should no longer be considered an invariably poor-prognostic disease. Data supports recent literature highlighting prognostic significance associated with maintenance of chemotherapy dose intensity (Martinez-Calle et al., Br J Haematol. 2020 Aug; 190(3):394-404. doi. 10.1111/bjh.16592). Figure 1 Figure 1. Disclosures Lewis: AstraZeneca: Consultancy, Honoraria; Janssen: Honoraria, Patents & Royalties: Conference attendance; Novartis: Patents & Royalties: Conference attendance; Roche: Consultancy, Honoraria. Gunjur: Myers Squibb: Honoraria. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy. Wight: Jannsen: Honoraria, Other: Travel subsidies; Abbvie: Honoraria, Other: Travel subsidies. Shortt: Amgen: Research Funding; Astex: Research Funding; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Talaulikar: Roche: Honoraria, Research Funding; Jansenn: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; EUSA Pharma: Honoraria, Research Funding. Hawkes: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Regeneron: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck KgA: Research Funding; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Specialised Therapeutics: Consultancy; Antigene: Membership on an entity's Board of Directors or advisory committees. Cheah: MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; TG Therapeutics: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; AstraZeneca: Consultancy, Honoraria, Other: advisory; Celgene: Research Funding; AbbVie: Research Funding; Beigene: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory; Gilead: Consultancy, Honoraria, Other: advisory. Opat: Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Sandoz: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Monash Health: Current Employment. Gregory: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy.

The role of upfront lenalidomide maintenance for primary central nervous system lymphoma following first‐line methotrexate treatment: A retrospective study

“…However, two real-world retrospective studies conducted in the United States and Australia reported no significant association between the intensity and type of high-dose methotrexate (HD-MTX) based induction regimens and PFS and OS. 15,16 Despite the lack of difference in PFS between the maintenance and observation groups, there was a slight increase in OS within the maintenance group (p = 0.091). The discrepancy in benefits between PFS and OS could be mainly attributed to the different recruitment periods.…”

“…These variations may have influenced the outcomes. However, two real‐world retrospective studies conducted in the United States and Australia reported no significant association between the intensity and type of high‐dose methotrexate (HD‐MTX) based induction regimens and PFS and OS 15,16 …”