Patterns of Treatment Failure in PCNSL

Abstract

<h3>Purpose/Objective(s)</h3> Primary CNS Lymphoma (PCNSL) is a rare and often fatal disease. Despite varied combinations of therapy with a backbone of high-dose methotrexate (HD-MTX), there remains no clear standard of care and treatment failure is a persistent challenge. This analysis evaluates factors that affect local disease control and patterns of failure. <h3>Materials/Methods</h3> Retrospective review of 95 consecutive patients with PCNSL pathologically confirmed from 2002 and 2021. The primary endpoints were Local Failure (LF) and pattern of first failure (distant only vs local). Univariate (UVA) and multivariate analyses (MVA) with backward selection at alpha of 0.2, Log-rank test and Cox proportional hazard models were used for time to event endpoints and associations with age, Karnofsky performance status (KPS; ≥70 vs <70), use of upfront WBRT, number of cycles of HD-MTX (≥6 vs 0-5), 1^st line chemo agents, type of surgery, and size of contrast-enhancing lesion(s) (≥14cc vs <14 cc). <h3>Results</h3> Most patients had KPS ≥70 (64.2%), were HIV negative (89.5%), and had no history of solid organ transplant (95.8%). Diagnosis was made by biopsy (73.7%) or resection (26.3%). 54.3% had <14 cc contrast-enhancing tumor volume (overall median 12.6 cc, range 0.5 - 67.8 cc). Of the 62 patients treated first line with at least 1 cycle of HD-MTX, 61.3% had HD-MTX + Rituximab (R). Of the 60 patients with evaluable CSF, 30.0% had positive cytology. IT chemotherapy (ITc) was administered to 12 patients (cytology positive for 5, negative for 4, and unknown for 3). WBRT for consolidation after chemotherapy used for 3 patients and as monotherapy for 9 patients with poor KPS. At 2-years, OS was 50%, PFS was 39%, and LF was 27%. For patients with progression (n=29), 7 had distant only progression while 5 had local and distant progression and 17 had local only progression. LF was numerically higher in patients with ≥14 cc tumors (2-yr LF 26% vs 42%, p=0.43). On MVA, hazard of LF was significantly associated with age (HR 1.08 per yr, 95% CI: 1.02-1.16, p=0.02), KPS (HR 0.10, 95% CI: 0.01-0.65, p=0.016), completion of at least 6 cycles HD-MTX (HR 0.10, 95% CI 0.03-0.34, p<0.01), and use of ITc (HR 0.03, 95% CI: 0.00-0.32, p<0.01). There were no significant associations with upfront WBRT (p=0.37), use of HD-MTX + R (p = 0.12), or type of surgery (p=0.94). On UVA, distant first failure trended to be significantly associated with age (p=0.06), ITc use (p=0.07), and size of lesion(s) (p=0.08). On MVA, distant only first failure was significantly associated with age (OR 0.91 per year, 95% CI: 0.83-0.99, p=0.04). <h3>Conclusion</h3> The majority of treatment failures were local only. LF of PCNSL was associated with not completing induction HD-MTX and not using ITc. There was no association with LF or type of first failure and use of WBRT or more aggressive surgery. Larger tumors trended to fail locally warranting further investigation as local disease can be devastating.