Reduced Intensity Therapy for Primary Central Nervous System Post-Transplant Lymphoproliferative Disorders (PTLD) Is Associated with Preserved Survival Outcomes: A Twenty-Year Single-Institutional Experience
Authors: Uyemura Bradley Shogo , Li Zhanhai , Yang David T , Fallon Michael , Odorico Jon S , Chang Julie E 
Published: December 2024

Introduction: PCNS-PTLD is a rare complication of solid organ transplant, and has distinct biology compared to PCNS lymphoma in immunocompetent patients (pts). With improved understanding of the biology of PCNS-PTLD, therapy has evolved to favor initial single-agent rituximab (RTX) over more toxic therapies such as high-dose methotrexate (HD-MTX) or whole-brain radiotherapy (WBRT).
Methods: Cases of PCNS-PTLD were identified at the University of Wisconsin (UW) from 1/1/2000-1/1/2022 utilizing 3 clinical, transplant (txp), and pathology databases. Institutional Review Board approval was obtained. Pts were excluded if additional systemic sites of lymphoma were identified. To determine statistical significance of progression-free survival (PFS) and overall survival (OS) outcomes, Fisher's Exact test was used for categorical variables and Student's t-test for continuous variables.
Results: Twenty cases of PCNS-PTLD were identified, all with monomorphic histology and 19/20 with positive Epstein Barr Virus (EBV) on biopsy. Twelve pts (60%) were women, and the majority were Caucasian (12); other pts were black (3), Hispanic (2), Native American (2) and Asian (1). The majority had solitary kidney txp (12), with 7 kidney/pancreas txps and 1 liver txp. The most common indications for txp were type I/II diabetes (9) and focal segmental glomerulosclerosis (5). The median time from txp to diagnosis of PCNS-PTLD was 74 months [mos] (range 9-364 mos) at a median age of 57 years [yrs] (range 27-69 yrs). Eastern Cooperative Oncology Group (ECOG) performance status (PS) was ≤1 in 6 pts (30%) and ≥2 in 14 pts (70%). At diagnosis, 2 pts had confirmed positive cerebral spinal fluid (CSF) cytology and 5 underwent subtotal resection of brain lesions. Twelve (60%) had elevated lactate dehydrogenase (LDH) serum levels, and 8 (40%) had detectable EBV viremia.
All pts received reduction of immunosuppression at diagnosis and received RTX as ≥1 line of systemic trt. Eleven pts (55%) received ≥2 lines of trt; 5 (25%) received ≥3 lines and 4 (20%) received ≥4 lines. HD-MTX was administered to 4 (20%) pts, WBRT to 8 (40%) pts, and RTX re-trt to 4 (20%) pts. Other therapies included ibrutinib (1), intrathecal MTX (4), and procarbazine (1).
Outcomes were evaluated for the total population and by decade of trt, with cohort (CHT) 1 including those diagnosed from 1/1/2000-1/1/2011 (8), and CHT2 including those diagnosed from 1/2/2011-1/1/2022 (12). Median age at diagnosis was younger in CHT1 (46 yrs) versus (vs) CHT2 (62 yrs). Other characteristics at diagnosis were similar.
Trt varied widely between cohorts. First-line RTX was given to 10/12 (83.3%) pts in CHT2 and 5/8 (62.5%) patients in CHT1. HD-MTX was given to 3 pts (37.5%) in CHT1 vs 1 pt (8.3%) in CHT2; WBRT was utilized more in CHT1 (6, 75%) compared with CHT2 (2, 16.7%). No pt in CHT1 received RTX re-trt, compared with 4 pts in CHT2 (33.3%).
Despite decreased usage of WBRT and HD-MTX, PFS and OS were similar amongst CHT1 and 2. Median PFS was 48 mos, and was not significantly different between CHT1 (66.5 mos) and CHT2 (44 mos) (p=0.80). Median OS was 71 mos, and was not significantly different between CHT1 (72.5 mos) and CHT2 (71 mos) (p=0.41). Thirteen deaths occurred, including 5 from PCNS-PTLD.
Comparing those experiencing PTLD progression with those in continuing remission on categorical variables of type of txp, indication for txp, date of trt (CHT1 vs 2), resection at diagnosis, ECOG PS (≤1 vs ≥2), &gt;1 line of trt, and trt with HD-MTX or WBRT, no categorical variable was predictive of worsened PFS. Evaluation of continuous variables of age at diagnosis, mos from txp to diagnosis, number of therapies, and baseline LDH showed that only lower baseline LDH was predictive of improved PFS (p=0.032). For OS, aside from lower baseline LDH (p=0.006), no categorical or continuous variables were predictive.
Conclusions: These data confirm that outcomes for PCNS-PTLD in the last 10-15 years have not worsened despite initial use of RTX monotherapy and more selective application of HD-MTX and WBRT, even with the older age of CHT2. Importantly, favorable outcomes were still possible even with ECOG PS ≥2 at diagnosis, as was present in 70% of pts. Baseline LDH may be predictive of PFS, as has been previously reported (Evens AM, et al. Am J Transplant 2013). Novel next steps in PCNS-PTLD trt may include measurable residual disease testing of CSF to identify patients at high risk of relapse post-RTX.