Outcomes and a New Prognostic Model in Posttransplantation Lymphoproliferative Disorders (PTLD): Intent-to-Treat (ITT) Analysis of 81 Patients in the Post-Rituximab Era.
Authors: Evens Andrew M. , David Kevin A. , Helenowski Irene , Kircher Sheetal M. , Mauro Lauren , Gimelfarb Alla , Van Besien Koen , Hattersley Elise , Nelson Beverly P , Mehta Jayesh , Gordon Leo I. , Shammo Jamile M. , Smith Scott E. , Smith Sonali 
Published: April 2020

The outcome of PTLD has a reported approximate 3-year (yr) overall survival (OS) rate of 35%–40% in the pre-RTX era (JCO2001; 19:772). The impact, if any, of RTX on the prognosis or outcome of PTLD is not known. We retrospectively studied the clinical features, treatment, outcomes (ITT), and prognostic factors among a large multi-center cohort of solid organ transplantation (SOT)-related PTLD cases over a 10-yr period in the post-RTX era (1/98–2/08) at 4 Chicago academic institutions. Prognostic factors were evaluated in Cox proportional hazards regression for indicators of progression-free survival (PFS) and OS. 81 pts were identified with a median age at PTLD diagnosis (dx) 48 yrs (range, 20–72) and median time from SOT to PTLD dx 42 months (mo) (range, 1-216 mo). EBV+ PTLD pts more commonly were treated by concurrent reduction of immune suppression (median reduction 75%) with single agent RTX whereas EBV-neg pts more frequently received RTX/chemotherapy with median immune suppression reduction of 90%. On ITT (median follow-up 36 mo), the 3-yr PFS for all pts was 58% and 3-yr OS was 62%. Of note, 13/81 (16%) pts died ≤6 weeks from PTLD dx, primarily due to progressive disease. Univariate analysis found several factors highly predictive of outcome (Table 1):

performance status (PS), serum albumin, &gt;1 extranodal (EN) site, bone marrow (BM) involvement, CNS disease, and RTX as part of initial therapy (alone or combined with chemotherapy).

Neither EBV status nor time to PTLD predicted outcome.

Table 1. PTLD characteristics and univariate predictors of EFS and OS (n=81).

Variable (at dx) Pt characteristics PFS OS No. % HR* P HR* P *Prognostic factors were tested for association with survival by proportional hazards analysis. Hazard ratios (HRs) &gt;1 indicate a poor prognosis, while HRs &lt;1 indicate a good prognosis. **Analysis was monomorphic PTLD (n=55) vs polymorphic and reactive (n=26). ***Analysis combined rituximab alone and rituximab/chemotherapy-treated pts (n=60) vs all other therapy (n=21). n/a = not available. Table 2 shows 3-yr survival rates based on these variables. On multivariate analysis, 4 factors remained significant: 1) RTX (EFS HR 0.26 (CI 0.11–0.60), p=0.002; OS HR 0.23 (CI 0.090.56), p=0.001), 2) &gt;1 EN site (EFS HR 2.15 (CI 1.04–4.42), p=0.04; OS HR 2.14 (CI 1.01–4.54), p=0.047), 3) low albumin (EFS HR 3.19 (CI 1.17–8.72), p=0.02; OS HR 4.73 (CI 1.39–16.16), p=0.01), and 4) CNS (EFS HR 4.48 (CI 1.80–11.17), p=0.01; OS HR 3.90 (CI 1.54–9.88), p=0.004). A prognostic model based on 3 factors: &gt;1 EN site, albumin, and CNS disease was constructed (EFS p=0.008, OS=p=0.006), suggesting that pts with differential outcomes can be identified. In summary, we show that the introduction of RTX appears to have improved the outcome of PTLD compared to published data. However, a significant minority of pts still experience short survival. Clinical features at PTLD dx can predict outcome and should be incorporated into future therapeutic strategies. Kidney 37 46 Kidney-pancreas 10 12 SOT Pancreas 4 5 0.74 0.38 0.71 0.36 Liver 17 21 Heart 8 10 Lung 5 6 Time to PTLD Early (&lt;1 yr) 30 37 1.02 0.95 0.91 0.81 Late (&gt; 1 yr) 51 63 Monomorphic 55 68 Histology** Polymorphic 22 27 1.61 0.27 2.18 0.11 Plasmacytic/reactive 4 5 EBV + (tumor) Yes 39 48 No 30 37 1.09 0.82 0.82 0.64 n/a 12 15 PS 2–4 25 31 2.87 0.002 3.31 0.001 0–1 56 69 CNS involvement Yes 10 12 2.57 0.03 2.47 0.050 No 71 88 BM involvement Yes 12 15 No 58 72 3.30 0.003 3.48 0.003 n/a 11 13 EN &gt; 1 Yes 29 36 No 50 62 2.01 0.04 2.19 0.03 n/a 2 2 High LDH Yes 49 60 No 27 33 1.64 0.21 2.00 0.11 n/a 5 7 Yes 56 69 Low serum albumin No 24 30 3.02 0.02 4.72 0.01 n/a 1 1 IPI 2–4 47 58 0–2 33 41 2.04 0.053 1.76 0.16 n/a 1 1 Immune suppression alone 7 9 Treatment*** Radiation or surgery alone 2 2 Chemotherapy alone 12 15 0.28 0.003 0.30 0.001 Rituximab alone 26 32 Rituximab/chemotherapy 34 42

Table 2. Three-year survival (Kaplan-Meier) based on prognostic variables (univariate).

Variable 3-year EFS* 3-year OS* *3-year PFS and OS by Kaplan-Meier analysis are reported (and their 95% CIs). PS p &lt; 0.0001 p &lt; 0.0001 0–1 65% (50%, 77%) 72% (57%, 82%) 2–4 36% (18%, 54%) 35% (15%, 56%) Albumin p = 0.002 p = 0.0004 Normal 75% (49%, 89%) 85% (59%, 95%) Low 49% (34%, 61%) 51% (37%, 64%) CNS p = 0.001 p = 0.004 No 60% (47%, 71%) 64% (51%, 74%) Yes 30% (7%, 58%) 40% (12%, 67%) Received rituximab p = 0.0002 p = 0.001 No 21% (7%, 42%) 32% (14%, 79%) Yes 69% (55%, 79%) 71% (57%, 81%) BM involvement p = 0.005 p = 0.005 No 64% (49%, 75%) 70% (56%, 80%) Yes 18% (3%, 44%) 18% (3%, 44%) &gt; 1 EN site p = 0.01 p = 0.008 No 64% (48%, 76%) 72% (57%, 82%) Yes 39% (22%, 58%) 40% (20%, 58%)