Outcomes and a New Prognostic Model in Posttransplantation Lymphoproliferative Disorders (PTLD): Intent-to-Treat (ITT) Analysis of 81 Patients in the Post-Rituximab Era.

Abstract

The outcome of PTLD has a reported approximate 3-year (yr) overall survival (OS) rate of 35%–40% in the pre-RTX era (JCO 2001; 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,>1 extranodal (EN) site,bone marrow (BM) involvement,CNS disease, andRTX 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 characteristicsPFSOSNo.%HR*PHR*PKidney3746Kidney-pancreas1012SOTPancreas450.740.380.710.36Liver1721Heart810Lung56Time to PTLDEarly (<1 yr)30371.020.950.910.81Late (> 1 yr)5163Monomorphic5568Histology**Polymorphic22271.610.272.180.11Plasmacytic/reactive45EBV + (tumor)Yes3948No30371.090.820.820.64n/a1215PS2–425312.870.0023.310.0010–15669CNS involvementYes10122.570.032.470.050No7188BM involvementYes1215No58723.300.0033.480.003n/a1113EN > 1Yes2936No50622.010.042.190.03n/a22High LDHYes4960No27331.640.212.000.11n/a57Yes5669Low serum albuminNo24303.020.024.720.01n/a11IPI2–447580–233412.040.0531.760.16n/a11Immune suppression alone79Treatment***Radiation or surgery alone22Chemotherapy alone12150.280.0030.300.001Rituximab alone2632Rituximab/chemotherapy3442*Prognostic factors were tested for association with survival by proportional hazards analysis. Hazard ratios (HRs) >1 indicate a poor prognosis, while HRs <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) >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), and4) 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: >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.Table 2. Three-year survival (Kaplan-Meier) based on prognostic variables (univariate).Variable3-year EFS*3-year OS*PSp < 0.0001p < 0.00010–165% (50%, 77%)72% (57%, 82%)2–436% (18%, 54%)35% (15%, 56%)Albuminp = 0.002p = 0.0004Normal75% (49%, 89%)85% (59%, 95%)Low49% (34%, 61%)51% (37%, 64%)CNSp = 0.001p = 0.004No60% (47%, 71%)64% (51%, 74%)Yes30% (7%, 58%)40% (12%, 67%)Received rituximabp = 0.0002p = 0.001No21% (7%, 42%)32% (14%, 79%)Yes69% (55%, 79%)71% (57%, 81%)BM involvementp = 0.005p = 0.005No64% (49%, 75%)70% (56%, 80%)Yes18% (3%, 44%)18% (3%, 44%)> 1 EN sitep = 0.01p = 0.008No64% (48%, 76%)72% (57%, 82%)Yes39% (22%, 58%)40% (20%, 58%)*3-year PFS and OS by Kaplan-Meier analysis are reported (and their 95% CIs).