Hodgkin Lymphoma Type Post-Transplant Lymphoproliferative Disorder (HL-PTLD) after Solid Organ Transplant (SOT): A Comprehensive and Comparative Analysis of Disease Characteristics, Prognosis, and Survival
Authors: Rosenberg Aaron S. , Klein Andreas K. , Ruthazer Robin , Evens Andrew M. 
Published: October 2019

Abstract
Background: HL-PTLD is a rare subtype of PTLD that carries an unknown prognosis as minimal clinical data are available. Furthermore, little is known regarding differences in clinical features between HL-PTLD and HL and the optimal treatment of HL-PTLD is not well defined.
Methods: Patients (pts) diagnosed with HL-PTLD from 1/1999 - 4/2011 were identified in the Scientific Registry of Transplant Recipients, a prospective database of SOT recipients. Additionally, non-PTLD HL pts (n=13,847) were identified in the Surveillance, Epidemiology and End Results (SEER) Program. Baseline characteristics were compared using Wilcoxon and Chi square testing. Further, we compared cohorts of HL-PTLD and HL-SEER pts exactly matched on age, sex, and year (yr) of diagnosis. Overall survival (OS) rates were estimated using Kaplan-Meier and compared with log rank test. Cox proportional hazards models estimated hazard ratios (HR) and adjusted HR (aHR).
Results: We identified 192 HL-PTLD pts. Compared with HL-SEER pts, HL-PTLD pts were older (median age 38 vs 51 yrs, respectively, P<0.04) and were more likely male (54% vs 73%, respectively, P<0.001), and had extranodal disease (3% vs 42%, respectively, P<0.001). Among pts with tumor Epstein-Barr Virus (EBV) status noted, 74% were positive. EBV negativity correlated with increased age (odds ratios/decade 1.52 (95% CI 1.20 – 1.99)). Median OS for the entire HL-PTLD cohort was 88 months and the 5-yr OS was 56% (95% CI 49% – 64%). In the exactly matched cohort, 5-yr OS for HL-PTLD (n=179) was significantly inferior compared with HL-SEER pts (n=1244) (57% vs 80%, respectively, P<0.001; see Fig 1). Further, the aHR of death for HL-PTLD compared with HL-SEER pts remained significantly increased after controlling for age, sex, race, extranodal disease, and yr of diagnosis (2.38, 95% CI 1.79 – 3.15). Detailed treatment data were available for 173 HL-PTLD pts. 75% (n=130) of pts had reduction in immune suppression (RIS) with 16% (n=27) having RIS + radiation (RT), 14% (n=24) RIS + rituximab (Rtx) and 60% (n=103) RIS with chemotherapy (Ctx). The other 24% (n=42) of pts received Ctx without RIS, while 1 pt received RT alone. In terms of all Ctx, 20% (n=38) of pts received ABVD or ABVD-like therapy and 13% (n=25) had other commonly utilized HL Ctx (eg, Stanford V, MOPP, BEACOPP); 18% of pts (n=35) received CHOP and 24% (n=47) had other non-traditional Ctx. Additionally, 17% (n=32) of all pts had Rtx and 18% (n=34) had RT as part of treatment. Among HL-PTLD pts, factors associated with decreased OS in univariate analysis were advanced age (HR 1.30/decade, 95% CI 1.15-1.45), heart transplant (HR 1.63, 95% CI 1.02 – 2.61), and increased baseline creatinine (Cr) (HR 1.78 per 0.1gm/dL increase, 95% CI 1.29 – 2.44). Karnofsky performance status (PS) <80 did not reach statistical significance (HR 1.50, 95% CI 0.80 – 2.73), but was entered into the multivariable models as part of a pre-specified analytic plan. In multivariable analysis, only age (aHR 1.26/decade, 95% CI 1.10 – 1.45) and elevated Cr (1.68/0.1gm/dL, 95% CI 1.15 – 2.46) remained significant for increased risk of death. In terms of treatment impact on HL-PTLD outcomes, use of any Ctx (n=144) was associated with improved OS (aHR 0.54 (95% CI 0.32 – 0.90)), while OS appeared inferior for pts who received CHOP or other Ctx (HRs (95% CI): 2.21 (1.11 – 4.39) and 2.07 (1.10 – 3.91; see Fig 2). Notably, after controlling for age, heart transplant, Cr, and poor PS on multivariable analysis, there was no statistical difference in OS for CHOP vs HL-specific regimens (aHR: 1.66, 95% CI 0.81 - 3.42); however, the risk of increased death for pts treated with other cytotoxic Tx or without Ctx remained significantly increased (aHR (95% CI) 2.01 (1.06 - 3.82) and 2.78 (1.43 - 5.40), respectively). Finally, treatment with RIS, RT, or Rtx were not associated with OS after controlling for age, heart transplant, Cr and PS.
Conclusions: To the best of our knowledge, this is the largest cohort of HL-PTLD reported to date. When compared with HL-SEER pts, HL-PTLD pts were older, more likely male, and had higher frequency of extranodal disease. Furthermore, HL-PTLD pts had significantly inferior OS. Among HL-PTLD pts, clinical factors at diagnosis identified pts with markedly divergent outcomes. In addition, treatment without Ctx (including RIS alone) appeared insufficient, and moreover, treatment with HL-specific Ctx (and possibly CHOP) resulted in the most optimal outcomes.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.