Prognosis and Outcomes of Patients with Post-Transplant Lymphoproliferative Disorder: A Single Center Retrospective Review

Abstract

Background Patients treated with chronic immunosuppression face a six-fold increase in their cumulative lifetime risk of lymphoma relative to age-matched immunocompetent counterparts. These malignances represent a spectrum of lymphoid and plasmacytic histologies collectively referred to as post-transplant lymphoproliferative disorders (PTLD). Accurate risk-stratification and optimal treatment strategies are unclear given wide histologic and clinical heterogeneity. Current standard-of-care models include immunosuppression reduction and sequential, response-adapted chemoimmunotherapy platforms, however 80% of patients will require chemotherapy exposure. Overall response rates (ORR) are >90%, however relapse is common and serious treatment-related toxicities including infection and allograft rejection pose significant challenges. Several risk-stratification schemes have been proposed to direct initial therapy and predict clinical outcomes, however their external validity has been inconsistent across patient populations. We report here the results of a single-center retrospective study assessing the treatment patterns and outcomes of patients diagnosed with PTLD and provide a risk-assessment profile that may help improve clinical outcomes. Methods Patients with a diagnosis of PTLD were identified by Electronic Medical Records database query. Inclusion criteria were: age ≥ 18 years at the time of diagnosis, confirmation of PTLD by internal pathology review, primary diagnosis from 2008-2018, and receipt of therapy and surveillance care at Northwestern University in Chicago, Illinois, USA. Exploratory univariate analyses were performed using Kaplan-Meier estimates with 95% confidence intervals and log-rank p-values for time-to-event outcomes; significance was set at p < 0.05. Response to treatment and disease progression were classified per provider-specific interpretations of clinical data as assessed by patient chart review. ORR is defined as complete or partial response. Progression-free survival (PFS) is defined as time from diagnosis to disease progression; patients who died before restaging or who were lost to follow-up were censored. Overall survival (OS) is defined as time from diagnosis to death from any cause; patients who were alive at last follow-up were censored. Results A total of 182 patients were identified by database query and 111 patients met our inclusion criteria. Demographics data are provided (Figure 1A). Five-year PFS and OS were 55.7% and 87.2%, respectively (Figure 1B). 92.6% of patients treated with immunosuppression agents underwent dose reduction and 16.8% experienced graft rejection, of which 27.8% required re-transplantation. Exploratory univariate analyses were performed on the following clinical factors: age, LDH, Ann-Arbor Stage, presence of extranodal disease, histologic EBER positivity, ECOG PS, comorbid conditions (type II diabetes, obesity, and coronary artery disease), CNS involvement, transplant type, presence of EBV viremia, and PTLD subtype. Established risk stratification models, including the IPI, R-IPI, Leblond score, Ghobrial score, and PTLD prognostic index, were applied to this cohort. We identified elevated LDH (p=0.04) and IPI score >3 (p=0.015) as predictors of PFS (Figure 1C); elevated LDH (p=0.02) and thoracic allograft transplantation (p=0.03) were predictors of OS (Figure 1D). The PTLD prognostic index significantly predicted PFS (p=0.03) and OS (p=0.013) (Figure 1E). 50.4% received Rituximab monotherapy prior to risk-stratification for combination chemoimmunotherapy; ORR and CR rates with Rituximab monotherapy were 67.9% and 41.1%, respectively. Overall response to Rituximab monotherapy was found to be a significant predictor of PFS (p<0.0001) but not OS (p=0.14) (Figure 1F). Conclusions This study represents one of the largest retrospective cohorts of PTLD patients to date. We show that the PTLD prognostic index is the most accurate risk stratification tool in predicting PFS and OS in this patient population and may have utility in guiding therapeutic approaches in PTLD patients. LDH, IPI score, and type of allograft transplantation are significant clinical variables in predicting clinical outcomes. Furthermore, response to Rituximab monotherapy was a significant predictor of PFS; improving frontline outcomes to high-risk patients remains a critical unmet need. Figure Disclosures Winter: Epizyme: Other: DSMB; Delta Fly Pharma: Consultancy; Amgen: Consultancy; CVS/Caremark: Consultancy; Ariad/Takeda: Consultancy; Norvartis: Consultancy, Other: DSMB; Merck: Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: advisory board. Gordon:Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Karmali:BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; Takeda: Research Funding; Karyopharm: Honoraria; AstraZeneca: Speakers Bureau. Ma:AbbVie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria, Research Funding, Speakers Bureau; Bioverativ: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno: Research Funding; Novartis: Research Funding; TG Therapeutics: Research Funding. Ganger:Mallinkrodt: Consultancy; Gilead: Speakers Bureau. Pro:Verastem Oncology: Research Funding.

HLA-E–restricted immune responses are crucial for the control of EBV infections and the prevention of PTLD

“…EBV reactivations are a main concern in transplant recipients, and EBV + PTLD is a life-threatening malignant complication following EBV reactivations. 4 Although our data now suggest that the occurrence of reactivation events is highly associated with the LMP-1 peptide variant of the infecting EBV strain, the question remains why some of these reactivating patients progress toward EBV + PTLD, whereas in others, the reactivation episode is limited. So far, the degree of immunosuppression, recipient age and ethnicity, allograft type, and distinct host genetic variations were considered as contributing to the risk for EBV + PTLD, 28 but cannot fully explain the progression toward this complication.…”

“…EBV reactivations in transplant recipients may result in development of life-threatening EBV + PTLD. 4 We, therefore, assessed whether there is an association between host HLA-E and EBV LMP-1 peptide variants, EBV reactivation, and EBV + PTLD in transplant recipients. We included 180 EBV-polymerase chain reaction-positive patients after hematopoietic stem cell transplant (N = 31) or solid organ transplant (N = 149), who were followed up for 3 years after transplantation (Table 1).…”

“…3 In solid organ and hematopoietic stem cell transplant recipients, EBV may cause posttransplant lymphoproliferative disorders (EBV + PTLDs), which are associated with poor survival. 4 As these complications occur only in a part of the EBV-seropositive patients, it was hypothesized that there are distinct, individually determined factors in the human immune response that may control EBV replication and eliminate EBV infected and transformed cells.…”

Characterization and outcome of post-transplant lymphoproliferative disorders within a collaborative study

“…These found a later onset, a higher ORR to treatment as well as a trend for a longer OS in the SOT group as compared to the allo-HSCT group. In contrast, the relapse rate was higher in the SOT as compared to the allo-HSCT group (24, 25,27,28). However, in most of these studies treatment is not comprehensively reported or patients from the prerituximab era are included.…”