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Article

Outcomes and Prognostic Assessment of Post-Transplant Lymphoproliferative Disorder: 20-Year Experience

1
Department of Hematology-Oncology and Bone Marrow Transplantation, University of Iowa Healthcare, Iowa City, IA 52242, USA
2
Department of Hematology-Oncology, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA
3
Department of Surgery, University of Cincinnati, Cincinnati, OH 45219, USA
4
Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15232, USA
*
Author to whom correspondence should be addressed.
Lymphatics 2025, 3(1), 5; https://doi.org/10.3390/lymphatics3010005
Submission received: 27 December 2024 / Revised: 8 February 2025 / Accepted: 8 February 2025 / Published: 12 February 2025

Abstract

:
Post-transplant lymphoproliferative disorder (PTLD) is the most common malignancy in adults who receive solid organ transplantation (SOT), apart from skin cancer. It is a serious and potentially fatal complication of chronic immunosuppression (ISI) in SOT recipients. This report describes a 20-year (2001–2021) clinicopathological experience with 59 PTLD patients at an urban center. The median time from transplant to PTLD was 8.5 years and the most common types of transplants were kidney (41%) and liver (31%). Epstein–Barr encoding region (EBER) was positive in 51% tumors, and 50% patients had Epstein–Barr virus (EBV) viremia at diagnosis. Overall survival (OS) at 1 year and 5 years was 78% and 64%, respectively. OS was significantly (p < 0.05) shorter in males (hazard ratio [HR] 3.7), certain organ transplants (lung HR 10.4; liver HR 3.9 relative to kidney), PTLD diagnosed within 12 months of transplant (HR 4.1), multi-organ involvement at diagnosis (HR 7.1), vitamin D deficiency at diagnosis (HR 4.5), and low serum albumin level at diagnosis (HR 3.6). Our study highlights the prognostic factors of PTLD and corroborates improved PTLD outcomes in the past 20 years.

1. Background

Post-transplant lymphoproliferative disease (PTLD) is a heterogeneous clinical and pathologic group of lymphoid disorders ranging from indolent polyclonal proliferation to aggressive monomorphic lymphoma that may complicate solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT) [1]. The spectrum of lymphoid proliferations ranges from Epstein–Barr virus (EBV)-positive or EBV-negative B cell lymphomas or T/NK cell lymphomas, as well as classic Hodgkin lymphoma. PTLD is the second most common malignancy in SOT recipients after non-melanoma skin cancers and is the most common cause of cancer-related death in SOT recipients [2,3]. While the overall incidence of lymphoproliferative disease is approximately 1% in the transplant population, the incidence varies dramatically with the type of allograft [4,5]. PTLD is seen in up to 10–15% of all SOT adult recipients, with the frequency being higher in multi-organ and intestinal transplantation (20%), followed by the lungs (5.7 per 1000 person-years), liver (2.4), heart (2.2), and kidney transplants (1.6), owing in part to the degree of immunosuppression (ISI) warranted in these cases [6,7].
Several risk factors have been elucidated over the past decade; further validation and analysis of these factors is needed to enrich the prediction of PTLD development. EBV pre-transplant status of the recipient and donor, along with age of the recipient, degree and duration of ISI, and type of organ transplanted are identified as strong risk factors for PTLD development [1,8,9]. CMV donor–recipient mismatch and other infections such as Hepatitis C virus (HCV) and Human Herpes Virus-8 (HHV-8) were also reported as risk factors, especially when they coincide with EBV infection [1,10,11].
About 55–65% of PTLD cases after SOT are associated with EBV infection, although this has not been associated with differences in response to therapy or survival, and these cases are treated similarly to EBV-negative (EBV–) PTLD patients [1,12,13,14]. It is postulated that ISI leads to depressed T cell function with associated lack of T cell control of B cell proliferation, resulting in uncontrolled proliferation of EBV-transformed B cells [1]. Several single-center analyses reported that pre-transplant EBV seronegativity can increase the incidence of PTLD by 10- to 76-fold when compared to EBV-seropositive (EBV+) patients due to primary EBV [12,13].
While the prognosis varies with clonality and the extent of the disease, historically, mortality rates in SOT-related PTLD were 50–70% and up to 70–90% in HSCT [12]. However, recent data suggest that outcomes have significantly improved [15,16]. Over 46,000 transplants were completed in the US in 2023, with transplantation numbers continuing to rise yearly after stagnation in the past decade [17,18]. Prognostication and optimization of the approach to PTLD is of importance because the prevalence of PTLD is expected to rise as transplant numbers continue to increase [12]. There is a paucity of information concerning the prognostic factors of patients with PTLD, and there are no validated prognostic risk stratification tools.

2. Results

2.1. Patient Demographics; Clinical and Transplant History

Our search identified 59 adult patients with PTLD who were evaluated at the UC Cancer Center from January 2001 to January 2021. The majority were males (66%) with a median age at transplant of 46.3 (9.3–73.1) years (Table 1). All patients had received SOT, mostly kidney (41%) or liver (31%) allografts. Diabetes was the most frequent indication for a transplant. Most donors were deceased males with a median age of 41.0 (21.0–69.0) years. Median follow-up was 17 (95% CI 10–19) years.

2.2. PTLD Characteristics

The median time from transplant to PTLD diagnosis was 8.5 (range 0.1–32.9) years, and the median age at diagnosis was 55.0 (range 10.0–82.0) years (Table 2). The majority had monomorphic histological type (80%), and two-thirds had extra nodal involvement, with the gastrointestinal (GI) tract (35%) being the most frequently involved site. The most common ISIs were CNI, antimetabolite agents, and steroids in varying combinations.
Epstein–Barr encoding region in situ hybridization status (EBER-ISH) was positive in 51%, and 50% had EBV viremia at diagnosis (Table 2). Among 24 patients who had quantitative EBV viral load (via PCR) available, the median EBV viral load was 1486 (range 200–1,000,000) IU/mL, and 58% had viral load > 1000 IU/mL. Discordance was observed between tumor EBER-ISH status and whole blood EBV DNA in limited patients. There were three tumor EBER-ISH-positive cases that were serum EBV PCR-negative, and there were three EBER-ISH-negative cases that showed EBV PCR positivity.

2.3. Treatment and Outcomes

ISI was changed in 76% of patients after PTLD diagnosis (Table 3). Additional treatments included ones with rituximab alone (20%) or with chemotherapy (56%), with two-thirds (66%) achieving a CR or PR. The most common type of chemotherapy used with rituximab was a combination of cyclophosphamide, doxorubicin, and vincristine (R-CHOP), which was given at the same time as rituximab. At the time of the last follow-up, 34% had died. The median time from PTLD diagnosis to death was 5.3 months. Four patients were noted to have relapsed in the group at last follow-up.

2.4. Time from Transplant to PTLD

Lung transplant recipients had the shortest mean time from transplant to PTLD diagnosis (3.3 years), followed by liver (6.9 years) and kidney transplant recipients (11.3 years), p = 0.0581 (Table 4). Deceased donor (6.3 vs. 10.6 years) and donor–recipient EBV mismatch (1.5 vs. 6.5 years) were also noted to be associated with shorter time to PTLD, but with a p > 0.05.
Median OS as measured by Kaplan–Meier analysis was not reached at data cutoff (December 2021). OS at 1 year was 77.9%, 68.6% at 2 years, and 63.7% at 5 years (Figure 1). When the data were available, the most common cause of death was disease, that is, PTLD (Table 3).
OS was significantly shorter in males (hazard ratio [HR] 3.7, p = 0.0401), for certain transplant types (lung, HR 10.4, p = 0.0013; liver, HR 3.9, p = 0.0236, when compared to kidney transplant), and in those with PTLD diagnosis within 12 months of transplant (HR 4.1, p = 0.0211), multiple organ involvement at diagnosis (HR 7.1, p = 0.0246), presentation with end-organ dysfunction (HR 3.0, p = 0.0319), vitamin D deficiency at diagnosis (HR 4.5, p = 0.0221), low serum albumin level at diagnosis (HR 3.6, p = 0.0002), and no response to treatment when compared with CR (HR 8.8, p = 0.0001), as seen in Table 5 and Figure 2.
Although EBV viral load > 1000 IU/mL had a trend towards lower survival (p > 0.05), tumor EBER-ISH did not show a similar pattern. Recipient EBV+ serostatus had a trend towards poos OS when compared with EBV−; however, this was not statistically significant.
Due to missing values, multivariate analysis was unable to be performed.

3. Discussion

In our study, the monomorphic type of PTLD was the most common type and male preponderance was common, which has also been noted in other studies [2,12,19,20]. Similar to prior analyses, we were able to demonstrate that gender had a significant association with survival, being shorter in males (HR 3.6, p = 0.0401) [21]. The majority of patients developed PTLD > 12 months from transplant (81%) and had better OS, when compared to those who developed PTLD diagnosis within 12 months of the transplant (HR 4.1, p = 0.0211). This is concordant with prior reports in the literature [20,22,23]. As expected, other indicators of high-risk disease such as multiple organ involvement at diagnosis (HR 7.1, p = 0.0246) and presentation with end-organ dysfunction (HR 3.0, p = 0.0319) also seemed to portend poor prognosis.
The median time from transplant to PTLD diagnosis in our study was 8.5 years. Comparing time to PTLD by organ transplanted, lung followed by liver transplant had the shortest time (3.3 and 6.9 years, respectively), while kidney transplant recipients had the longest time to PTLD (11.3 years). In contrast, two studies have reported overall median times from transplant to PTLD diagnosis of 5.2 and 5.5 years, the shortest of which were in liver transplants (0.49 years) and lung transplants (0.65 years) [2,12]. This difference in timing in the development of PTLD could be linked to a larger proportion of kidney transplants in our group, along with varying ISI durations used for different organs, that is, longer duration for the kidney compared to the liver. PTLD also occurs early and has higher cumulative incidence after lung transplantation, likely due to abundant transplanted lymphoid tissue [24]. Additionally, Lau et al. [12] also included infants and children and had more heart transplants in their study, which have been noted to have a longer time from transplant to PTLD. Whether these results should guide our screening strategies for different organ transplants remains an unclear area where more research is needed.
In our study, 50% of patients had EBV viremia at the time of PTLD diagnosis, with a median EBV viral load of 1486 (range 200–1,000,000) IU/mL. Some studies have reported presence of EBV viremia but not the quantitative viral load being associated with development of PTLD [14,25], while others have challenged this finding [26]. Presence of EBV viremia at diagnosis and EBV viral load > 1000 (IU/mL) in our study seemed to portend lower survival, but this was not statistically significant, likely due to the small number of patients with these data available. Lau et al. reported a median pre-treatment EBV viral load of 4393 copies/mL in their study, with longer median OS in patients with lower viral loads [12]. All these results confirm the association of EBV viremia with the diagnosis and outcome of PTLD. Thus, clinicians should have high suspicion of PTLD in post-SOT patients with high EBV viral load and concern for lymphoproliferative disorder. Additionally, EBV needs to be consistently monitored post-SOT in prospective studies to confirm this association.
EBV+ and EBV− PTLD have different genomic signatures and clinical presentations [27,28]. EBV+ PTLD typically occurs early and is most often polymorphic, nondestructive, or non-GCB monomorphic subtypes [27,28]. The role of EBV in pathogenesis is very well known, but its effect on survival is not entirely apparent. Our finding of no significant association of EBV serostatus with survival is concordant with some reports in the literature [14,25], while others have presented conflicting data [23,29]. This can be explained because most reports are retrospective and single-center, with heterogeneous patient cohorts, including age and transplant types. They also span decades during which immunosuppression regimens and diagnostic and management strategies have evolved.
Most of the patients (76%) in our group had changes in their ISI regimen either by adjusting the dose or switching to a different class following the diagnosis of PTLD. Additionally, 76% received rituximab-based therapy, alone or in combination with chemotherapy, and 54% achieved CR. Rituximab-based treatment was associated with a longer survival compared with chemotherapy alone, but this was not statistically significant (rituximab alone HR 2.2, p = 0.5367; rituximab with chemotherapy HR 1.5, p = 0.7026; chemotherapy alone HR 4.1, p = 0.2903). The National Cancer Comprehensive Network (NCCN) guidelines on PTLD have recommended the use of reduction in immunosuppression (RIS) for all patients, if possible, and the use of rituximab therapy with or without chemotherapy for systemic PTLD, while definitive local management can be employed for non-systemic PTLD [30]. Our findings are in line with Katz-Greenberg et al., in which the majority of patients (97%) were managed by RIS and 87% received chemotherapy alone or with rituximab resulting in CR in 67% of patients [2]. Further data are required to identify the outcomes of patients with various chemotherapy regimens alone or with rituximab. As expected, patients who did not respond to treatment had poor outcomes (HR 8.8, p = 0.0001) when compared to those who achieved CR [31]. This emphasizes that patients with no response to early treatment options should be managed aggressively.
In our cohort, median survival was not reached, which is longer than studies conducted in the past two decades [32,33]. The 1-year and 5-year OSs were 78% and 64%, respectively, which is similar to most of the published rates [2].
Among the serum biomarkers at diagnosis, vitamin D deficiency (HR 4.5, p = 0.0221) and low serum albumin level (HR 3.6, p = 0.0002) were associated with poor outcomes. Hypoalbuminemia has also been portrayed as a factor of OS in other studies [20,32], but it is not commonly evaluated by most. Vergote et al. noted hypoalbuminemia as a strong predictor of poor outcomes, with significant association to PTLD-related death and OS in multivariate analysis [20]. However, it is not included in the international prognostic index (IPI) risk scoring typically used for lymphomas including PTLD [34]. In contrast, vitamin D deficiency has not been commonly evaluated in PTLD, except in one study [35], although it has been frequently studied in multiple malignancies, including hematological cancers [36]. Further studies are needed to consolidate the role of serum biomarkers at diagnosis, including vitamin D deficiency and low serum albumin levels in prognostic stratification. These are not commonly included in risk stratification models but should be considered, as our study and Evens et al. demonstrated [32].
Our study is limited by the same inherent factors that affect studies that rely on retrospective review of data, such as missing data and lack of control over confounding factors. Due to missing values, multivariate analysis could not be performed. Some data regarding EBER-ISH, EBV serology, and EBV PCR were missing in a significant proportion of subjects, which we believe is related to the fact that most of these studies only came into practice in the past 20 years. Additionally, there is a recruitment bias with the absence of heart transplants and a high number of kidney transplants, which may have positively affected survival (Table 1). Due to multi-organ involvement of PTLD and multidisciplinary management, data collection is constrained, as diagnosis and management are often distributed over several institutions and subspecialties, including pathology, medical oncology, surgery, radiation oncology, and transplants. Although individual records exist, they need to be collected in unison.

4. Methods

4.1. Data Collection

All adult patients diagnosed with documented histopathologic diagnosis of PTLD who were evaluated at the University of Cincinnati (UC) Cancer Center from January 2001 to January 2021 were included. TriNetx version 5.1 and EMERSE (the Electronic Medical Record Search Engine) software was used to identify patients who satisfied the inclusion criteria, with the assistance of UC’s Center for Health Informatics. These software programs also have the capability to retrieve demographics from the institutional electronic health record (EHR) for selected patients. These data were validated and further details, including those related to cancer diagnosis and treatment, were extracted by the study members through chart review in the EHR. The UC performed more than 350 SOTs in 2022, which included majorly liver and kidney, followed by pancreas, lung, and heart.
Patient-related clinical characteristics reviewed and recorded for each subject included patient demographics, performance status, comorbidities, viral infections, transplant details, immunosuppressive regimen, donor demographics, EBV−, CMV−, and human leukocyte antigen (HLA) mismatch. Transplant-related characteristics included type of SOT, time from transplant to PTLD diagnosis, and type of ISI. PTLD-related characteristics included year of PTLD diagnosis, PTLD subtype according to WHO 2017 classification [37], Ann Arbor staging [38], organ involvement, extra nodal sites, laboratory parameters at diagnosis (albumin, vitamin D level, lactate dehydrogenase [39]), EBV viral load at diagnosis, tumor Epstein–Barr encoding region (EBER) in situ hybridization status (ISH), treatment and response, and date of last follow-up or date of death (if applicable, to calculate overall survival [OS]).
The data were collected and stored in a secured drive under Institutional Review Board (IRB) #2019-1249. IRB waived informed consent, and Health Insurance Portability and Accountability Act authorization was obtained given the retrospective nature of the study with minimal risk to the research patients.

4.2. Clinical Definitions

The higher stage of PTLD was considered as stage III or IV. Vitamin D level < 30 ng/mL was noted as deficient. Multi-organ transplant was defined as having received more than one SOT simultaneously or at a later time. For two patients, where only the year of transplant was known, 1 January of the respective year was included as the date of transplant for analysis. Treatment response was assessed by clinicians’ documented response according to the Lugano criteria [40] and defined as complete response (CR), partial response (PR), stable disease (SD), or no response.
Histologic subtypes of PTLD and Epstein–Barr encoding region in situ hybridization status (EBER-ISH) were obtained from pathology reports. Whole blood EBV DNA viral loads obtained via polymerase chain reaction (PCR) at the time of diagnosis were extracted from laboratory data. For our lab, the limit of detection (LoD) for EBV PCR assay is 18.8 IU/mL. Drugs used for ISI were classified as a calcineurin inhibitor (CNI), which was either tacrolimus or cyclosporine A; mTOR inhibitors sirolimus or everolimus; steroids; and an antimetabolite agent, either mycophenolate mofetil or azathioprine.
Time from transplant to PTLD diagnosis was calculated from date of transplant to the date of histologic diagnosis of PTLD. The time from PTLD diagnosis to death was calculated from the date of histologic diagnosis of PTLD to date of death. OS was calculated from the date of histologic diagnosis of PTLD to the date of death from any cause or censored at last follow-up. The date of the last follow-up was December 2021.

4.3. Data Analysis

An exploratory data analysis was used to identify variables and outcomes. For descriptive analysis, continuous variables such age, weight, height, and body mass index (BMI) were summarized and expressed as medians (interquartile range [IQR]), and categorical or binary variables such as sex, race, stage, and performance status (PS) scale were summarized and expressed as frequencies (%). Kaplan–Meier survival analysis with the log-rank test was used to estimate OS. All p-values were two-sided, and p ≤ 0.05 was considered statistically significant. Outcome estimates were given at specified time points with 95% confidence intervals (95% CIs) for the estimates. Gamma regression techniques were used to assess the relationship of patient and disease characteristics with time from transplant to PTLD diagnosis, while Cox proportional hazards regression was performed to assess the effects of patient and disease characteristics on OS. All statistical analyses were performed using the statistical package SAS 9.4 (SAS Institute, Cary, NC, USA). GraphPad Prism version 9 (Boston, MA, USA) was used for figures.

5. Conclusions

This study highlights the prognostic factors of PTLD that could be helpful in the management of patients; they may also guide future research. Moreover, clinical factors at diagnosis recognized patients with distinctly divergent outcomes. Our data highlight some less commonly sought factors such as vitamin D deficiency and hypoalbuminemia, which should be considered in the risk stratification prognostic models.

Author Contributions

Conceptualization, H.S.; methodology, H.S.; validation, H.S.; formal analysis, K.W.; investigation, Z.O., T.M. and H.S.; data curation, Z.O., T.M. and H.S.; writing—original draft preparation, Z.O. and H.S.; writing—review and editing, Z.O., T.M., H.S, S.A.S., K.W. and T.L.; visualization, H.S.; supervision, T.L.; project administration, H.S.; funding acquisition, T.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board (IRB) of the University of Cincinnati, procol #2019-1249. IRB waived informed consent, and Health Insurance Portability and Accountability Act authorization was obtained given the retrospective nature of the study with minimal risk to the research patients.

Informed Consent Statement

Patient consent was waived due to retrospective nature of the study with minimal risk to the research patients.

Data Availability Statement

No publicly archived datasets were used for this study.

Conflicts of Interest

The authors declare no relevant conflict of interest.

Abbreviations

CIConfidence interval
CMVCytomegalovirus
CRComplete response
EBVEpstein–Barr virus
EBER-ISHEpstein–Barr-encoded RNA in situ hybridization
GIGastrointestinal
HLAHuman leukocyte antigen
HCVHepatitis C virus
HRHazard ratio
HSCTHematopoietic stem cell transplant
ISIImmunosuppression
IUInternational units
LDHLactate dehydrogenase
NSNot significant
OSOverall survival
PTLDPost-transplant lymphoproliferative disorder
RISReduction in immunosuppression
SOTSolid organ transplantation

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Figure 1. Overall survival (OS) by Kaplan–Meier curves for the entire PTLD cohort. OS at 1 year, 2 years, and 5 years was 77.9%, 68.6%, and 63.7%, respectively.
Figure 1. Overall survival (OS) by Kaplan–Meier curves for the entire PTLD cohort. OS at 1 year, 2 years, and 5 years was 77.9%, 68.6%, and 63.7%, respectively.
Lymphatics 03 00005 g001
Figure 2. Overall survival by gender (a), transplant type (b), treatment response (c), recipient EBV time from transplant to PTLD (e) using Kaplan–Meier curves. CR—complete response, PR—partial response, SD—stable disease.
Figure 2. Overall survival by gender (a), transplant type (b), treatment response (c), recipient EBV time from transplant to PTLD (e) using Kaplan–Meier curves. CR—complete response, PR—partial response, SD—stable disease.
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Table 1. Baseline patient and donor demographics in relation to transplant. Continuous data are represented as medians (IQR). All categorical data are presented as numbers (percent). Percentages were rounded to nearest decimal point.
Table 1. Baseline patient and donor demographics in relation to transplant. Continuous data are represented as medians (IQR). All categorical data are presented as numbers (percent). Percentages were rounded to nearest decimal point.
CharacteristicsValue
Gender, % (n)
   Male 66.1% (39/59)
   Female33.9% (20/59)
Race, % (n)
   Caucasian91.5% (54/59)
   Black6.8% (4/59)
   Asian1.7% (1/59)
Age at transplant, median (range)46.3 (9.3–73.1) years
Diabetes at transplant, % (n)
   Yes46.7% (21/45)
   No53.3 (24/45)
   NA(14)
Type of transplant, % (n)
   Kidney 40.7% (24/59)
   Liver 30.5% (18/59)
   Kidney–pancreas 13.5% (8/59)
   Lung 10.2% (6/59)
   Other5.1% (3/59)
Indication of transplant, % (n)
   Diabetes 20.5% (8/39)
   Drug-induced injury 12.8% (5/39)
   Hypertensive nephrosclerosis10.3% (4/39)
   Other56.4% (22/39)
   NA(20)
Donor gender, % (n)
   Male54.3% (19/35)
   Female45.7% (16/35)
   NA(24)
Donor age, median (range)41.0 (21.0–69.0) years
Donor status, % (n)
   Deceased77.8% (28/36)
   Alive22.2% (8/36)
   NA(23)
HLA mismatch (≥6—HLA-A, B, DR), % (n)
   Yes26.9% (7/26)
   No73.1% (19/26)
   NA(33)
Recipient EBV serostatus, % (n)
   Positive69.7% (23/33)
   Negative30.3% (10/33)
   NA(26)
Donor–Recipient EBV mismatch, % (n)
   Yes 19.2% (5/26)
   No80.8% (21/26)
   NA(33)
Donor–Recipient CMV mismatch, % (n)
   Yes 32.3% (11/34)
   No67.7% (23/34)
   NA(25)
CMV—cytomegalovirus, EBV—Epstein–Barr virus, HLA—human leukocyte antigen, NA—not available.
Table 2. PTLD distribution and clinical manifestations at diagnosis. Continuous data are represented as medians (IQR). All categorical data are presented as numbers (percent). Percentages were rounded to the nearest decimal point.
Table 2. PTLD distribution and clinical manifestations at diagnosis. Continuous data are represented as medians (IQR). All categorical data are presented as numbers (percent). Percentages were rounded to the nearest decimal point.
VariablesValue
Time from transplant to PTLD diagnosis,
median (range)
8.5 (0.1–32.9) years
Time from transplant to PTLD diagnosis, % (n)
   ≤12 months20.3% (12/59)
   >12 months80.7% (47/59)
Patient age at diagnosis, median (range)55.0 (10.0–82.0) years
Subtype of PTLD, % (n)
   Non-destructive2.2% (1/45)
   Polymorphic 15.6% (7/45)
   Monomorphic 80.0% (36/45)
   Hodgkin2.2% (1/45)
   NA(14)
Ann Arbor stage of PTLD, % (n)
   I20.0% (6/30)
   II13.3% (4/30)
   III16.7% (5/30)
   IV50.0% (15/30)
   NA(29)
Site involvement by PTLD, % (n)
   GI35.0% (14/40)
   Lymph nodes35.0% (14/40)
   Other30.0% (12/40)
   Multiple organs20.0% (8/40)
   NA(19)
Among other/multiple organs, liver (n = 5), central nervous system (n = 4), and lung (n = 59) were most common.
Tumor EBER-ISH status, % (n)
   Positive51.3% (19/37)
   Negative48.7% (18/37)
   NA(22)
EBV viremia at diagnosis, % (n)
   Present (>18.8 IU/mL)50.0% (26/52)
   Absent50.0% (26/52)
   NA(7)
EBV viral load > 1000 IU/mL at diagnosis, % (n)
   Yes58.3% (14/24)
   No41.7% (10/24)
   NA(35)
EBV viral load at diagnosis, median (range)1486 (200–1000,000) IU/mL
Serum LDH at diagnosis, % (n)
   Elevated41.7% (20/48)
   Normal (110–270 U/L)58.3% (28/48)
   NA(11)
Serum LDH at diagnosis, median (range)247 (83–1004) U/L
Serum albumin at diagnosis, % (n)
   Normal (3.5–5.7 g/dL)60.7% (34/56)
   Low39.3% (22/56)
   NA(3)
Serum albumin at diagnosis, median (range)3.7 (<1.5–4.8) g/dL
Serum vitamin D at diagnosis, % (n)
   Deficient (<30 ng/mL)56.4% (22/39)
   Normal43.6% (17/39)
   NA(20)
Presentation with end organ dysfunction, % (n)
   Yes20.3% (12/59)
   No79.7% (47/59)
Type of immunosuppression at PTLD diagnosis,
% (n)
   Calcineurin inhibitors90.0% (45/50)
      Tacrolimus   84.0% (42/50)
      Cyclosporine   6.0% (3/50)
   Antimetabolite86.0% (43/50)
      Mycophenolate mofetil   68.0% (34/50)
      Azathioprine   18.0% (9/50)
   Steroids36.0% (18/50)
   mTOR inhibitors4.0% (2/50)
      Sirolimus   2.0% (1/50)
      Everolimus   2.0% (1/50)
   NA(9)
EBV—Epstein–Barr virus, EBER-ISH—Epstein–Barr encoding region in situ hybridization status, GI—gastrointestinal, LDH—lactate dehydrogenase, NA—not available.
Table 3. Management of PTLD and patient outcomes. Continuous data are represented as medians (IQR). All categorical data are presented as numbers (percent). Percentages were rounded to the nearest decimal point.
Table 3. Management of PTLD and patient outcomes. Continuous data are represented as medians (IQR). All categorical data are presented as numbers (percent). Percentages were rounded to the nearest decimal point.
VariablesValue
Management of PTLD, % (n)
   Observation *1.7% (1/59)
   Rituximab alone20.3% (12/59)
   Rituximab–chemotherapy55.9% (33/59)
   Rituximab–chemotherapy followed by HSCT **1.7% (1/59)
   Chemotherapy alone 5.1% (3/59)
   Reduction of immunosuppression alone6.8% (4/59)
Change in immunosuppression, % (n)
   Yes76.3% (45/59)
   No23.7% (14/59)
Response to treatment, % (n)
   Complete response (CR)54.2% (32/59)
   Partial response (PR)11.9% (7/59)
   Stable disease (SD)3.4% (2/59)
   No response13.5% (8/59)
Last known status, % (n)
   Alive66.1% (39/59)
   Dead33.9% (20/59)
Cause of death
   Disease (PTLD)54.5% (6/11)
   Infection18.2% (2/11)
   Graft failure9.1% (1/11)
   Other18.2% (2/11)
   Unknown(9)
Time from PTLD diagnosis to death, median (range)5.3 (0.7–87.4) months
Relapse, % (n)
   Yes6.8% (4/59)
* Observation refers to no treatment including no reduction in immunosuppression (RIS). ** Included in rituximab–chemotherapy group for further analysis. Most common type of chemotherapy used with rituximab was cyclophosphamide, doxorubicin, and vincristine (R-CHOP).
Table 4. Time from transplant to PTLD diagnosis in relationship with patient, donor, and transplant variables by univariate gamma regression models.
Table 4. Time from transplant to PTLD diagnosis in relationship with patient, donor, and transplant variables by univariate gamma regression models.
VariablesMean Time from Transplant to PTLD (Years) (SD)p-Value
Gender 0.5250
   Male8.59 (6.99)
   Female9.93 (8.76)
Race 0.1325
   Caucasian8.67 (7.54)
   Black14.53 (8.04)
Type of transplant 0.0581
   Liver6.86 (8.30)
   Kidney11.27 (7.37)
   Kidney–pancreas9.30 (4.54)
   Lung3.31 (4.19)
   Other15.05 (9.40)
Indication of transplant 0.8843
   Diabetes7.91 (4.19)
   Hypertensive nephrosclerosis5.14 (5.40)
   Drug induced injury6.35 (7.13)
Donor Gender 0.3483
   Male8.23 (5.89)
   Female6.19 (6.81)
Donor living status at transplant 0.0879
   Deceased6.31 (6.23)
   Alive10.57 (5.33)
HLA mismatch 0.7325
   Yes10.08 (5.89)
   No9.15 (6.12)
EBV mismatch 0.1109
   Yes1.51 (2.27)
   No6.45 (6.49)
SD—standard deviation.
Table 5. Univariate analysis of overall survival by patient, transplant, and PTLD characteristics by univariate logistic regression models.
Table 5. Univariate analysis of overall survival by patient, transplant, and PTLD characteristics by univariate logistic regression models.
Hazard Ratio95% CIp-Value
Gender
   FemaleReference
   Male3.6631.0752, 12.65820.0401 *
   Race
CaucasianReference
   Black1.8840.529, 6.7100.3284
   Asian5.8950.742, 46.8440.0934
Transplant Type
   KidneyReference
   Liver3.4941.183, 10.3200.0236 *
   Lung10.4112.490, 43.5250.0013 *
   Other0.8930.103, 7.7490.9179
Time from transplant to PTLD diagnosis
   >12 monthsReference
   ≤12 months4.11521.2368, 13.69110.0211 *
PTLD subtype
   MonomorphicReference
   Non-destructive0.0000.0000.9948
   Hodgkin-type0.0000.0000.9980
   Polymorphic0.3710.049, 2.8330.3389
Ann Arbor stage of PTLD
   IReference
   II1.0740.095, 12.1830.9542
   III1.9740.259, 15.0640.5117
   IV2.0000.382, 10.4670.4116
Site involved by PTLD
   GI
   Lymph nodes2.3190.548, 9.8240.2533
   Other, single site3.1210.756, 12.894 0.1158
   Multiple organs7.1121.285, 39.3490.0246 *
Presentation with end-organ dysfunction
   NoReference
   Yes3.0031.100, 8.1970.0319 *
Recipient EBV serostatus
   NegativeReference
   Positive2.3380.4787, 11.420.2939
Tumor EBER-ISH
   NegativeReference
   Positive0.5270.159, 1.7430.2940
   EBV viremia
   AbsentReference
   Present1.4220.559, 3.6190.4601
EBV viral load > 1000 (IU/mL)
   NoReference
   Yes3.3230.647, 17.0580.1502
Serum Vitamin D at diagnosis
   Normal levelReference
   Deficient (<30 ng/mL)4.5331.253, 16.5380.0221 *
Age at diagnosis (Unit = 10)1.0130.837, 1.5400.4150
Donor age (Unit = 10)1.0100.703, 1.7220.6758
Serum LDH at diagnosis (U/L)1.0010.983, 1.0340.5333
Low serum albumin at diagnosis (g/dL) (Unit = 0.5)3.5461.3513, 2.63150.0002 *
Change in immunosuppression
   NoReference
   Yes0.5380.205, 1.4070.2061
Management of PTLD
   ObservationReference
   Reduction in immunosuppression alone0.0000.0000.9938
   Rituximab alone2.1500.190, 24.3760.5367
   Rituximab–chemotherapy1.5330.171, 13.7320.7026
   Chemotherapy alone4.0740.302, 55.0110.2903
Response to treatment
   Complete responseReference
   No response8.7752.936, 26.2250.0001 *
   Partial response2.4550.484, 12.4440.2783
   Stable disease0.5510.051, 5.9300.623
* denotes p < 0.05. EBV—Epstein–Barr virus, EBER-ISH—Epstein–Barr encoding region in situ hybridization, GI—gastrointestinal, LDH—lactate dehydrogenase.
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Shaikh, H.; Omer, Z.; Wima, K.; Magge, T.; Shah, S.A.; Latif, T. Outcomes and Prognostic Assessment of Post-Transplant Lymphoproliferative Disorder: 20-Year Experience. Lymphatics 2025, 3, 5. https://doi.org/10.3390/lymphatics3010005

AMA Style

Shaikh H, Omer Z, Wima K, Magge T, Shah SA, Latif T. Outcomes and Prognostic Assessment of Post-Transplant Lymphoproliferative Disorder: 20-Year Experience. Lymphatics. 2025; 3(1):5. https://doi.org/10.3390/lymphatics3010005

Chicago/Turabian Style

Shaikh, Hira, Zulfa Omer, Koffi Wima, Tara Magge, Shimul A. Shah, and Tahir Latif. 2025. "Outcomes and Prognostic Assessment of Post-Transplant Lymphoproliferative Disorder: 20-Year Experience" Lymphatics 3, no. 1: 5. https://doi.org/10.3390/lymphatics3010005

APA Style

Shaikh, H., Omer, Z., Wima, K., Magge, T., Shah, S. A., & Latif, T. (2025). Outcomes and Prognostic Assessment of Post-Transplant Lymphoproliferative Disorder: 20-Year Experience. Lymphatics, 3(1), 5. https://doi.org/10.3390/lymphatics3010005

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