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- Materials and Methods
Significant mortality is associated with post-transplant lymphoproliferative disorder (PTLD) in kidney transplant recipients (KTX). Univariate/multivariate risk factor survival analysis of US PTLD KTX reported to Israel Penn International Transplant Tumor Registry from November 1968 to January 2000 was performed. PTLD presented 18 (median) (range 1–310) months in 402 KTX. Death rates were greater for those diagnosed within 6 months (64%) versus beyond 6 months (54%, p = 0.04). No differences in death risk for gender, race, immunosuppression, EBV, B or T cell positivity were identified. Death risk increased for multiple versus single sites (73% vs. 53%, hazards ratio (HR) 1.4). A 1-year increase in age increased HR for death by 2%. Surgery was associated with increased survival (55% vs. 0% without surgery) (p < 0.0001). Patients with allograft involvement, treated with transplant nephrectomy alone (n = 20), had 80% survival versus 53% without allograft removal (n = 15) (p < 0.001). Overall survival was 69% for allograft involvement alone versus 36% for other organ involvement plus allograft (n = 19 alive) (p < 0.0001). Death risk was greater for multiple site PTLD and increasing age, and risks were additive. Univariate analysis identified increased death risk for those not receiving surgery, particularly allograft involvement alone.
Materials and Methods
- Top of page
- Materials and Methods
An analysis of all United States KTX voluntarily reported to the IPITTR with PTLD from November 1968 to January 2000 was retrospectively carried out in December 2001. Factors evaluated included age at transplant, gender, race, type of transplant (living or cadaveric), age at PTLD diagnosis, time of occurrence of PTLD, immunosuppression, PTLD characteristics (Epstein–Barr virus status, morphology, clonality), sites of PTLD presentation, treatment of PTLD, causes of death and patient survival.
A Cox regression model was performed to explain survival outcomes. A Kaplan–Meier time to event analysis was performed for survival (Tables 1 and 2). A p-value of less than 0.05 was considered to be statistically significant.
Table 1. Multivariate analysis of risk factors for survival in patients diagnosed with PTLD
|Variable||Survival||Hazard ratio (HR)||p-value|
| Single vs. multiple||47% vs. 27%||1.4||p < 0.04|
|B Cell (yes/no)||49% vs. 33%||1.5||p < 0.03|
|ATG/ALG,OKT3||44% vs. 35%||0.52||p < 0.002|
|EBV (yes/no)||54% vs. 50%||1.5||p = ns|
|CYA (yes/no)||43% vs. 33%||1.1||p = ns|
|AZA (yes/no)||42% vs. 39%||1.5||p = ns|
| Female vs. male||45% vs. 42%||1.2||p = ns|
| Caucasian vs. African American||45% vs. 45%||1.5||p = ns|
|Age at diagnosis||A 1-year increase in age increases the risk of death by 2%||0.98||p = 0.0004|
Table 2. Univariate analysis of risk factors for survival in patients diagnosed with PTLD
|Surgery for PTLD (yes/no)||55% vs. 0%||p < 0.0001|
|Transplant nephrectomy for isolated allograft alone PTLD involvement||80% vs. 53%||p = ns|
|Patients diagnosed with PTLD < or > 6 months post-transplant||36% vs. 46%||p < 0.0013|
|Patients diagnosed with PTLD < or > 12 months post-transplant||40% vs. 45%||p < 0.04|
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- Materials and Methods
The present series represents a multivariate risk factor analysis performed on the largest experience of PTLD in KTX reported to date. Time from transplantation to PTLD presentation varies widely in the literature, ranging from less than 1 month to several years. In this series, PTLD presented relatively early post-transplant, occurring at a median of 18 months.
The incidence of PTLD in pediatric transplant recipients has been reported as higher than that in adults, and is thought to be related to a higher rate of EBV infection in children (10,11). Interestingly, our multivariate analysis revealed that, at time of PTLD diagnosis, for each year of increased age the risk of death rose by 2%. This observation suggests a bimodal effect of age on PTLD risk. No difference in survival between patients of different gender or race was determined (Table 1).
In this IPITTR experience, the majority of patients with PTLD were on cyclosporine, azathioprine, prednisone based regimens. This observation, however, may reflect the historic nature of IPITTR as PTLD has been noted in all transplant immunosuppressive eras. A significant difference in survival was observed between patients who received ATG/ALG or OKT3 therapy for induction or rejection versus those who did not. This may be reflective of the risks associated with greater amounts of immunosuppression exposure in these patients.
Cancer development is linked to the immunosuppressed state per se which among other factors, makes transplant recipients prone to a variety of virus-related tumors (10,12–14). Transplant recipients, have demonstrated a susceptibility to infection from viruses such as EBV and cytomegalovirus which have been implicated as co-factors in malignancy formation (12,15–18). The majority of the PTLDs in this series were B cell predominant, EBV positive, monoclonal and polymorphic. Our analysis did find B cell predominance as a factor associated with lower survival. Interestingly, EBV serologic status did not influence survival. However, this may be reflective of the limited amount of data available for this variable.
In distinct contrast to lymphomas in the general population where lymph nodes are almost always involved, 84% of PTLDs did not involve lymph nodes. Surprisingly, one of the most frequent extra-nodal sites was the central nervous system, which was involved in 19% of patients with PTLD. The reasons for neurotropism, however, are not clear from the present series.
Allograft involvement represents an interesting feature of PTLD. A relatively high proportion (21%) of patients presented with renal allograft involvement. Patients with PTLD isolated to the allograft may be surgically cured and often undergo ISD, possibly allowing reconstitution of the immune system to act against PTLD and more adequately prevent deadly opportunistic infections. In the IPITTR series, survival in patients with PTLD restricted to the renal allograft alone who underwent transplant nephrectomy was increased compared to those patients who did not have an allograft nephrectomy, although this was not statistically significant. This observation is similar to the more general observation where patients with single site involvement of PTLD had superior survival compared to those with multiple site involvement. This may be due to the greater extent of disease, which requires increased intensity of therapy and therefore greater toxicities. It is not possible to determine from the present experience whether the increased survival in patients with isolated involvement of the renal allograft is a function of (1) a fundamentally different biologic behavior of PTLD in these patients, (2) allograft removal, (3) the degree of ISR or (4) a combination of all of these factors.
The death rate in patients diagnosed with PTLD within 6 months post-transplant (64%) was greater than that in patients diagnosed beyond 6 months post-transplant (54%, p = 0.04). Similarly, 60% of patients within 12 months from transplant died compared to 55% of those after 1-year post-transplant (p < 0.04). There are several possible explanations for this including (1) late PTLD recurrence, (2) toxicities from PTLD therapy and (3) late presentation of opportunistic infections.
Our analysis also demonstrated that death risk increased with increasing age at diagnosis. The reasons for this finding are not apparent from the present study. However, older patients may not tolerate chemotherapy as well as younger patients due to concomitant medical complications such as cardiovascular disease, and toxicities in this patient population are not as well known, as elderly patients are often underrepresented in oncology therapeutic intervention trials (19,20).
This first multivariate analysis of IPITTR data provides insight into various questions regarding PTLD in KTX. Although the time of PTLD diagnosis decreased from a median of 23.9 years post-transplant in the 1960s to a median of 0.7 years post-transplant in the 1990s, no difference in survival was observed between 1960 and 1999. Moreover, when comparing the larger numbers of patients diagnosed with PTLD in 1980 to those diagnosed with PTLD in 1990, no significant difference was observed in terms of the effects of any risk factors on survival. We hypothesize that the decrease in the median time to PTLD diagnosis is the result of the development of more potent immunosuppression and the transplantation of higher immunologic risk patients that require greater amounts of immunosuppression for the prevention of rejection. Improvements in treatment for PTLD may also account for the lack of difference in survival throughout the decades, despite an earlier occurrence of PTLD in the 1990s. Future research should be focused on defining risk factors for PTLD in the current immunosuppressive era, and further analyzing outcomes in patients with PTLD.
Overall, risk factors that influence survival demonstrated a significantly higher death risk with multiple site PTLD involvement, B cell predominance, exposure to ALG/ATG, OKT3 and increasing age. Univariate analysis also found increased death risk for renal transplant recipients who did not undergo surgery. Additionally, survival in patients with PTLD restricted to the renal allograft alone who underwent transplant nephrectomy was higher than that in those patients who did not have an allograft nephrectomy, although this did not reach statistical significance. The death rate in patients diagnosed with PTLD within 6 and 12 months post-transplant was also found to be greater than that in patients diagnosed beyond 12 months post-transplant and although further research is needed, we hypothesize that this may be related to a more aggressive PTLD. A limitation of this study is that due to the voluntary nature of the registry, we are not able to analyze the underlying transplant population from which these PTLD cases were derived. Future studies are warranted for further comparison of risk factors and outcomes.
Currently, there is no uniform standard for defining PTLD, and PTLD treatment varies widely. Due in part to the small number of patients affected by PTLD at various transplant centers, there are no randomized-controlled trials to determine the efficacy of preventative or therapeutic interventions. Efforts should also focus on the prevention of PTLD. Current and future research efforts should be aimed at (1) identifying risk factors for PTLD, (2) standardizing a PTLD definition and (3) evaluating the role of therapeutic interventions to improved patient survival in renal transplant recipients affected with PTLD.