PTLD is a major cause of morbidity and mortality after solid organ transplantation. Despite advances in immunosuppression, the risk of PTLD remains significant, affecting 1–30% of transplant recipients(23
). In this study we aimed to determine the outcome of the common initial step in the management of PTLD – withdrawal of immunosuppression. It follows common wisdom established more than 20 years ago(5
): if PTLD is caused by the unchecked proliferation of EBV-transformed lymphocytes under immunosuppressive therapy, then withdrawal of immunosuppression will allow the anti-tumor effects of the immune system to recover, resulting in tumor regression.
Our study demonstrates a response rate of 45% in patients selected for treatment with RI alone, with the majority being complete responses. Only 4 relapsed/refractory patients never received 2nd-line therapy, illustrating that most patients have the potential for second-line salvage if they fail RI.
Our second cohort included 30 patients who underwent surgical excision of a skin lesion, gastrointestinal mass or a graft containing PTLD, rendering them free of disease prior to adjuvant RI, intended to prevent relapse. We think of lymphoid proliferative disorders as systemic diseases and normally favor systemic therapy. Several reports have utilized surgery in PTLD(28
), and here we describe a large group of patients, in which surgical treatment followed by RI resulted in successful control of the disease and most often permanent cure (only 27% relapsed). We did not identify a sufficient number of patients who underwent surgery without
adjuvant RI and whether RI was necessary is a question that cannot be answered by this study.
The safety of RI has been a major concern. We demonstrated a 32% acute rejection rate with RI-containing regimens. Some of these patients recovered and others underwent a second transplantation following resolution of their PTLD (Figure S1
). Keeping in mind that cytotoxic chemotherapy agents are very effective immunosuppressants, 2nd
-line therapy after failure of RI can salvage an acute rejection episode. If allograft rejection becomes irreversible, a second transplant is a valid option, as demonstrated in our study and others(33
). Interestingly, the extent of RI failed to predict rejection, but RI strategies were unbalanced across organs and firm conclusions cannot be drawn.
Should we attempt RI alone in all patients presenting with PTLD? This study provides significant insight. First, some presumed risk factors — such as EBV negativity or monomorphic PTLD — did not show association with response. As opposed to previously published work, our study included multiple allograft types and a significant number of patients with EBV-negative disease (30% of the RI alone cohort), allowing us to demonstrate that RI can be effective in EBV-negative PTLD(35
) and across all histologic subtypes and allograft types, including “high-risk” organs such as heart and lung. Second, lack of response is predictable. In the current study, we identified bulky disease, advanced stage and older age as adverse factors that predict failure to respond. Patients who lacked these factors had a 77% chance of response to RI alone. The validity of these conclusions is limited by the retrospective nature of our study and the lack of data availability for some of the important variables. Prospective studies are needed to clarify the role of previously reported biomarkers of response, such as quantitative PCR for EBV(36
) and analysis of EBV-specific cytotoxic T-lymphocytes(37
Finally, our survival analysis identified several strong predictors of poor survival, which generally reconcile with known risk factors in lymphoid malignancies (age, high LDH, B symptoms, BM involvement). These findings partially overlap previous PTLD studies, which identified age, BM and CNS involvement, LDH, performance status, and high-risk histology (Burkitt-like, T-cell) as important prognostic factors(22
). EBV status, stage and late PTLD have been identified by some studies (22
) but not by others (38
), which illustrates the heterogeneity in study design, size and population (pediatric vs. adult, organ-focused vs. mixed). Our study focused on adult patients treated with RI alone and had a baseline imbalance towards monomorphic PTLD and lack of CNS involvement. Our survival analysis may therefore not apply to all PTLD patients.
Approximately 35% of patients in this study were diagnosed before the availability of rituximab, which can be used either alone or in combination with chemotherapy resulting in response rates of 50–80%(9
). Rituximab can spare patients the risks of cytotoxic chemotherapy, but still has serious side effects, mainly infusion reactions, immune suppression and other idiosyncratic reactions(46
). A recent retrospective report demonstrated favorable outcome and 3-year OS of 73% with the use of rituximab early in therapy, but all patients in that series also underwent RI initially(19
). The relative contributions of RI and rituximab to the high response rate in that study are unknown. Similarly, other reports on rituximab for PTLD have focused on 2nd
). Considering the poor survival that was demonstrated in our study for patients who never underwent RI, including patients who received rituximab (), our study underscores the importance of RI either alone or in conjunction with rituximab. Notably, our survival analysis failed to demonstrate a difference in survival between patients treated with RI alone before and after the year 2000 (p=0.91). A similar analysis performed on our entire patient cohort (n=153) also showed a non-significant difference (p=0.39), implying that the introduction of rituximab may not have resulted in a significant improvement in outcome.
Our survival analysis demonstrated two subgroups of low-risk patients, in which treatment with RI alone resulted in 3-year overall survival rates of 100% and 79%, respectively. These outcomes are similar or better compared to the recent report about rituximab(19
), allowing us to hypothesize that RI alone may be sufficient in low-risk patients. It is also notable that rituximab did not seem to protect against rejection ().
Our study was not powered to differentiate between RI strategies. Complete and partial withdrawals of immunosuppression resulted in similar rates of response and rejection and in similar survival hazards, but were used in different allograft types and possibly different clinical scenarios, making it difficult to draw any conclusions on a better strategy. More specific information about RI strategies and organ-specific rates of rejection has been published(48
Our observations support initial therapy with RI and close monitoring in low-risk patients. Patients who have an initial response can often be observed with frequent imaging and fine-tuning of the immunosuppressive regimen. With this strategy, many patients avoided cytotoxic chemotherapy and the associated risk of complications. Conventional chemotherapy often requires dose reductions due to underlying organ dysfunction and is associated with a poor outcome; patients in our study who required chemotherapy at any stage of their treatment had a median survival of 19 months.
Certain limitations of this study should be acknowledged. The retrospective observational nature of this study is prone to confounding and may lead to a bias in our estimates of the effects of RI and the predictors of these effects. Sample size limitations may result in failure to detect significant predictors of response or survival. In addition, our conclusions may not apply to the pediatric population, which has special characteristics and a higher incidence of primary EBV infection. Our cohort did not include a sufficient number of patients with CNS involvement or rare subtypes of PTLD such as T-cell or Hodgkin-like disease. Our conclusions may not be applicable to such patients.
To summarize, in our retrospective analysis, RI alone as initial therapy for PTLD has a high response rate and can lead to a favorable outcome. Relapse is uncommon in patients who experience a complete response to RI. Rejection is common but manageable by further adjustment of immunosuppressive therapy, second-line therapy including cytotoxic chemotherapy and in some cases a second transplant. RI can also be used efficiently and safely for patients in the adjuvant setting following resection of PTLD lesions. Older age, bulky disease and advanced stage (particularly stage IV) are associated with poor response to RI. Low-risk patients should be considered for treatment with RI alone and can expect a favorable outcome.