In this issue of ONCOLOGY, Jacobson and LaCasce present a complete review of the risk factors, prognosis, and treatment of post-transplantation lymphoproliferative disorders (PTLD) following hematopoietic stem cell transplant (SCT) and solid organ transplant (SOT). They aptly describe the continued relatively high rate of PTLD in transplant recipients; approximately 2% to 3% of all SOT subjects will ultimately develop this potentially fatal disorder, a rate that is more than 30 times higher than that in the general population. Furthermore, lymphoproliferative diseases represent approximately 20% of all malignancies in SOT subjects, compared with ~5% in the general population.[2,3]
In terms of epidemiology, the authors reference the increased risk of PTLD within the first year after transplantation. Historically, PTLD was reported to occur at a median of 6 months after SOT (70% to 80% within 1 year). However, several recent reports suggest that this interval is likely longer, with the median being 36 to 40 months after SOT.[5-9] This is likely related in part to the increased recognition of Epstein-Barr virus (EBV)-negative PTLD, which occurs “later” (more than 1 year) after SOT. In our recent Chicago PTLD analysis, the median time to PTLD diagnosis for EBV-positive patients was 11.5 months (2-216 months), whereas time to diagnosis for EBV-negative patients was 69 months (2-192 months; P<.002).
As the authors describe, pathologically, PTLDs are heterogeneous lesions that are sometimes difficult to separate into clinically relevant categories, especially with regard to the distinction between polymorphic and monomorphic PTLD. One distinguishing factor is that most monomorphic PTLDs contain clonal rearrangements of the immunoglobulin genes. Also, the majority of monomorphic lesions have a phenotypic expression profile that indicates a late– or post–germinal center (GC) origin, while many, if not all, contain structural alterations in oncogenes and/or tumor suppressor genes such as TP53, MYC, and RAS.[10-13]Additionally, cytogenetic karyotyping abnormalities may be found in more than 70% of monomorphic lesions, most frequently trisomy 9, trisomy 11, and rearrangements involving 8q24.1, while gene expression profiling (GEP) has identified a significant number of chromosomal abnormalities.
Comparison of EBV-positive and EBV-negative PTLDs has shown that EBV-negative lesions less often exhibit the non-GC phenotype, are less often MUM1 positive, and tend to be BCL6-positive more often than EBV-positive cases. GEP shows that EBV-positive cases over-express genes associated with viral-induced immune response and under-express genes associated with cell proliferation, transcription regulation, and protein metabolism/transport. However, GEP still remains primarily a research tool; also, there is often too little diagnostic tissue to allow supplemental pathologic studies. This is in part due to the frequent extra-nodal presentation of PTLD (up to 80% in some series), including the relatively frequent (15% to 30%) direct involvement/infiltration of the organ graft by lymphoma.[6,18-20] Still, it is critical that molecular-based research continue in PTLD, not only for diagnostic and prognostic purposes, but also for discovery of potential targeted therapeutic options.
As the authors note, treatment of PTLD is not standardized. Treatment strategies are often tailored to specific clinical settings that encompass the heterogeneity of pathologic and clinical factors, including risk of rejection, type of organ graft, patient comorbidities, and tumor burden/disease presentation. Reduction of immune suppression (RI) has been an important component of the treatment of PTLD for over 25 years; however, several factors should be considered. Most series have found responses to RI alone to be durable in less than 10% to 20% of cases.[6-9,19,20,22] One group has reported higher responses and better outcomes utilizing RI, although most other series have noted less positive results. [6-9,18-20,22,23] Clinical factors associated with the lack of response to RI include elevated lactate dehydrogenase (LDH), organ dysfunction, late-onset PTLD, and multi-organ involvement.[4,22] Unfortunately, these are relatively common disease manifestations. Further, the median time to response of RI is longer than 3 to 4 weeks; patients with aggressive disease and/or high tumor burden often warrant more immediate treatment. Additionally, the risk of organ rejection is significantly elevated when RI is used as the primary treatment modality, although the rate/risk of rejection has not been adequately characterized in most reports.
The incorporation of rituximab into the PTLD treatment paradigm continues to be defined. We recently reported results among 80 PTLD patients treated at 4 Chicago centers over 10 years. A common treatment paradigm was the use of immediate (first-line) rituximab-based therapy in conjunction with RI. The majority of patients received first-line rituximab-based therapy (weekly single-agent or combined with chemotherapy). Among those who received first-line rituximab-based therapy, the 3-year progression-free survival (PFS) and overall survival were 70% and 73%, respectively.
Trappe et al recently presented findings from the largest prospective PTLD study conducted to date. The initial 64 patients received 4 weeks of rituximab immediately followed by 4 sequential cycles of rituximab/CHOP (cyclophosphamide, doxorubicin, oncovin, and prednisone) therapy (called sequential treatment [ST]). An interim analysis showed that response to the first 4 weeks of rituximab strongly correlated with survival (P=0.007). Thus, the trial was modified for patients who achieved clinical remission (CR) with the initial course of rituximab to continue to a second course of rituximab (without chemotherapy). Patients not in CR proceeded to rituximab/CHOP therapy (known as risk-stratified sequential therapy [RSST]). The response rates for ST and RSST were 89% and 93%, respectively, while the CR rates were 69% and 74%, respectively. Further, the 1-year PFS for ST and RSST were 81% and 93%, respectively.
Based on these encouraging data, our approach to the treatment of polymorphic and monomorphic PTLD is immediate rituximab-based therapy together with RI (single-agent rituximab for low tumor burden; rituximab/CHOP for higher tumor burden). Some reports have found the monomorphic subtype to be associated with an inferior outcome compared with the polymorphic subtype; however, most series have not confirmed this.[5-9,19] Older data also suggested that EBV-negative PTLDs behave more aggressively than EBV-positive disease. However, recent data do not support these assumptions. [5-7,9,20] The discrepancy in prognostic factors throughout PTLD series is likely related to the heterogeneity of patient populations as well as to the varying treatment approaches across and within individual series. Further, many PTLD series have been single-institution reports that examined outcomes over several decades (more than 30 to 40 years), during which time diagnostic techniques, supportive care measures, and treatment regimens have evolved greatly. Nevertheless, continued investigation of prognostic factors, especially among rituximab-treated patient populations, will be important in determining the most relevant risk factors. This may help identify particular high-risk PTLD sub-groups that warrant more aggressive or innovative therapy. Further, continued analysis of populations treated with RI alone is warranted in part to potentially identify a subset of PTLD patients in whom rituximab, with or without chemotherapy, may be safely avoided.
One clinical area not discussed by the authors that warrants special consideration is central nervous system (CNS)-related PTLD. CNS presentations occur with increased frequency in PTLD (up to 10% to 15%)[5,26] compared with lymphoma in the general population. Moreover, the presence of CNS disease has been associated with significantly inferior survival.[1,5,7-9,27] The optimal therapy for primary CNS PTLD is not known, but data from small series suggest that treatment approaches similar to those used in immunocompetent primary CNS lymphoma are important (eg, inclusion of high-dose methotrexate-based therapy).[28-31] Continued study of this group of high-risk PTLD patients is needed to define the optimal therapy.
Finally, as the authors note, a number of novel therapeutic strategies are being investigated in PTLD. An interesting approach involves the use of arginine butyrate to induce expression of EBV lytic phase genes and gene products, including thymidine kinase.[32,33] A confirmatory phase II clinical trial of this approach is ongoing. Immunotherapeutic strategies, including use of autologous immune cells and generation of EBV-specific T cells, are being explored. Use of individual-based EBV-specific T cells has been hampered by cost and the more than 2- to 3-month processing time needed to generate the cells. Moosmann et al have reported on a system that allowed rapid isolation and generation of clinical-grade, EBV-specific T cells for the treatment of hematopoietic stem cell transplantation–related PTLD. They isolated EBV-specific T cells by stimulation of donor cells with peptides from 11 EBV antigens followed by interferon-gamma capture, along with immuno-magnetic separation; moreover, this was accomplished in less than 36 hours. The authors noted immune reconstitution as well as early clinical activity.
In summary, a significant amount of knowledge has been gained over the last several decades regarding PTLD. This includes increased insight into the biologic underpinnings and molecular pathogenesis of PTLD as well as improved delineation of the clinical manifestations of the disease. It will be critical in future studies to determine which particular subsets of PTLD may be most amenable to treatment with first-line single-agent rituximab, versus initial combination rituximab/chemotherapy, versus RI alone. Further, incorporation of novel adoptive immunotherapeutic approaches should continue to be examined. Finally, prospective investigations in SOT populations must continue the study of how to decrease the risk of PTLD.
Financial Disclosure: Dr. Evens serves on the advisory boards of Seattle Genetics and Millennium.
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