Posttransplant Lymphoproliferative Disorders
PTLDs constitute a heterogeneous group of diagnostic entities that mirror the spectrum described in the earlier section on IA-LPD. This umbrella of lymphoproliferative disorders ranges from early lesion/ nondestructive PTLD (reactive EBV-associated B-cell hyperplasia) to polymorphic, destructive PTLD (polymorphic but invasive and often clonal lymphocytic infiltrates) all the way to monomorphic, destructive PTLD (overt lymphoma). PTLD is the specific category of IA-LPD that occurs in patients who are iatrogenically immunosuppressed post-allogeneic HSCT (to prevent graft-versus-host disease [GVHD]) or post SOT (to prevent graft rejection). In the setting of SOT, the reported incidence of EBV+ PTLD ranges from 1% to 25%, with the highest risk in seronegative recipients, patients receiving intensive immunosuppressive therapy, and patients receiving grafts with a high lymphoid content. Host factors such as younger age (and higher chance of being EBV-naïve at time of transplant) and recipients of heart, lung, and intestinal transplants carry a higher risk of PTLD.
After allogeneic HSCT, the incidence of EBV-PTLD varies with the transplant regimen and may be as high as 25%. Risk factors for the development of EBV-PTLD post HSCT include the use of stem cells from an HLA-mismatched family member (including haploidentical donors) or HLA-matched unrelated donor, T-cell depletion of the donor cells, intensive immunosuppression, and an underlying diagnosis of primary immunodeficiency. The incidence is much lower when methods that also deplete B cells are used in the conditioning regimen (i.e., receiving alemtuzumab instead of antithymocyte globulin).
The clinical presentation of PTLD is variable. Patients can mani fest with systemic symptoms (fevers, night sweats, weight loss), involvement of lymphoid (lymphadenopathy, hepatosplenomegaly, tonsillar/adenoidal hypertrophy) or extranodal tissue (GI symptoms such as malabsorption, nausea/vomiting, or bloody stool), or with dysfunction of the allograft. Fulminant PTLD is a relatively rare phenomenon but is severe and characterized by rapid progression of multiorgan failure with severe cytopenias. Careful history taking and physical exam are critical tools in evaluating patients post transplant, particularly in the setting of EBV viremia.
The onset of EBV-PTLD seems to be preceded by a large increase in viral load as well as the proliferation of EBV-infected B cells. Frequent monitoring of the EBV DNA load in peripheral blood is a valuable screening test for early detection of EBV-PTLD after HSCT or SOT. However, it remains a subject of debate which is the optimal sample (whole blood, isolated peripheral blood mononuclear cells, plasma) for EBV DNA quantitation. Lastly, the threshold level of EBV-DNA suggestive of impending EBV-PTLD varies according to the polymerase chain reaction (PCR) method of quantifying viral DNA. However, it should be emphasized that not all patients with high EBV-DNA levels, especially those with an SOT, develop EBV PTLD. Several distinct patterns of EBV latent gene expression have been identified in the memory B cells of high-load EBV carriers, with type III latency conferring the highest risk for EBV-LPD development. Besides EBV-DNA levels, determining the frequency of EBV specific T cells or the functionality of T cells in patients with high EBV-DNA load might also assist in identifying patients who are at increased risk for developing EBV-PTLD. In addition, host factors such as polymorphisms in the promoter regions of cytokines have been implicated in increasing the risk for developing EBV-PTLD. Thus an elevated EBV-DNA load can lead to early diagnosis of EBV PTLD, with consequent reductions in mortality and treatment related morbidity, although additional results such as clinical signs and symptoms, as well as radiographic findings, must be taken into account before therapy is initiated. Besides EBV and a dysfunctional cellular immune system, genetic alterations in B cells have also been implicated in the pathogenesis of PTLD, especially in SOT recipients. These alterations can be characterized by microsatellite instability, DNA hypermethylation, aberrant somatic hypermutation, and mutations in specific genes such as MYCC, BCL-6, N-ras, and p53.
Treatment of Posttransplant Lymphoproliferative Disorders
The treatment of PTLD will depend on the specific diagnostic histology and the involvement of EBV, with a variety of therapeutic considerations available (Fig.1). Treatment also differs for recipients of SOT versus HSCT.
Fig1. ALGORITHM FOR FOLLOWING PATIENTS WITH INCREASED EPSTEIN-BARR VIRUS (EBV)-DNA LOAD. With the caveat that many individualized factors contribute to clinical decisions, a general diagnostic and clinical approach is outlined. HSCT, Hematopoietic stem cell transplant; LPD, lymphoproliferative diseases; RI, reduction of immunosuppression; SOT, solid organ transplant.
For patients who are post allogeneic HSCT, strict monitoring of EBV viral loads is performed in the posttransplant period to monitor for viral reactivation manifest by persistent EBV viremia. For asymptomatic patients with a reassuring radiographic work-up, PTLD can essentially be ruled out and patients would be categorized as post transplant EBV viremia. It is commonly accepted to preemptively treat HSCT recipients with rituximab, not only to prevent potential development of PTLD, but just as importantly to avoid graft failure caused by EBV reactivation. For those patients who do develop PTLD, treatment would be similar to the approach outlined later for SOT recipients with PTLD.
Preemptive rituximab for patients post SOT with persistent EBV viremia is not a universally standard practice. Weaning of immunosuppression, when feasible, is typically the first intervention upon recognition of post-SOT EBV viremia. If it persists, there are some institutions that prefer to give preemptive rituximab with the goal of suppressing the EBV viral load. Although definitive evidence that this practice is effective in preventing PTLD is lacking, it is a widely accepted practice. For those clinicians who opt to use preemptive rituximab, it is typically based on the rationale that it is well tolerated, and any potential mitigation of risk for PTLD may have benefit, particularly if it helps to avoid future exposure to multiagent chemo therapy. Conversely, it is also evident that many patients post SOT have persistent EBV viremia and never develop PTLD. Therefore the counterargument to preemptive therapy is that patients may unnecessarily be exposed to the adverse effects of rituximab without definitive clinical benefit.
For SOT or HSCT recipients who develop PTLD, the therapeutic approach depends heavily on the underlying histology. Patients with early lesion/nondestructive PTLD are almost always EBV associated and typically improve after reduction of immunosuppression. This diagnostic entity has three morphologic variants, including IM-like, plasmacytic, and florid follicular hyperplasia. These reactive B-cell hyperplasias stain positive for EBV on histology, with only rare exceptional cases of florid follicular hyperplasia having been described as EBV negative. Typically, weaning of immune sup pression, when feasible without compromising the allograft, is sufficient to restore cellular immune function enough to suppress this EBV-driven benign lymphoproliferation. However, this approach is limited by the risk for graft rejection, and it is not useful after HSCT because of the profound immunosuppression and the risk for inducing GVHD. In such cases, treatment with rituximab monotherapy is indicated and often successful in treating early lesion/nondestructive PTLD.
Polymorphic PTLD is more aggressive than early lesion PTLD; however, it is similarly responsive to reductions of immunosuppression and/or treatment with rituximab. Unlike early lesion PTLD, polymorphic disease is a destructive lymphoproliferative lesion that effaces the affected lymphoid organ tissue. It is usually EBV+ and often responsive to weaning of immunosuppression. Especially in SOT patients for whom consequences of allograft rejection can be dire, it is important to balance risk of weaning immune suppression versus relative risks of rituximab monotherapy, which is generally well tolerated and effective. This is of particular importance in recipients of allografts for whom the regenerative potential is less robust and the risk of graft rejection is severe. Patients with polymorphic PTLD tend to have excellent responses to rituximab monotherapy, and their overall prognosis is favorable. In both EBV+ polymorphic and early lesion PTLD, EBV viral load monitoring can be useful as a biomarker to monitor treatment response and potential for future relapse.
For patients with monomorphic PTLD, the therapeutic approach hinges on the specific underlying histology. The majority of cases of monomorphic PTLD are DLBCL histology. Occasionally, these get more generically classified as an aggressive, mature B-cell lymphoma, NOS. DLBCL PTLD is often EBV associated but is more likely to be EBV-negative than polymorphic PTLD. The treatment approach to DLBCL PTLD is similar to that of polymorphic PTLD; however, the chance of improvement sim ply by weaning immunosuppression is low. Treatment approaches combining rituximab with low-dose cyclophosphamide and prednisone, or even rituximab monotherapy, have resulted in approximately 70% event-free survival. Treatment for those patients with DLBCL PTLD who relapse or do not achieve complete remission is a bigger challenge. In such scenarios, conventional multiagent chemotherapy, radiation for localized disease, and adoptive transfer of T cells or EBV-specific T cells are all considerations. Recently, traction has gained on adoptive cellular therapies for EBV+ PTLD, and this will be discussed in depth in the following section on immunotherapy.
Finally, for those patients with non-DLBCL monomorphic dis ease, the treatment approach must be tailored to the specific histological diagnosis. For patients with BL PTLD (sometimes EBV+) or HL PTLD (usually EBV+), disease-specific multiagent chemotherapy is indicated. On rare occasion, peripheral T-cell lymphomas or plasma cell neoplasms present as monomorphic PTLD. These histologies are less frequently EBV+ and also require disease-specific treatment plans. The aforementioned strategy of rituximab monotherapy or rituximab with low-dose chemotherapy will not be successful for these non DLBCL monomorphic PTLD diagnoses.
Epstein-Barr Virus–Associated Non-Hodgkin Lymphoma in Human Immunodeficiency Virus Patients
Patients infected with HIV are at high risk to develop NHL. The incidence increases with age, and the male-to-female ratio is approximately 2:1. Depending on specific histologies, the EBV association ranges from 30% in systemic HIV-related BL, to 70% to 80% in HIV-related DLBCL, and virtually all cases of HIV-related PCNSL are EBV-positive. In biopsies of EBV-associated HIV-NHL, there is considerable variation in the number of EBV-positive cells, and the pattern of EBV latent gene expression varies among tumor types as in immunocompetent individuals (see Fig.2E and F). As dis cussed in the section on EBV-associated B-cell lymphomas, other specific diagnoses that are more prominent in HIV-infected patients include PEL and plasmablastic lymphoma. In addition, HL is EBV positive in upwards of 80% of HIV-related cases.
Fig2. EXAMPLES OF EPSTEIN-BARR VIRUS–POSITIVE LYMPHOID MALIGNANCIES. Posttransplant lymphoproliferative disorder (PTLD), Hodgkin lymphoma, and large B-cell lymphoma. PTLD in the duodenum of a 15-month-old (A) with history of liver transplant. (B) The PTLD was classified as a polymorphic type and was Epstein-Barr virus (EBV)-positive. Hodgkin lymphoma (C) and EBV-positive Reed-Sternberg cells (D). Large B-cell lymphoma (plasmablastic type) in a human immunodeficiency virus–positive patient (E), diffusely EBV-positive (F). Note, all EBV studies are in situ hybridizations for EBV messenger RNA, EBER.
In HIV-infected patients, the development of EBV-associated HIV-NHL is preceded by a loss of functional EBV-specific T cells, suggesting that strategies to boost the endogenous EBV-specific T-cell response might prevent lymphomas. Additional factors known to pre dispose HIV-infected patients to EBV-associated lymphomas include underlying cytokine dysregulation and proinflammatory state. Restoring CD4+ T-cell counts in patients with HIV with highly active antiretroviral therapy (ART) has decreased the incidence of PCNSL and HIV-related DLBCL. The incidence of HIV-related BL, which tends to occur in patients with higher CD4 counts and with less HIV viremia, has remained stable over time despite improved access to ART.
Oral hairy leukoplakia (OHL) develops frequently, although not exclusively, in patients who are HIV-positive. It is a non-malignant hyperplasia of epithelial cells, and most patients present with white, corrugated lesions on the tongue. Besides IM, OHL is the only EBV associated disease in which active viral replication is apparent, and multiple strains are often present within the same lesion. Inhibiting EBV replication in vivo with antivirals such as valacyclovir results in resolution of OHL. However, after valacyclovir treatment, EBV replication recurs in normal tongue epithelial cells, indicating that productive EBV replication is necessary but not sufficient to induce OHL.
