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Chapter 54 Infectious Mononucleosis and Other Epstein-Barr Virus–Associated Diseases 757

of the literature that included articles and abstracts published between persist long-term post infusion, they have significant anti EBV-LPD
1999 and 2008 reported that the use of rituximab as preemptive activity, supporting the development of third-party banks for the
therapy prevented the development of EBV-LPD in 90% of 341 therapy of EBV-LPD in the transplant setting.
HSCT recipients, while therapy was associated with a response rate
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of 63% in 126 HSCT patients. However, response rates varied
widely, likely reflecting heterogeneity in patient populations and the Epstein-Barr Virus-Positive Hodgkin Disease and
fact that early diagnosis and treatment leads to better outcomes. For Non-Hodgkin Lymphomas
EBV-LPD after SOT, a recent multicenter analysis of 80 patients
reported that rituximab-based therapy had a 3-year progression-free EBV is associated with HD as well as NHLs in immunocompetent
survival of 70% compared with 21% for patients treated without patients (see Chapters 74, 83). An increased incidence of EBV-
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3
rituximab. Half of the patients treated with rituximab also received positive diffuse large B-cell lymphomas has been seen in older adults.
chemotherapy, most of them having bulky disease and a high Inter- All EBV lymphomas are associated with the virus latent cycle
2
national Prognostic Index. A recent prospective multicenter study (Fig. 54.3). The majority of immunocompetent patients with EBV-
suggests that sequential therapy of rituximab followed by chemo- associated lymphomas are latency type II and express EBNA1, LMP1,
therapy results in excellent disease control and overall survival. and LMP2, except for BL, which is latency type I and only expresses
However, at present it remains unclear for which group of patients EBNA1.
rituximab monotherapy is sufficient. Retrospective studies have
identified risk factors including extralymphatic disease, high LDH,
low albumin, and poor performance status, but these risk factors need Hodgkin Disease
25
to be validated in prospective studies. In summary, rituximab has
led to a dramatic improvement in outcome of EBV-LPD. However, HD is a malignant neoplasm of lymphoreticular cell origin, and 40%
rituximab does not restore the cellular immune response to EBV, to 50% of cases in immunocompetent individuals are associated with
which may be crucial for the long-term control of EBV-mediated expression of EBV-derived antigens in malignant Hodgkin and Reed-
B-cell proliferation. EBV-infected B cells may therefore increase with Sternberg (HRS) cells and their variants (Fig. 54.6, B, C). EBV-positive
B-cell recovery, and EBV-LPD may recur. Although rare, the recur- HD is more commonly seen in young children and in less developed
rence of CD20-negative lymphomas with the use of rituximab has countries. EBV association with HD differs by histologic subtype,
been reported. Patients who fail to respond to chemoimmunotherapy being highest with the mixed-cellularity subtype. Evidence linking
strategies may respond to high-dose chemotherapy followed by EBV to the pathogenesis of HD includes the findings that (a) every
autologous HSCT or adoptive T-cell therapies. HRS cell in an EBV-positive tumor mass carries the virus, and (b) the
EBV genome is clonal, indicating that the malignant HRS cells origi-
T-Cell Therapies nated from a single EBV-infected cell. In addition, LMP1, one of the
Donor T-cell infusions have been used successfully to treat EBV-LPD EBV proteins expressed in HRS cells, activates the transcription factor
post-HSC transplantation but carry the inherent risk for GVHD. nuclear factor kappa-B (NFκB), which is thought to play an important
One strategy to prevent GHVD after T-cell infusion is the adminis- role in the HD pathogenesis. EBV-positive HD patients also differ in
26
tration of polyclonal EBV-specific T cells. Initially, donor-derived their antibody response to the major EBV-associated antigens in
EBV-specific T cells were generated ex vivo by repeated stimulation comparison with healthy controls. The overall outcome of EBV-
with autologous LCLs. Clinical studies in HSCT recipients have positive and EBV-negative HD is similar; with combination chemo-
shown that these cells are safe, do not cause significant GVHD, therapy and radiation, the prognosis is excellent for low-stage disease,
reconstitute EBV-specific cellular immunity, and are effective as and overall survival rate for advanced-stage disease is between 65%
prophylaxis and therapy for EBV-LPD. In SOT recipients who and 80% (see Chapter 75). Depending on age and histologic subtype,
develop EBV-LPD, donor-derived T cells are of limited value, because the presence of EBV might be associated with better survival.
the tumor almost always arises in recipient B cells, and donor T cells
are unlikely to survive in the recipient’s hematopoietic system. Initial
studies using autologous EBV-specific T cells for the treatment or Non-Hodgkin Lymphomas
prevention of EBV-LPD after SOT have shown promising results but
need further investigation. NHLs expressing type II latency include diffuse large B-cell lym-
+
Although donor-derived EBV-specific T cells have potent clinical phoma (DLBCL), CD30 Ki-1 anaplastic large cell lymphoma
activity post-HSCT, their generation using LCLs as antigen presenting (ALCL) of B-cell type, T-cell–rich B-cell NHLs and lymphomatoid
cells is a lengthy process, requiring 6 weeks to establish LCLs, then at granulomatosis (see Chapter 76). The association of these lymphomas
least 4 weeks for T-cell expansion, followed by 2 weeks for quality with EBV varies, ranging from 10% to 95%.
control testing. Thus, several groups have developed strategies to EBV-associated NK/T-cell lymphomas include extranodal NK/T-
rapidly select or generate EBV-specific T cells. Rapid selection strate- cell lymphoma (nasal type), angioimmunoblastic lymphoma, and
gies rely on the use of HLA-peptide multimers or Streptamers, or large granular lymphocyte (LGL) leukemia/lymphoma (NK- or T-cell
so-called interferon (IFN)-γ capture, in which T cells that secrete type). Between 30% and 100% of these lymphomas are EBV-positive,
IFN-γ in response to antigen stimulation are selected. While these expressing a type II latency pattern. In addition, CAEBV of NK/T-
selection procedure require no or only limited (>24 hours) ex vivo cell type has been associated with fulminant forms of lymphoma,
culture, they require a leukopheresis product. In addition, HLA- more than 95% of which are positive for EBV. The overall outcome
peptide multimer or streptamer selection require knowledge of a of EBV-associated NHL depends on histologic subtype and risk
+
particular epitope and is restricted to the selection of CD8 T cells. factors present at diagnosis, but most are high-grade malignancies
Our group has therefore focused on rapid expansion protocols in with an unfavorable prognosis using current treatment modalities,
which virus-specific T-cell products are activated and expanded for 10 which are described in detail in Chapters 79 to 85.
days with overlapping peptide libraries spanning the viral antigens of
interest in the presence of cytokines. Resulting cell lines are polyclonal Adoptive Immunotherapy for Epstein-Barr Virus-
+
+
and contain CD4 and CD8 T cells recognizing MHC class I as well
as class II restricted viral antigens. EBV-specific T cells were generated Positive Hodgkin Disease and Non-Hodgkin
as part of multivirus-specific T-cell product, and were effective in five Lymphomas in Immunocompetent Individuals
patients with EBV-LPD or EBV viremia. In addition, banked “off the
shelf” third-party EBV-specific T cells are actively being explored for In contrast to EBV-LPD only a limited number of EBV-derived
the therapy of EBV-LPD as a single or as part of a multivirus-specific antigens (EBNA1, LMP1, and LMP2) are present in EBV-positive
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T-cell product. Although third-party EBV-specific T cells did not HD and NHL. Initial studies with patient-derived, LCL-generated