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Epidemiology and Pathogenesis of AIDS-Related Lymphomas

Epidemiology and Pathogenesis of AIDS-Related Lymphomas

Acquired immunodeficiency syndrome (AIDS)-related lymphoma is a complex disease process with a range of features that are distinct from both non-Hodgkin’s lymphoma (NHL) outside of the context of immunodeficiency and the lymphoproliferative disease seen in immunodeficiency unrelated to human immunodeficiency virus-1 (HIV-1). Dr. Aboulafia lucidly summarizes the issues contributing to the unique aspects of this disease.

Recent Changes in Incidence of AIDS-Related Tumors

Data that were recently reported at the National AIDS Malignancy Conference may further enhance an appreciation of this disorder. Most notably, data presented by several investigators indicated that the incidence of some AIDS-related tumors is changing dramatically in the era of potent antiretroviral therapy.

The general clinical impression that the incidence of Kaposi’s sarcoma (KS) is now lower has been corroborated by studies such as that conducted by Rabkin and colleagues They noted a drop in the incidence of KS in patients treated with indinavir (Crixivan) in AIDS Clinical Trials Group (ACTG) protocol 320 in 1996, as compared with those treated in ACTG trials 015, 073, 085, 093, and 129 in 1991 to 1992, prior to the advent of protease inhibitor therapy.[1]

Furthermore, Buchbinder et al noted a reduction in KS incidence when they compared patients cared for in San Francisco in 1993 with those treated in 1996, at which time 43% of patients were receiving a two- or three-drug regimen.[2] The frequency per 100 patient-years fell from 3 to 0 for KS (P = .06). Importantly, the incidence of NHL fell minimally from 2.2 to 1.8 per 100 patient-years (P = .019).

The incidence of primary central nervous system (CNS) lymphoma has not followed the same trends noted for systemic lymphoma, however, with reductions of up to 75% observed.[F. Boue, personal communication] Therefore, the change in control of HIV-1 replication and its attendant improvement in immunologic function have substantially affected KS and primary CNS lymphoma but not systemic lymphoma.

Fundamental Differences in Pathogenetic Mechanisms?

The associations of KS with Kaposi’s sarcoma herpesvirus (KSHV) and primary CNS lymphoma with Epstein-Barr virus (EBV) are very strong and may indicate responsiveness of these virally associated tumors to improved immunologic control of the persistent underlying viral infections. In contrast, systemic lymphoma has been variably associated with the presence of the EBV genome in tumor tissue and a variable pattern of EBV latent gene expression.

The genetic changes summarized in Dr. Aboulafia’s review, such as bcl-6, c-myc, and TP53 mutations, may indicate a fundamentally distinct set of mechanisms participating in the multistep development of some systemic AIDS lymphomas. It may be hypothesized that such genetic lesions may render the tumor cells less responsive to immunologic control.

New Treatment Approaches

Currently, the clinical approach to AIDS lymphomas does not distinguish those with the various mechanistic considerations cited above. Tumors related to EBV are treated in the identical manner as those associated with KSHV or those without detectable viral genomes but with other genetic abnormalities. With our increasingly sophisticated ability to evaluate the genetic components of tumor tissue, it is likely that real-time diagnostic testing could provide such information to clinicians.

In addition, there is a growing literature on rapid analytic measures of immunologic responses to particular antigens or pathogens, in the form of elispot analyses[3] or tetramer-binding analyses.[4] These may ultimately become diagnostic methods that can be factored into the profile of a patient presenting with lymphoma.

A number of new approaches to treating lymphoma depend on such information as the genetic profile or immune reactivity. For example, we have evaluated the potential of an EBV-dependent gene therapy approach to lymphoma in which the expression of the EBV-latent gene, EBNA-2, is necessary for the induction of a suicide gene, which renders the cell selectively sensitive to ganciclovir (Cytovene).[5] Other genetically dependent therapeutic approaches are being tested outside of the setting of AIDS, such as TP53-dependent cell killing, that ultimately may also be adopted to specific subsets of AIDS-related lymphomas.

In a more immediately available approach, the use of adoptively transferred lymphocytes has proven to be an extremely potent antitumor therapy in the post-transplantation lymphoproliferative disease setting.[6] This therapy is based on augmenting immunity to restore the balance of EBV-induced B-cell proliferation and cytotoxic T-lymphocyte control. Assessment of the presence of such immune targets and the relative abundance of effector cells in donor and host may determine whether such approaches can be meaningfully applied.

The current challenge is to bring information that has been gained in understanding the epidemiology and pathophysiology of AIDS-related lymphoma into the clinical realm. Enhanced laboratory analysis of tumors and the host’s response to the tumor will continue to be pursued. Translating this type of analysis into more refined therapeutic approaches is an achievable goal that may change the currently poor outlook for patients with AIDS-related lymphoma.

References

1. Grulich A, Wan X, Law M et al: Risk factors for AIDS associated non-Hodgkin’s lymphoma: A case-control study. J Acquir Immune Defic Syndr Hum Retrovirol 17:A39, 1998.

2. Shiramizu B, Herndier B, Meeker T et al: Molecular and immunophenotypic characterization of AIDS-associated, Epstein-Barr virus-negative, polyclonal lymphoma. J Clin Oncol 10:383-389, 1992.

3. Butz EA, Bevan MJ: Massive expansion of antigen-specific CD8+ T cells during an acute virus infection. Immunity 8:167-168, 1998.

4. Murali-Krishna K, Altman JD, Suresh M: Counting antigen-specific CD8 T cells: A reevaluation of bystander activation during viral infection. Immunity 8:177-187, 1998.

5. Franken M, Estabrooks A, Cavacini L: Epstein-Barr virus-driven gene therapy for EBV-related lymphomas. Nat Med 2:1379-1382, 1996.

6. Papadopoulos Emanuel D, et al: Infusion of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N Engl J Med 330:1185-1192, 1994.

 
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