Acquired immunodeficiency syndrome (AIDS)-related lymphoma is a
complex disease process with a range of features that are distinct
from both non-Hodgkins 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 Kaposis
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.
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. 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 Kaposis 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. Aboulafias 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
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 or tetramer-binding analyses. 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).
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
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. 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 hosts 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.
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