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Incidence and Management of AIDS-Related Lymphoma

Incidence and Management of AIDS-Related Lymphoma

ABSTRACT: Over time, the spectrum of the acquired immune deficiency syndrome (AIDS) epidemic has changed, especially with the advent of highly active antiretroviral therapy (HAART). The goal of this article is to delineate changes occurring in the incidence and management of lymphoma over the course of the AIDS epidemic. Lymphoma usually occurs rather late in the course of human immunodeficiency virus (HIV) infection and is the cause of death in up to 20% of HIV-infected individuals. It is seen in all population groups at risk for HIV and is more common in men than in women. It is usually diagnosed in patients with markedly decreased CD4 cell counts, consistent with prolonged periods of HIV infection and subsequent immunosuppression. Recent data from several large series have demonstrated a substantial decline in the median CD4 cell count among patients with newly diagnosed AIDS-related lymphoma despite the recent widespread use of HAART. While still somewhat controversial, use of HAART has generally not produced a significant decline in the incidence of AIDS-related lymphoma. Patients treated with low-dose vs standard-dose chemotherapy for AIDS-related lymphoma have achieved similar response and survival rates, although standard-dose therapy is associated with greater toxicity. Adapting therapy to prognostic factors has not produced a significant improvement in survival. Use of antiretroviral therapy along with chemotherapy appears safe, and may be associated with longer survival. An infusional regimen called EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, doxorubicin HCl) shows promise in the future management of AIDS-related lymphoma. No regimen is currently considered the standard of therapy for patients with relapsed AIDS-related lymphoma, and survival is short in this setting. [ONCOLOGY 15(5):629-646, 2001]

Introduction

Although primary central nervous
system (CNS) lymphoma was
included among the first acquired immunodeficiency syndrome (AIDS)-defining
illnesses,[1] it was not until 1985 that systemic lymphoma, of high or
intermediate grade, was recognized as AIDS-defining.[2] The later recognition of
lymphoma as part of the spectrum of AIDS is consistent with the fact that
lymphoma usually occurs rather late in the course of HIV infection.[3] Thus,
while serving as the initial AIDS-defining diagnosis in approximately 3% of
patients, lymphoma is the cause of death in approximately 16% to 20% of
HIV-infected individuals.[4,5] Moreover, the relative risk of developing
lymphoma increases substantially in patients who have already been diagnosed
with full-blown AIDS.[6,7] Hence, subsequent to an earlier diagnosis of AIDS,
the risk of immunoblastic lymphoma increases approximately 627-fold, the risk of
Burkitt’s lymphoma approximately 220-fold, and the risk of diffuse large cell
lymphoma 145-fold over what is expected in the general population.[6,7] Notably,
when linking cancer and AIDS registries, Goedert and colleagues found that even
the risk for low-grade lymphoma increased 14-fold in individuals who had already
been diagnosed with an AIDS-defining condition.[6,7] As these data suggest,
lymphoma is usually diagnosed in patients with markedly decreased CD4 cell
counts, consistent with prolonged periods of HIV infection and subsequent
immunosuppression.[3]

Risk Factors for
AIDS-Related Lymphoma

Unlike Kaposi’s sarcoma, which occurs primarily in men who
have sex with men, lymphoma is seen in all population groups at risk for HIV,[3]
and like de novo lymphoma, which occurs in HIV-negative individuals,
AIDS-related lymphoma is more common in men than in women.[8] All age groups are
affected, and lymphoma is the most common malignancy in HIV-infected
children.[9] Epidemiologic studies have failed to identify major environmental
factors associated with lymphoma among HIV-infected individuals.[10-12]
However, host factors may be operative. Thus, HIV-infected patients who are
heterozygotes for the CCR5-delta-32 deletion are statistically less likely to
develop lymphoma,[13] whereas those with stromal cell-derived factor 1 (SDF-1)
mutations (eg, the 3¢A variant) are statistically more likely to develop
lymphoma.[14]

An interplay between genetic and other host factors may also
play a role in the development of AIDS-related lymphoma. Grulich and
colleagues[15] recently reported the results of a case-control study of 219
patients with AIDS-related lymphoma, who were compared with 219 HIV-infected
controls, matched for CD4 cell counts and date of specimen collection. On
multivariate analysis, an increased risk of lymphoma was found with longer
duration of immunodeficiency (as determined by the time from seroconversion) and
lower CD4 cell counts 1 year before the diagnosis of lymphoma. In addition,
chronic B-cell stimulation was also predictive of lymphoma, using a higher serum
globulin level (as a surrogate for higher immunoglobulins) as a marker of B-cell
stimulation. Additionally, although controversial and clearly requiring
validation in other studies, the use of acyclovir (Zovirax) has been associated
with a decreased risk for AIDS-related lymphoma in one small case-control study
of 29 patients,[16] while another, larger study yielded the opposite
results.[15]

In trying to predict the incidence of AIDS-related lymphoma in
the years ahead, it will be necessary to take all of these factors into account.

Impact of Highly Active Antiretroviral Therapy
on Incidence

Role of Immunosuppression

Recent data from several large series[15,17] have demonstrated a
substantial decline in the median CD4 cell count among patients with newly
diagnosed AIDS-related lymphoma. In the early years of the epidemic, the median
CD4 cell count of the patients described by Levine and colleagues was 177/dL. In
patients diagnosed recently, however, the median CD4 count was only 55/dL.[17]
This recent drop in the median CD4 count in patients with newly diagnosed AIDS
lymphoma may also be seen in several large, prospective national trials
conducted through the AIDS Clinical Trials Group (ACTG). Patients with newly
diagnosed AIDS-related lymphoma accrued to a phase II study of low-dose m-BACOD
(methotrexate, bleomycin [Blenoxane], doxorubicin [Adriamycin], cyclophosphamide
[Cytoxan], vincristine [Oncovin], dexamethasone) between June 1987 and November
1988 had a median CD4 cell count of 150/dL (range: 16 to 1,079/dL).[18] In a
subsequent ACTG study comparing low-dose with standard-dose m-BACOD,[19] in
which patients were accrued from February 1991 to October 1994 and eligibility
requirements were similar, a median CD4 cell count of approximately
100/dL at study entry was reported.[19] The drop in the median CD4 cell count in
these recently diagnosed patients is of interest, especially because the
widespread use of highly active antiretroviral therapy (HAART) occurred during
the same time frame, and would be expected to be associated with an increase in
CD4 cells.[20]

The paradoxical decrease in median CD4 count in recent patients
with newly diagnosed AIDS-related lymphoma may reflect the lack of HAART use, or
the lack of long-term efficacy of HAART in these individuals. Alternatively, the
use of HAART may simply have allowed these patients to live long enough to
eventually develop lymphoma. If the latter explanation is validated, the
incidence of lymphoma would clearly be expected to increase over time, despite
the use of HAART.

Incidence of AIDS-Related Lymphoma in the Era of HAART

While HAART has been associated with a significant decline in
the incidence of various opportunistic infections and Kaposi’s sarcoma,[20-22]
such a major and significant decline has not yet been seen in patients with
systemic AIDS-related lymphoma. In a cohort of 6,636 HIV-infected individuals
from Switzerland, reflecting over 18,000 person-years of follow-up, Lederberger
and colleagues[21] compared the incidence of various AIDS-defining conditions in
the period from 1992 to 1994 (prior to the widespread use of HAART) with the
period from July 1997 to June 1998. No decrease in AIDS-related lymphoma was
seen (relative hazard = 0.61, 95% confidence interval = 0.30-1.29). Likewise,
although patient numbers were quite small (27 cases), no decrease in the
incidence of primary CNS lymphoma was evident from these data.[21]

A recent report of AIDS cases from 17 Western European countries
evaluated the incidence of systemic and primary CNS lymphoma in 1988, compared
with that in 1997.[23] The number of lymphoma cases among all AIDS patients rose
steadily from 1988 to 1996, and then declined somewhat in 1997. As a percentage
of all AIDS cases, however, systemic lymphoma actually increased from 3.6% in
1994 to 4.9% in 1997. This would be consistent with the significant decline in
opportunistic infections reported with the advent of HAART.[20] A total of 989
cases of primary CNS lymphoma were diagnosed in this cohort, representing
approximately 0.5% of all AIDS cases, with no significant change in incidence
over time.[23] In contrast, investigators from Italy have documented a
significant decrease in primary CNS lymphoma prevalence from 1991-1997 to 1997-1998.[24]

In Australia, national HIV reporting has been ongoing since
1985, with seroconversion data available from 1991 on. Almost the entire
population of HIV-infected persons in that
country has been tabulated, providing a unique ability to track trends in cancer
incidence over time. In this large
and comprehensive database, the standardized incidence rates of lymphoma among
seroconverters decreased from 67 prior to July 1996 to 33.3 thereafter,
indicating a 50% reduction in AIDS-related lymphoma coincident with the widespread use of HAART.[25]

Data from the International Collaboration on HIV and Cancer were
presented recently.[26] Investigators representing over 20 cohort or
case-control studies conducted around the world were convened after submitting
initial raw data from these various studies for re-review in the United Kingdom.
Different methods were used to analyze cohort vs case-control studies, but all
relative risk estimates were adjusted for age, sex, and race. In the
case-control studies, additional adjusting factors included number of sexual
partners and parity.

Eleven of the studies allowed assessment of cancer risk in the
years before and after widespread use of HAART. In this subgroup, rate ratios of
the AIDS-defining cancers were calculated for the period 1992-1996, and were
compared with the rate ratios for 1997-1999, when HAART was widely available
in resource-rich areas
of the world.[26] For non-Hodgkin’s lymphoma (NHL), the rate fell from 6.2 to
3.6 per 1,000 patient-years, indicating a significant decline, with a rate ratio
between the two periods of 0.58. No decline in Burkitt’s lymphoma was seen. A
significant reduction in the incidence of primary central nervous system
lymphoma was also documented.[26]

These studies are thus inconsistent in terms of the incidence of
systemic or primary CNS lymphoma in the era of HAART. While most studies do not
indicate a statistically significant decline in the incidence of AIDS-related
lymphoma, other large studies, such as the International Collaborative Study,
indicate that there has been a meaningful decline. However, one fact remains
clear: the decrease in the incidence of AIDS-related lymphoma is not as
impressive as the decline in the incidence of Kaposi’s sarcoma.[21]
Furthermore, while initial controlled clinical trials indicated that
approximately 80% of treated subjects will achieve a nondetectable HIV viral
load after HAART, only about 40% will achieve this end point in "real
world" conditions.[27] The effect of HAART on the incidence of AIDS-related
lymphoma will clearly be dependent upon the long-term efficacy of combination
antiretroviral therapy when assessed at the population level. Issues of access,
compliance, drug resistance, and underlying host and environmental factors will
all likely be operative. Thus, further time will be required to elucidate the
full impact of HAART on the incidence
of AIDS-related systemic and CNS lymphoma.

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