Full text of DOI:10.2165/00003495-200161090-00006

Drugs 2001; 61 (9): 1301-1315
0012-6667/01/0009-1301/$27.50/0
THERAPY IN PRACTICE
© Adis International Limited. All rights reserved.
Management of AIDS-Related
Non-Hodgkin’s Lymphomas
Marie José Kersten1 and Rien H.J. Van Oers2
1
Department of Medical Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis,
Amsterdam, The Netherlands
2
Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands
Contents
Abstract
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1301
1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1302
2. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1303
2.1 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1303
2.2 Prognostic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1303
3. Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1304
4. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1304
4.1 Disrupted Immunosurveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1304
4.2 Chronic Antigenic Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1305
4.3 Cytokine Dysregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1305
4.4 Epstein-Barr Virus Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1305
4.5 Other Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1305
4.6 Genetic Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1306
4.6.1 Oncogenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1306
4.6.2 Tumour Suppressor Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1306
4.7 Zidovudine Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1306
4.8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1306
5. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1307
5.1 Systemic Non-Hodgkin’s Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1307
5.1.1 Combination Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1307
5.1.2 Haematopoietic Growth Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1310
5.1.3 New Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1310
5.1.4 Biological Response Modifiers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311
5.1.5 Antiretroviral Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311
5.1.6 Central Nervous System (CNS) Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . 1311
5.1.7 Infection Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311
5.2 CNS Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1312
The incidence of non-Hodgkin’s lymphoma in individuals infected with HIV
Abstract
is approximately 60- to 100-fold increased over the general population. The ma-
jority of patients with AIDS-related lymphoma (ARL) present with stage III-IV
disease and with B-symptoms. They often have multiple extranodal localisations,
with a high incidence of central nervous system involvement. Histologically,

1302
Kersten & Van Oers
most tumours are either diffuse large cell lymphomas or Burkitt lymphomas.
Several factors, such as disrupted immune surveillance, Epstein-Barr virus infec-
tion, chronic antigenic stimulation, cytokine dysregulation and the acquisition of
genetic lesions, are thought to contribute to the pathogenesis.
Patients with ARL have a poor prognosis: overall survival ranges from 1.5 to
18 months. The most important adverse prognostic factors are poor performance
status, a low CD4+ cell count and a history of opportunistic infections. Results
of treatment with polychemotherapy compare unfavourably to results in patients
without HIV infection.
Since the advent of highly active antiretroviral therapy (HAART), there ap-
pears to be a decrease in the incidence of ARL. In addition, the use of HAART
in combination with chemotherapy and the use of new treatment modalities may
improve the outcome of this disease.
AIDS-KS and NHL appears to be reduced in those
who are heterozygous for an inactivating 32 base
1. Epidemiology
Non-Hodgkin’s lymphomas (NHL) are mono-
clonal expansions of B or T lymphocytes. B cell
lymphomas have long been known to arise more
frequently in patients with either congenital or ac-
quired cellular immunodeficiency.[1,2] The first re-
ports of NHL occurring in homosexual males were
in 1982,[3] only one year after the first reports on
Pneumocystis carinii pneumonia (PCP) and Kapo-
si’s sarcoma (KS) in this patient group, and well
before the human immunodeficiency virus (HIV)
was identified as the cause of the immunodefi-
ciency. Whereas primary central nervous system
lymphoma (PCNSL) was considered one of the ini-
tial criteria for a diagnosis of AIDS, systemic NHL
was included as an AIDS-indicator diagnosis in the
revised case definition of AIDS proposed by the
Centers for Disease Control in 1985.[4]
The incidence of NHL is increased equally in all
HIV-risk groups, such as homosexual or bisexual
males, intravenous drug users,[5] patients with hae-
mophilia[6] and transfusion recipients.[7] In the San
Francisco City Clinic Cohort, the frequency of
NHL as initial AIDS-defining diagnosis was 4.2%,
whereas the lifetime incidence was 12.6%.[8] In in-
dividuals infected with HIV-1, the risk of NHL is
more than 100-fold increased compared with the
general population.[9] The risk of NHL may be re-
lated to a polymorphism in the stromal cell derived
factor 1 (SDF1-3’A), which is associated with in-
creased levels of B cell chemokines.[10] The risk for
pair deletion in the CC chemokine receptor CCR5.
NHL is often a late complication of AIDS and
it has been noted over the past several years that
the incidence has increased, presumably because of
the increased life expectancy due to antiretroviral
therapy and the improved management of opportu-
nistic infections.[11] In contrast, the incidence of
another virus-associated malignancy [KS, associ-
ated with the human herpesvirus 8 (HHV-8)] has
decreased by approximately 60% since the advent
of highly active combination antiretroviral therapy
(HAART) in 1995/1996. As for non-Hodgkin’s
lymphoma in patients with AIDS [AIDS-related
lymphoma (ARL)], it appears that there is a signif-
icant decrease in the incidence of primary central
nervous system (CNS) lymphoma and that we are
now beginning to see a reduction in the incidence
of all lymphomas.[12,13]
Although the frequency of Hodgkin’s disease,
in particular the mixed cellularity type, is increased
approximately 8-fold in persons infected with
HIV,[14] Hodgkin’s disease is not included in the
case definition of AIDS. Interestingly, the propor-
tion of intravenous drug users is higher among pa-
tients with AIDS-related Hodgkin’s disease than
among patients with AIDS with NHL. Other infre-
quently reported lymphoproliferations in patients
with AIDS include multiple myeloma,[15] periph-
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AIDS-Related Lymphomas
1303
eral T cell lymphoma, T lymphoblastic lymphoma
and multicentric Castleman’s disease.[16]
Patients presenting with lymphomatous pleural,
pericardial or ascitic fluid represent a new disease
entity closely related to HHV-8. These primary ef-
fusion lymphomas (PEL, or body cavity based
lymphomas) account for less than 5% of all ARL and
have a unique set of morphological, immunophen-
otypic and molecular genetic characteristics that
distinguish them from other ARL.[25] Recently, an-
other unusual type of extranodal lymphoma with a
distinctive immunophenotype has been described
which has been named plasmablastic lymphoma of
the oral cavity.[26]
Standard staging procedures for ARL should in-
clude routine blood tests, CT scanning of chest, ab-
domen and pelvis, Gallium-67 or fluoro-deoxy-
glucose PET (FDG-PET) scanning, bone marrow
biopsy and lumbar puncture.
2. Clinical Features
2.1 Clinical Presentation
When compared to high grade B cell NHL in the
general population, patients with ARL have sev-
eral distinctive features.[17-20] The median age at
presentation is 35 to 42 years. 40 to 60% of patients
have a previous diagnosis of AIDS. The majority
of patients have widespread (Ann Arbor stage III
or IV) disease already at presentation and most pa-
tients have B symptoms (fever, weight loss). About
70 to 97% of patients have extranodal disease, of-
ten at unusual localisations such as the heart, mus-
cle, soft tissues, anus and rectum.
Particularly striking is the high incidence of
CNS involvement: whereas CNS localisations oc-
cur in only 2% of patients with NHL in the general
population, CNS involvement (either primary CNS
lymphoma or leptomeningeal localisation) is seen
in 20 to 40% of patients with ARL. This is also true
for other immunodeficiency-related lymphomas,
such as post-transplant lymphoproliferative dis-
ease. Presenting symptoms are headache, seizures,
confusion, lethargy or focal neurological defi-
cits,[21] but the diagnosis is often made at autopsy.
A computed tomography (CT) scan will show 1 or
2 slightly hypodense mass lesions with ring en-
hancement after intravenous contrast. This is in
contrast to the main differential diagnosis, toxo-
plasmosis, where more lesions are usually seen.
Persistence of cerebral symptoms and lesions after
a trial treatment with anti-toxoplasmosis therapy is
a strong indicator of NHL. Although a definite di-
agnosis of PCNSL can be made only by brain bi-
opsy, the demonstration of Epstein-Barr virus (EBV)
DNA by polymerase chain reaction (PCR) in the
cerebrospinal fluid together with a positive posi-
tron emission tomography (PET) or thallium-
SPECT scan have been shown to be highly sensi-
tive and specific diagnostic tools.[22-24]
2.2 Prognostic Factors
The prognosis for patients with ARL is ex-
tremely poor: the median survival reported in var-
ious studies ranges from 1.5 to 18 months. In a
recent epidemiological survey of survival in pa-
tients with AIDS according to type of AIDS-defin-
ing event, median survival after NHL was only 5
months.[27] The most important adverse prognostic
factors are a CD4+ cell count <0.2 x 109/L,[28]
a
diagnosis of AIDS and poor performance status.
Other factors adversely influencing survival are
older age, the presence of extranodal disease, bone
marrow and/or CNS involvement, intravenous
drug use and constitutional symptoms.[20,28,29]
Several studies have shown that the International
Prognostic Index can also be used in patients with
ARL,[30,31] even though the majority of patients
fall into the high-intermediate or high risk catego-
ries.
AIDS-related Hodgkin’s disease tends to dis-
play more aggressive clinical and biological fea-
tures than Hodgkin’s disease in the immunocom-
petent host, and although a complete response can
often be achieved with polychemotherapy, relapse
rates are high and median survival after diagnosis
is only 16 months.[32-34]
The incidence of bone marrow, gastrointestinal
and liver involvement in ARL is also high.
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Kersten & Van Oers
3. Histopathology
4. Pathogenesis
The pathogenesis of lymphomas in the face of
HIV-1 infection is still incompletely understood,
but a multi-step model is presumed.[35,36] The first
phase is characterised by polyclonal B cell expansion
[clinically corresponding to persistent generalised
lymphadenopathy (PGL)]. Factors important in
this phase are thought to be latent EBV-infection
in combination with disruption of immunosurveill-
ance, chronic antigen stimulation and cytokine de-
regulation, all resulting from HIV-1 infection. In
the second phase, multiple genetic lesions accumu-
late, leading to clonal evolution. This model is sup-
ported by a study by Pelicci et al.,[35] demonstrating
the existence of multiple clonal B cell expansions
in biopsies from patients with PGL, possibly rep-
resenting precursor lesions of lymphoma. More-
over, the presence of EBV in PGL biopsies has
been associated with an increased risk of concur-
rent or subsequent development of NHL.[37] Al-
though the pathogenesis for the two major histo-
logical subgroups (BL and DLCL) in ARL may
differ, several of these factors are shared. In this
review, they are first discussed separately, after
which a model of lymphomagenesis in AIDS is
presented.
In contrast to lymphomas in the general popula-
tion, the lymphomas found in patients with AIDS
are almost invariably of intermediate or high grade
malignancy according to the Working Formulation.
Morphologically, the majority (60 to 70%) are
classified as diffuse large cell lymphomas which
are either polymorphic centroblastic or im-
munoblastic according to the Kiel classification.
They often show pronounced tumour cell polymor-
phism and multiple bizarre nuclei. In the
REAL/WHO-classification
(revised
Eu-
ropean/American classification of lymphoid neo-
plasms) they are classified as diffuse large cell lym-
phomas (DLCL). However, 30 to 40% of the
tumours are of the high grade small noncleaved cell
variety (Burkitt- or Burkitt-like). Interestingly, this
extremely high proportion of Burkitt-type tumours
is not seen in immunosuppressed transplant pa-
tients. AIDS-related Burkitt lymphomas (BL)
resemble sporadic more than endemic BL in their
pattern of molecular alterations, in addition to shar-
ing a more immature phenotype with these lym-
phomas. Primary effusion lymphomas are charac-
terised by an immunoblastic morphology with
Reed-Sternberg like cells. They usually do not ex-
4.1 Disrupted Immunosurveillance
press any of the B or T cell associated markers.[17-
20,25]
The risk of NHL (especially DLCL) increases
with the duration of HIV-infection and the decline
in CD4+ cell count, and is greatest when CD4+
counts are <50 per μl.[38] The immune deficiency
presumably contributes to B cell expansion via re-
activation of EBV. This would be analogous to
other states of cellular immune deficiency associ-
ated with increased risk of NHL. In vitro, defective
regulation of EBV infection in patients with AIDS
has been shown, causing an increase in the number
of EBV-infected B cells in the peripheral blood.[39]
We have studied EBV-load and EBV-CTL (cyto-
toxic T lymphocyte) precursor frequencies long-
itudinally in individuals chronically and asymp-
tomatically infected with HIV-1, patients with
opportunistic infections and patients with NHL,
On the basis of the presence of either surface
immunoglobulin, B cell specific membrane mark-
ers or immunoglobulin gene rearrangement, virtu-
ally all ARL (including PEL) are found to be of B
cell origin.[18,19] Although oligo- and polyclonal
tumours have also been described, most lympho-
mas are monoclonal.[18,35] The expression of EBV-
related antigens is discussed in section 4.4.
In AIDS-related Hodgkin’s disease the most
frequent histological types are the mixed cellular-
ity type and the lymphocyte depletion type, the lat-
ter being a diagnosis that has largely disappeared
in the non-HIV setting.
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1305
and found a decrease in EBV-CTLp and an in-
crease in EBV-load in the patients with NHL prior
to the onset of lymphoma in patients who went on
to develop NHL.[40]
DNA circularises to form an episomal nuclear
structure, which encodes only a limited number of
proteins.[50] They include 6 EBV nuclear antigens
[EBNA 1, 2, 3A, 3B, 3C and leader protein (LP)],
and 3 latent membrane proteins (LMP1 and
LMP2A/2B). Of these latent antigens, EBNA1 is
essential for maintenance of the episome;[51]
EBNA2 and LMP1 are considered to be important
for malignant transformation of B cells.
Using a sensitive RNA in situ hybridisation
technique, EBER (EBV- small RNAs) can be de-
tected in up to 80% of patients with systemic
DLCL, in 90 to 100% of those with primary central
nervous system lymphomas[52] or AIDS-associ-
ated Hodgkin’s disease, but in only 30 to 40% of
patients with Burkitt-type NHL.[53] The fact that
several studies have found evidence for clonal
EBV-infection in ARL indicates that EBV integra-
tion occurred before clonal B cell expansion and
thus supports a causative role for EBV in lympho-
magenesis.[54]
In ARL, the expression of latent antigens differs
between BL and DLCL: whereas patients with BL
usually express only EBNA1, in those with DLCL
expression of all latent antigens can be found.[55]
This explains why tumours with expression of all
latent antigens (including the highly immunogenic
EBNA3 proteins) can only occur in immuno-
suppressed individuals,[56] whereas BL can evade
immunosurveillance and can thus be found in pa-
tients with relatively normal immune status.
4.2 Chronic Antigenic Stimulation
B cell hyperplasia and hypergammaglobulinae-
mia (sometimes even an oligo- or monoclonal para-
protein can be demonstrated) are often already
found early in the course of HIV-1 infection and
can be caused by HIV-1 itself.[41] B cell clonal se-
lection driven by a self antigen or by a viral antigen
can contribute to the development of NHL.[42]
4.3 Cytokine Dysregulation
Cytokine dysregulation is one of the early key
features of HIV-1 infection.[43] HIV-1 infection
has been shown to induce monocyte production of
interleukin (IL)-6,[44] a paracrine growth factor in
multiple myeloma, non-HIV–associated NHL and
also AIDS-related DLCL.[45] Using a bio-assay, el-
evated levels of IL-6 have been shown to be asso-
ciated with an increased risk of NHL in patients
with HIV infection.[38] B cell lines from patients
with AIDS and BL constitutively secrete large
quantities of IL-10, a potent B cell growth fac-
tor.[46] IL-10 (both viral and human) can also con-
tribute to lymphomagenesis by interfering with the
generation of CTL and downregulating human leu-
cocyte antigen (HLA) class I, thereby enabling tu-
mour cells to escape (EBV-specific) immuno-
surveillance.[47] IL-10 antisense oligonucleotides
have been shown to inhibit proliferation of lym-
phoma cell lines in vitro.[48]
4.5 Other Viruses
In 1994, DNA sequences were identified in KS
lesions which are derived from a novel virus,
HHV-8.[57] This virus bears great sequence homol-
ogy to other herpesviruses (especially EBV). Al-
though extensively searched for, HHV-8 se-
quences have not been found in patients with ARL,
except for the rare variant termed primary effusion
lymphoma.[25] Therefore, although able to infect B
cells in addition to endothelial cells and spindle
cells, HHV-8 is associated with specific types of
malignancies and immunosuppression rather than
being a general feature of HIV-1–related prolifer-
4.4 Epstein-Barr Virus Infection
EBV is a ubiquitous human γ-herpesvirus. Es-
sentially all individuals infected with HIV-1 are
EBV-seropositive. EBV shows tropism for epithe-
lial cells in the oropharynx and B cells. Although
a potent EBV-specific CTL response is elicited af-
ter primary infection (which often occurs in child-
hood),[49] the virus remains latent presumably in
the memory B cell pool. During latency, the EBV
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Kersten & Van Oers
ative disorders. The neoplastic cells in these body
cavity-based lymphomas (BCBL) usually also
harbour EBV, suggesting a synergistic role for both
viruses in this disorder.[25]
DLCL, but are consistently absent in BL. c-Myc
and BCL-6 rearrangements in DLCL are mutually
exclusive.[59,60] Ras mutations, although never
present in NHL in immunocompetent patients, are
found in 15% of both AIDS-related BL and DLCL.
Recently, overexpression of the TCLI oncogene
has been demonstrated in AIDS-associated im-
munoblastic lymphomas.[61]
There is no evidence that HIV-1 itself is directly
involved in lymphomagenesis. Although HIV-1
has been shown to be able to infect peripheral B
cells from EBV-seropositive/HIV-seronegative
individuals, HIV-1 sequences are generally not de-
tectable in lymphoma tissue by Southern blot anal-
ysis. However, HIV-1 does contribute to lympho-
magenesis indirectly by inducing polyclonal B cell
expansion, reactivation of EBV infection, chronic
antigen stimulation and cytokine deregulation. In
addition, HIV-1 infection of endothelial cells has
been shown (through induction of CD40) to en-
hance the adhesion of lymphoma cells to the endo-
thelium, thus bringing the neoplastic population
into close proximity of membrane-bound growth
and survival factors and facilitating lymphoma ex-
travasation into the tissues. This enhanced adhe-
sion may in part be mediated by HIV-1 Tat.[58]
Other viruses, such as cytomegalovirus, HHV-6,
and human T-lymphotrophic virus (HTLV)-1 have
not been implicated in the pathogenesis of ARL.
4.6.2 Tumour Suppressor Genes
Inactivation of p53 through point mutation of
one allele and deletion of the other is detected in
60% of AIDS-BL but never in DLCL. They occur
in both EBV-positive and EBV-negative tumour
clones.[62] The frequent association of c-myc and
p53 mutations in BL suggests a synergistic role for
these genetic lesions. 6q-deletions clustering to
6q27 and 6q21-23 occur in 20 to 25% of ARL and
represent the putative site of two distinct tumour
suppressor genes.[63]
4.7 Zidovudine Treatment
Several studies have suggested that use of
zidovudine or other antiretroviral drugs may be
aetiologically linked to development of NHL.[64]
However, in a population-based case-control study
of patients with ARL in Los Angeles, no increased
risk of lymphoma was found in those patients
treated with zidovudine.[65] Zidovudine probably
merely functions to prolong survival, providing ad-
ditional time for NHL to develop.
4.6 Genetic Lesions
A number of genetic lesions have been demon-
strated involving dominantly acting oncogenes as
well as tumour suppressor genes in ARL biopsies.
4.6.1 Oncogenes
Deregulation of c-myc (through reciprocal trans-
location between 8q24 and one of the Ig loci) is
seen in 100% of AIDS-associated BL but only in
20% of DLCL. C-myc can cause tumourigenic con-
version in lymphoblasts, and is responsible for
down-regulation of the adhesion molecules leuco-
cyte function antigen (LFA)-1 and intercellular ad-
hesion molecule (ICAM)-1, which are necessary
for immune recognition requiring intercellular
contact. BCL-1 and BCL-2 are infrequently associ-
ated with ARL. BCL-6 is a newly identified
oncogene which encodes a member of the zinc-fin-
ger family of transcription factors. BCL-6 muta-
tions or rearrangements occur in up to 60% of
4.8 Summary
Several factors are thought to contribute to
lymphomagenesis in individuals infected with
HIV-1, and in the two major histological subgroups
different pathways appear to exist.
BL tend to occur in younger, less immuno-
compromised individuals. They are monoclonal
and are nearly always associated with c-myc rear-
rangements and often with loss of the p53 tumour
suppressor gene. Only 30 to 40% are EBV-posi-
tive, and when EBV-positive, they only express
EBNA1 and thus do not express target antigens for
EBV-specific CTL. Chronic antigenic stimulation
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AIDS-Related Lymphomas
1307
and cytokine deregulation caused by HIV-1 itself
and by other infections leads to increased B cell
proliferation, rendering these cells more suscepti-
ble to genetic hits. This clinical setting is compa-
rable to the relative immunodeficiency and anti-
genic stimulation seen in chronic malarial
infestation in those regions of Africa where BL is
endemic.[66]
To facilitate the comparison of the studies, the per-
centages of patients with known adverse prognos-
tic factors such as low CD4+ cell count, poor per-
formance status and a prior diagnosis of AIDS are
listed. In most trials, patients with relatively good
prognosis were enrolled (less than 25% of patients
had a diagnosis of AIDS and/or a Karnofsky score
of <70%).
DLCL on the other hand, are more similar to
NHL seen in other immunodeficiency states, in
that they are often EBV-positive and can express
transforming latent antigens such as LMP1 and
EBNA2. They tend to occur later in HIV-1 infec-
tion at lower CD4+ cell counts, and are thought to
arise because of uncontrolled EBV-driven prolif-
eration of B lymphocytes. They are less often as-
sociated with specific genetic lesions.
Only few results are as yet available of trials
employing different treatment regimens in patients
who were stratified according to risk factors. As
can be seen in table I, both dose-intensive regimens
such as MACOP-B (methotrexate with folinic acid
rescue, doxorubicin, cyclophosphamide, vincristine,
prednisone and bleomycin) and LNH84 (doxo-
rubicin, cyclophosphamide, vindesine, bleomycin,
prednisolone, high dose methotrexate, ifosfamide,
etoposide, L-asparaginase, cytarabine), and low-
dose regimens such as modified M-BACOD re-
sulted in complete remission rates of 43 to 67%.
Contrary to what would be expected in these highly
malignant tumours, in a randomised study low
dose M-BACOD was found to be as effective as
high dose M-BACOD with significantly less tox-
icity. However, in a prospective study by the
French-Italian Cooperative Study Group a 50%
dose-reduced regimen CHVmP/BV (cyclophosph-
amide, doxorubicin, teniposide and prednisone,
with bleomycin and vincristine added mid-cycle)
resulted in only 4 complete remissions in 29 evalu-
able patients.[71] This group recently reported on a
clinical trial in which 101 patients who were con-
sidered to have intermediate risk, were randomised
between standard CHOP (cyclophosphamide, doxo-
rubicin, vincristine and prednisone) and CHOP
with a 50% reduction of the cyclophosphamide and
doxorubicin dose. Dose reduction in this trial led
to a significant decrease in complete response rate,
but there was no difference in disease free and
overall survival.[81]
5. Treatment
5.1 Systemic Non-Hodgkin’s Lymphomas
5.1.1 Combination Chemotherapy
Since patients with ARL often present with dis-
seminated disease, combination chemotherapy is
in general the treatment of choice. In some patients
(e.g. those with bulky disease) additional involved
field radiotherapy is given. In view of the aggres-
sive nature of the tumours in this patient group,
intensive treatment appears warranted. However,
patients infected with HIV-1 often have limited
bone marrow reserve and are at high risk of (op-
portunistic) infections. In fact, early retrospective
analyses have shown that more intensive treatment
was associated with shorter survival,[19] and one
trial employing high dose methotrexate, cyclo-
phosphamide and cytarabine was stopped early be-
cause of the extremely high incidence of opportu-
nistic infections.[67] These findings have led to the
development of other or modified treatment regimens,
such as low dose M-BACOD (methotrexate with
folinic acid rescue, bleomycin, doxorubicin, cyclo-
phosphamide, vincristine and dexamethasone).
The majority of prospective therapy trials are
reviewed in table I.[19,67-81] Therapeutic trials were
identified using PubMed and CancerLit databases.
The median survival in complete responders in
all studies is approximately 15 months but overall
survival does not exceed 12 months in most studies.
In a study by Sparano,[75] an infusional CDE regi-
men containing cyclophosphamide, doxorubicin
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Drugs 2001; 61 (9)

Table I. Results of prospective chemotherapy trials in patients with AIDS-related non-Hodgkin’s lymphoma (NHL)
CD4+ counte
Reference
Regimen
No.d
Stage
III/IVf
Prior AIDSf PS
<70g
CRh
Opp. inf.i Adverse progn.j
Survival
monthsk
NHL cause
of deathl
Gill et al.[67]
1987
M-BACOD
AraC/MTXc
13
9
0.36
0.17
100
88
NA
21
23
(70)
(90)
54
33
8
78
PS
11
6
NA
Kaplan et al.[19]
1989
COMET-Ac
38
(33)
0.16
87
68
(75)
18
58
43
34
21
NA
24
43
NA
NA
19
10
12
5.2
36
(71)m
CD4+,PS
AIDS
Levine et al.[68]
1991
M-BACOD Low
+AZTc
42
(35)
57
0.15
5.6
(1-43)
50
CD4+,stIV,
AIDS,BM
Kaplan et al.[69]
1991
16
10
0.22
0.29
48
70
20
10
67
67
NA
10
9
35
50
CHOP+GMCSF
-GM-CSFc
(83)
(80)
Sawka et al.[70]
1992
MACOP-Bc
30
76
0.06
77
69
72
63
62
76
76
47
32
28
15
19
14
20
33
14
39
63
50
62
56
8.1
3.5
59
CD4+
Tirelli et al.[71]
1992
CHVmP/VBc
+ AZT
37
(29)
0.03
0.07
27
100
28
NA
40
CD4+,CNS
CD4+,PS
Remick et al.[72]
1993
CCEP
oral regimen
18
7
(1-36)
Gisselbrecht et al.[73] LNH84c
1993
141
25
9.3
(1-45+)
50
CD4+,PS,
AIDS
Walsh et al.[74]
1993
M-BACODc
+ GM-CSF
17
(16)
n.a.
0.08
0
(83)
NA
NA
NA
14
NA
33
Sparano et al.[75]
1994
infusional CDEc
21
(70)
NA
18.0
8.1
Levine et al.[76]
1996
M-BACOD low
+ddC +G-CSF
28
(25)
54
0.16
NA
Aviles et al.[77] 1999
Little et al.[78]a 1999
60
23
30
100
90
80
50
NA
NA
18
NA
NA
10
54
NA
NA
PS, IPI
NA
13.6
45
CEVB +G-CSF
0.25
0.26
70
NA
EPOCH + G-CSF
23+
Bower et al.[79] 2000 BEMOP/CAc
2 yrs OS 46% NA

Kaplan et al.[80]b
1997
M-BACOD low
M-BACOD high
94
81
0.1
0.1
71
64
53
48
18
17
41
52
22
23
7.8
6.9
70
57
CD4+, IPI
NA
Tirelli et al.[81]a,b
1999 low risk
ACVB
CHOP +G-CSF
80
79
0.2
0.2
NA
NA
NA
NA
NA
NA
66
60
NA
NA
1 yr OS 51%
1 yr OS 46%
NA
NA
Tirelli et al.[81]a,b
1999 int. risk
CHOP
CHOP 50%
59
51
0.06
0.06
63
39
NA
1 yr OS 25%
1 yr OS 30%
(3-61+)
NA
NA
a
b
c
d
e
f
Studies reported in abstract form.
Randomised clinical trials.
Treatment regimens that included prophylactic intrathecal administration of either methotrexate or cytarabine.
Number of patients enrolled in the trial (no. of evaluable patients).
Percentage of patients with CD4+ cell counts less than 0.2 x 109/L or median CD4+ cell count (x 109/L).
Percentage of patients presenting with stage III or IV NHL, or % of patients with a diagnosis of AIDS.
Percentage of patients with a Karnofsky performance score <70%, or median performance score (%).
Percentage of patients attaining a complete remission.
g
h
i
Percentage of patients developing an opportunistic infection during chemotherapy.
Independent prognostic factors predictive of survival.
j
k
l
Survival in months (median and range).
Percentage of patients in whom NHL was the major cause of death.
m
Although NHL was considered the major cause of death in 36% of this patient group, active NHL was present at the time of death in 71% of patients.
ACVB = doxorubicin, cyclophosphamide, vincristine, bleomycin; AraC/MTX = high dose cytarabine and methotrexate; AZT = zidovudine; BEMOP/CA = bleomycin, etoposide,
vincristine, methotrexate, prednisone/cyclophosphamide, doxorubicin; BM = bone marrow; CCEP = lomustine (CCNU) cyclophosphamide, etoposide, procarbazine; CDE =
cyclophosphamide, doxorubicin, etoposide; CEVB = cyclophosphamide, epirubicin, vincristine, bleomycin; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CHVmP
= cyclophosphamide, doxorubicin, teniposide, prednisone, vincristine, bleomycin; COMET-A = cyclophosphamide, vincristine, methotrexate, etoposide, cytarabine; CR = complete
remission; ddC = zalcitabine; EPOCH = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; GM-CSF = granulocyte-monocyte colony stimulating factor; IPI =
international prognostic index; LNH84 = doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisolone, high dose methotrexate, ifosfamide, etoposide, L-asparaginase,
cytarabine; M-BACOD = methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone; MACOP-B = methotrexate, doxorubicin, cyclophosphamide,
vincristine, bleomycin, prednisone; NA = not available; OS = overall survival; PS = performance status; stIV = stage IV disease.

1310
Kersten & Van Oers
and etoposide was used. This resulted in an esti-
mated survival of 18 months. A similar study in
which didanosine was added to infusional CDE re-
sulted in comparable survival.[82] A study by Avi-
les et al.[77] in 60 patients treated with
cyclophosphamide, epirubicin, vincristine and
bleomycin, showed an overall survival of 14
months. Recently, very promising preliminary re-
sults were shown with a dose-adjusted EPOCH
(etoposide, prednisone, vincristine, cyclophosph-
amide, doxorubicin) regimen in 24 patients.[78] In
this regimen, vincristine, etoposide and
doxorubicin were administered by continuous in-
travenous infusion, and the dose of cyclophosph-
amide was adjusted to the baseline CD4+ cell count
and to the white blood cell and platelet nadir. All
patients received granulocyte-colony stimulating
factor (G-CSF). This regimen has shown a very
high complete remission rate of 94% in patients
with CD4+ counts >100 per μl, and a median pro-
gression free survival exceeding 23 months.[78]
This regimen is now being studied combined with
HAART.
Durable disease-free remissions of 3 to 5 years
in complete responders have been reported in all
studies, indicating that treatment of ARL is not
hopeless per se. Treatment seems particularly
worthwhile in younger patients with relatively nor-
mal immune function and a low International Prog-
nostic Index (IPI) score. However, most complete
responders do relapse, and in more than half of the
patients, NHL is the major cause of death. Oppor-
tunistic infections and other HIV-related syn-
dromes (wasting) are responsible for the other
deaths. Dose intensification, followed by autolo-
gous, allogeneic or syngeneic stem cell transplan-
tation has been attempted in a few patients, but is
associated with high morbidity and mortality,[83,84]
and at this point cannot be encouraged outside the
context of clinical trials.
Thus, both complete remission rates and relapse
rates in ARL compare unfavourably to those found
in non-HIV-related NHL, and well-designed clini-
cal trials are very important for guiding treatment.
Results of large studies combining chemotherapy
with HAART are eagerly awaited.
5.1.2 Haematopoietic Growth Factors
Since the advent of haematopoietic growth fac-
tors, two prospective studies were published using
recombinant human granulocyte-macrophage CSF
(rhu-GM-CSF). In a study by Kaplan et al.[69] pa-
tients receiving CHOP were randomised to GM-
CSF or no GM-CSF. Although there was a signif-
icant reduction in neutropenia and febrile episodes,
there was no difference in complete remission rates
or survival. A randomised trial comparing full-
dose M-BACOD with GM-CSF with low-dose M-
BACOD without GM-CSF also shows comparable
results for both treatment arms with respect to com-
plete remission rates (52 versus 41%) and median
survival (6.9 versus 7.8 months)[80] and thus no
clear advantage of the administration of GM-CSF
is demonstrated. On the other hand, treating HIV-
infected patients with GM-CSF is not without risk,
since GM-CSF (but not G-CSF) has been shown to
increase HIV-1 replication.[85] In fact, in the study
by Kaplan et al.[69] HIV-1 p24 antigen levels in-
creased in the GM-CSF arm, whereas they de-
creased in the control group receiving only CHOP.
In this study, HIV-RNA levels, which are a much
better reflection of viral load, were not measured.
G-CSF can be used safely to sustain haematopoie-
sis during chemotherapy in patients with ARL
since it does not increase HIV-RNA levels.[86]
5.1.3 New Drugs
One of the newer chemotherapeutic agents used
with some success in relapsed or refractory ARL is
mitoguazone (MGBG). Mitoguazone single agent
therapy has resulted in a 23% response rate in re-
lapsed patients, with some durable remissions.[87]
Unfortunately, this agent has not been approved by
the FDA and is currently not available.
With the advent of humanised chimeric anti-
CD20 antibodies, monoclonal antibody therapy of
NHL has become clinically feasible. Single agent
For patients with relapsed or resistant disease
few treatment options are available. Second line
regimens such as DHAP (doxorubicin, cytarabine
and cisplatin) in this patient group are associated
with low response rates and high toxicity.
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Drugs 2001; 61 (9)

AIDS-Related Lymphomas
1311
rituximab treatment (with a monoclonal antibody
targeting CD20, a pan B cell antigen) leads to a
response rate of 50% in relapsed follicular lym-
phoma and 30% in diffuse large cell lymphoma
with minimal toxicity.[88] The non-overlapping
toxicity and differing mechanisms of action make
it an attractive drug in ARL as well, and several
trials are underway. Preliminary results of the ad-
dition of rituximab to infusional CDE have been
published.[89] In 12 patients there was no increase
in toxicity compared to CDE alone. Nine of 12
patients had a complete response (75%). However,
the follow-up period is still short.[89] The effective-
ness of monoclonal antibodies can be increased by
conjugation to a radioisotope such as I131 or Y90.
Thusfar, there have been no reports on the use of
radiolabelled antibodies in ARL.
tease inhibitors are non-myelosuppressive, and
combination of triple or quadruple antiretroviral
therapy with chemotherapy has been shown to be
feasible. However, protease inhibitors may in-
crease the risk of severe mucositis, possibly through
alteration of the pharmacokinetics of one or more
cytotoxic agents.[90,91] A close cooperation be-
tween medical oncologists, pharmacologists and
AIDS specialists is essential in designing future
studies.
5.1.6 Central Nervous System (CNS) Prophylaxis
Although the effectiveness of CNS prophylaxis
with intrathecal administration of either metho-
trexate or cytarabine has never been studied in a
randomised trial, it is incorporated in most treat-
ment regimens (table I), and appears to reduce the
incidence of relapse in the CNS. It is especially
recommended in patients with lymphomatous bone
marrow involvement and patients with high grade
histology.[92]
5.1.4 Biological Response Modifiers
Treatment of ARL with biological response
modifiers such as IL-2 or anti–IL-6 monoclonal
antibody has resulted in clinically significant tu-
mour responses in anecdotal cases only. The use of
IL-2 has also been proposed in patients with com-
plete or partial remission to augment host re-
sponse, but at this point, there appears to be no role
for biological response modifiers outside of clini-
cal trials.
5.1.7 Infection Prophylaxis
In a case control study, in patients matched for
CD4+ cell counts and prior opportunistic infec-
tions, treatment for ARL with chemotherapy was
shown to result in a significantly greater and sus-
tained decrease in CD4+ counts and a 2-fold in-
crease in the occurrence of opportunistic infections
in patients compared with control subjects.[93]
Since opportunistic infections are a frequent
cause of morbidity and mortality in patients with
NHL, the use of PCP prophylaxis (either low dose
cotrimoxazole or aerosolised pentamidine) is rec-
ommended in all patients receiving chemotherapy,
regardless of their CD4+ cell count. Candida pro-
phylaxis is recommended, especially in patients
with corticosteroid containing regimens. In addi-
tion, herpes labialis through reactivation of herpes
simplex virus frequently occurs and can easily be
confused with chemotherapy-induced mucositis.[93]
Here as well, a close collaboration between medi-
cal oncologists and infectious disease specialists is
essential for the prophylaxis, recognition and man-
agement of opportunistic infections.
5.1.5 Antiretroviral Treatment
Although the use of zidovudine has been epide-
miologically linked to the emergence of NHL in
vitro, zidovudine has not only antiviral but also
antineoplastic activity and its use has been associ-
ated with regression of lymphoma in a few case
reports. Several studies have included antiretrovi-
ral therapy in the treatment regimens in an attempt
to also slow down progression of the underlying
HIV-infection[68,71] and to restore immune func-
tion. In a study recently published by Levine et
al.,[76] zalcitabine (ddC) was used in combination
with low-dose M-BACOD, which did not result in
increased (neuro)toxicity.
Currently, continuation or initiation of combi-
nation antiretroviral therapy is recommended
throughout treatment for NHL. Most of the non-
nucleoside reverse transcriptase inhibitors and pro-
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Drugs 2001; 61 (9)

1312
Kersten & Van Oers
5.2 CNS Lymphoma
lymphoproliferative disease, the feasibility of
treatment with either autologous or allogeneic in
vitro expanded EBV-specific CTL is currently be-
ing explored. Hopefully, the introduction of HA-
ART will also have a positive effect on treatment
outcome in ARL.
At this time, treatment decisions in individual
patients should be based on a careful consideration
of prognostic factors such as performance status,
CD4+ cell counts and a history of opportunistic
infections, and on a discussion of the different op-
tions with the patient. Whenever possible, treatment
in the context of clinical trials should be encour-
aged. Information on current clinical trials can be
obtained from local comprehensive cancer centers, the
AIDS Clinical Trials Group or the AIDS Malig-
nancy Consortium (http://cancernet.nci.nih.gov).
Patients with AIDS who develop PCNSL are usu-
ally severely immunocompromised with CD4+ cell
counts <0.05 x 109/L and they often have a diagno-
sis of AIDS. The median survival of these patients
is only 2 to 6 months. In view of difficult accessi-
bility for tissue diagnosis, the standard practice for
patients infected with HIV-1 with CNS lesions has
been to treat them empirically with anti-
toxoplasmosis treatment for approximately 2
weeks, followed by a diagnostic biopsy in those
patients who do not respond. Treatment of CNS
lymphomas with radiotherapy and/or dexametha-
sone can result in clinical and radiological im-
provement, but survival is not prolonged.[94] One
group reported remissions of 11 to 16 months in
patients treated with whole brain irradiation and
chemotherapy, which shows that selected patients
with AIDS and PCNSL may benefit from more in-
tensive treatment.[95]
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Correspondence and offprints: Dr Marie José Kersten, De-
partment of Medical Oncology, Netherlands Cancer Insti-
tute/Antoni van Leeuwenhoekhuis, Plesmanlaan 121, 1066
CX Amsterdam, The Netherlands.
E-mail: kersten@nki.nl
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