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Modern management of non-Hodgkin lymphoma inHIV-infected patients
Nicolas Mounier1,2, Michele Spina3 and Christian Gisselbrecht1
1Groupe d’Etude des Lymphomes de l’Adulte, GELA, 1 av C Vellefaux, Paris, France, 2Onco-VIH consortium, INSERM U720, 56 Bd V
Auriol, Paris, France, and 3Gruppo Italiano Cooperativo AIDS e Tumori, GICAT, 12 Via Pedemontana Occ, Aviano, Italy
Summary
Patients infected with human immunodeficiency virus (HIV)
are at greater risk of developing non-Hodgkin lymphoma than
the general population and aggressive B-cell lymphoma has
become one of the most common of the initial acquired
immunodeficiency syndrome (AIDS)-defining illnesses. This
review considers the prognostic factors and new approaches to
the treatment of patients with AIDS-related lymphoma (ARL).
As highly active antiretroviral therapy (HAART) became
available, the survival of many ARL patients has become
comparable to that of HIV-negative patients. This is partly due
to the decrease in the incidence of opportunistic infections and
improved prognosis. Both developments can also be attributed
to new treatment strategies for ARL, such as the use of effective
infusional regimens, Rituximab combinations and high-dose
therapy with autologous stem-cell transplantation for relapsed
disease. However, unresolved issues persist, such as the optimal
therapy for patients with Burkitt ARL or central nervous
system involvement.
Keywords: AIDS-related lymphoma, highly active antiretrovi-
ral therapy, rituximab, peripheral blood stem-cell transplan-
tation, prognosis.
Non-Hodgkin lymphoma (NHL) has been recognised as being
associated with human immunodeficiency virus (HIV) infec-
tion since the beginning of the acquired immune deficiency
syndrome (AIDS) epidemic. The incidence of NHL in HIV-
infected individuals is over 100 times the incidence among the
general population (Goedert et al, 1998). Worldwide, NHL is
the second most common HIV-associated cancer, and
accounts for AIDS-defining illness in about 3% of patients in
the USA, and 3Æ6% in Europe (Franceschi et al, 1999). Since
1996, the use of combination antiretroviral therapy, consisting
of protease inhibitors and nucleoside analogues to achieve
maximal viral load (VL) reduction, a treatment known as
highly active antiretroviral therapy (HAART), has been
followed by a substantial reduction in morbidity and mortality
secondary to HIV infection. In addition, it appears that the use
of HAART has reduced the incidence of AIDS-related
lymphoma (ARL).
Different chemotherapy regimens have been tested in ARL
patients (Gisselbrecht et al, 1993; Kaplan et al, 1997; Little
et al, 2003; Costello et al, 2004; Sparano et al, 2004) but there
is still disagreement regarding the optimal treatment, even in
the post-HAART era. Overall improvement was observed by
some investigators (Besson et al, 2001; Gerard et al, 2002) but
not others (Matthews et al, 2000; Noy, 2004). The four-drug
CHOP regimen (cyclophosphamide, adriamycin, vincristine
and prednisone) seems to confer some benefit with regard to
the duration of remission, and to improve the results of the
standard treatments for HIV-negative patients with high-grade
NHL (Fisher et al, 1993). However, the aggressive presentation
of ARL suggests the need for more intensive treatment
regimens, which have resulted in high complete response
(CR), and survival rates for patients with HIV-negative NHL
(Tilly et al, 2003; Pfreundschuh et al, 2004; Reyes et al, 2005).
On the contrary, the poor tolerability associated with chemo-
therapy has prompted investigators to test reduced-dose
regimens (Tirelli et al, 1992; Kaplan et al, 1997; Mounier et al,
2006a). Recently, the impressive results of anti-CD20 mono-
clonal antibody therapy in HIV-negative NHL patients, and
the fact that most cases of ARL are CD20-positive, prompted
several teams to conduct multicentre phase 2 and phase 3 trials
to evaluate the safety and efficacy of adding rituximab to the
chemotherapy regimen (Spina et al, 2005a; Kaplan et al, 2005;
Boue et al, 2006). The aim of the present review was to assess
the results of these trials, which focused on modern treatments
for ARL.
Pathology and epidemiology
AIDS-related lymphoma is generally a late event in the course
of HIV infection. Risk factors for the development of NHL
include a low CD4-cell count, a high HIV VL and advanced
age. ARL pathogenesis and pathology have been the subjects of
two recent reviews (Carbone & Gloghini, 2005; Navarro &
Correspondence: Dr Nicolas Mounier, Onco-Haematology
Department, Hospital l’Archet, 151 Route de Saint Antoine-Ginestiere,
06000 Nice, France. E-mail: [email protected]
review
ª 2006 The Authors First published online 3 January 2007Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 136, 685–698 doi:10.1111/j.1365-2141.2006.06464.x
Kaplan, 2006). According to the World Health Organisation,
ARL is divided into three categories: first, lymphomas also
occurring in immunocompetent patients, such as Burkitt
lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL)
including centroblastic, immunoblastic and anaplastic var-
iants; secondly, lymphomas occurring more specifically in
HIV-infected patients, such as primary effusion lymphoma
(PEL) and plasmablastic lymphoma; and thirdly, lymphomas
also occurring in other immunodeficiency states, such as the
polymorphic or post-transplant lymphoproliferative disorders
associated with HIV infection, such as B-cell lymphoma
(Harris et al, 1999).
AIDS-related lymphoma is more common in men than in
women, which is consistent with the sex ratio for de novo
lymphoma in HIV-negative patients. The usual age of ARL
patients seems to vary according to a bimodal distribution.
Thus, the first peak of disease appears in adolescents and
young adults, and the second peak, in middle age (below
60 years). Younger patients are more likely to present with BL,
and immunoblastic lymphoma has been seen in older patients.
Diffuse large B-cell lymphoma and BL are the most common
forms of ARL (about 90% of cases; Besson et al, 2001; Stebbing
et al, 2004a). Burkitt lymphoma exhibits the special feature of
occurring at relatively higher CD4-cell counts (>0Æ2 · 109/l)
than immunoblastic lymphomas (<0Æ05 · 109/l; Gabarre et al,
1995; Powles et al, 2000). Patients are usually diagnosed as
having advanced disease, B symptoms, extranodal disease,
including bone marrow involvement (Levine et al, 2000;
Aboulafia et al, 2004) and leptomeningeal disease (Sparano,
2001). Unusual sites may be involved in ARL, including the
lung, oral cavity, adrenal glands, kidney, gall bladder, heart, or
even the earlobe. In HIV infection, primary central nervous
system lymphoma (PCNSL) constitutes a distinctly extranodal
presentation of DLBCL, usually of the immunoblastic type
associated with severe immunosuppression (CD4-cells
<0Æ05 · 109/l), Epstein–Barr virus (EBV)-positivity and a poor
prognosis. Note that imagery alone cannot distinguish between
PCNSL and cerebral toxoplasmosis, which is the most
common cause of focal cerebral lesions. Leptomeningeal
involvement in lymphoma occurs in about 20% of patients
with newly diagnosed ARL. It is associated with higher CD4-
cell counts than those seen in patients with primary central
nervous system (CNS) lymphoma and is confined to the
craniospinal axis; there is no systemic involvement. Patients
may be entirely asymptomatic as regards the CNS (Stebbing
et al, 2004a). When symptoms occur, the most common
include altered mental status, cranial nerve palsy and headache.
Primary effusion lymphoma accounts for <5% of ARL cases
and is associated with infection by Human-Herpes virus 8
(HHV-8) and frequent coinfection by EBV. Two types of PEL
have been described: classic PEL or ‘body cavity-based
lymphoma,’ which exhibits a unique tropism for serous body
cavities, and extracavitary or solid PEL, an extraserous
lymphoma reported in HIV-positive patients, with or without
associated effusions. In classic lymphomatous PEL, effusions
may involve the pleural, pericardial or peritoneal body cavity.
In solid PEL, the tumour primarily involves extraserous sites,
such as the large bowel, skin, lung and lymph nodes. Despite
the B-cell origin of lymphomas, they rarely express CD20.
Prognosis is poor, as PEL occurs in advanced AIDS and seems
resistant to chemotherapy (Boulanger et al, 2005). Ongoing
gene expression profile analysis of PEL may help to explain its
pathogenesis, and also facilitate the identification of potential
therapeutic targets (Fan et al, 2005).
Plasmablastic lymphoma (PBL) is another unique large B-
cell lymphoma subtype, characterised by plasmacytoid differ-
entiation that typically involves the jaw and oral cavity of HIV-
infected individuals. In this condition, the tumour is closely
associated with EBV infection. Pathological findings include
large plasmablasts that retain the blastoid morphology of
immunoblasts but otherwise have acquired the immunophen-
otypic features of plasma cells. Immunophenotypically, PBL
can be distinguished by the absence of CD20-cells and the
presence CD138/syndecan-1, VS38c and CD79a cells (Delec-
luse et al, 1997). HHV-8 may play a role in HIV-associated
PBL, though it is still unclear whether that role is causative or
whether HHV-8 infection of PBL tumour cells is secondary
(Cioc et al, 2004). PBL has been documented in sites other
than the oral cavity, including the anorectum, nasal and
paranasal regions, skin, testes, bones and lymph nodes
(Schichman et al, 2004). Its prognosis is poor despite the use
of HAART and chemotherapy.
Since 1996, the use of HAART to achieve maximal VL
reduction has led to differences between the estimates of ARL
epidemiology (Ho, 1995; Carpenter et al, 1997; Besson et al,
2001). The EuroSIDA cohort reported that the proportion of
AIDS-defining illnesses attributed to NHL increased from 4%
in 1994 to 16% in 1998 (Mocroft et al, 2000) mainly due to a
decrease in Kaposi sarcoma. In contrast, a large meta-analysis
of 23 cohort studies (International Collaboration on HIV and
Cancer, 2000) found a decline in ARL, from 0Æ62% per year
between 1992 and 1996, to 0Æ36% per year between 1997 and
1999. The decline was marked for PCNSL and immunoblastic
NHL, but was not found for BL.
This variable decline in only certain NHL subsets underlines
the possibility that immune function involvement in ARL is
differential (Kirk et al, 2001). As the CD4-cell count is
predictive of the development of ARL, immune reconstitution
with HAART may lead to the decrease of the incidence of ARL
(Stebbing et al, 2004b). Nevertheless, ARL remains one of the
leading causes of death among HIV patients (Mocroft et al,
2000; Dore et al, 2002).
Prognostic factors
During the pre-HAART era, some of the features indicating a
poor prognosis included lymphoma-specific factors (e.g.
aggressive histology or extranodal disease) and HIV-specific
factors (e.g. poor bone marrow reserve, a CD4-cell count
<0Æ1 · 109/l or opportunistic infection). Straus et al (1998)
Review
ª 2006 The Authors686 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 136, 685–698
proposed an index that included the CD4 cell count, stage III
or IV disease, age over 35 years, a history of drug injection, and
elevated lactate dehydrogenase (LDH). The European groups
GELA (Groupe d’Etude des Lymphomes de l’Adulte) and
GICAT (Gruppo Italiano Cooperativo AIDS e Tumori) used
an index comprising a combination of three independent risk
factors: Eastern Cooperative Oncology Group (ECOG) per-
formance status of 2–4, prior AIDS, and a CD4-cell count
below 0Æ1 · 109/l. (Gisselbrecht et al, 1993) The pathological
type of lymphoma did not influence survival, and patients with
DLBCL or BL fared similarly, with median survival times of
6 months.
Today, in the post-HAART era, patients with DLBCL exhibit
markedly longer median survival, from 6 months to 4 years
(Lim et al, 2005a), which is similar to the survival of patients
with HIV-negative aggressive lymphoma. Prognostic factors
have also changed. In the post-HAART era, only lymphoma-
related factors, such as the attainment of complete remission
or a high International Prognostic Index (IPI) score remained
independent risk factors for survival (see Table I; Lim et al,
2005b; Mounier et al, 2006a). The impact of a low CD4 cell
count is still a matter for discussion (Bower et al, 2005). It may
provide further independent prognostic information, in par-
ticular regarding the infectious toxicity of intensified chemo-
therapy. In addition, after HAART combined with standard
chemotherapy, patients with AIDS-related BL still have a
median survival time of only 6 months, i.e. unchanged from
the pre-HAART era. Consequently, ARL treatment strategy
should focus not only on the efficacy of chemotherapy but also
on the interactions between optimal HAART and pre-existing
risk factors.
Low versus standard doses
Various chemotherapy regimens have been tested (Kaplan
et al, 1989; Tirelli et al, 1992; Gisselbrecht et al, 1993; Little,
2003; Costello et al, 2004; Sparano et al, 2004) but there is still
disagreement regarding the optimal treatment. The four-drug
CHOP regimen seems to confer some benefit with regard to
the duration of remission, and has also given positive results as
the standard treatment for HIV-negative patients with high-
grade NHL (Fisher et al, 1993).
On the contrary, the poor tolerability associated with
chemotherapy has prompted investigators to test reduced-
dose regimens (Tirelli et al, 1992; Kaplan et al, 1997). During
the early period of AIDS, phase II and III clinical trials showed
that low-dose chemotherapy regimens, such as low-dose m-
BACOD (methotrexate, bleomycin, adriamycin, cyclophosph-
amine, vincristine and dexamethasone), were as effective as
standard dose regimens, but had the advantage of possessing
statistically lower rates of haematological and other forms of
toxicity. In the randomised study (Kaplan et al, 1997), there
was no difference between the CR rates for standard and
reduced-dose m-BACOD chemotherapy (42% vs. 41%), but
there was less toxicity in the reduced-dose group. In the non-
randomised study (Ratner et al, 2001), the CR rate was 30% in
the low-dose CHOP group and 48% in the full-dose group,
with comparable toxicity in both groups but a relatively short
duration of CR in the low-dose group.
Together, GELA and GICAT initiated the NHL-HIV-93 trial
of risk-adapted CHOP-based intensive chemotherapy in ARL
patients (Mounier et al, 2006a). Four hundred and eighty five
patients, aged 18–67 years, were randomly assigned to che-
motherapy after stratification according to an HIV score based
on performance status, prior AIDS and CD4-cell counts
<0Æ1 · 109/l. Two hundred and eighteen low-risk patients
(HIV score 0) received either ACVBP (i.e. adriamycin,
cyclophosphamide, vindesine, bleomycin and prednisone) or
CHOP, 177 intermediate risk patients (HIV score 1), CHOP or
low-dose CHOP (Ld-CHOP) and 90 high-risk patients (HIV
score 2–3), Ld-CHOP or VS (vincristine and steroid). In the
intermediate risk patients (n ¼ 95), the theoretical dose
intensities for the doxorubicin and cyclophosphamide in the
CHOP regimen, were 17 and 250 mg/m2/week, respectively,
and the median doses actually administered were 96% and
96% of the designated doses respectively. For the Ld-CHOP
regimen (n ¼ 82), the theoretical dose intensities of doxoru-
bicin and cyclophosphamide were 8Æ5 and 125 mg/m2/week,
respectively, and the median doses actually administered were
96% and 96% of the designated doses respectively. There was a
significantly beneficial CR rate for CHOP versus Ld-CHOP
(49% vs. 32%, P ¼ 0Æ02). Despite the systematic use of
granulocyte colony-stimulating factor (G-CSF), the only
difference in toxicity was for grade 3–4 leucopenia, with 52%
vs. 30% (P ¼ 0Æ01). Seventeen of the 177 patients died during
chemotherapy. Other deaths were due to lymphoma in 46
(75%) of those on Ld-CHOP and 35 (54%) of those on CHOP
(P ¼ 0Æ003), and to infection in 11 (18%) and 20 patients
(31%) in these groups respectively. Five-year overall survival
(OS) was 28% for the CHOP group vs. 24% for the Ld-CHOP
group (P ¼ 0Æ19). This seems to indicate a balance between
Table I. Prognostic factor analysis in 335 ARL patients treated by
CHOP in the LNH-HIV 93 trial.
Pre-HAART (n ¼ 199) Post-HAART (n ¼ 136)
3-year OS (%), P-value 3-year OS (%), P-value
aa-IPI score (0–1) 27 0Æ0001 54 0Æ0001
2–3 12 22
HIV score 0 39 0Æ0001 56 0Æ13
1 19 50
2–3 2 34
Straus score 0–1 36 0Æ0006 61 0Æ06
2 20 40
3–4 9 34
Pathological sub-type
DLBC 29 0Æ21 49 0Æ10
Immunoblastic 17 33
Burkitt 24 32
AaIPI, age-adjusted International Prognostic Index.
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ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 136, 685–698 687
efficacy and toxicity, with more deaths due to infection among
patients on full-dose CHOP than Ld-CHOP (31% vs. 18%).
However, this hypothesis needs to be confirmed by competing
risk analysis of the causes of death; in order to ascertain
whether, among patients on CHOP, death due to infection
occurred early in the trial, i.e. while subjects were on therapy
and their neutrophil count was depressed. In that case, the
cause of death cannot have been lymphoma.
With the addition of HAART to chemotherapy, standard-
dose therapy has become feasible and advantageous. Recent
trials of CHOP-like regimens in ARL patients resulted in CR
rates of 45–65% (Sparano, 2003; Noy, 2004). In the GELA-
GICAT randomised study referred to above, CHOP and Ld-
CHOP, each combined with HAART (the latter typically
consisting of stavudine, lamivudine and indinavir), were
compared. We confirmed the difference of 15% in CR rates
with HAART for CHOP versus Ld-CHOP but again found
no increase in OS or event-free survival (EFS). The use of
HAART together with dose-reduced and standard-dose
CHOP was evaluated by the AIDS Malignancy Consortium
(AMC) sponsored by the USA National Cancer Institutes
(NCI), in a group of 65 patients with newly diagnosed ARL
(Ratner et al, 2001) HAART consisted of indinavir, stavudine
and lamivudine; indinavir is a protease inhibitor, and
stavudine and malivudine are nucleoside reverse transcriptase
inhibitors. Grade 3–4 neutropenia was more common among
patients receiving full-dose CHOP (25% vs. 12%), but the
numbers of patients with other forms of toxicity were similar.
The doxorubicin clearance and indinavir concentration
curves were also similar in the patients in this study
compared to the curves for historical controls. Cyclophosph-
amide clearance decreased 1Æ5-fold in patients compared to
controls, although the decrease had no apparent clinical
consequences.
All these results suggest that HAART could be administered
safely with concomitant low-dose or standard-dose CHOP
chemotherapy. Under these conditions, the CD4 cell count
declines by about 50% and then recovers within 1 month of
the completion of chemotherapy, without any significant
change in the VL (Powles et al, 2002). It is generally
recommended that azothioprine (AZT) be avoided during
chemotherapy because of its myelosuppressive effects (Gabarre
et al, 1995). HAART containing protease inhibitors such as
indinavir and saquinavir or the nucleoside analogue didano-
sine is well tolerated when administered with standard CHOP-
like regimens, and their concurrent use is recommended.
Standard versus intensified dose
Several studies recently confirmed that HIV-negative patients
with DLBCL could benefit from more intensive treatment than
standard CHOP (Tilly et al, 2003; Milpied et al, 2004; Mounier
et al, 2004; Pfreundschuh et al, 2004; Reyes et al, 2005).
However, dose-intensive chemotherapy for ARL remains a
matter of debate.
Our first cooperative trial of the ACVBP regimen in ARL
patients demonstrated that this regimen was not excessively
toxic for patients with no adverse prognostic factors for HIV,
which led us to evaluate these patients’ HIV scores (Gisselbr-
echt et al, 1993). Consequently, the NHL-HIV-93 trial was
designed to evaluate different dose-intensive treatments,
according to the patient’s HIV score. In low-risk patients on
the ACVB regimen (n ¼ 109), the theoretical dose intensities
of doxorubicin and cyclophosphamide were 37Æ5 and 600 mg/
m2/week, respectively, and the median doses actually admin-
istered were 91% and 91% of the designated doses respectively.
For the CHOP regimen (n ¼ 109), the theoretical dose
intensities of doxorubicin and cyclophosphamide were 17
and 250 mg/m2/week, respectively, and the median doses
actually administered were 98% and 98 % of the designated
doses respectively. Nine of the 218 patients died during
chemotherapy. Other deaths were due to lymphoma in 77
patients (67%), infection in 28 (24%) and toxicity or other
factors in 11 (9%). There was no difference regarding the cause
of death between the ACVBP and CHOP treatment groups.
Most cases of haematological toxicity and mucositis occurred
in the ACVBP treatment group. Leucopenia and thombopenia
were more frequent with ACVBP than CHOP (75% vs. 36%
and 46% vs. 12% respectively). CR was higher for ACVBP
(61% vs. 51%), but not significantly. Five-year OS was
estimated at 51% for ACVBP vs. 47% for CHOP (P ¼ 0Æ85).
Because of our past experience of tolerance in 1993, we chose
to give only 3 cycles of ACVBP (Gisselbrecht et al, 1993).
However, we wondered whether the treatment outcome would
have been better if chemotherapy had been prolonged (i.e. had
comprised 2 additional cycles after CR).
This issue seems to have been approached differently in the
pre- and post-HAART eras. In the latter, a minimum of six
cycles of CHOP and up to eight seems to be the standard
protocol. In our randomised LNH-HIV-93 trial of ACVBP
versus CHOP, which included 86 patients during the post-
HAART era, intensive ACVBP treatment was not shown to be
at all beneficial for low-risk patients (3-year OS: 60% vs. 57%).
The time-dependent Cox model demonstrated that the only
significant factors for OS were HAART [relative risk (RR): 1Æ6,
P ¼ 0Æ0002], HIV score (RR: 1Æ7, P ¼ 0Æ0001) and the
International Prognostic Index (IPI) score (RR: 1Æ5,
P ¼ 0Æ0012), but not the intensity of the CHOP-based
chemotherapy. These results for ACVBP are similar to those
of Costello et al (2004), who showed that at a median follow
up of 40 months, a modified high-dose CHOP regimen
including high-dose cyclophosphamide (2000 mg/m2), gave
OS and EFS estimates of 43% and 39% respectively. Encour-
aging results were reported for the EPOCH infusional regimen
(etoposide, prednisolone, vincristine, cyclophosphamide and
doxorubicin) in which the doses were individualised on the
basis of nadir counts. CR was achieved in 74% of the patients,
and at a median follow up of 53 months, the OS was 60%
(Little, 2003). Note that the CR rate and OS in this study were
the best reported to date. Outside the framework of a clinical
Review
ª 2006 The Authors688 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 136, 685–698
trial, infusional dose-intensified regimens (see Table II) might
be a reasonable strategy for the treatment of ARL patients.
The place of HAART within the dose-intensityframework
With the availability of HAART, the administration of inten-
sified dose chemotherapy became feasible as infectious com-
plications were reduced. However, there is concern about
potential drug interactions between chemotherapy and con-
current HAART. It should be noted that, in this connection, the
use of azidothymidine with intensified chemotherapy is contra-
indicated, because it is associated with potential marrow failure
and may worsen chemotherapy-induced haematological toxi-
cities (Gabarre et al, 1995). Another cause for concern is the
possible increase in organ toxicity due to the reduction, by
protease inhibitors, of the activity of specific cytochrome P-450
enzymes, which are important for chemotherapy metabolism.
This reduction leads to increased intracellular drug levels. Thus,
in a case report of solid organ transplantation in a patient with
HIV, the patient developed seizures, probably due to impair-
ment of his metabolism by supratherapeutic levels of the
immunosuppressive agents which were part of his HIV
antiretroviral regimen (Sparano et al, 1998) The increased
neurotoxicity and hepatotoxicity seen with concomitant HA-
ART and chemotherapy may be additional causes of concern
within the dose-intensity framework.
To avoid possible pharmacokinetic interactions between
HAART and chemotherapy, Little et al (2003), at the NCI,
investigated the feasibility of omitting HAART during the
administration of intensified-dose chemotherapy. In their
study, six cycles of dose-adjusted EPOCH were administered
to 39 patients with newly diagnosed ARL. The dose of
cyclophosphamide in cycle 1 was based on the patient’s CD4-
cell count at study entry (<0Æ1 · 109/l vs. > 0Æ1 · 109/l) and
was thereafter adjusted by increments or decrements of
187 mg/m (maximum dose, 750 mg/m2) according to the
absolute neutrophil nadir. Antiretroviral agents were not used
during chemotherapy but were restarted immediately after its
completion. Three-quarters of the patients received all six
planned chemotherapy cycles, and the administered dose
intensity was 100% for doxorubicin, 99% for etoposide, 99%
for vincristine and 65% for cyclophosphamide. This intensity
was achieved with acceptable toxicity. The CR rate was 74%,
and among patients with CD4-cell counts >0Æ1 · 109/l, 87%.
Five-year OS was 87%, but it was only 16% for patients with
CD4-cell counts <0Æ1 · 109/l. Although by the end of chemo-
therapy the median CD4-cell count had decreased to
0Æ19 · 109/l and the VL had increased by 0Æ5–1Æ0 log10 cop-
ies/ml, the CD4-cell count returned to baseline 6–12 months
after the resumption of HAART. No opportunistic infections
occurred during chemotherapy, but three patients developed
such infection during the 3 months after its completion.
This suggests that withholding HAART until the completion
of chemotherapy does not result in the progression of AIDS
but does allow the full delivery of chemotherapy. When
considering whether HAART should be omitted during
chemotherapy, the degree of immunosuppression required in
the individual patient (which would in turn affect the risk of
death from bacterial and opportunistic infections), and the
benefit of viral suppression for survival and tumour response,
should be weighed against the possible overlapping of HAART
and chemotherapy toxicities. In this connection, the study by
Little et al (2003) showed, in particular, that the outcome for
patients with CD4-cell counts <0Æ1 · 109/l remained unsatis-
factory. In this series, it might also have been possible to avoid
certain cases of opportunistic infection if HAART had not
been discontinued during chemotherapy. In addition, the drug
toxicities of chemotherapy with HAART were reported not to
differ from those of chemotherapy alone (Levine et al, 2004).
Sparano et al, (2004) aimed to determine the effectiveness of
infusional chemotherapy with CDE (cyclophosphamide, doxo-
rubicin and etoposide) plus filgrastim before and after the
administration of HAART in routine clinical practice. Ninety-
eight patients were studied; and for the first 43 patients
enrolled in the pre-HAART group, concurrent antiretroviral
treatment consisted of the nucleoside analogue didanosine. CR
occurred in 45% of the entire series and 2-year EFS and OS
were 36% and 43% respectively. At the time of the analysis,
30% of the pre-HAART group were alive compared with 47%
in the HAART group. After adjustment for the various of
follow up times, the OS of patients in the HAART group
improved more than that of pre-HAART patients (P ¼ 0Æ039).
HAART group patients also experienced less grade 4 non-
haematological toxicity (22% vs. 42%, P ¼ 0Æ04), thrombocy-
topenia (31% vs. 52%, P ¼ 0Æ03) and less anaemia (9% vs.
27%, P ¼ 0Æ02) and had fewer treatment-associated deaths
(0% vs. 10%; P ¼ 0Æ01).
Overall, infusional intensified chemotherapy together with
HAART has proved an effective and potentially curative
Table II. Infusional chemotherapy regimens.
CDE
Cyclophosphamide, 187Æ5–200 mg/m2/d for 4 d
Doxorubicin, 12Æ5 mg/m2/d for 4 d
Etoposide, 60 mg/m2/d for 4 d, continuous intravenous
infusion over 96 h
Granulocyte colony-stimulating factor filgrastim (G-CSF),
5/kg/d, subcutaneous injection from day 6 until neutrophil recovery
Every 28 d, repeat for a maximum of six cycles
EPOCH
Etoposide, 50 mg/m2/d for 4 d
Vincristine, 0Æ4 mg/m2/d for 4 d
Doxorubicin, 10 mg/m2/d for 4 d
Cyclophosphamide, 187 mg/m2 IV on day 5 when
CD4-cell count <0Æ1 · 109/l
or 375 mg/m2 IV on day 5 when CD4-cell count >0Æ1 · 109/l
Prednisone, 60 mg/m2 orally, from days 1 to 5
Granulocyte colony-stimulating factor: start on day 6
Every 21 d, repeat for a maximum six cycles
Review
ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 136, 685–698 689
treatment for ARL patients. However, as prevention of
infection seems crucial within the dose-intensity framework;
we recommend continuing Trimethoprime–Sulfamethoxazole
(TMP–SMX) and oral acyclovir for zoster prophylaxis for
3 months after chemotherapy (see Table III). In addition,
azithromycin could be used for Mycobacterium avium
prophylaxis until CD4-cell counts increase.
High-dose therapy and autologous stem-celltransplantation (ASCT)
ASCT is the treatment of choice for HIV-negative patients with
relapsed aggressive NHL who still respond to salvage chemo-
therapy (Philip et al, 1995), but whether ASCT has a role as
front-line therapy is still a matter of debate. So far, several
randomised phase III studies have shown controversial results.
Some of the authors concerned claimed that ASCT was
beneficial because it at least ensured freedom from progression
in patients who achieved CR after induction (Gianni et al,
1997; Santini et al, 1998; Haioun et al, 2000a; Milpied et al,
2004; Mounier et al, 2004). However, because of concern over
the potential toxicities associated with ASCT, it has not been
routinely proposed to patients with ARL. The literature
describing the use of ASCT in ARL is limited. Most of the
reports published originate from French and Italian groups
and the American City of Hope Medical Center (COHMC;
Gabarre et al, 2000, 2004, , Krishnan et al, 2001; Re et al,
2003).
French investigators reported results for 14 patients with
relapsed or resistant ARL (eight with NHL and six with
Hodgkin disease) who were treated with ASCT while on
HAART (Gabarre et al, 2004). For eight of them, the
conditioning regimen was radiotherapy-based, and for six,
chemotherapy-based. The HIV-1 VL was quantified in 11
cases. Haematological reconstitution was good and no deaths
occurred from toxicity. Despite the large number of cells
containing VL re-infused with the graft (105–109), HAART
controlled HIV replication and led to CD4-cell reconstitution
in seven of the eight patients who were still alive six months
after ASCT. Only two patients had opportunistic infections
after ASCT. There were transient increases in the VL of two of
the nine patients whose VL was previously undetectable.
Although the difference in the VL or CD4-cell count for the 14
patients before and after ASCT was marked, it was not
significant; neither were there any significant changes in the VL
or CD4-cell count. One month after ASCT, 10 patients were in
CR. Seven died of lymphoma between 1 and 10 months after
ASCT, and another two died in CR (one of AIDS at 16 months
and the other of a neoplastic tumour at 28 months). Five
patients were alive: four are in CR, respectively 14, 19, 32 and
49 months after ASCT (median CD4-cell count: 0Æ45 · 109/l;
undetectable VL in three patients) and one was being treated
for relapsed lymphoma 36 months after ASCT. Although
Gabarre et al (2004) also demonstrated that ASCT is feasible;
eight of the patients in their cohort have died, mostly of
relapsed lymphoma. The patients in their study had more
advanced disease at the time of transplant, suggesting that
ASCT should be proposed earlier in the course of poor-risk
ARL.
Similarly, the Italian group reported the results of a multi-
institutional programme of ASCT as salvage therapy in 16
patients with resistant or relapsed ARL after first-line chemo-
therapy (Re et al, 2003). Effective HAART was maintained
during the entire programme. Adequate collection was
obtained in 80% of patients. Three patients experienced early
progression. Ten (62%) received a chemotherapy-based con-
ditioning regimen and ASCT, with prompt engraftment in all
cases (neutrophil and platelet engraftment after medians of 10
and 13 d respectively). No patient died of opportunistic or
other infections or treatment-related complications. Eight of
the nine assessable patients achieved CR and one patient
achieved PR. Two patients experienced relapse and died 10 and
14 months after treatment. Six patients are alive and disease-
free at a median of 8 months after transplantation.
The COHMC studies attempted to apply the same criteria
to ARL patients as those used for HIV-negative lymphoma
patients evaluated for transplant (i.e. chemosensitive relapse
or first remission disease with poor-risk features by IPI
criteria; Krishnan et al, 2001). Most of the patients con-
cerned had relapsed chemosensitive disease, although three
in first remission and two with refractory disease were also
treated. Sixteen ARL patients were given a chemotherapy-
based conditioning regimen and three, a radiotherapy-based
regimen. All 19 patients were maintained on HAART
throughout the transplant, although 10 could not tolerate
it because of gastrointestinal toxicity manifested by nausea,
vomiting or mucositis. Three patients developed grade 3–4
liver toxicity, which was a result of the conditioning regimen
in two cases. The remaining patient developed late liver
toxicity 10 months after ASCT, which was ultimately
ascribed to his antiretroviral regimen. The median time to
neutrophil engraftment was 11 d (range: 9–23). Three of the
Table III. Practical points.
Diagnosis
Lumbar puncture with cytology
Bone marrow biopsy
Assessment of viral load
History of recent opportunistic infection
Standard Chemotherapy Treatment
Continue HAART but watch for drug interactions
Non-zidovudine HAART regimen
Pneumocystis prophylaxis with trimethoprime-sulfamethoxazole
Herpes zoster prophylaxis (acyclovir)
Granulocyte colony-stimulating factor: start on day 6
Antifungal prophylaxis using fluconazole
Monitor for hepatoxicity
Intensified regimen
Mycobacterium avium infection prophylaxis (azithromycin)
Monitoring for CMV till day +100
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ª 2006 The Authors690 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 136, 685–698
19 patients have died, two of relapsed lymphoma soon after
ASCT and one of regimen-related toxicity. The remaining 16
patients are alive and in remission at a median follow up of
27Æ5 months (range: 6–57Æ5). CD4-cell counts dropped to
their nadir after ASCT in all patients, whether they were on
or off HAART. This was observed at a median of 4Æ5 months
in eight patients. Most of the 16 patients had recovered
normal CD4-cell counts 1 year after ASCT, but two failed to
recover their counts and three died before such recovery.
Most patients exhibited transient increases in VL in the first
2 months after ASCT. Rises in VL persisted in three patients
who failed to comply with HAART.
Centres other than the COHMC and European centres, have
transplanted smaller numbers of patients with a variety of
conditioning regimens, some of them non-myeloablative
(Campbell et al, 1999; Serrano et al, 2005) Regimen-related
toxicities were not reported to increase in an HIV-negative
setting. The overall trend was similar in that engraftment was
achieved and the increases in VL were only transient.
Thanks to the availability of current treatment options and
appropriate prophylaxis against opportunistic infection, no
patient in the three main series reviewed here died of an
infectious complication. During cell transplantation, levofl-
oxacin is used for gut decontamination, TMP–SMX for
pneumocystis prophylaxis, intravenous acyclovir for herpes
prophylaxis and fluconazole, for antifungal prophylaxis. After
ASCT, TMP–SMX and high-dose oral acyclovir should be
continued for zoster prophylaxis for 1 year. In addition,
azithromycin is used for Mycobacterium avium prophylaxis
until CD4-cell counts reach stable levels. Surveillance cultures
for cytomegalovirus (CMV) are performed weekly until day
100 after ASCT; immunoglobulin levels are checked for a year
and replacement therapy is given.
High-dose therapy with ASCT in ARL patients should be
considered as the standard treatment of chemosensitive
relapse, whereas the use of allogeneic stem-cell-transplantation
remains an investigational approach. Interactions between
chemotherapy and HAART have not caused significant
increases in regimen-related toxicity. Patient selection is still
a matter of debate when proposed as upfront consolidation
treatment, especially when rituximab treatment is possible.
Lastly, it is crucial to evaluate patients for their ability to
comply with their HAART, in order to optimise the outcome
of the transplantation.
Chemotherapy combined with rituximab
Recent studies indicate that the prognosis of ARL has
improved in the HAART era, possibly owing to higher CD4-
cell counts at lymphoma onset, effective antiretroviral therapy
and certain features of the lymphomas. On the basis of the
impressive results of anti-CD20 monoclonal antibody therapy
in HIV-negative patients (Coiffier et al, 2002) and the fact that
most cases of ARL are CD20-positive, multicentre phase 2 and
phase 3 trials have been conducted to evaluate the safety and
efficacy of rituximab adjunction to the standard chemotherapy
regimen.
Spina et al (2005a) reported the pooled results of three
phase II trials using rituximab plus infusional chemotherapy in
patients with ARL. The trials were conducted by the Italian
GICAT, the Division of Haematology at Vienna University and
the Albert Einstein Cancer Center in New York. Patients were
treated with intravenous R-CDE including 375 mg/m2 of
rituximab on day 1 of each cycle, followed by a 96-h
continuous daily intravenous infusion consisting of cyclo-
phosphamide, doxorubicin and etopside every 4 weeks, for up
to six cycles. Patients were also given preventive filgrastim and
HAART was recommended in all cases, thus avoiding zidovu-
dine and ritonavir. Seventy-four patients were treated. Their
median CD4-cell count was 0Æ16 · 109/l; 72% had DLBCL and
70%, stage III-IV disease. Grade 3–4 toxicity included
neutropenia in 78%, anaemia in 32% and thrombocytopenia
in 24% of patients; in addition, 31% developed an infection
during the treatment or within 3 months of the end of
chemotherapy. Ten patients (14%) developed opportunistic
infections, including CMV retinitis (n ¼ 3), cryptosporidiosis
(n ¼ 3), pulmonary tuberculosis (n ¼ 2), Pneumocystis carinii
pneumonia (n ¼ 1) and salmonellosis (n ¼ 1). Overall, there
were six deaths due to infection, including bacterial sepsis
attributed to R-CDE (n ¼ 2) and four cases of opportunistic
infection that occurred after the completion of the treatment.
The opportunistic infections included cryptosporidiosis
(n ¼ 2), pulmonary tuberculosis and pulmonary aspergillosis
and they developed 5, 8, 2 and 8 months, respectively, after
completion of R-CDE. Fifty-two patients (70%) achieved CR
and 4 (5%), PR, so that the overall response rate was 75%.
Twenty-seven patients (36%) have since had progressive or
relapsed disease, including seven of the 52 who achieved
complete remission (14%). Two-year OS and EFS were 64%
and 52% respectively.
Recently, Boue et al (2006) reported a phase 2 trial including
61 patients with CD20-positive ARL. They were given ritux-
imab at the standard dose of 375 mg/m2 on day 1 of each cycle,
plus CHOP. This combination was repeated every 3 weeks for
up to six cycles. All patients received preventive filgrastim and
HAART was recommended in all cases, again thus avoiding the
need for zidovudine and ritonavir. The median baseline CD4-
cell count was 0Æ17 · 109/l; 69% of the patients had DLBCL
and 70% had stage III or IV ARL. Half the patients had an age-
adjusted IPI of 0 or 1. The most common forms of toxicity in
stages III and IV included anaemia (32%) and febrile
neutropenia (25%). Only two patients (4%) experienced an
AIDS-defining event (one developed CMV disease and the
other, HIV encephalitis). Of the 18 patients who died (35%),
the cause of death was lymphoma in 14, infection in one and
heart failure in one. Forty patients (67%) achieved CR and
10% obtained a PR. Estimated 2-year OS and 2-year EFS were
75% and 65% respectively. When this trial was designed in
1998, the safety of R-CHOP was uncertain in patients with very
advanced HIV disease and the investigators therefore decided
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ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 136, 685–698 691
to enrol only patients with no more than one of the following
adverse prognostic factors: CD4-cell count <0Æ1 · 109/l, prior
opportunistic infections and poor general status. Nevertheless,
the baseline characteristics of the patients are similar to those
of patients enrolled in other trials and observational studies.
Thus, patients with an IPI score of 0 or 1 and a CD4-cell count
above 0Æ1 · 109/l appear to form a subgroup for which the
results of R-CHOP are very satisfactory.
Taken together, these two trials showed that R-CHOP and
R-CDE were feasible and highly effective for ARL and that
these treatments exhibited an acceptable toxicity level which
was comparable to that observed in a HIV-negative popula-
tion(Coiffier et al, 2002).
The only randomised (2:1) phase 3 trial held to date was
conducted by the AMC. In this trial, the results of the standard
CHOP regimen were compared with those of R-CHOP in 150
patients with newly diagnosed ARL (Kaplan et al, 2005).
Patients were randomly assigned to receive a minimum of six
cycles of either standard CHOP (n ¼ 50) or R-CHOP
(n ¼ 99). After the achievement of CR, the R-CHOP patients
also received maintenance rituximab. All patients received
HAART and filgrastim. Their median baseline CD4-cell count
was 0Æ13 · 109/l, 69% had DLBCL and 79%, stages III–IV
disease. The incidence of febrile neutropenia was similar in the
two groups (30% for R-CHOP vs. 21% for CHOP, P ¼ 0Æ86).
Treatment-related infectious deaths occurred in 15 of the
patients receiving R-CHOP, i.e.14%, compared with 2% in the
CHOP group (P ¼ 0Æ035). Nine of these 15 deaths occurred in
patients who had a baseline CD4-cell count of <0Æ05 · 109/l
and six occurred during the maintenance phase of rituximab
treatment (n ¼ 35), a strategy not routinely used in aggressive
NHL. The CR rate was 57% for R-CHOP to 47% for CHOP
(P ¼ 0Æ147). With a median follow-up of 137 weeks, the
median times to progression, EFS and OS were 125, 45 and
139 weeks, respectively, for R-CHOP and 85, 38 and
110 weeks, respectively, for CHOP (P not significant for any
comparisons; 2-year OS ¼ 55%). EFS was significantly affec-
ted by the CD4-cell count and IPI score.
This randomised phase III trial raised several issues.
Although the authors noted that most treatment-related
deaths from infection occurred in patients with CD4-cell
counts below 0Æ05 · 109/l, survival curves were only shown for
counts below, equal to and >0Æ1 · 109/l, which did not enable
the effects of rituximab to be estimated in patients at the lowest
risk of death from infection. The time course of disease in the
patients whose death was jointly attributed to R-CHOP and
infection varied, suggesting different causes of death. Sixty-two
per cent of the deaths occurred during cycle 1 or 2 and were
attributed to chemotherapy-related neutropenia, whereas 38%
occurred during or within 6 months of maintenance rituxim-
ab. The combination of rituximab with chemotherapy is
known to increase the risk of grade 4 neutropenia and of
infection during treatment and the risk of late-onset neu-
tropenia after treatment (Dunleavy et al, 2005). Nevertheless,
the benefit of rituximab for tumour control should not be
underestimated. It is well established that rituximab is an
important treatment adjunct in HIV-negative DLBCL, especi-
ally for bcl-2 positive tumours (Mounier et al, 2003, 2006b;
Bonavida & Vega, 2005, ). In the study by Kaplan et al (2005),
both the progression of disease and the number of deaths due
to lymphoma diminished significantly in patients treated with
R-CHOP.
The USA NCI lymphoma group, headed by W. Wilson, is at
present investigating EPOCH treatment with high-dose ritux-
imab (375 mg/m2 on days 1 and 5) in untreated ARL patients.
The results for 21 patients suggest that rituximab is beneficial
for patients with CD4-cell counts below 0Æ1 · 109/l, because
OS in this group was 57% compared with only 16% for
treatment with EPOCH alone, whereas among patients with
CD4-cell counts above 0Æ1 · 109/l, the proportions of survi-
vors in each treatment group (90% and 87%) were similar
(Dunleavy et al, 2004). In particular, it is noteworthy that the
results for R-EPOCH were achieved with half the number of
cycles used for treatment with EPOCH alone. More cases of
neutropenia were observed with R-EPOCH, but these were
managed without the occurrence of any deaths
Hence, routinely increased medical surveillance during
rituximab-based chemotherapy seems necessary for patients
with low CD4-cell counts and all patients should be informed
of the risk of neutropenia and fever after this treatment.
Nevertheless, we believe it is unwise to omit rituximab from
the treatment of ARL and we hasten to add that treatment-
related deaths from infection can be reduced by careful
medical attention. The AMC is committed to exploiting the
beneficial effects of rituximab while minimising its potential
risks in this patient population. One way to accomplish this is
through the use of antibiotic prophylaxis for enteric organ-
isms. Recently published data suggest that this approach is
beneficial for non-immunocompromised patients with solid
tumours and lymphomas (Bucaneve et al, 2005; Cullen et al,
2005). The current AMC trial is evaluating the use of
sequential versus concurrent rituximab with the same dose-
escalated EPOCH regimen as that used by the USA NCI.
Unlike the previous AMC trial, the patients in the current
study are being given enteric prophylaxis.
We look forward to the final results of both the AMC and
NCI EPOCH-rituximab trials, in the hope that these will better
define the most beneficial use of rituximab (see Table IV). In
Table IV. Research agenda with Rituximab combinations.
ARL therapy with Rituximab is recent and many aspects of
this treatment remain to be explored.
What is the best timing for HAART (during or after chemotherapy)
to prolong the remission of lymphoma?
Should patients with relapsed/refractory ARL be offered
transplantation as second-line therapy?
Should PET assessment after induction chemotherapy help to
select patients for a more intensive approach, such as
transplantation or radio immunotherapy?
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ª 2006 The Authors692 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 136, 685–698
the meantime, patients with an IPI score of 0 or 1 and a CD4-
cell count above 0Æ1 · 109/l appear to form a subgroup in
which the results for R-CHOP are very satisfactory.
Special considerations
Burkitt lymphoma (BL)
Before the availability of HAART, the pathological type of
lymphoma did not affect survival and patients with BL or
DLBCL fared similarly, with median survival times in the
range of 6 months. However, in the post-HAART era, these
prognostic factors have changed and the pathological type of
lymphoma seems to affect the results of treatment. Thus,
many authors reported that with CHOP-like regimens,
patients with AIDS-related BL lymphoma were shown to
have median survival times of only 6 months, unlike those
with DLBCL, whose median survival progressed markedly, to
about the same extent as that of patients with HIV-negative
NHL.
Lim et al (2005a)) compared the outcomes of HIV patients
with BL and DLBCL after treatment with CHOP or
M-BACOD in the pre-HAART versus the post-HAART era,
and retrospectively reviewed 363 patients diagnosed between
1982 and 2003, 262 of them in the pre-HAART era (BL, 117;
DLBCL, 145) and 101 in the post-HAART era (BL, 18;
DLBCL, 83). Compared with BL, DLBCL was associated with
significantly lower CD4-cell counts before the introduction of
HAART but not afterwards. Although overall median survival
was similar for both groups without HAART (BL, 6Æ4 months
vs. DLBCL, 8Æ3 months; P ¼ 0Æ43), survival with HAART was
significantly worse for patients with BL (BL 5Æ7 months vs.
DLBCL, 43Æ2 months; P ¼ 0Æ0003). Failure to attain CR and
a CD4-cell count below 0Æ1 · 109/l were independent pre-
dictors of poor survival in the pre-HAART era, and the
histology of BL and failure to attain complete remission, in
the HAART era.
In their report of a phase II prospective study using R-CDE,
i.e. rituximab plus infusional cyclophosphamide, doxorubicin
and etoposide for 74 patients with ARL, Spina et al (2005a)
included both DLBCL and BL. In their multivariate analysis, a
diagnosis of BL was significantly associated with a worse
outcome than that of patients with a diagnosis of DLBCL.
Patients with BL had a significantly lower CR rate than patients
with DLBCL (52% vs. 77%; P ¼ 0Æ05) and their median OS
was significantly worse (14 months versus not reached;
P ¼ 0Æ01). The same authors also retrospectively reviewed
253 ARL patients diagnosed and treated at the Italian NCI
from 1984 to 2003, including 125 cases during the pre-HAART
era (77 of DLBCL and 48 of BL) and 128 during the post-
HAART era (93 of HIV-DLBCL and 35 of BL; Spina et al,
2005b). All the patients with DLBCL and BL were treated with
the same chemotherapy regimens. In the pre-HAART era,
median OS was similar in patients with BL and those with
DLBCL (7 vs. 10 months) whereas in the post-HAART era, the
median OS of BL patients was significantly shorter than that of
DLBCL patients (8 months vs. 22).
Consequently, the data reported by both Spina et al
(2005a,b and Lim et al (2005a)) suggest that as HAART is
now available, BL and DLBCL should not be treated using the
same approach. In addition, despite impressive results and the
use of HAART, the outcomes of patients with BL treated with
infusional R-CDE were significantly worse than those of
similarly treated patients with DLBCL, suggesting that BL is
indeed a more aggressive histological entity. Taking into
consideration the possibility that in the HAART era, ARL
patients are likely to tolerate intensive chemotherapy regimens,
a more intensive approach, similar to that used for HIV-
negative patients, should be prospectively investigated in HIV-
positive BL patients.
To evaluate the feasibility of intensive chemotherapy in BL,
Wang et al (2003) studied 14 HIV-positive adults treated
between 1988 and 2000 (Wang et al, 2003). Eight patients were
treated between 1996 and 2000 with cyclophosphamide,
doxorubicin, high-dose methotrexate/ifosfamide, etoposide
and high-dose cytarabine (CODOX-M/IVAC), one of the
currently preferred intensive-dose chemotherapy regimens for
BL. The other six received other chemotherapy regimens.
Outcomes were compared with those of 24 HIV-negative BL
patients with similar characteristics who were treated con-
comitantly (13 with CODOX-M/IVAC and 11 with other
regimens). Of the 14 HIV-positive patients, 63% achieved CR
in response to CODOX-M/IVAC treatment, compared with
67% of patients receiving other chemotherapy combinations.
Two-year EFS was 60% after both CODOX-M/IVAC and other
regimens. Outcomes were similar, despite the fact that 88% of
the CODOX-M/IVAC-treated HIV-positive patients had Stage
IV disease, compared with 33% of HIV-positive patients
treated with other chemotherapy regimens. HIV status did not
adversely affect long-term EFS. HIV-positive patients treated
with CODOX-M/IVAC tolerated chemotherapy well, but their
rates of myelosuppression and infectious complications were
close to those for HIV-negative patients. Similarly, in the
Programa para el Estudio de la Terapeutica en Hemopatıa
Maligna acute lymphoblastic leukaemia trial (PETHEMA-
LAL3/97), in which patients with BL were treated with an
intensive regimen regardless of their HIV status, Oriol et al
(2005) failed to find differences between HIV-positive and
HIV-negative individuals (2-year OS: 51%). These two groups
of patients achieved CR in 71% and 77% of cases respectively.
HIV patients who received HAART seemed to have slightly
better disease-free survival. The only adverse prognostic factor
was age above 60 years.
As intensive chemotherapy regimens used for BL outside
an HIV setting seem to meet with similar success within such
a setting, probably due to tolerance of treatment thanks to
the relatively well-preserved immune function seen in ARL
BL patients, intensive chemotherapy may, in the post-
HAART era, prove to be appropriate for all adult patients
with BL.
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ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 136, 685–698 693
Central nervous system involvement
Meningeal involvement is common in ARL patients and
indicates a poor prognosis. Thus, despite the use of intrathecal
methotrexate treatment, CNS involvement remained a poor
prognostic factor in the GELA-GICAT trial (5-year OS: 19%
vs. 30% without, P ¼ 0Æ07).
In addition to systemic chemotherapy, patients received
methotrexate, administered intrathecally to avoid the phar-
macological sanctuary resulting from the breakdown of the
blood-brain barrier. In the absence of cerebrospinal fluid
(CSF) involvement, CNS prophylaxis consisted of intrathecal
injection of 12 mg methotrexate before each chemotherapy
course (maximum: four injections). In the presence of CSF
involvement, intrathecal chemotherapy was administered at
least twice weekly until the disappearance of NHL cells
(maximum: nine injections). Similarly, for patients with
leptomeningeal disease, chemotherapy maintenance should
be considered after 9–12 intrathecal methotrexate injections, to
reduce the risk of relapse.
The risk of meningeal relapse has been investigated in HIV-
negative lymphoma patients in many studies. In a cohort of
DLBCL patients, its incidence was 5% in the absence of
prophylaxis, and rose to 20% in the presence of certain adverse
prognostic factors, including increased LDH, disseminated
stage and bone marrow involvement (Haioun et al, 2000b).
The improvement of lymphoma cell detection by immuno-
phenotyping is under study (Schinstine et al, 2006). CNS
prohylaxis is warranted in patients with adverse prognostic
factors. However, despite the use of intrathecal methotrexate
prophylaxis, 33 of the 485 patients in the GELA-GICAT trial
experienced CNS relapses.
Treatment of meningeal involvement at presentation was
reported by Mazhar et al (2006) in 22 ARL patients during the
post-HAART era. They compared the results of a standard
treatment comprising the alternative use of intrathecal met-
hotrexate and cytarabine with those of a sustained-release
formulation of intrathecal cytarabine (DepoCyt). This formu-
lation maintains drug concentrations in the CSF by means of
intraventricular diffusion, thus avoiding the use of an Ommaya
reservoir in many cases. Compared to conventional intrathecal
chemotherapy, the DepoCyt regimen also resulted in a higher
rate of tumour clearance from the CSF and prolonged the time
to neurological progression (Cole et al, 2003).Ten of the 22
ARL patients (45%) achieved a remission of CSF involvement:
they comprised seven of the 17 patients on intrathecal
methotrexate and cytarabine (41%) and three of the five on
fivfDepoCyt (60%). However, six of these 10 patients in
remission relapsed and again developed CSF disease, and all six
died (2-year OS: 34%). Nevertheless, these results show that
for compliant patients with well-documented outcomes,
DepoCyt offers an effective alternative to the limited number
of intrathecal agents.
Primary CNS ARL (PCNSL) has a very poor prognosis, with
a median OS of about 3 months when treated with radiother-
apy (RT) and chemotherapy. Improved survival with HIV-
PCNSL has been associated with the use of HAART after
diagnosis. Recently, Newell et al (2004) evaluated factors
influencing survival in 111 patients treated between 1987 and
1998. The median survival period was 50 d, with improved
survival for patients diagnosed after 1993. Patients treated with
two or more antiretroviral agents had improved survival
(P ¼ 0Æ01), as did patients treated by RT (P < 0Æ0001). For the
latter, completion of the prescribed course of at least 30 Gy
was an independent predictor of a more favourable outcome.
The combined use of RT and HAART had a cumulative
positive effect on survival. These results suggest that RT+
chemotherapy indeed improve survival for PCNSL patients.
However, late complications of RT, such as leucoencephalo-
pathy and radiation necrosis are an emerging concern. To limit
RT in front line patients, one possible alternative is to use
high-dose methotrexate (3 mg/m2 every 14 d) as this was
shown to induce CR in seven out of 15 patients, whose median
OS was 290 d (Skiest & Crosby, 2003). In HIV-negative
PCNSL patients, an induction regimen based on high-dose
methotrexate was successfully followed by consolidation RT.
This combination of therapies may provide the basis for
further trials combining functional and quality-of-life assess-
ment in HIV-positive patients.
Future prospects
The poor prognosis of ARL and the palliative approach to
treatment are no longer the rule since the introduction of
HAART. Most ARL patients can now, like HIV-negative
lymphoma patients, be treated with intensive-dose chemo-
therapy combined with HAART. Long-term CR can be
observed with a possible cure of lymphoma. Obviously, ARL
remains a serious disease and, despite HAART, the presence of
a severe immunodeficiency syndrome may prevent the use of
adequate chemotherapy. The different prognostic factors
should be carefully evaluated, using a multidisciplinary
approach, by the departments of haematology and infectious
diseases. Prophylaxis of infection is mandatory during treat-
ment. Patients will benefit from the introduction of rituximab
combined with chemotherapy and eventually from the
development of new agents directed against lymphoma. Within
this framework, special attention should be paid to the
question of whether a classification of responses based on the
addition of fluorine-18-fluorodeoxyglucose positron emission
tomography to the International Workshop Criteria would
allow more accurate assessment of ARL patient responses than
the present criteria alone, as already shown for HIV-negative
patients (Cheson et al, 1999; Juweid et al, 2005).
Acknowledgements
The authors thank Pr Jill-Patrice Cassuto for helpful discus-
sions and comments on their review. They also thank Mathilde
Dreyfus for editing the English.
Review
ª 2006 The Authors694 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 136, 685–698
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