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: mounier.n@chu-nice.fr

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)

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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

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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

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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.

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ª 2006 The Authors694 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 136, 685–698

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