Acquired Immunodeficiency Syndrome-Related
Simultaneous Treatment with Combined Cyclophosphamide, Doxorubicin, Vincristine,
and Prednisone Chemotherapy and Highly Active Antiretroviral Therapy Is Safe and
Improves Survival—Results of the German Multicenter Trial
Rudolf Weiss, M.D.1
Paris Mitrou, M.D.2
Keikawus Arasteh, M.D.3
Dirk Schuermann, M.D.4
Marcus Hentrich, M.D.5
Ulrich Duehrsen, M.D.6
Hinrich Sudeck, M.D.7
Ingo G. H. Schmidt-Wolf, M.D.8
Ioannis Anagnostopoulos, M.D.9
Dieter Huhn, M.D.10
1Private Practice for Hematology, Oncology and
Infectious Diseases, Bremen, Germany.
2Department of Hematology, Johann Wolfgang
Goethe University Hospital, Frankfurt, Germany.
3Department of Infectious Diseases, Auguste Vik-
toria Hospital, Berlin, Germany.
4Department of Infectious Diseases, Charite Hos-
pital, Humboldt University, Berlin, Germany.
Harlaching Hospital, Munich, Germany.
6Department of Hematology and Oncology, Uni-
versity of Essen Hospital, Essen, Germany.
7Bernhard Nocht Institute for Tropical Medicine,
8Department of Hematology and Oncology, Uni-
versity of Bonn Hospital, Bonn, Germany.
9Department of Pathology, Benjamin Franklin
Branch, Charite Hospital, Humboldt University,
10Department of Hematology and Oncology, Charite
Hospital, Humboldt University, Berlin, Germany.
Address for reprints: Rudolf Weiss, M.D., Private
Practice for Hematology, Oncology, and Infectious
Diseases, Kirchbachstrasse 110, 28211 Bremen,
Germany; Fax: (011) 49421-4307610; E-mail:
Received June 1, 2005; revision received October
3, 2005; accepted October 19, 2005.
BACKGROUND. Highly active antiretroviral therapy (HAART) has improved the
survival of patients with acquired immunodeficiency syndrome-related lymphoma
(ARL). The German ARL Study Group investigated whether HAART administered
concomitantly with cyclophosphamide, doxorubicin, vincristine, and prednisone
(CHOP) chemotherapy compromised the course of immune parameters during
and after chemotherapy and exerted a positive effect on remission and survival.
METHODS. From 1997 to 2001, 72 patients with ARL were stratified prospectively
into a standard-risk group (n ? 48 patients) and a high-risk group (n ? 24 patients)
with either 0-1 or 2-3 of the following risk factors: CD4 ? 50/?L, prior opportunistic
infection, and/or a World Health Organization performance status ? 3. Patients in
the high-risk group received ?75% of the CHOP regimen.
RESULTS. In the standard-risk group (CD4 ? 223/?L; age-adjusted International
Prognostic Index [aaIPI], 38% ? 2), the complete remission (CR) rate was 79%, and
median survival was not reached after a median 47 months of follow-up. CD4
counts did not change from baseline to 4 weeks after the end of chemotherapy
(206/?L). In the high-risk group (CD4 ? 34/?L; aaIPI, 88% ? 2), the CR rate was
29%, and the median survival was 7.2 months (3 patients survived for ? 3 yrs).
Toxicity was moderate: Leukopenia Grade 3 or 4 occurred in 100 of 249 chemo-
therapy cycles (40%) in the standard-risk group and in 70 of 102 cycles (69%) in the
CONCLUSIONS. Based on the aaIPI, the survival of patients in the standard-risk
group was very similar to that achieved by nonhuman immunodeficiency virus-
infected patients who had aggressive lymphomas. Concurrent CHOP plus HAART
can be administered in an outpatient setting. Thus, the authors recommend using
this modality as first-line therapy for patients with ARL. Cancer 2006;106:1560–8.
© 2006 American Cancer Society.
KEYWORDS: non-Hodgkin lymphoma, human immunodeficiency virus, chemother-
apy, International Prognostic Index, HIV.
drome (AIDS)-related lymphoma (ARL).1,2Although the incidence of
AIDS-related primary central nervous system (CNS) lymphoma has
decreased significantly, the decline in ARL has been less pronounced
or absent.3–13Since the introduction of HAART, CD4 counts at diag-
nosis have become higher, and the survival of patients with systemic
ARL has increased; hence, the prognosis of systemic ARL has im-
proved.14,15Because of to the decreasing incidence of Kaposi sarcoma
and opportunistic infections, an increasing proportion of mortality
ighly active antiretroviral therapy (HAART) has changed the biol-
ogy and clinical presentation of acquired immunodeficiency syn-
© 2006 American Cancer Society
Published online 27 February 2006 in Wiley InterScience (www.interscience.wiley.com).
and morbidity in human immunodeficiency virus
(HIV)-infected patients is related to ARL.3,16,17Treat-
ment options for patients with ARL recently were re-
Because it has been found that HAART improves
the survival and quality of life of these patients, it
would appear to be detrimental to withhold HAART
during chemotherapy. Nevertheless, primary reduc-
tion of the intensity of chemotherapy may not be
appropriate because of the aggressive nature of ARL.
Furthermore, combining HAART with chemotherapy
may lead to an increase in adverse drug interactions
and toxicity, thereby compromising remission and
This uncertainty has led to the development of
different treatment approaches. Some investigators
consider chemotherapy with concomitant HAART to
be effective and tolerable,22–24whereas others prefer
to suspend antiretroviral therapy during chemother-
apy to avoid excessive toxicity.25Consequently, the
question of whether combining HAART with chemo-
therapy outweighs the potential risk of increased tox-
icity remains controversial.
Therefore, the German AIDS-Related Lymphoma
Study Group initiated a prospective, multicenter
Phase II trial to address this question. The objective of
the current study was to assess the efficacy of com-
bined cyclophosphamide, doxorubicin, vincristine,
and prednisone (CHOP) plus concomitant HAART and
to determine whether this treatment modality leads to
MATERIALS AND METHODS
HIV-positive patients, as determined by Western blot
analysis, who were diagnosed with malignant lym-
phoma were documented by the German AIDS-Re-
lated Lymphoma Study Group. Biopsy materials were
reviewed and diagnoses were confirmed by one of
three German lymphoma reference centers. Patients
who were eligible for this trial had aggressive B-cell
lymphomas (the Revised European-American Lym-
phoma [REAL] classification).26Patients whose organ
function was adequate unless impaired by non-
Hodgkin lymphoma (NHL) were treated as specified
below. Patients with infections that prevented treat-
ment or primary CNS lymphomas were ineligible. Par-
ticipants were enrolled consecutively between 1997
and 2001. Each participating center’s local ethics com-
mittee approved the trial protocol, and all patients
gave their written informed consent.
According to these criteria, 157 patients with lym-
phoproliferative diseases were registered on the study.
Seventy-seven of those patients were excluded (see
below), and 8 patients were lost to follow-up before
chemotherapy was started. Of the 72 patients who
were treated according to protocol, 48 patients were
classified as “standard risk,” and 24 patients were clas-
sified as “high risk” (see Fig. 1).
Exclusion criteria included refractory, active in-
fections and opportunistic infections; serious cardio-
vascular, pulmonary, psychiatric, or metabolic dis-
ease; inadequate renal or hepatic function; treatment
with chemotherapy or cytokines within the preceding
4 weeks with the exception of granulocyte-colony
stimulating factor (G-CSF), granulocyte-macrophage-
colony stimulating factor, or erythropoetin; pregnan-
cy; life expectancy ? 4 weeks; primary CNS involve-
ment, and Ann Arbor Stage IA lymphoma (not Stage
IE) located above the diaphragm. Patients who ful-
filled these criteria were excluded without follow-up.
Patients with Stage IA lymphomas above the dia-
phragm and patients with primary CNS lymphoma
received radiation therapy only and were documented
off-study. This treatment was standard practice in
Germany at the time the study was planned.27–30
Patients who were included in the prospective
treatment protocol were stratified into two subgroups.
High-risk patients had 2 or 3 of the following risk
factors: CD4 lymphocytes ? 50/?L at the time of lym-
phoma diagnosis, a World Health Organization (WHO)
performance status ? 3, or a previous AIDS-defining
opportunistic infection. Standard-risk patients had
none or only one of those risk factors.
The histologic diagnosis was made according the
REAL classification.26One of three German lymphoma
FIGURE 1. This is a flow chart of patient recruitment. “All patients”
(n ? 157) included all human immunodeficiency virus-positive patients with a
preliminary diagnosis of malignant lymphoma that was yet to be confirmed by
one of the German lymphoma reference centers and recorded by the German
Simultaneous CHOP and HAART in ARL/Weiss et al.1561
reference centers (Prof. Dr. H. Stein, Berlin and Prof.
Dr. M.-L. Hansmann, Frankfurt; Prof. Dr. H.-K. Muel-
ler-Hermelink, Wuerzburg) reviewed the biopsy mate-
rial and confirmed the diagnosis.
The stage of the disease at the time of diagnosis
was determined by computed tomographic scans of
the chest, abdomen, and pelvis; unilateral bone mar-
row aspiration and biopsy; and lumbar puncture, in-
cluding quantitative and qualitative cytologic evalua-
tions for the presence of lymphoma cells. Lymphomas
were staged according to the Ann Arbor classification.
Additional tests at baseline included blood cell counts,
blood chemistry, CD3, CD4, CD8 lymphocyte counts,
quantitative serum immunoglobulins, viral load, and
Patients in the standard-risk group received CHOP on
the following schedule: intravenous cyclophospha-
mide 750 mg/m2, intravenous doxorubicin 50 mg/m2,
and intravenous vincristine 1.4 mg/m2(maximum
dose, 2.0 mg) all given on Day 1 of each cycle together
with oral prednisolone 100 mg/m2on Days 1-5. Each
cycle was repeated at Day 22. Patients in the high-risk
group received ? 75% of the CHOP regimen in the first
cycle, but dose escalation to 100% was permissible
based on the neutrophil count and the occurrence of
infectious complications. The objective of this strategy
was to avoid excessive toxicity in this vulnerable risk
Both standard-risk patients and high-risk patients
received six cycles of CHOP. In both groups, antiret-
roviral therapy was continued or started with induc-
tion therapy in all but six patients. Three of those
patients had viral loads ? 50,000 copies/?L, and 3
patients refused parallel therapy after they had been
included in the study. Two of the latter patients (all in
the high-risk group) did not achieve complete remis-
Intrathecal methotrexate (15 mg) was given to
each patient initially and subsequently was continued
with each chemotherapy cycle in patients who had
Stage IV disease or who had lactate dehydrogenase
(LDH) levels ? 800 U/L (normal range, 80-240 U/L).
Patients who had Grade 3 or 4 granulocytopenia or
prolongation of the treatment interval received G-CSF
beginning on Day 4 of the subsequent cycle. Pentam-
idine inhalation or trimethoprim-sulfamethoxazole
(TMP)/SMZ prophylaxis was used to prevent Pneumo-
cystis carinii pneumonia. Standard-risk patients re-
ceived maintenance therapy with interferon-?. This
part of the study was omitted later to guarantee full-
dose antiretroviral therapy.
Treatment response was assessed after Cycles 2, 4 and
6. Posttreatment follow-up examinations were per-
formed bimonthly. CR was defined as the complete
disappearance of all known lymphoma manifestations
that lasted ? 4 weeks. Partial remission (PR) was de-
fined as a reduction ? 50% in of the sum of the
products of the greatest cross-sectional dimensions of
all known measurable lesions. Nonresponders were
patients who attained less than PR or who experienced
progressive disease (PD).
WHO criteria were used to assess toxicity. The
age-adjusted International Prognostic Index score
(aaIPI) was used to ensure the comparability of our
results with results from other studies.31–33
In an intention-to-treat analysis, survival was calcu-
lated as the time from diagnosis of malignant lym-
phoma until the date of death or of last patient con-
tact. Survival functions and median survival were
estimated with the Kaplan–Meier method and were
compared by using the log-rank test and a Cox pro-
portional hazard model. Factors that influenced re-
mission rates or recurrences were included in a logis-
tic regression analysis. The criterion for inclusion in
the multivariate model was a level of significance of
P ? .1 (univariate statistics). Quantitative measures
were compared by using the Wilcoxon rank-sum test
and the chi-square test. The Fisher exact test was used
in small subgroups. A Friedman variance analysis was
used to assess the course of parameters during main-
tenance therapy. Statistical analyses were performed
according to the regulations of the Institute for Med-
ical Informatics, Biometry, and Clinical Epidemiology
at the Benjamin Franklin Hospital of the Free Univer-
sity of Berlin (Prof. Dr. W. Hopfenmueller).
Patient characteristics are shown in Table 1. Standard-
risk patients exhibited a better performance status and
better aaIPI scores; no prior opportunistic infections,
higher lymphocyte counts, including T-cell subsets;
and lower viral loads. The standard-risk and high-risk
groups did not differ with respect to age, lymphoma
stage, extranodal manifestations, presence of B-symp-
toms, LDH levels, or immunoglobulin G levels. Histo-
logic subgroups were distributed evenly between the
two risk groups.
A dose intensity of 97% was achieved in the standard-
risk group. In the high-risk group, 17 of 24 patients
1562 CANCER April 1, 2006 / Volume 106 / Number 7
(71%) received 100% of the CHOP regimen in the first
cycle, and the overall CHOP dose intensity was 91%.
Response to Treatment
The median follow-up was 26.2 months for the overall
group and 47 months for the standard-risk group. The
number of patients who achieved CR was 79% in the
standard-risk group versus 29% in the high-risk group
(Table 2, Fig. 2). The median survival was 26.1 months
for the overall group and 7.2 months for the high-risk
group. The median survival for the standard-risk
group had not yet been reached after a median follow-
up of 47 months. Currently, 60% of patients in the
standard-risk group are alive after 3 years of follow-up,
and 33% are alive after 5 years. The aaIPI-based overall
survival and remission data are shown in Table 3 and
in Figures 3-5.
The effects of major prognostic parameters on
response and survival for the overall group and for the
standard-risk group are shown in Table 4. Indepen-
dent of risk group, aaIPI scores ? 2, prior opportunis-
tic infections, low CD4 cell counts, advanced lym-
phoma stage, and increased LDH levels had a negative
impact on the probability of achieving CR and pro-
longed survival. Thrombocytopenia predicted shorter
In the standard-risk-group, aaIPI scores ? 2, prior
opportunistic infections, CD4 lymphocytes, and ele-
vated LDH levels had a negative impact on CR. aaIPI
scores ? 2, prior opportunistic infections, bone mar-
row involvement, thrombocytopenia, and elevated
LDH levels predicted shorter survival.
Patient Characteristics in the Different Risk Groups*
P No. No.% No.%
No. of patients
Median age, y
High-risk and intermediate-
WHO PS 3–4
Lymphoma (Stages III, IV)
Platelet count, ?L
CD3 lymphocytes, ?L
CD4 lymphocytes, ?L
CD8 lymphocytes, ?L
Viral load, copies/?L
Diffuse large cell
21 88 ? .00001†
83 ? .00001‡
42 ? .001§
CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisolone; HAART: highly active antiret-
roviral therapy; NS: not significant (at the 10% level); aaIPI: age-adjusted International Prognostic
Index; OI: opportunistic infection; WHO PS: World Health Organization performance status; WBC:
white blood cells; LDH: lactate dehydrogenase; IgG: immunoglobulin G.
* Median values are given for blood chemistry and blood cell counts.
†Differences between risk groups were calculated by using the Wilcoxon test.
‡Differences between risk groups were calculated by using the chi-square test.
§Differences between risk groups were calculated by using the Fisher exact test.
?Included patients who were unclassifiable because of technical problems.
Response Within the Different Risk Groups*
No.% No.% No.%
No. of patients
CR indicates complete response; PR, partial response; NC, no change; and PD, progressive disease.
* State of remission in one patient was not available.
FIGURE 2. These Kaplan–Meier plots illustrate survival for the overall group
(n ? 72 patients) and for the normal-risk group (n ? 48 patients) and the
high-risk group (n ? 24 patients).
Simultaneous CHOP and HAART in ARL/Weiss et al.1563
Factors that were significant at the .1 level were
included in a multivariate analysis (Cox model/logistic
regression), which yielded the following results: For the
overall group, CD4 lymphocytes ? 100/?L (P ? .00001),
a previous opportunistic infection (P ? .05), LDH ? 300
U/L (normal range, 80-240 U/I; P ? .05), and (tangen-
tially) aaIPI scores ? 2 (P ? .1) were predictors of failure
opportunistic infections (P ? .01) predicted shorter sur-
In the standard-risk group, CD4 lymphocytes
? 200/?L (P ? .00001) and LDH ? 300 U/L (P ? .01)
were predictors of failure to reach CR, and aaIPI scores
? 2 (P ? .001) and prior opportunistic infections (P ?
.1) were (tangentially) predictors for shorter survival.
The high-risk group was omitted from separate mul-
tivariate analysis because of the small number of pa-
Immune Parameters and Viral Load
Lymphocyte counts for the standard-risk group at the
start of chemotherapy, during chemotherapy, and 4
weeks after the completion of chemotherapy are
shown in Figure 6. Lymphocyte counts decreased sig-
nificantly during treatment; but CD3, CD4, and CD8
cell counts assessed 4 weeks after the completion of
chemotherapy did not differ significantly from base-
line counts. HIV viral loads decreased during chemo-
therapy, and counts measured during treatment were
significantly lower that those measured at baseline.
Complete Remission Within the Different Risk Groups According to
the Age-Adjusted International Prognostic Index*
No.% No.% No.%
No. of patients
* aaIPI (age-adjusted International Prognostic Index) scores were not available for 3 patients, and state
of remission was not available for one patient.
FIGURE3. These Kaplan–Meier plots illustrate survival for the low-risk group
(n ? 8 patients), the low-intermediate risk group (n ? 22 patients), the high-
intermediate risk group (n ? 26 patients), and the high-risk group (n ? 13
patients), as calculated based on the age-adjusted International Prognostic
FIGURE 4. These Kaplan–Meier plots illustrate survival for the combined
low-risk and low-intermediate risk groups (n ? 30 patients) and for the
combined high-risk and high-intermediate risk groups (n ? 39 patients), as
calculated based on the age-adjusted International Prognostic Index.
FIGURE 5. These Kaplan–Meier plots illustrate survival for the combined
low-risk and low-intermediate risk groups (standard risk, n ? 28 patients) and
for the combined high-risk and high-intermediate risk groups (standard risk,
n ? 18 patients), as calculated based on the age-adjusted International Prog-
1564CANCER April 1, 2006 / Volume 106 / Number 7
Grade 3 and 4 leukopenia occurred in 48% of all che-
motherapy cycles in the overall group. In the stan-
dard-risk group, Grade 3 or 4 leukopenia occurred in
40% of cycles, and G-CSF was administered in 26% of
cycles. In high-risk patients, Grade 3 or 4 leukopenia
occurred in 69% of the chemotherapy cycles, and G-
CSF was given in 53% of cycles. Neutropenic fever
occurred in 28 cycles (11%) in the standard-risk group
and in 31 cycles (30%) in the high-risk group.
Grade 3 and 4 peripheral neurologic disorders
were seen in 8 patients in the standard-risk group and
in 2 patients in the high-risk group (Table 5). The first
4 chemotherapy cycles lasted a median 21, 22, 21, and
21 days, respectively, in the standard-risk group and
slightly longer (21, 23, 24, and 24 days) in the high-risk
Independent of the risk group, progression and
recurrence of lymphoma were the most frequent
causes of death. Thirty-eight patients died during the
course of this study (17 standard-risk patients, 21
high-risk patients). Regarding the 17 deaths in the
standard-risk group, 10 patients died of PD, 1 patient
died during PR (cirrhosis, 4.9 mos; cytomegalovirus
pneumonia, 6.1 mos), 4 patients died during CR (sep-
sis, 8.7 mos; cirrhosis, 26.2 mos; heroin overdose, 42.8
mos; myocardial infarction, 64.7 mos), and 1 patient
died on Day 27 because of sepsis during neutropenia.
Regarding the 21 deaths in the high-risk group, 17
patients died of PD, and 1 patient died of wasting
syndrome (5.2 mos). The other 3 patients died during
CR (cirrhosis, 6.2 mos; sepsis, 10 mos; myocardial
infarction, 16.8 mos).
In the current study, all patients with lymphoprolif-
erative diseases diagnosed in the participating clinics
were documented and subsequently evaluated for el-
igibility in the study. Screening was carried out by the
study center to avoid patient selection by the treating
physician. Ultimately, 72 of 157 documented patients
qualified for inclusion in the trial. Of the 72 patients
who were treated according to protocol, 48 were de-
fined as standard-risk patients (0-1 risk factor), and 24
were defined as high-risk (2-3 risk factors). The risk
factors were as follows: CD4 count ? 50/?L, prior
opportunistic infections, and/or a performance status
? 2. These criteria, as demonstrated in a previous
The Significance of Major Prognostic Parameters on Response and Survival*
All Patients Standard-Risk Patients
Complete RemissionSurvival Complete RemissionSurvival
P MosP No.NR
aaIPI ? 2
Prior OI, yes
? 50 ?L
? 100 ?L
? 200 ?L
WHO PS 3-4
Age ? 40 y
B symptoms, yes
BM involvement, yes
Diffuse large cell
Hemoglobin ? 12 g/dL
WBC ? 5000 ?L
Platelets ? 100,000 ?L
LDH ? 300 units/mL
Viral load ? 100,000 copies/?L
? .05 9.4
NR: the number of patients at risk; aaIPI: age-adjusted International Prognostic Index; OI: opportunistic infection; WHO PS: World Health Organization performance status; BM: bone marrow; WBC: white blood
cells; LDH: lactate dehydrogenase.
* For the sake of clarity, remission data are not shown if cross-tabs could not be calculated. Survival data are not shown if subgroups were too small or if the estimated survival was comparable.
†The level of significance was calculated over three subtypes.
Simultaneous CHOP and HAART in ARL/Weiss et al. 1565
study,34can differentiate sharply between a “stan-
dard-risk group” of patients who have a good chance
of long-lasting remission and a tolerable number of
toxic or infectious events and a “high-risk group” of
patients who will not tolerate even standard chemo-
therapy. These results are well in line with a recently
published prognostic score for patients with ARL.35
In the high-risk group, HAART plus CHOP in-
duced CR in 7 of 24 (29%) patients. The median sur-
vival was 7.2 months, and 9 patients had either stable
disease or PD. The high rate of progression also led to
premature termination of therapy, as is reflected by
the lower number of chemotherapy cycles in this
group. The prognosis for high-risk patients generally is
dismal: The median survival was only 4.5 months in
the earlier trial,34and it was 7.2 months in the current
trial. Nevertheless, 3 of our high-risk patients have
survived for ? 3 years.
In the standard-risk group, HAART plus CHOP
produced a considerable rate of CRs (79%), and the
median survival had not been reached after a median
47 months of follow-up. This result is superior to that
achieved in the previous Phase II study34that was
carried out in the pre-HAART era (21.1 mos). The data
presented here demonstrate that, in standard-risk pa-
tients, CHOP plus HAART can achieve results compa-
rable to those achieved in non-HIV-infected pa-
Regarding toxicity, combined CHOP and HAART
was assessed as tolerable. In standard-risk patients,
the median length of the first 4 chemotherapy cycles
was 21 days; Grade 3 and 4 leukopenia occurred in 100
of 249 chemotherapy cycles (40%), and G-CSF was
administered in 65 of 249 cycles (26%). In high-risk
patients (102 chemotherapy cycles), Grade 3 and 4
leukopenia occurred in 70 cycles (69%), and G-CSF
was given in 54 cycles (53%). One patient died of
neutropenia, which was caused by an infection of
The single, main cause of death in both risk
groups was malignant lymphoma, as evidenced by the
fact that fatal PD occurred in 10 of 48 standard-risk
patients and in 17 of 24 high-risk patients. This con-
trasts with our previous findings, which demonstrated
a high rate of deaths related to infections, and to
opportunistic infections in particular.34
These results suggest that concomitant HAART
contributed considerably to improving the response
rates and survival of patients in the standard-risk
group who were treated in the current study. In addi-
tion, their immune parameters recovered shortly after
the completion of chemotherapy, and their viral load
decreased during the treatment cycles.
counts and HIV viral loads are in accordance with
previously published results on chemotherapy in
combination with HAART.22Inversely, the HIV viral
load increases when HAART is withheld during che-
motherapy.25The importance of a functioning im-
mune system was illustrated by Stebbing et al., who
demonstrated that successful HAART and the subse-
quent improvement of immune parameters lowered
the incidence of malignant lymphomas.37With the
exception of one study,25neither low-dose nor inten-
sified chemotherapy improved the response or sur-
vival rates in patients with ARL compared with stan-
dard CHOP. This is true for both the pre-HAART era
and the HAART era.22–24,34,38–42Little and colleagues
FIGURE 6. Lymphocyte counts and viral load during treatment (standard-risk
group) are illustrated. The Wilcoxon test was used to test for differences from
baseline (Start) to Weeks 6 and 12 of treatment and from baseline until 4
weeks after the end of chemotherapy. Levels of significance between Week 12
and 4 weeks after chemotherapy are listed on the left. Single asterisk, P ? .05;
double asterisks, P ? .01; triple asterisks, P ? .001.
Adverse Events and Use of Granulocyte-Colony Stimulating Factor
No.% No.% No.%
Cycles of chemotherapy
351 249 102
G-CSF: granulocyte-colony stimulating factor.
1566CANCER April 1, 2006 / Volume 106 / Number 7
achieved excellent response and survival results with
an infusional regimen. In their study, suspension of
HAART during chemotherapy and 50% reduction of
the initial cyclophosphamide dose in patients with low
CD4 lymphocytes did not affect outcomes negatively
and appeared to be associated with less toxisity.25In
the current study, we achieved comparable results in
our group of standard-risk patients, who had very
similar baseline patient characteristics, by using stan-
dard CHOP in an outpatient setting.
Future studies will be needed to determine
whether treatment modifications can improve patient
outcomes and further reduce the toxicity of CHOP
plus HAART, particularly in high-risk patients. The
treatment of non-HIV-infected patients with aggres-
sive lymphomas was improved by adding monoclonal
antibodies to CHOP43,44; similarly, combining anti-
CD20 monoclonal antibody to CHOP plus HAART may
improve outcomes further among patients with ARL.
However, the problem of the long-lasting deteriora-
tion of B-lymphocyte function must be addressed ad-
equately. Three different trials with chemoimmuno-
therapy resulted in significantly divergent response,
survival, and toxicity results; and those differences
could not be attributed to differences in baseline pa-
tient characteristics.42,45,46However, short follow-up
in some reports makes it difficult to compare or inter-
pret the data. In a recent publication,47the pooled
results of 3 Phase II trials (rituximab with cyclophos-
phamide, doxorubicin, and vepeside) showed promis-
ing remission and survival data; however, compared
with cyclophosphamide, doxorubicin, and vepeside, a
high rate of treatment-related toxicity was observed.
In conclusion, the current results show that our
risk-adapted strategy for concomitant administration
of HAART with CHOP is effective and safe. In stan-
dard-risk patients, the treatment achieved median
survival rates that were comparable to those obtained
in non-HIV-infected patients who had aggressive lym-
phomas. Future studies should focus on dose-intense
CHOP-like regimens or on the potential of chemoim-
munotherapy for further improving outcomes in pa-
tients with ARL. Another advantage of CHOP plus
HAART is that it can be administered in an outpatient
setting, thus saving treatment resources. Therefore,
we recommend the use of CHOP plus HAART as first-
line therapy for patients with ARL.
1.Tirelli U, Bernardi D. Impact of HAART on the clinical man-
agement of AIDS-related cancers. Eur J Cancer. 2001;37:
2.Simonelli C, Zanussi S, Cinelli R, et al. Impact of concomi-
tant antiblastic chemotherapy and highly active antiretrovi-
ral therapy on human immunodeficiency virus (HIV) vire-
mia and genotyping in HIV-infected patients with non-
Hodgkin lymphoma. Clin Infect Dis. 2003;37:820-827.
Kirk O, Pedersen C, Cozzi-Lepri A, et al. Non-Hodgkin lym-
phoma in HIV-infected patients in the era of highly active
antiretroviral therapy. Blood. 2001;98:3406-3412.
Vilchez RA, Jorgensen JL, Kroll MH. Systemic non-Hodgkin
lymphoma in HIV-infected patients in the era of highly active
antiretroviral therapy [letter]. Blood. 2002;99:4250-4251.
Matthews GV, Bower M, Mandalia S, Powles T, Nelson MR,
Gazzard BG. Changes in acquired immunodeficiency syn-
drome-related lymphoma since the introduction of highly
active antiretroviral therapy. Blood. 2000;96:2730-2734.
Levine AM, Seneviratne L, Espina BM, et al. Evolving charac-
teristics of AIDS-related lymphoma. Blood. 2000;96:4084-4090.
Jones JL, Hanson DL, Dworkin MS, Ward JW, Jaffe HW.
Effect of antiretroviral therapy on recent trends in selected
cancers among HIV-infected persons. Adult/Adolescent
Spectrum of HIV Disease Project Group. J AIDS. 1999;
Jacobson LP, Yamashita TE, Detels R, et al. Impact of potent
antiretroviral therapy on the incidence of Kaposi’s sarcoma
and non-Hodgkin’s lymphomas among HIV-1-infected in-
dividuals. Multicenter AIDS Cohort Study. J AIDS. 1999;
Franceschi S, Dal Maso L, La Vecchia C. Advances in the
epidemiology of HIV-associated non-Hodgkin’s lymphoma
and other lymphoid neoplasms. Int J Cancer. 1999;83:481-
10. Buchbinder SP, Holmberg SD, Scheer S, Colfax G, O’Malley
P, Vittinghoff E. Combination antiretroviral therapy and in-
cidence of AIDS-related malignancies. J AIDS. 1999;21(Suppl
11. Ledergerber B, Telenti A, Egger M. Risk of HIV related Ka-
posi’s sarcoma and non-Hodgkin’s lymphoma with potent
antiretroviral therapy: prospective cohort study. BMJ. 1999;
12. International Collaboration on HIV Infection and Cancer.
Highly active antiretroviral therapy and incidence of cancer
in human immunodeficiency virus-infected adults. J Natl
Cancer Inst. 2000;92:1823-1830.
13. Rabkin CS. AIDS and cancer in the era of highly active
antiretroviral therapy (HAART). Eur J Cancer. 2001;37:1316-
14. Besson C, Goubar A, Gabarre J, et al. Changes in AIDS-
related lymphoma since the era of highly active antiretrovi-
ral therapy. Blood. 2001;98:2339-2344.
15. Tam HK, Zhang ZF, Jacobson LP, et al. Effect of highly active
antiretroviral therapy on survival among HIV-infected men
with Kaposi sarcoma or Non-Hodgkin lymphoma. Int J Can-
16. Grulich AE. AIDS-associated non-Hodgkin’s lymphoma in
the era of highly active antiretroviral therapy. J AIDS. 1999;
17. Rabkin CS, Testa MA, Huang J, Von Roenn JH. Kaposi’s
sarcoma and non-Hodgkin’s lymphoma incidence trends in
AIDS Clinical Trial Group study participants. J AIDS. 1999;
18. Scadden DT. AIDS-related malignancies. Annu Rev Med.
19. Volberding PA, Baker KR, Levine AM. Human immunodefi-
ciency virus hematology. In: Broudy V, Prchal JT, Tricot GJ,
eds. Education Program Book: Proceedings of the American
Society of Hematology. San Diego, CA: American Society of
Simultaneous CHOP and HAART in ARL/Weiss et al.1567
20. Schmidt-Wolf IG, Rockstroh JK, Schlegel U, Pels H, Weiss R, Download full-text
Huhn D. New aspects in the treatment of AIDS-related lym-
phoma. Eur J Med Res. 2002;7:295-303.
21. Schmidt-Wolf IG, Rockstroh JK, Schlegel U, et al. Treatment
options of AIDS-related lymphoma. Expert Opin Pharmaco-
22. Ratner L, Lee J, Tang S, et al. Chemotherapy for Human
immunodeficiency virus-associated non-Hodgkin’s lym-
phoma in combination with highly active antiretroviral ther-
apy. J Clin Oncol. 2001;19:2171-2178.
23. Vaccher E, Spina M, di Gennaro G, et al. Concomitant cy-
clophosphamide, doxorubicin, vincristine, and prednisone
chemotherapy plus HAART in patients with HIV-related,
non-Hodgkin lymphoma. Cancer. 2001;91:155-163.
24. Sparano JA, Lee S, Chen MG, et al. Phase II trial of infusional
cyclophosphamide, doxorubicin, and etoposide in patients
with HIV-associated non-Hodgkin’s lymphoma: an Eastern
Cooperative Oncology Group trial (E1494). J Clin Oncol.
25. Little RF, Pittaluga S, Grant N, et al. Highly effective treat-
ment of acquired immunodeficiency syndrome-related lym-
phoma with dose-adjusted EPOCH: impact of antiretroviral
therapy suspension and tumor biology. Blood. 2003;101:
26. Harris NL, Jaffe ES, Stein H, et al. A revised European-
American classification of lymphoid neoplasms: a proposal
from the International Lymphoma Study Group. Blood.
27. Hoppe RT. The role of radiation therapy in the management
of the non-Hodgkin’s lymphomas. Cancer. 1985;55:2176-
28. Frank C, Flentje M, Goldschmidt H, Hunstein W, Wannen-
macher M. Results of radiotherapy and combined modality
treatment in early stage high grade non-Hodgkin’s lym-
phoma. Strahlenther Onkol. 1994;170:383-390.
29. Vaughan Hudson B, Vaughan Hudson G, MacLennan KA,
Anderson L, Linch DC. Clinical Stage 1 non-Hodgkin’s lym-
phoma: long term follow-up of patients by the British Na-
tional Lymphoma Investigation with radiotherapy alone as
initial therapy. Br J Cancer. 1994;69:1088-1093.
30. Hoederath A, Sack H, Stuschke M, Lampka E. Radiotherapy
of primary extranodal non.Hodgkin’s lymphoma of the head
and neck region. Results of a prospective multicenter study.
Study Group NHL: early studies. Strahlenther Oncol. 1996;
31. [No authors listed.] A predictive model for aggressive non-
Hodgkin’s lymphoma. The International Non-Hodgkin’s
Lymphoma Prognostic Factors Project. N Engl J Med. 1993;
32. Navarro JT, Ribera JM, Oriol A, et al. International Prognos-
tic Index is the best prognostic factor for survival in patients
with AIDS-related non-Hodgkin’s lymphoma treated with
CHOP. A multivariate study of 46 patients. Haematologica.
33. Rossi G, Donisi A, Casari S, Re A, Cadeo G, Carosi G. The
International Prognostic Index can be used as a guide to
treatment decisions regarding patients with human immu-
nodeficiency virus-related systemic non-Hodgkin lym-
phoma. Cancer. 1999;86:2391-2397.
34. Weiss, R, Huhn D, Mitrou, P, et al. HIV-related non-
Hodgkin’s lymphoma: CHOP induction therapy and inter-
feron-?-2b/zidovudine maintenance therapy. Leuk Lym-
35. Bower M, Gazzard B, Mandalia S, et al. A prognostic index
for systemic AIDS-related non-Hodgkin lymphoma treated
in the era of highly active antiretroviral therapy. Ann Intern
36. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a
standard regimen (CHOP) with three intensive chemother-
apy regimens for advanced non-Hodgkin’s lymphoma.
N Engl J Med. 1993;328:1002-1006.
37. Stebbing J, Gazzard B, Mandalia S, et al. Antiretroviral treat-
ment regimens and immune parameters in the prevention
of systemic AIDS-related non-Hodgkin’s lymphoma. J Clin
Oncol. 2004; 22:2177-2183.
38. Gisselbrecht C, Oksenhendler E, Tirelli U, et al. Human
immunodeficiency virus-related lymphoma treatment with
intensive combination chemotherapy. French-Italian Coop-
erative Group. Am J Med. 1993;95:188-196.
39. Kaplan LD, Straus DJ, Testa MA, et al. Low-dose compared
with standard-dose m-BACOD chemotherapy for non-
Hodgkin’s lymphoma associated with human immunodefi-
ciency virus infection. National Institute of Allergy and In-
fectious Diseases AIDS Clinical Trials Group. N Engl J Med.
40. Sparano JA, Wiernik PH, Hu X, Sarta C, Henry DH, Ratech H.
Saquinavir enhances the mucosal toxicity of infusional cy-
clophosphamide, doxorubicin, and etoposide in patients
with HIV-associated non-Hodgkin’s lymphoma. Med Oncol.
41. Oksenhendler E, Gerard L, Dubreuil ML, et al. Intensive
chemotherapy (LNHIV-91) regimen) and G-CSF for HIV as-
sociated non-Hodgkins’s lymphoma. Leuk Lymphoma.
42. Kaplan LD, Lee JY, Ambinder RF, et al. Rituximab does not
improve clinical outcome in a randomized Phase 3 trial of
CHOP with or without rituximab in patients with HIV-asso-
ciated non-Hodgkin lymphoma: AIDS-Malignancies Con-
sortium Trial 010. Blood. 2005;106:1538-1543.
43. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy
plus rituximab compared with CHOP alone in elderly pa-
tients with diffuse large cell-B-cell lymphoma. N Engl J Med.
44. Pfreundschuh MG, Truemper L, Oesterborg DMA, et al.
Randomized intergroup trial of first line treatment for pa-
tients ?60 years with diffuse large B-cell non-Hodgkin’s
lymphoma (DLBCL) with a CHOP-like regimen with or with-
out the anti-CD20 antibody rituximab—early stopping after
the first interim analysis [abstract]. J Clin Oncol. 2004;22 (14
45. Boue F, Gabarre J, Gisselbrecht C, et al. CHOP chemother-
apy plus rituximab in HIV patients with high grade lympho-
ma-results of an ANRS trial [abstract]. Blood. 2002;100:470a.
46. Spina M, Simonelli C, Vaccher E, et al. Rituximab and infu-
sional cyclophosphamide, doxorubicin and etoposide (CDE)
in combination with HAART: a save and highly active regi-
men in HIV-related non-Hodgkin’s lymphomas (NHL) [ab-
stract]. Blood. 2003;102:123a.
47. Spina M, Jaeger U, Sparano JA, et al. Rituximab plus infu-
sional cyclophosphamide, doxorubicin, and etoposide in
HIV-associated non-Hodgkin lymphoma: pooled results
from 3 Phase 2 trials. Blood. 2005;105:1891-1897.
1568 CANCER April 1, 2006 / Volume 106 / Number 7