Although primary central nervous
system (CNS) lymphoma was
included among the first acquired immunodeficiency syndrome (AIDS)-defining
illnesses, it was not until 1985 that systemic lymphoma, of high or
intermediate grade, was recognized as AIDS-defining. The later recognition of
lymphoma as part of the spectrum of AIDS is consistent with the fact that
lymphoma usually occurs rather late in the course of HIV infection. Thus,
while serving as the initial AIDS-defining diagnosis in approximately 3% of
patients, lymphoma is the cause of death in approximately 16% to 20% of
HIV-infected individuals.[4,5] Moreover, the relative risk of developing
lymphoma increases substantially in patients who have already been diagnosed
with full-blown AIDS.[6,7] Hence, subsequent to an earlier diagnosis of AIDS,
the risk of immunoblastic lymphoma increases approximately 627-fold, the risk of
Burkitt’s lymphoma approximately 220-fold, and the risk of diffuse large cell
lymphoma 145-fold over what is expected in the general population.[6,7] Notably,
when linking cancer and AIDS registries, Goedert and colleagues found that even
the risk for low-grade lymphoma increased 14-fold in individuals who had already
been diagnosed with an AIDS-defining condition.[6,7] As these data suggest,
lymphoma is usually diagnosed in patients with markedly decreased CD4 cell
counts, consistent with prolonged periods of HIV infection and subsequent
Unlike Kaposi’s sarcoma, which occurs primarily in men who
have sex with men, lymphoma is seen in all population groups at risk for HIV,
and like de novo lymphoma, which occurs in HIV-negative individuals,
AIDS-related lymphoma is more common in men than in women. All age groups are
affected, and lymphoma is the most common malignancy in HIV-infected
children. Epidemiologic studies have failed to identify major environmental
factors associated with lymphoma among HIV-infected individuals.[10-12]
However, host factors may be operative. Thus, HIV-infected patients who are
heterozygotes for the CCR5-delta-32 deletion are statistically less likely to
develop lymphoma, whereas those with stromal cell-derived factor 1 (SDF-1)
mutations (eg, the 3¢A variant) are statistically more likely to develop
An interplay between genetic and other host factors may also
play a role in the development of AIDS-related lymphoma. Grulich and
colleagues recently reported the results of a case-control study of 219
patients with AIDS-related lymphoma, who were compared with 219 HIV-infected
controls, matched for CD4 cell counts and date of specimen collection. On
multivariate analysis, an increased risk of lymphoma was found with longer
duration of immunodeficiency (as determined by the time from seroconversion) and
lower CD4 cell counts 1 year before the diagnosis of lymphoma. In addition,
chronic B-cell stimulation was also predictive of lymphoma, using a higher serum
globulin level (as a surrogate for higher immunoglobulins) as a marker of B-cell
stimulation. Additionally, although controversial and clearly requiring
validation in other studies, the use of acyclovir (Zovirax) has been associated
with a decreased risk for AIDS-related lymphoma in one small case-control study
of 29 patients, while another, larger study yielded the opposite
In trying to predict the incidence of AIDS-related lymphoma in
the years ahead, it will be necessary to take all of these factors into account.
Role of Immunosuppression
Recent data from several large series[15,17] have demonstrated a
substantial decline in the median CD4 cell count among patients with newly
diagnosed AIDS-related lymphoma. In the early years of the epidemic, the median
CD4 cell count of the patients described by Levine and colleagues was 177/dL. In
patients diagnosed recently, however, the median CD4 count was only 55/dL.
This recent drop in the median CD4 count in patients with newly diagnosed AIDS
lymphoma may also be seen in several large, prospective national trials
conducted through the AIDS Clinical Trials Group (ACTG). Patients with newly
diagnosed AIDS-related lymphoma accrued to a phase II study of low-dose m-BACOD
(methotrexate, bleomycin [Blenoxane], doxorubicin [Adriamycin], cyclophosphamide
[Cytoxan], vincristine [Oncovin], dexamethasone) between June 1987 and November
1988 had a median CD4 cell count of 150/dL (range: 16 to 1,079/dL). In a
subsequent ACTG study comparing low-dose with standard-dose m-BACOD, in
which patients were accrued from February 1991 to October 1994 and eligibility
requirements were similar, a median CD4 cell count of approximately
100/dL at study entry was reported. The drop in the median CD4 cell count in
these recently diagnosed patients is of interest, especially because the
widespread use of highly active antiretroviral therapy (HAART) occurred during
the same time frame, and would be expected to be associated with an increase in
The paradoxical decrease in median CD4 count in recent patients
with newly diagnosed AIDS-related lymphoma may reflect the lack of HAART use, or
the lack of long-term efficacy of HAART in these individuals. Alternatively, the
use of HAART may simply have allowed these patients to live long enough to
eventually develop lymphoma. If the latter explanation is validated, the
incidence of lymphoma would clearly be expected to increase over time, despite
the use of HAART.
Incidence of AIDS-Related Lymphoma in the Era of HAART
While HAART has been associated with a significant decline in
the incidence of various opportunistic infections and Kaposi’s sarcoma,[20-22]
such a major and significant decline has not yet been seen in patients with
systemic AIDS-related lymphoma. In a cohort of 6,636 HIV-infected individuals
from Switzerland, reflecting over 18,000 person-years of follow-up, Lederberger
and colleagues compared the incidence of various AIDS-defining conditions in
the period from 1992 to 1994 (prior to the widespread use of HAART) with the
period from July 1997 to June 1998. No decrease in AIDS-related lymphoma was
seen (relative hazard = 0.61, 95% confidence interval = 0.30-1.29). Likewise,
although patient numbers were quite small (27 cases), no decrease in the
incidence of primary CNS lymphoma was evident from these data.
A recent report of AIDS cases from 17 Western European countries
evaluated the incidence of systemic and primary CNS lymphoma in 1988, compared
with that in 1997. The number of lymphoma cases among all AIDS patients rose
steadily from 1988 to 1996, and then declined somewhat in 1997. As a percentage
of all AIDS cases, however, systemic lymphoma actually increased from 3.6% in
1994 to 4.9% in 1997. This would be consistent with the significant decline in
opportunistic infections reported with the advent of HAART. A total of 989
cases of primary CNS lymphoma were diagnosed in this cohort, representing
approximately 0.5% of all AIDS cases, with no significant change in incidence
over time. In contrast, investigators from Italy have documented a
significant decrease in primary CNS lymphoma prevalence from 1991-1997 to 1997-1998.
In Australia, national HIV reporting has been ongoing since
1985, with seroconversion data available from 1991 on. Almost the entire
population of HIV-infected persons in that
country has been tabulated, providing a unique ability to track trends in cancer
incidence over time. In this large
and comprehensive database, the standardized incidence rates of lymphoma among
seroconverters decreased from 67 prior to July 1996 to 33.3 thereafter,
indicating a 50% reduction in AIDS-related lymphoma coincident with the widespread use of HAART.
Data from the International Collaboration on HIV and Cancer were
presented recently. Investigators representing over 20 cohort or
case-control studies conducted around the world were convened after submitting
initial raw data from these various studies for re-review in the United Kingdom.
Different methods were used to analyze cohort vs case-control studies, but all
relative risk estimates were adjusted for age, sex, and race. In the
case-control studies, additional adjusting factors included number of sexual
partners and parity.
Eleven of the studies allowed assessment of cancer risk in the
years before and after widespread use of HAART. In this subgroup, rate ratios of
the AIDS-defining cancers were calculated for the period 1992-1996, and were
compared with the rate ratios for 1997-1999, when HAART was widely available
in resource-rich areas
of the world. For non-Hodgkin’s lymphoma (NHL), the rate fell from 6.2 to
3.6 per 1,000 patient-years, indicating a significant decline, with a rate ratio
between the two periods of 0.58. No decline in Burkitt’s lymphoma was seen. A
significant reduction in the incidence of primary central nervous system
lymphoma was also documented.
These studies are thus inconsistent in terms of the incidence of
systemic or primary CNS lymphoma in the era of HAART. While most studies do not
indicate a statistically significant decline in the incidence of AIDS-related
lymphoma, other large studies, such as the International Collaborative Study,
indicate that there has been a meaningful decline. However, one fact remains
clear: the decrease in the incidence of AIDS-related lymphoma is not as
impressive as the decline in the incidence of Kaposi’s sarcoma.
Furthermore, while initial controlled clinical trials indicated that
approximately 80% of treated subjects will achieve a nondetectable HIV viral
load after HAART, only about 40% will achieve this end point in "real
world" conditions. The effect of HAART on the incidence of AIDS-related
lymphoma will clearly be dependent upon the long-term efficacy of combination
antiretroviral therapy when assessed at the population level. Issues of access,
compliance, drug resistance, and underlying host and environmental factors will
all likely be operative. Thus, further time will be required to elucidate the
full impact of HAART on the incidence
of AIDS-related systemic and CNS lymphoma.
1. Centers for Disease Control: Diffuse, undifferentiated
non-Hodgkin’s lymphoma among homosexual malesUnited States. MMWR Morb
Mortal Wkly Rep 31:507-508; 513-514, 1982.
2. Centers for Disease Control: Revision of the case definition
of acquired immunodeficiency syndrome for national reportingUnited States.
MMWR Morb Mortal Wkly Rep 34:373-375, 1985.
3. Levine AM: AIDS-related lymphoma (review). Blood 80:8-20,
4. Beral V, Peterman T, Berkelman R, et al: AIDS-associated
non-Hodgkin’s lymphoma. Lancet 337:805-809, 1991.
5. Peters BS, Beck EJ, Coleman DG, et al: Changing disease
patterns in patients with AIDS in a referral centre in the United Kingdom: The
changing face of AIDS. Br Med J 302:203-207, 1991.
6. Cote TR, Biggar RF, Rosenberg PS, et al: Non-Hodgkin’s
lymphoma among people with AIDS: Incidence, presentation, and public health
burden. Int J Cancer 73:645-650, 1997.
7. Biggar RJ, Rosenberg PS, Cote T: Kaposi’s sarcoma and
non-Hodgkin’s lymphoma following the diagnosis of AIDS. Int J Cancer
8. Hartge P, Devesa SS, Fraumeni JF Jr: Hodgkin’s and
non-Hodgkin’s lymphomas. Cancer Surv 20:423-453, 1994.
9. Granovsky MO, Mueller BU, Nicholson HS, et al: Cancer in
human immunodeficiency virus infected children: A case series from the Children’s
Cancer Group and the National Cancer Institute. J Clin Oncol 16:1729-1735, 1998.
10. Holly EA, Chitra Lele C: Non-Hodgkin’s lymphoma in
HIV-positive and HIV-negative homosexual men in the San Francisco Bay area:
Allergies, prior medication use, and sexual practice. J Acquir Immune Defic
Syndr 15:211-222, 1997.
11. Holly EA, Lele C, Bracci P: Non-Hodgkin’s lymphoma in
homosexual men in the San Francisco Bay area: Occupational, chemical, and
environmental exposures. J Acquir Immune Defic Syndr 15:223-231, 1997.
12. Armenian H, Hoover DR, Rubb S, et al: Risk factors for
Non-Hodgkin’s lymphomas in acquired immunodeficiency syndrome (AIDS). Am J
Epidemiol 143:374-379, 1996.
13. Dean M, Jacobson LP, McFarlane G, et al: Reduced risk of
AIDS lymphoma in individuals heterozygous for the CCR5-delta 32 mutation. Cancer
Res 59:3561-3564, 1999.
14. Rabkin CS, Yang Q, Goedert JJ, et al: Chemokine and
chemokine receptor gene variants and risk of non-Hodgkin’s lymphoma in human
immunodeficiency virus-1 infected individuals. Blood 93:1838-1842, 1999.
15. Grulich AE, Wan X, Law MG, et al: B cell stimulation and
prolonged immune deficiency are risk factors for non-Hodgkin’s lymphoma in
people with AIDS. AIDS 14:144-140, 2000.
16. Fong IW, Ho J, Toy C, et al: Value of long-term
administration of acyclovir and similar agents for protecting against
AIDS-related lymphoma: Case-control and historical cohort studies. Clin Infect
Dis 30:757-761, 2000.
17. Levine AM, Seneviratne L, Espina B, et al: Evolving
characteristics of AIDS-related lymphoma. Blood 96: 4084-4090, 2000.
18. Levine AM, Wernz JC, Kaplan L, et al: Low-dose chemotherapy
with central nervous system prophylaxis and azidothymidine maintenance in
AIDS-related lymphoma: A prospective multi-institutional trial. JAMA 266:84-88,
19. 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 immunodeficiency virus infection. N Engl J Med 336:1641-1648, 1997.
20. Palella FJ, Delaney KM, Moorman AC, et al: Declining
morbidity and mortality among patients with advanced human immunodeficiency
virus infection. N Engl J Med 338:853-860, 1998.
21. Ledergerber B, Telenti A, Effer M: Risk of HIV-related
Kaposi’s sarcoma and non-Hodgkin’s lymphoma with potent antiretroviral
therapy: Prospective cohort study. Br Med J 319:23-24, 1999.
22. Jacobson LP: Impact of highly effective antiretroviral
therapy on the incidence of malignancies among HIV-infected individuals
(abstract S5). 2nd AIDS Malignancy Conference, Bethesda, Md, 1998.
23. Dal Maso L, Serraino D, Hamers F, et al: Non-Hodgkin’s
lymphoma and primary brain lymphoma as AIDS-defining illness in Western Europe,
1988-1997. 3rd AIDS Malignancy Conference, Bethesda, Md, 1999 (abstract 97). J
Acquir Immune Defic Syndr 21:A34, 1999.
24. Ammassari A, Cingolani A, Pezzotti P, et al: AIDS-related
central nervous system lymphoma: Changes of epidemiological trend and of
diagnostic attitudes in the era of HAART. 3rd AIDS Malignancy Conference,
Bethesda, Md, 1999 (abstract 99). J Acquir Immune Defic Syndr 21:A34, 1999.
25. Grulich A: National linkage of HIV, AIDS, and cancer
incidence data. Abstracts of the 4th International AIDS Malignancy Conference;
May 16-18, 2000; Bethesda, Md (abstract 1). J Acquir Immune Defic Syndr Hum
Retrovirol 23:A15, 2000.
26. International Collaboration on HIV and Cancer: Highly active
antiretroviral therapy and incidence of cancer in human immunodeficiency virus
infected adults. J Natl Cancer Inst 92:1823-1830, 2000.
27. Lucas GM, Chaisson RE, Moore RD: Highly active
antiretroviral therapy in a large urban clinic: Risk factors for virologic
failure and adverse drug reactions. Ann Intern Med 31:81-87, 1999.
28. Levine AM, Sullivan-Halley J, Pike MC, et al: HIV-related
lymphoma: Prognostic factors predictive of survival. Cancer 68:2466-2472, 1991.
29. Vaccher E, Tirelli U, Spina M, et al: Age and serum LDH
level are independent prognostic factors in HIV-related non-Hodgkin’s
lymphoma: A single institution study of 96 patients. J Clin Oncol 14:2217-2223,
30. Straus DJ, Juang J, Testa MA, et al: Prognostic factors in
the treatment of Human Immunodeficiency Virus-associated non-Hodgkin’s
lymphoma: Analysis of AIDS clinical trials group protocol 142: Low-dose vs
standard-dose m-BACOD plus granulocyte-macrophage stimulating factor. J Clin
Oncol 16:3601-3606, 1998.
31. Rossi G, Donisi A, Casari S, et al: The International
Prognostic Index can be used as a guide to treatment decisions regarding
patients with HIV-related systemic non-Hodgkin’s lymphoma. Cancer
32. Tirelli U, Spina M, Gabarre J, et al: Treatment of HIV
related non-Hodgkin’s lymphoma adapted to prognostic factors. 3rd National
AIDS Malignancy Conference, Bethesda, Md, 1999 (abstract 91). J Acquir Immune
Defic Syndr 21:A32, 1999.
33. Gisselbrecht C, Oksenhendler E, Tirelli U, et al:
HIV-related lymphoma: Treatment with intensive combination chemotherapy. Am J
Med 95:188-196, 1993.
34. Ratner L, Redden D, Hamzeh F, et al: Chemotherapy for HIV
associated non-Hodgkin’s lymphoma in combination with highly active
antiretroviral therapy (HAART) is not associated with excessive toxicity. 3rd
National AIDS Malignancy Conference, Bethesda, Md, 1999 (abstract 92). J Acquir
Immune Defic Syndr 21:A32, 1999.
35. McKelvy EM, Gottlieb JA, Wilson HE, et al: Hydroxydaunomycin
(Adriamycin) combination chemotherapy in malignant lymphoma. Cancer
36. Vaccher E, Spina M, Santarossa S, et al: Concomitant CHOP
chemotherapy and highly active antiretroviral therapy (HAART) in patients with
HIV-related non-Hodgkin’s lymphoma. 12th World AIDS Conference, Geneva,
Switzerland, 1998. Abstract 22289.
37. Gill PS, Rarick MU, Brynes RK, et al: Azidothymidine and
bone marrow failure in AIDS. Ann Intern Med 107:502-505, 1987.
38. Sparano JA, Wiernik PH, Hu X, et al: Pilot trial of
infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine and
filgrastim in patients with Human Immunodeficiency Virus-associated non-Hodgkin’s
lymphoma. J Clin Oncol 14:3026-3035, 1996.
39. Sparano JA, Wiernik PH, Hu X, et al: Pilot trial of
saquinavir and nucleoside analogues plus infusional cyclophosphamide,
doxorubicin, and etoposide in patients with HIV- associated non-Hodgkin’s
lymphoma (abstract 78). 2nd AIDS Malignancy Conference, Bethesda, Md, 1998.
40. Sparano JA, Lee S, Henry DH, et al: Infusional
cyclophosphamide, doxorubicin and etoposide in HIV-associated non-Hodgkin’s
lymphoma: A review of the Einstein, Aviano, and ECOG experience in 182 patients.
Abstracts of the 4th International AIDS Malignancy Conference; May 16-18, 2000;
Bethesda, Md (abstract S15). J Acquir Immune Defic Syndr Hum Retrovirol 23:A11,
41. Sparano JA, Lee S, Chen M, et al: Phase II trial of
infusional cyclophosphamide, doxorubicin, and etoposide (CDE) in HIV-associated
non-Hodgkin’s lymphoma: An Eastern Cooperative Oncology Group trial (E1494).
3rd AIDS Malignancy Conference, Bethesda, Md, 1999 (abstract 120). J Acquir
Immune Defic Syndr 21:A39, 1999.
42. Little RF, Pearson D, Franchini G, et al: Dose-adjusted
EPOCH chemotherapy in previously untreated HIV-associated non-Hodgkin’s
lymphoma: Preliminary report of efficacy, immune reconstitution, and HIV control
following therapy. 3rd National AIDS Malignancy Conference, Bethesda, Md, 1999
(abstract 93). J Acquir Immune Defic Syndr 21:A33, 1999.
43. Little RF, Pearson D, Gutierrez M, et al: Dose-adjusted
chemotherapy with suspension of antiretroviral therapy for HIV-associated
non-Hodgkin’s lymphoma. Abstracts of the 4th International AIDS Malignancy
Conference; May 16-18, 2000; Bethesda, Md (abstract S16). J Acquir Immune Defic
Syndr Hum Retrovirol 23:A11, 2000.
44. Kahn J, Kaplan LD, Northfelt D, et al:
2-chlorodeoxyadenosine (2-CDA) for AIDS-associated non-Hodgkin’s lymphoma
(abstract 12). Proc Am Soc Clin Oncol 10:34a, 1991.
45. Levine AM, Tulpule A, Tessman D, et al: Mitoguazone therapy
in patients with refractory or relapsed AIDS-related lymphoma: Results from a
multicenter phase II trial. J Clin Oncol 15:1094-1103, 1997.
46. Bernstein ZP, Gould MA, Van Hoff, N et al:
Continuous-infusion gallium nitrate in refractory AIDS-associated lymphoma. 3rd
AIDS Malignancy Conference, Bethesda, Md, 1999 (abstract 123). J Acquir Immune
Defic Syndr 21:A40, 1999.
47. Tulpule A, Espina BM, Palmer M, et al: Peg-L-asparaginase
has activity in relapsed/refractory AIDS-related lymphomas. 3rd AIDS Malignancy
Conference, Bethesda, Md, 1999 (abstract 116). J Acquir Immune Defic Syndr
48. Kaplan LD, Herndier B, Klenke B, et al: Diethylhomospermine
for HIV- associated non-Hodgkin’s lymphoma. 3rd AIDS Malignancy Conference,
Bethesda, Md, 1999 (abstract 117). J Acquir Immune Defic Syndr 21:A39, 1999.
49. Tulpule A, Dezube B, Doweiko J, et al: A phase II trial of
liposomal daunorubicin in relapsed and refractory AIDS-related lymphomas
(abstract MoPpB 1087). XIII International AIDS Conference; July 9-14, 2000;
Durban, South Africa.
50. Tirelli U, Errante D, Spina M, et al: Second-line
chemotherapy in HIV-related non-Hodgkin’s lymphoma. Cancer 77:2127-2131, 1996.
51. Tulpule A, Upadhyahya G, Espina BM, et al: Infusional
cyclophosphamide, mitoxantrone, and etoposide (CME) in AIDS-related non-Hodgkin’s
lymphoma. Blood (suppl) 88:503a, 1996.
52. Tosi P, Gherlinzoni F, Mazza P, et al: 3’-Azido-3’-deoxythimidine
plus methotrexate as a novel antineoplastic combination in the treatment of
human immunodeficiency virus-related non-Hodgkin’s lymphoma. Blood 89:419-425,
53. Kaplan LD, Moran T, Song L, et al: Continuous-infusion
ifosfamide/mesna with daily etoposide for refractory HIV-associated non-Hodgkin’s
lymphoma. Proc Am Soc Clin Oncol 17:48a, 1998.
54. Errante D, Santarossa S, Antinori A, et al: Second-line
chemotherapy with CDE (cyclophosphamide, doxorubicin, etoposide) in patients
with resistant human immunodeficiency virus-related non-Hodgkin’s lymphoma
(abstract). Proc Am Soc Clin Oncol 17:57a, 1998.
55. Yuzon R, Espina BM, Tulpule A, et al: Treatment of
relapsed/refractory AIDS related lymphoma with high-dose cytarabine/cisplatin
combination regimens (abstract MoPpB 1085). XIII International AIDS Conference;
July 9-14, 2000; Durban, South Africa.
56. Tulpule A, Anderson LJJ, Levine AM, et al: Anti-B4 (CD19)
monoclonal antibody, conjugated with ricin (B4-blocked ricin) in refractory
AIDS-lymphoma (abstract 10). Proc Am Soc Clin Oncol 13:52, 1994.
57. Kaplan LD, Robles R, Kahn J, et al: Phase I trial of
anti-CD22-ricin-A chain immunotoxin (IgG-RFB4-dgA) for treatment of AIDS
lymphoma. National AIDS Malignancy Conference, Bethesda, MD, 1997 (abstract 90).
J Acquir Immune Defic Syndr 13:A38, 1997.
58. Barrett JC, Linn CA, Saleh MN: Rituxan for the treatment of
AIDS-associated non-Hodgkin’s lymphoma. 3rd AIDS Malignancy Conference,
Bethesda, Md, 1999 (abstract 121). J Acquir Immune Defic Syndr 21:A40, 1999.
59. Gabarre J, Leblond V, Sutton L, et al: Autologous bone
marrow transplantation in relapsed HIV-related non-Hodgkin’s lymphoma. Bone
Marrow Transplant 18:1195-1197, 1996.
60. Molina A, Krishnan A, Forman SJ: Autologous stem cell
transplantation for the treatment of HIV-associated non-Hodgkin’s lymphoma in
the era of highly active antiretroviral therapy. 3rd AIDS Malignancy Conference,
Bethesda, Md, 1999 (abstract 115). J Acquir Immune Defic Syndr 21:A38, 1999.
61. Campbell P, Iland H, Gibson J, et al: Syngeneic stem cell
transplantation for HIV-related lymphoma. Br J Hemat 105:795-798, 1999.