Current Trends Opportunistic Non-Hodgkin's Lymphomas Among Severely Immunocompromised HIV-Infected Patients Surviving for Prolonged Periods on Antiretroviral Therapy -- United States

Since 1982, high-grade B-cell non-Hodgkin's lymphomas (NHLs) have been reported among persons with human immunodeficiency virus (HIV) infection (1); in 1985, CDC revised the surveillance case definition for acquired immunodeficiency syndrome (AIDS) to include certain high-grade NHLs. Recent surveillance findings indicate that NHLs occur among approximately 3% of all adults with AIDS reported to CDC. This report characterizes the occurrence of NHLs in a cohort of persons with AIDS or severe HIV infection who have received long-term zidovudine (AZT)-based therapy.

In 1985, the National Cancer Institute (NCI) began to follow a cohort of patients with AIDS or symptomatic HIV infection (oral thrush or weight loss). These patients, who participated in three separate clinical trials of AZT-based therapy, were among the first to receive antiretroviral drugs (2). A total of 55 patients were enrolled (10 are still alive); through May 1991, some of these patients had been followed for up to 4-1/4 years.

Through May 1991, NHLs had occurred in eight of the patients. NHL was diagnosed a median of 23.6 months (range: 15.4-34.8 months) after initiation of antiretroviral therapy and a median of 21.8 months (range: 2.7-76.6 months) after the diagnosis of AIDS. Based on the method of Kaplan and Meier, the estimated probability of developing NHL within 24 months of initiating antiretroviral therapy (updated from a previous estimate (2)) is 12% (95% confidence interval (CI)=5%-27%), increasing to 29% (95% CI=15%-49%) after 36 months (Figure 1). Among this patient cohort, the incidence rate of developing an NHL is 0.077 per patient-year of follow-up.

The median CD4 cell count for the 55 patients at initiation of antiretroviral therapy was 71 cells/mm3 (range: 0-953 cells/mm3). The risk for NHL varied inversely with the CD4 cell count--patients with greater than 50 CD4 cells/mm3 had no lymphomas during 56.8 patient-years of observation, whereas those with less than 50 CD4 cells/mm3 had eight lymphomas during 45.8 patient-years (p less than 0.002 by the test for difference in Poisson rates (3)). Among patients who survived for 18 months with a count of less than 50 CD4 cells/mm3, the risk for NHL was 28% (95% CI=13%-50%). The eight patients who developed NHLs had a median of six CD4 cells/mm3 (range: 4-30 cells/mm3) at the time of NHL diagnosis.

The NHLs among patients in this cohort were typical of those previously associated with HIV infection (4). All NHLs occurred in extranodal sites; for five patients, NHLs occurred in the central nervous system (CNS). Of these five, two occurred in patients with cerebral toxoplasmosis, and one was diagnosed at autopsy and involved only the leptomeninges. Seven patients presented with B-cell tumors, and one, a null-cell tumor (this patient subsequently developed a second lymphoma of B-cell origin). On histologic examination, four consisted of small noncleaved cell (includes diffuse undifferentiated, Burkitt's, and non-Burkitt's), and four, large-cell immunoblastic lymphomas. Response to treatment was generally poor, with a median survival of 1.8 months (range: 0.6-3.2 months) for patients with primary CNS involvement and 7 months (range: 0.5-18.0 months) for those with primary visceral involvement. Reported by: National Cancer Institute, National Institutes of Health. Office of the Deputy Director (HIV), CDC.

Editorial Note

Editorial Note: HIV-associated NHLs are typically aggressive, B-cell lymphomas occurring in extranodal sites, particularly the CNS (4). Although NHLs occur in approximately 3% of adults with AIDS reported to CDC, this proportion represents predominately AIDS-defining illnesses rather than NHLs that develop in patients with previously diagnosed AIDS. The findings in this report suggest that the incidence of HIV-associated NHL may be higher than previously estimated, particularly among patients with less than 50 CD4 cells/mm3 who survive for prolonged periods. These findings are based on follow-up of a small, highly selected patient sample studied at a research hospital. Although no patient had lymphoma at entry into the studies, the patients were followed on an oncology/AIDS service where the clinical level of suspicion for tumors was especially high. In particular, the diagnoses of NHL in three of the patients may not have been made in certain other settings; for example, two cases were diagnosed by brain biopsy in patients with advanced AIDS and preexisting cerebral toxoplasmosis.

A review of the records of 1030 patients with advanced HIV infection receiving AZT therapy during a 2-year period (5) identified 24 NHLs, yielding an estimated risk for NHL of 3.2%, a lower 2-year incidence than that in the NCI cohort. This lower incidence may have reflected the patients' better clinical status (median entry CD4 count of 104 cells/mm3) or differences in the length and intensity of follow-up. In a necropsy study of HIV-related deaths, NHLs were diagnosed in 20 (20%) of 101 HIV-related deaths (6); in eight (40%) patients, this condition was not suspected antemortem.

NCI's Surveillance, Epidemiology, and End Results (SEER) Program has documented a 56.9% increase in the incidence of NHL in the general population from 1973 through 1988. Although this trend reflects an increase in NHL among never-married men aged 20-49 years beginning in 1983 (Figure 2), there also appears to be an underlying longer-term increase. Based on the SEER database (which includes both AIDS-defining NHLs and NHLs associated with previously diagnosed AIDS), estimates of future AIDS incidence, and the findings in this report, the prevalence of patients with HIV-associated NHL in the United States in 1992 may range from 2900 to 9800 (7). Nearly 80% of these cases may occur among patients with a prior diagnosis of AIDS.

The pathogenesis of HIV-associated NHL is incompletely understood. However, multiple factors are believed to be involved (including polyclonal B-cell activation, IL-6 or other cytokine production, or coinfection with other viruses such as Epstein-Barr virus), which may increase the likelihood of molecular events such as t(8:14) or other translocations involving the c-myc gene locus. Immunosuppression induced by HIV appears to play a role similar to that in patients with primary immunodeficiency disorders such as the Wiskott-Aldrich syndrome (WAS) and severe combined immunodeficiency (8). In patients with WAS, improved supportive measures that prolong survival are believed to have increased the incidence of NHL (9). In this report, the prolonged survival of HIV-infected patients with less than or equal to 50 CD4 cells/mm3 appeared to be a major risk factor for NHL. These results support the value of CD4 cell counts as risk markers for HIV-associated complications.

Based on available data, the use of AZT is not considered to directly increase the risk for HIV-associated NHL. In this report, patients who developed lymphomas were all severely immunosuppressed, and the lymphomas were typical of those previously reported among HIV-infected patients not receiving antiretroviral therapy (4). In addition, in a placebo-controlled study of asymptomatic HIV-infected patients with greater than 200 CD4 cells/mm3, the use of AZT was not associated with an increased incidence of NHL (10).

Because the life expectancy of HIV-infected patients has been substantially prolonged by more effective treatment of HIV and associated complications, new clinical problems related to prolonged survival of persons with profound immunodeficiency have emerged. The emergence of HIV-associated NHL as described in this report requires continuing epidemiologic and clinical assessment. Therapies or strategies for preventing the development of severe immunosuppression, particularly sustaining CD4 cells at levels greater than 50 cells/mm3, may delay or even prevent the risk for NHL. Further studies of the risk for, or occurrence of, NHL in persons with HIV infection and on the use of CD4 cells as a risk marker for HIV-associated complications are in progress.

References

1. Ziegler JL, Miner RC, Rosenbaum E, et al. Outbreak of Burkitt's-like lymphoma in homosexual men. Lancet 1982;2:631-3.

2. Pluda JM, Yarchoan R, Jaffe ES, et al. Development of non-Hodgkin lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Ann Intern Med 1990;113:276-82.

3. Cox DR, Hinckley DV. Theoretical statistics. London: Chapman and Hall, 1974:136.

4. Ziegler JL, Becksted JA, Volberding PA, et al. Non-Hodgkin's lymphoma in 90 homosexual men: relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N Engl J Med 1984;311:565-70.

5. Moore RD, Kessler H, Richman DD, et al. Non-Hodgkin's lymphoma patients with advanced HIV infection treated with zidovudine. JAMA 1991;265:2208-11.

6. Wilkes M, Fortin AH, Felix JC, et al. Value of necropsy in acquired immunodeficiency syndrome. Lancet 1988;2:85-8.

7. Gail MH, Pluda JM, Rabkin CS, et al. Projections of the incidence of non-Hodgkin's lymphoma related to acquired immunodeficiency syndrome. J Natl Cancer Inst 1991;83: 695-701.

8. Kersey JH, Spector BD, Good RA. Primary immunodeficiency diseases and cancer: the Immunodeficiency-Cancer Registry. Int J Cancer 1973;12:333-47.

9. Cotelingam JD, Witebsky FD, Hsu SM, et al. Malignant lymphoma in patients with the Wiskott-Aldrich syndrome. Cancer Invest 1985;3:515-22.

10. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med 1990;322:941-9.

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