AIDS-Related Lymphoma Treatment (PDQ®)–Health Professional Version

General Information About AIDS-Related Lymphoma

Background and Definitions

AIDS was first described in 1981, and the first definitions included certain opportunistic infections, Kaposi sarcoma, and central nervous system (CNS) lymphomas. In 1984, a multicenter study described the clinical spectrum of non-Hodgkin lymphomas (NHLs) in the populations at risk of AIDS.[1] The incidence of NHL has increased in a course almost parallel to that of the AIDS epidemic and accounts for 2% to 3% of newly diagnosed AIDS cases.[2] Since the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s, the incidence of lymphomas has decreased, and outcomes have improved.[3] Higher CD4-positive T-lymphocyte (CD4) counts in the HAART era have been associated with a shift in histologic diagnoses. The shift is away from primary effusion lymphoma and primary CNS lymphoma, which occur with the lowest CD4 counts, and toward histologies that occur at higher CD4 counts, such as Burkitt lymphoma and Hodgkin lymphoma (HL).[4-6] In contrast to less-frequent incidences of all the lymphoproliferative disorders in the HAART era, the incidence rate of anal cancer has not changed.[7]

Histology

Pathologically, AIDS-related lymphomas comprise a narrow spectrum of histologic types consisting almost exclusively of B-cell tumors of aggressive type. These include the following:

  • Diffuse large B-cell lymphoma (including B-cell immunoblastic lymphoma).
  • Small noncleaved lymphoma, either Burkitt or Burkitt-like.

The HIV-associated lymphomas can be categorized into the following:

  • Aggressive B-cell lymphoma (see above).
  • Primary central nervous system lymphoma (PCNSL).
  • Primary effusion lymphoma.
  • Plasmablastic multicentric Castleman disease.
  • HL.

HIV-associated Hodgkin lymphoma

Multiple reviews of HL occurring in patients at risk of AIDS have been done;[8,9] however, HL is still not part of the Centers for Disease Control and Prevention (CDC) definition of AIDS because no clear demonstration of its increased incidence in conjunction with HIV has been shown, as is the case for aggressive NHL. The CDC, in conjunction with the San Francisco Department of Public Health, has reported a cohort study in which HIV-infected men had an excess risk that was attributable to the HIV infection in 19.3 cases of HL per 100,000 person-years and 224.9 cases of NHL per 100,000 person-years. Although this report found an excess incidence of HL in HIV-infected homosexual men, additional epidemiologic studies will be needed before the CDC will reconsider HL as an HIV-associated malignancy.[10]

HIV-associated HL presents in an aggressive fashion, often with extranodal or bone marrow involvement.[8,9,11] A distinctive feature of HIV-associated HL is the lesser frequency of mediastinal adenopathy compared with non–HIV-associated HL. Most patients in these series had either mixed cellularity or lymphocyte-depleted HL, expression of Epstein-Barr virus (EBV)-associated proteins in Reed-Sternberg cells, B symptoms, and a median CD4 lymphocyte count of 300/dL or lower.[12] In a retrospective multicenter review of 62 patients, those receiving HAART with chemotherapy had a 74% 2-year overall survival (OS) rate versus a 30% OS rate for those not receiving HAART (P < .001).[13][Level of evidence: 3iiiA] Among 201 patients with classical HL and HIV positivity, the 2- to 5-year OS rate of 88% to 90% after treatment with ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine), or similar regimens, and HAART, was not significantly different from the OS rate of HIV-negative patients with newly diagnosed HL in two uncontrolled comparisons.[14,15][Level of evidence: 3iiiDiv] These studies confirm that patients with HL who were treated with standard regimens and HAART have outcomes that are similar to those of the uninfected population.[16] Furthermore, immune function recovers over the course of 6 to 9 months after completion of chemotherapy.[15]

Primary effusion lymphoma

Primary effusion lymphoma has been associated with Kaposi sarcoma (KS)-associated herpesvirus (KSHV)/human herpes virus type 8 (HHV8).[17,18] Primary effusion lymphoma presents as a liquid phase spreading along serous membranes in the absence of masses or adenopathy.[17] In addition to HHV8, many cases are also associated with EBV. Extension of lymphoma from the effusion to underlying tissue may occur.

Multicentric Castleman disease

The plasmablastic type of multicentric Castleman disease is also associated with a coinfection of KSHV/HHV8 and HIV.[19] Patients typically present with fever, night sweats, weight loss, lymphadenopathy, and hepatosplenomegaly. Patients may progress to primary effusion lymphoma or to plasmablastic or anaplastic large cell lymphoma. Anecdotal responses to rituximab, the anti-CD20 monoclonal antibody, alone (along with HAART), have been reported.[20-23][Level of evidence: 3iiiDiv] For a prospective cohort of 84 patients treated with rituximab for HIV and HHV8 multicentric Castleman disease, the 5-year rate of relapse-free survival was 82% (95% confidence interval [CI], 72–92), and all patients responded again to rituximab at relapse.[23][Level of evidence: 3iiiDiii]

Incidence and Prevention

An international database of 48,000 HIV-seropositive individuals from the United States, Europe, and Australia found a 42% decline in the incidence of NHLs from 1997 to 1999 compared with the same incidences in 1992 to 1996, both for PCNSL and for systemic lymphoma.[24] The introduction of HAART is the proposed explanation for this decline.[25] The diagnosis of AIDS precedes the onset of NHL in approximately 50% of the patients; however, in the other half of the patients, the diagnosis of AIDS is made at the time of the diagnosis of NHL and HIV positivity.[3] The geographic distribution of these lymphomas is also similar to the geographic spread of AIDS. Unlike KS, which has a predilection for homosexual men and appears to be on the decline in incidence, all risk groups appear to have an excess number of NHLs; these risk groups include intravenous drug users and children of HIV-positive individuals.

Clinical Presentation

In general, the clinical setting and response to treatment of patients with AIDS-related lymphoma is very different from that of the non-HIV patients with lymphoma. The HIV-infected individual with aggressive lymphoma usually presents with advanced-stage disease that is frequently extranodal.[26]

Common extranodal sites include the following:

  • Bone marrow.
  • Liver.
  • Meninges.
  • Gastrointestinal tract.

Very unusual sites are also characteristic and include the following:

  • Anus.
  • Heart.
  • Bile duct.
  • Gingiva.
  • Muscles.

The clinical course is more aggressive, and the disease is both more extensive and less responsive to chemotherapy. Immunodeficiency and cytopenias, common in these patients at the time of initial presentation, are exacerbated by the administration of chemotherapy. Treatment of the malignancy increases the risk of opportunistic infections, which further compromise the delivery of adequate treatment.

Prognosis and Survival

Prognoses of patients with AIDS-related lymphoma have been associated with the following:[27]

  • Stage (i.e., extent of disease, extranodal involvement, lactate dehydrogenase level, and bone marrow involvement).
  • Age.
  • Severity of the underlying immunodeficiency (measured by CD4 lymphocyte count in peripheral blood).
  • Performance status.
  • Prior AIDS diagnosis (i.e., history of opportunistic infection or KS).

Patients with AIDS-related PCNSL appear to have more severe underlying HIV-related disease than do patients with systemic lymphoma. In one report, this severity was evidenced by patients with PCNSL who had a higher incidence of previously diagnosed AIDS (73% vs. 37%), lower median number of CD4 lymphocytes (30/dL vs. 189/dL), and a worse median survival time (2.5 months vs. 6.0 months).[28] This report also showed that patients with poor risk factors—defined as Karnofsky Performance Status score lower than 70%, history of previously diagnosed AIDS, and bone marrow involvement—had a median survival time of 4.0 months compared with patients in a good prognosis group who had none of these risk factors, and who had a median survival time of 11.3 months.

In another report (NIAID-ACTG-142), prognostic factors were evaluated in a group of 192 patients with newly diagnosed AIDS-related lymphoma who were randomly assigned to receive either low-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) or standard-dose m-BACOD with granulocyte-macrophage colony-stimulating factor.[29] No differences existed between these two treatments in terms of efficacy for disease-free survival, median survival, or risk ratio for death.[29][Level of evidence: 1iiA] On multivariate analysis, factors associated with decreased survival included age older than 35 years, history of intravenous drug use, stage III or stage IV disease, and CD4 counts lower than 100 cells/mm3. The International Prognostic Index may also be predictive for survival.[30-32] In a multicenter cohort study of 203 patients, in a multivariable Cox model, response to HAART was independently associated with prolonged survival (relative hazard, 0.32; 95% CI, 0.16–0.62).[33][Level of evidence: 3iiiDii]

Related Summaries

Other PDQ summaries containing information about AIDS-related lymphoma include the following:

References
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