The article by Drs. Levine, Seneviratne, and Tulpule is an excellent review of the available literature on the incidence and treatment of lymphoma related to the acquired immunodeficiency syndrome (AIDS).
In 1987, the Centers for Disease Control broadened its case definition of AIDS to include human immunodeficiency virus (HIV)-seropositive individuals with intermediate- or high-grade non-Hodgkin’s lymphoma of B-cell or indeterminate phenotype (even in the absence of opportunistic infections or Kaposi’s sarcoma). It is now appreciated that such tumors are the second most common malignancy in persons with AIDS. Advanced extranodal disease also occurs more commonly in the AIDS population, and median survival times tend to be short. These diseases can be classified as systemic and primary central nervous system (CNS) lymphomas.
Epidemiology and Incidence
The emergence of non-Hodgkin’s lymphoma as a malignancy characteristic of AIDS is not surprising since its association with various congenital and acquired immunodeficiency states has been documented for more than a decade. The risk of developing non-Hodgkin’s lymphoma in the setting of HIV infection is approximately 100 times greater than that observed in the general population. The majority of AIDS-associated non-Hodgkin’s lymphoma occurs in adult men. However, unlike Kaposi’s sarcoma, which has a significantly higher incidence among homosexual men, non-Hodgkin’s lymphoma occurs in all AIDS risk groups.
The clinical and pathologic spectrum of the disease also appears similar among the various HIV-transmission categories. This finding suggests that environmental cofactors are probably less important in the etiology of non-Hodgkin’s lymphoma. The risk of developing non-Hodgkin’s lymphoma increases with longer duration of immunodeficiency and lower CD4 cell counts.
The authors have provided a comprehensive review of the various studies conducted to determine the impact of highly active antiretroviral therapy (HAART) on the incidence of lymphoma. The reported results are inconsistent for both systemic and primary CNS lymphomas. It is clear, however, that the decline in the incidence of lymphoma is not as impressive as the decline in the incidence of Kaposi’s sarcoma. More time and studies are needed to ascertain the full impact of HAART on the incidence of non-Hodgkin’s lymphoma in AIDS patients.
Treatment
There is little to add to Dr. Levine and colleagues’ detailed summary of the trials evaluating chemotherapeutic approaches to the management of AIDS-related non-Hodgkin’s lymphoma. I will take the opportunity, however, to highlight avenues worthy of further investigation. The presence of an underlying immunodeficiency necessitates a unique approach to treatment—one that is not immunosuppressive or myelosuppressive, and can be used alone or as an adjunct to cytotoxic therapy.
Monoclonal Antibodies
Rituximab (Rituxan)—an anti-CD20 antibody—has shown activity in low-grade and some refractory aggressive non-Hodgkin’s lymphomas in patients without HIV infection. However, its efficacy in HIV-associated non-Hodgkin’s lymphoma remains to be determined. More than 90% of HIV-associated non-Hodgkin’s lymphoma patients are anti-CD20 positive; hence, it is an appropriate treatment modality to evaluate in this population.
The AIDS Malignancy Consortium, is currently evaluating the adjunctive use of rituximab(Drug information on rituximab) with standard-dose CHOP chemotherapy (cyclophosphamide, doxorubicin(Drug information on doxorubicin) HCl, vincristine [Oncovin], prednisone(Drug information on prednisone)). Radioimmunotherapy with iodine-131 anti-CD20 and anti-CD22 monoclonal antibodies are also potential treatment modalities.
Cytokines
In addition to mechanisms that directly stimulate B-cell expansion, suppression of helper T-cell antiviral or cytotoxic surveillance activities can permit the establishment of opportunistic infections as well as malignant clones. Interleukin (IL)-10 is a T-cell suppressor that has been implicated in the development of AIDS-related non-Hodgkin’s lymphoma. The gradual decline of the type 1 cytokine profile (ie, associated with IL-2 and gamma-interferon) has been attributed to the impaired production of IL-2 and gamma-interferon by HIV-infected CD4 cells and impaired IL-2 production by monocytes.
Exogenous subcutaneous administration of low-dose IL-2 potentially improves the type 1 cytokine deficiency in vivo, and restores some degree of immune competence, which may, in turn, impede the increased incidence of opportunistic infections and virally associated malignancies in these patients.[1,2] The activity of this well-tolerated outpatient treatment in preventing opportunistic infections or malignant disease progression in patients with low or clinically undetectable tumor burden is currently being studied in phase II trials.
Conclusions
Median survival times for these patients range from 4 to 18 months in various studies. Subgroups of patients with better immune function (CD4 cell count > 100/mm3) and a superior performance status have higher survival rates. Standard-dose treatment with growth factor support may be appropriate for these patients. Low-dose treatment may be selected for patients who are more severely immunocompromised, have a history of opportunistic infections, or have a marginal performance status. Therapy should probably not be administered to individuals who are extremely ill.
HAART has changed the prognosis of HIV disease, and has been associated with an increase in CD4 cell counts, a decrease in opportunistic infections, and a significant prolongation in survival. Several trials have confirmed that combination therapy can be administered safely with HAART. Therefore, HAART should be incorporated into the treatment regimen of AIDS-related non-Hodgkin’s lymphoma. Moreover, patients should be encouraged to participate in clinical trials that will engender the development of more effective treatment strategies in the future.
