Treatment outcomes for patients with HIV-related lymphoma have improved since the advent of combination antiretroviral therapy. Standard regimens, including intensive regimens, are being used with encouraging results in patients with diffuse large B-cell lymphoma, Burkitt lymphoma, Hodgkin lymphoma, and primary central nervous system lymphoma. Approaches to salvage therapy also parallel those used in patients without HIV infection, including autologous and allogeneic hematopoietic stem cell transplant. Drug interactions with particular antiretrovirals warrant close attention. At a population level, outcomes in patients with HIV infection and lymphoma remain inferior to outcomes achieved in the general population—but a great deal of progress has been made.
With combination antiretroviral therapy (cART), the overall risk of lymphoma has decreased, although standardized incidence ratios (SIRs) for AIDS-defining lymphomas (Burkitt lymphoma, primary central nervous system [CNS] lymphoma, and diffuse large B-cell lymphoma [DLBCL]) and Hodgkin lymphoma remain elevated, and lymphoma continues to be the leading cause of cancer-related death among patients with HIV infection in the era of cART. Data from the US Centers for AIDS Research network gathered from 23,050 patients with HIV infection diagnosed between 1996 and 2011 provide some insights. Lymphomas developed in 2.1% of these patients. Most of these were DLBCL (42.2%), followed by Hodgkin lymphoma (16.6%), Burkitt lymphoma (11.8%), primary CNS lymphoma (11.3%), and other non-Hodgkin lymphomas (18.1%). Patients with Hodgkin and Burkitt lymphoma had the highest CD4 counts, while patients with primary CNS lymphoma had the lowest. During the study period, which spans the introduction of antiretroviral therapy, at lymphoma diagnosis CD4 count progressively increased and HIV RNA levels at time of lymphoma diagnosis decreased. Early in the epidemic, aggressive treatment regimens were not well tolerated. With cART, however, most therapy approaches, including very aggressive approaches, have had success in HIV-positive patients. Somewhat more recent and prospective data from a smaller group of patients at a single center are available from the United Kingdom. In a review of 615 patients diagnosed over 3 decades, investigators reported a similar evolution of the clinical demographics. Over time, the CD4 cell count at lymphoma diagnosis has risen and the histologic subtypes have shifted. In particular, there has been a decline in the incidence of primary CNS lymphoma and DLBCL. Primary CNS lymphoma accounted for only 1% of lymphoma diagnoses in HIV-positive patients in the period 2006 to 2015. Survival in HIV-positive patients with lymphoma substantially improved with each decade. A review of patients with lymphoma in the National Cancer Database, a US hospital–based cancer registry dataset, showed that HIV infection continues to be an independent risk factor for death among patients diagnosed with lymphoma. Here we update aspects of lymphoma treatment in HIV-positive patients.
Several prospective trials and retrospective analyses of treatment outcomes have been reported over the last few years. Two somewhat similar multicenter retrospective analyses of DLBCL patients with and without HIV infection treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) have been reported. In a report from England of patients treated between 2003 and 2011, HIV infection was associated with a 5-year overall survival rate of 78% (compared with 64% in patients without HIV infection). In a report from Spain of patients treated between 2001 and 2011, HIV infection was associated with a 5-year survival rate of 56% (compared with 74% in patients without HIV infection). In the study from Spain, the HIV-infected patients had a worse performance status, more frequent B symptoms, and higher Ann Arbor stages than patients without HIV infection; when complete response rates were compared among patients with high tumor burdens, there was no difference between the two groups. In both the English and Spanish studies, the disease-free survival (defined for patients achieving complete response as the time from response to disease recurrence or death as a result of DLBCL or acute toxicity of treatment) was superior for HIV-positive patients. In the United States, dose-adjusted etoposide, prednisone, vincristine, and doxorubicin (EPOCH) with rituximab (R-EPOCH) has been used in a multicenter study, and complete remission was achieved in 73% of patients. Five-year survival data are not available. Clearly, treatment with both R-CHOP and R-EPOCH is usually effective at achieving remission, and the evidence suggests that most patients who achieve remission maintain remission.
There has been interest in determining whether R-CHOP or R-EPOCH is best for patients with AIDS-related lymphomas. In two retrospective pooled analyses, Barta et al concluded that infusional EPOCH is superior to CHOP, but the data did not permit comparison of dose-adjusted R-EPOCH and R-CHOP.[7,8] Further, the comparison was limited by the fact that the experience with CHOP and R-CHOP was earlier than the experience with EPOCH and R-EPOCH. The investigators attempted to account for factors that might have changed over time but acknowledged that improved outcomes associated with R-EPOCH might be secondary to confounding factors; they concluded their report noting that the large randomized intergroup trial of treatment for DLBCL in the general population might provide level 1 evidence. That trial in the general population has now been reported and showed no difference between R-CHOP and dose-adjusted R-EPOCH in event-free survival or overall survival. Thus, the optimal therapy for HIV-associated DLBCL remains unresolved.
Gene expression analysis in patients with AIDS-related DLBCL has attracted considerable interest. However, reports from different groups of investigators have yielded somewhat different conclusions. Molecular profiling using the Hans algorithm in 56 patients included in AIDS Malignancy Consortium trials identified a germinal center B-cell (GCB) origin in 59%, while a non-GCB origin was found in 41%. A study from Kaiser Permanente in California of 80 patients with HIV infection and DLBCL (also using the Hans algorithm) identified 39% as belonging in the GCB category and 51% in the non-GCB category (with 10% unknown). In a third study of 51 patients with AIDS-related DLBCL, analysis of immunohistochemistry results using the Tally algorithm suggested that activated B-cell (ABC) DLBCL occurred in 83%. Clearly no consensus has emerged. Different algorithms for assignment of the cell of origin, different time periods (and thus differences in antiretroviral use), and other differences in the populations studied likely all contributed to the divergent results. In contrast to cell-of-origin analyses, however, there is a clear consensus that Epstein-Barr virus (EBV) is almost exclusively found in those with non-GCB (or ABC) tumors.[10,12]
With regard to clinical prognostic factors, there has been some evolution with time. Early in the AIDS epidemic, CD4 count and prior AIDS diagnosis overwhelmed other factors in predicting the clinical course of HIV-associated DLBCL; since the advent of cART, other factors have emerged as important. Barta and colleagues have developed an AIDS-related lymphoma International Prognostic Index that employs the age-adjusted International Prognostic Index and an HIV severity score incorporating CD4 count, viral load, and prior history of AIDS to risk-stratify HIV-related lymphomas. A subsequent analysis by Barta and colleagues suggested that individual HIV-related factors such as low CD4 counts (< 50/μL) and prior history of AIDS were no longer associated with poor outcomes in the most recent clinical data analyzed (2005–2010). For perspective, it should be noted that this analysis considered only patients entered in clinical trials. Patients with poor performance status, active opportunistic infections, and organ dysfunction were generally excluded from these trials.
CNS involvement by systemic DLBCL has been recognized as a problem since early in the AIDS epidemic. A retrospective review of pooled data from 886 patients from multiple institutions was recently published. At presentation, CNS involvement was found in 13% of patients and was not associated with reduced overall survival. However, CNS relapse was associated with a median overall survival of only 1.6 months. Multivariate analysis identified two risk factors for relapse: presence of CNS involvement at baseline and failure to achieve a complete response with initial systemic chemotherapy. There have not been any formal studies to evaluate the role of intrathecal prophylaxis. This retrospective study was unable to address the question because more than 90% of patients received intrathecal prophylaxis. In the absence of definitive data, we routinely administer prophylaxis to patients with extranodal involvement of ≥ 2 sites, elevated lactate dehydrogenase levels, or bone marrow or testicular involvement.
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