Highly aggressive lymphomas emerge in the setting of acquired immunodeficiency syndrome (AIDS) due to human immunodeficiency virus 1 (HIV-1) infection. Prior to effective treatment for HIV, AIDS-related lymphomas (ARLs) were extremely difficult to effectively treat because of poor tolerance of chemotherapy and concurrent superinfections. That preantiretroviral therapy era was marked by efforts to define minimally toxic lymphoma therapy, recognizing that the balance between fatal diseases was often on a razor's edge. These dark days remain for most of the world's infected, but for those with access to highly active antiretroviral therapy (HAART), there has been a dramatic change. ARL is now a highly curable disease. What then is the best therapy? Is this the same disease as that seen prior to the advent of HAART? And how might cancer chemotherapy be combined with the panoply of anti-HIV drugs?
Little and colleagues (page 4653) have gone a long way to addressing all 3 questions. They provide highly encouraging results using a dose-adjusted infusional regimen, EPOCH. The 74% CR (87% overall) and 73% progression-free survival at 53 months appears to be a substantial improvement over what has been seen with more standard CHOP chemotherapy or other infusional regimens. The results need confirmation in a multicenter trial, and such is already underway through the US AIDS Malignancy Consortium. Why might an infusional approach be particularly active in this tumor? Infusional regimens are thought to be more effective against highly proliferative tumors, a feature the authors document in 85% of ARLs. Might responses be more likely in the setting of HAART because of differences in tumor biology? This likelihood, too, is supported by their study. Unlike ARLs seen before the era of HAART, these tumors have 2 features associated with an improved outcome: they have low BCL-2 expression and they likely represent a germinal center, rather than a postgerminal center, B cell. Finally, how can the complicated anti-HIV medications be given in the context of cancer chemotherapy? Prior studies continued both therapies, restricted anti-HIV medications, and measured drug levels and toxicities, with favorable results. The ever-shifting sand of antiretroviral drugs simply does not allow such an approach any longer. Rather, Little and colleagues stopped all anti-HIV drugs and noted transient, but tolerable, increases in HIV cells and decreases in CD4 cells. Both parameters returned to baseline or better within 6 to 12 months following the resumption of HAART. Therefore, Little and colleagues have provided new information on an ARL therapy to pursue, evidence for evolving tumor biology based on use of HAART, and a practical strategy for handling the complex balance of anticancer and anti-HIV therapy.
