HIV-associated lymphoma

The role of infusional chemotherapy and the value of rituximab with chemotherapy have not been clearly defined in patients with HIV-associated lymphoma. Recent data have provided insights into these questions.

Although the optimal therapeutic strategies for patients with HIV-associated lymphoma have remained controversial, recent studies by Dunleavy et al and Sparano et al in this issue of Blood have brought clarity to several contentious issues.^1,2  First, should rituximab be included within the regimen? Second, does the benefit of a prolonged infusion, such as the EPOCH regimen,³  outweigh the inconvenience and cost? Third, should antiretroviral therapy be suspended during chemotherapy? Fourth, are there subtypes of lymphomatous disease that should be treated differently than others? Fifth, is FDG-PET scanning a useful restaging and prognostic tool in HIV lymphoma?

The addition of rituximab to the CHOP regimen has resulted in remarkable prolongation in long-term disease-free survival among patients with HIV-negative diffuse large B-cell lymphoma (DLBCL),⁴  and early results among patients with HIV-associated lymphoma appeared also to show benefit.⁵  Unexpectedly, a randomized phase 3 study of CHOP with or without rituximab, performed by the AIDS Malignancy Consortium (AMC), found only a trend toward greater efficacy in patients on the rituximab arm, with a statistically significant increase in death due to infection.⁶  When analyzed more carefully, these infectious deaths occurred primarily among patients with severe immunodeficiency. If patients with CD4 lymphocyte counts less than 50/μL were excluded from the analysis, no significant difference in infectious death was seen. Severe HIV-related immunodeficiency in itself has been associated with an increased risk of septic death, even in the absence of chemotherapy.⁷  Nonetheless, rituximab has been associated with various viral infections, as well as progressive multifocal leukoencephalopathy and hepatitis B reactivation, and could theoretically be a concern.⁸  The results of the AMC study served to emphasize these concerns, and was in all likelihood responsible for a change in treatment paradigm away from the use of rituximab in HIV-infected patients. In this issue of Blood, a subsequent randomized phase 2 study from the AMC did not show an increased risk of infectious death among patients receiving concomitant chemotherapy and rituximab.²  The study by Dunleavy et al, also reported in this issue, has again confirmed the efficacy of rituximab, allowing an abbreviated course of infusional EPOCH while noting no treatment-related deaths or new opportunistic infections. Whereas it behooves the clinician to be aware of the potential for rituximab-related infections, especially in patients with severe immunocompromise, it is time to put this question to rest. Similar to the case in HIV-negative lymphoma, patients with HIV-associated DLBCL clearly benefit from the use of concomitant rituximab and chemotherapy.

Results of infusional short-course EPOCH with double-dose rituximab (SC-EPOCH-RR), even when given for only 3 or 4 cycles, were remarkably good in the Dunleavy study, with 85% progression-free and 68% overall survival at a median follow-up of 5 years. CHOP-based regimens have not been associated with these kinds of results, and the AMC studies of EPOCH²  and of CHOP⁶  would seem to confirm that infusional EPOCH is the superior regimen in the setting of HIV-associated DLBCL. Greater ease of administration would be nice, but a shortened total treatment time may partially compensate for the inconvenience of a prolonged infusion. In the final analysis, the patient deserves to receive the regimen associated with the best chance of long-term survival.

Tumor histogenesis was found to be the only factor associated with lymphoma-specific outcome in the Dunleavy study,¹  with non–germinal center (GCB)–DLBCL patients faring significantly worse than their GCB-DLBCL counterparts. Although optimal techniques to allow confirmation that these non–GCB-DLBCL cases did, in fact, represent the activated B-cell type of DCLBC, still, this conclusion is quite likely and indicates that new treatment paradigms will be necessary in these persons, be they HIV-infected or not.

Although multiple aspects of the pathogenesis and optimal therapy of DLBCL appear similar among HIV-negative and -positive patients, the Dunleavy study has shown that the utility of FDG-PET scanning in the 2 populations is quite different.¹  Whereas FDG-PET after 2 cycles of SC-EPOCH-RR had an excellent negative predictive value, a positive scan was not necessarily clinically meaningful. This would be consistent with the fact that FDG-PET may be positive in the setting of inflammation or infection, conditions that are not uncommon among HIV-infected patients. With the Dunleavy data in mind, the role of FDG-PET in patients with HIV-associated lymphoma will clearly require additional evaluation prior to clinical adoption.