A new standard for HIV-associated lymphoma

In this issue of Blood, Alvarnas et al report a prospective multicenter clinical trial demonstrating that autologous hematopoietic cell transplantation (AHCT) can be performed safely and effectively in patients with HIV-associated lymphomas, with success rates comparable to those in the HIV-negative population.¹ 

When HIV/AIDS was first identified in the early 1980s, the diagnosis was nearly universally fatal, given the lack of effective treatments. The transformation of HIV/AIDS from a virtual death sentence into a survivable chronic illness is a major achievement of modern biomedical science, driven by patient and community activism. People with HIV/AIDS have long been recognized to have an increased risk of numerous malignancies, including both non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Although modern combination antiretroviral therapy has significantly decreased the incidence of HIV-associated NHL, the incidence remains higher than among HIV-negative individuals.²  In contrast, the incidence of HL appears to have increased somewhat since the advent of modern antiretroviral therapy.³ 

People with HIV-associated lymphoma can be treated effectively with combination chemotherapy induction regimens, resulting in progression-free survival (PFS) in approximately two-thirds of patients at 2 years.⁴  However, for people with refractory or relapsed HIV-associated lymphoma, the optimal treatment has been unclear. In the HIV-negative population, such patients are routinely offered high-dose chemotherapy with AHCT as the most effective and potentially curative treatment. Although case reports and 1 prospective study have reported the use of AHCT in HIV-associated lymphoma,⁵  HIV is considered an exclusion for most transplant-based clinical trials, and AHCT in HIV-positive patients has generally been restricted to centers with dedicated expertise, due to concerns about the management of antiretroviral therapy, drug-drug interactions, and a perceived increase in the risk of regimen-related toxicity and infections in the HIV-positive population. Thus, widespread access to this potentially curative therapy for people with relapsed or refractory HIV-associated lymphoma remains a major unmet clinical need, driven by uncertainty over its safety and efficacy in the HIV-positive population.

To address this need, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) and the AIDS Malignancy Consortium (AMC) collaborated on a prospective multicenter phase 2 clinical trial of AHCT in HIV-associated lymphoma, with results reported in this issue of Blood by Alvarnas et al. The trial used a uniform conditioning regimen (BEAM) and standardized management of antiretroviral therapy. Aside from HIV infection, inclusion criteria mirrored those commonly used to identify candidates for AHCT, including chemosensitive disease and the absence of uncontrolled infections. Forty patients were transplanted, with 2-year overall and PFS of 82% and 80%, respectively. The authors compared the study population to an HIV-negative, but otherwise matched, control cohort of 151 patients identified from the Center for International Bone Marrow Transplant Research database and found no significant association between HIV infection and mortality, lymphoma relapse, or other negative outcomes.

These results deserve widespread dissemination, because they demonstrate that AHCT can be performed safely and effectively using standard transplant approaches in people with HIV-associated lymphoma. On the basis of these results, HIV infection should not be considered a contraindication to AHCT in otherwise medically eligible patients with relapsed or refractory lymphoma. Rather, AHCT should be considered the standard of care for such patients, as it is in the HIV-negative setting.

Several other aspects of the BMT CTN/AMC trial are noteworthy. Although there was no specified standard antiretroviral regimen, patients stopped their HIV treatment medications at the start of BEAM conditioning (with the exception of efavirenz, which required a longer washout period), and resumed them after recovery from regimen-related mucositis. This approach is intended to minimize drug-drug interactions with the conditioning regimen, and to limit the number of treatment interruptions in order to reduce the risk of viral resistance. Although transient increases in viral load were noted in some patients, by 1 year, 82% of patients had undetectable viral loads (unchanged from the 80% with undetectable viral loads pretransplant), suggesting that this approach does not sacrifice viral control. The authors also report that CD4⁺ T-cell numbers were virtually unchanged at 2 months, 6 months, and 1 year after AHCT, compared with pretransplant CD4⁺ counts. Of note, ∼25% of patients had not recovered full hematopoietic function at 1 year posttransplant. Although the authors provide no formal comparison with hematologic recovery in HIV-negative patients, this percentage seems significantly increased from the usual experience with AHCT. It may be that ongoing antiretroviral therapy impairs full recovery of blood counts; this issue warrants ongoing follow-up and attention because increasing numbers of HIV-positive individuals undergo AHCT.

In summary, Alvarnas et al demonstrate prospectively that AHCT can be performed safely and effectively for HIV-associated lymphoma, with results comparable to those seen in the HIV-negative population. The authors, and the BMT CTN and AMC, deserve credit for identifying an unresolved clinical question and for conducting a well-designed and expeditious multicenter clinical trial to address it. These results can and should inform the standard of care for the HIV-positive population. HIV positivity should no longer constitute a contraindication to AHCT for lymphoma, and clinicians should provide access for HIV-positive people to this potentially curative therapy with the confidence provided by these results.