In those with DLBCL, Burkitt lymphoma, and Hodgkin lymphoma, cure is often achieved. Furthermore, in the salvage setting, whether auto-HCT or allo-HCT is used, the same appears to be true. A great deal of progress has been made in the treatment of lymphoma in patients with HIV infection, but more remains to be done before outcomes are comparable to those of the general population.
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.[1] 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.[1] 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.[2] 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.[3] 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).[4] 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).[5] 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.[6] 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.[8] 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.[9] 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%.[10] 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).[11] 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%.[12] 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.[13] 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).[14] 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.[15] 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.
A standard combination chemotherapy regimen that includes cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (referred to as modified CODOX-M/IVAC) with rituximab was evaluated prospectively in a multicenter Burkitt lymphoma trial; this showed that the regimen could be safely and effectively administered to HIV-positive patients receiving cART.[16] The 2-year overall survival rate for 34 patients with HIV-related Burkitt lymphoma was 69.0%. In a study of short-course low-intensity R-EPOCH in 13 patients with Burkitt lymphoma and immunodeficiency (of whom 11 patients had HIV infection), the overall survival rate at a median follow-up of 73 months was 90%.[17] Clearly both regimens are effective in most patients, although, as with DLBCL, no randomized data exist. However, there are differences with regard to patients with CNS involvement. Of the 34 patients treated with CODOX-M/IVAC, 4 had meningeal disease, and only a single patient treated with CODOX-M/IVAC experienced CNS relapse. On the other hand, patients with active CNS disease were excluded from the R-EPOCH trial; thus, the efficacy of R-EPOCH in patients with CNS involvement remains to be established.
One area of uncertainty in the 2000s centered around the use of rituximab in HIV-positive patients with DLBCL, given reports of increased infections in patients with lower CD4 counts.[18] However, in subsequent trials rituximab has been used and there is a general consensus that outcomes are improved.[8,19,20] Similarly, the two Burkitt lymphoma trials just mentioned both involved rituximab. Moreover, a multicenter retrospective review of 74 patients with HIV infection and Burkitt lymphoma who were treated with CODOX-M/IVAC chemotherapy suggested that the addition of rituximab was not associated with additional toxicity and was associated with improved overall survival and progression-free survival.[21] Thus, for both DLBCL and Burkitt lymphoma, rituximab should be regarded as the standard of care.
Historically, radiation was important in treating primary CNS lymphoma in HIV-negative patients; however, late relapse was common, as was radiation-related decline in cognitive function. As a result, there has been a shift to systemic therapy, almost uniformly with regimens that include high-dose methotrexate. Adoption of these regimens in HIV-positive patients has been slower, but a retrospective report of 20 patients treated with methotrexate-based regimens demonstrated good outcomes.[22] In this report, the median survival in patients treated before cART and without high-dose methotrexate was 2 months, whereas with cART and high-dose methotrexate-based regimens, the median survival had not yet been reached with a median follow-up of 27 months. Some of the patients involved were treated with high-dose methotrexate alone, some with high-dose methotrexate and rituximab, and some with regimens that included a variety of other agents. We believe that high-dose methotrexate should now be regarded as the standard of care. Because no particular regimen has been extensively studied in HIV-positive patients, we recommend following local institutional standards for treating patients with primary CNS lymphoma, emphasizing the importance of concomitant antiretroviral therapy for patients with HIV infection.
A multicenter German study of 108 patients with HIV infection and Hodgkin lymphoma used a stage- and risk-adapted strategy that included doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (baseline BEACOPP); and involved-field radiation in discrete strategies for early favorable, early unfavorable, and advanced-stage disease.[23] The complete remission rates were 96%, 100%, and 86%, respectively, and the 2-year progression-free survival rate for the entire population was 91.7%. The investigators concluded that stage- and risk-adapted treatment is feasible and effective in patients with HIV infection and Hodgkin lymphoma, and that the prognosis for patients with HIV infection and Hodgkin lymphoma may approach that of patients with Hodgkin lymphoma without HIV infection. A single-institution retrospective study from Spain compared ABVD treatment for Hodgkin lymphoma in 21 HIV-positive patients and 48 patients without HIV infection.[24] At presentation, the HIV-positive patients had worse performance status, more frequent bone marrow involvement, and mixed cellularity histologic subtype, but there were no differences in complete response rate or overall survival rate at 10 years. Thus, as with DLBCL, outcomes comparable to those in patients without HIV infection can be anticipated. We suggest that institutional approaches to Hodgkin lymphoma in general are appropriate for patients with HIV infection and Hodgkin lymphoma.
Response-adapted therapy has been studied in HIV-positive Hodgkin lymphoma patients. A recent intergroup cooperative trial that used fluorodeoxyglucose–positron emission tomography (FDG-PET) after cycle 2 of ABVD to guide further therapy included 12 patients with HIV infection who were treated.[25] Although there had been concerns that HIV lymphadenopathy might confound the interpretation of PET results, this proved not to be the case. The investigators concluded that it was appropriate to include patients with HIV infection and Hodgkin lymphoma in further studies of response-adapted therapy. In this trial, 75% of the HIV-positive patients achieved complete remission following initial ABVD therapy, compared with 96% of patients without HIV infection.
Brentuximab vedotin, a monoclonal antibody against CD30, was approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of relapsed/refractory Hodgkin lymphoma-although HIV-infected patients were excluded from trials leading to this approval. A phase I dose de-escalation study of brentuximab combined with standard doses of doxorubicin, vinblastine, and dacarbazine in HIV-positive patients was carried out.[26] There were no dose-limiting toxicities in the first cycle and thus there was no dose de-escalation. All 5 patients who had completed therapy at the time of publication were in PET-defined complete remission. The phase II portion of the trial is ongoing. With the caveat that serious drug interactions are a risk with brentuximab in patients whose regimens include ritonavir, cobicistat, or other CYP3A inhibitors, we believe that brentuximab should be considered for HIV-positive patients with Hodgkin lymphoma in the same circumstances in which it is used for patients without HIV infection.
Nivolumab and pembrolizumab are both FDA-approved for the treatment of Hodgkin lymphoma. Hodgkin lymphoma has a unique sensitivity to immune checkpoint inhibition, reflecting amplification of the programmed death ligand 1 locus on chromosome 9p24.1 in Reed-Sternberg cells.[27,28] There is also evidence that immune checkpoint inhibition may impact the HIV reservoir in patients.[29] A simian model (involving simian immunodeficiency virus) has provided evidence that programmed death 1 blockade enhances a virus-specific immune response.[30] However, while checkpoint inhibitors have been found to have potent activity in Hodgkin lymphoma in general, these agents have not yet been studied in HIV-positive patients.
Plasmablastic lymphoma has historically been associated with dismal outcomes. In 2012, in a collaborative retrospective review that included 53 HIV-positive patients diagnosed with plasmablastic lymphoma between 2000 and 2010 from 13 institutions from the United States, Europe, and South America, the authors reported a median overall survival of 11 months and concluded that there was no survival benefit from regimens that were more intensive than CHOP.[31] Evidence has been accumulating that while outcomes in HIV-positive patients with plasmablastic lymphoma are inferior to those achieved in patients with Burkitt lymphoma or DLBCL, they are not quite so dismal as they once were. A retrospective single-institution Spanish study reported on 15 patients treated with CHOP or CHOP-like regimens (with radiation used as consolidation therapy for bulky disease or locally aggressive disease, and autologous stem cell transplant used as consolidation in 5 patients).[32] Complete remission was achieved in 14 patients (93.3%), while the only patient treated in the pre-cART era died with disease progression. Four patients relapsed and one other patient died of other AIDS-related complications while in complete remission. The overall survival rate at 3 years was 66.7%. There were no relapses after 3 years. A retrospective study from the French Lymphoma Study Association included 79 patients without HIV infection (17 posttransplant and 62 others) and 56 HIV-positive patients.[33] The median follow-up was 49 months. The median overall survival for the posttransplant patients was 32 months; for the other HIV-negative patients, 16 months; and for the HIV-positive patients, the median overall survival has not been reached. In univariate analysis, HIV infection was a positive prognostic factor. In this series, CHOP or CHOP-like regimens were the most commonly used. In a 2014 report of 25 patients from the Parkland Hospital in Dallas, Texas, it was suggested that EPOCH might improve survival compared with CHOP.[34] HIV infection was present in 92% of the patients. The median overall survival was 17 months for those treated with EPOCH vs 7 months for those treated with CHOP or CHOP-like regimens. However, the results are very difficult to evaluate since they have only been presented in abstract form. A retrospective report from AIDS Malignancy Consortium centers sought to identify which first-line therapy might be most promising in HIV-positive patients with plasmablastic lymphoma.[35] The investigators identified 10 patients with plasmablastic lymphoma and HIV infection, treated with a variety of chemotherapy regimens. Complete responses were seen in 7 patients. At a median follow-up of 73 weeks, median survival had not yet been reached; thus, the outcomes were not dismal. CHOP was administered to 4 patients, all of whom achieved a complete response. EPOCH was administered to 2 patients, who also achieved complete responses. In sum, it is clear that both CHOP and EPOCH are often effective regimens in patients with plasmablastic lymphoma and HIV infection. The very grim assessment of prognosis for plasmablastic lymphoma may not be relevant to HIV patients on antiretroviral therapy.
For many, HIV infection was considered a strong contraindication to autologous or allogeneic hematopoietic stem cell transplantation.[36] In the 1990s, European and US groups began to offer autologous hematopoietic stem cell transplant (auto-HCT) to HIV-positive patients with lymphoma, with encouraging results-although most studies were retrospective, meaning that cART and transplant preparative regimens varied widely.[36] Several prospective trials in the 2000s have demonstrated the safety and efficacy of auto-HCT in HIV-positive patients.[37] However, most smaller centers have continued to exclude patients with HIV infection from transplant.[36] A cooperative group study to evaluate the safety and efficacy of auto-HCT for HIV-positive lymphoma patients has been reported. Forty HIV-positive patients with persistent or recurrent HIV-related lymphomas (DLBCL, plasmablastic lymphoma, Burkitt or Burkitt-like lymphoma, or classical Hodgkin lymphoma) underwent auto-HCT at 16 different centers. The preparative regimen was carmustine, etoposide, cytarabine, and melphalan (BEAM).[36] Overall survival and time to progression were compared with matched controls without HIV infection, and outcomes were not different, providing evidence that HIV-positive patients should not be excluded from auto-HCT if they are otherwise suitable transplant candidates.[36] For this study, concerns with toxicity related to drug interactions led the investigators to hold cART during the preparative regimen and for at least 7 days thereafter, or until recovery from gastrointestinal toxicity could be demonstrated.
The first prospective cooperative group trial of matched related or unrelated allogeneic hematopoietic stem cell transplant (allo-HCT) in HIV-positive patients has been reported.[38] Myeloablative or nonmyeloablative preparative regimens were used at the investigator’s discretion. The malignancies involved were acute leukemias, myelodysplasia, and Hodgkin and non-Hodgkin lymphomas. The trial was motivated by concern that allo-HCT might be associated with early mortality from opportunistic infection. Thus, the primary endpoint was nonrelapse mortality at 100 days. Seventeen patients underwent transplantation, and there was no nonrelapse mortality at 100 days. At 1 year, there were no infectious disease–related deaths. The overall survival rate at 1 year was 57%. Deaths were from relapsed/progressive disease in 5 patients, and acute graft vs host disease, adult respiratory distress syndrome, and liver failure in 1 patient each. Median follow-up of survivors was 24 months at the time of the report. The investigators concluded that allo-HCT should be considered the standard of care for HIV-positive patients who meet usual transplant eligibility criteria.
In one case, allo-HCT had the additional benefit of curing the HIV infection.[39,40] The donor’s cells were resistant to HIV infection by virtue of a homozygous deletion polymorphism in the CCR5 gene, which encodes the CCR5 chemokine receptor that serves as a coreceptor for most HIV infection. In other instances where an HIV-resistant donor was not used, although allo-HCT led to apparent disappearance of the viral reservoir in parallel with disappearance of patient T cells, discontinuation of cART was associated with an aggressive/dangerous HIV rebound syndrome.[41,42] This rebound probably reflects the persistence of small numbers of latently infected host cells, which subsequently reactivate and lead to the infection of donor cells. It should be noted that the experience with cART interruption after allo-HCT is so limited that we don’t know how often the rebound syndrome will occur. Because the donor cells are naive to HIV, the consequences of interruption of cART may be much more serious than interruption of cART in other settings where HIV-experienced T cells form a bulwark that slows the spread of infection. Efforts to engineer gene-modified auto- and allo-HCT with HIV-resistant cells are being explored.[43,44]
Several chemotherapeutic agents used in cART have the potential for serious drug interactions. High on the list are ritonavir and cobicistat. Both drugs are used in combinations because they inhibit CYP3A4 metabolism and thus prolong the half-life of antiretrovirals that are metabolized by CYP3A4. These agents can be especially dangerous when used with brentuximab vedotin. However, there are many choices for cART regimens that are unlikely to lead to problematic drug-drug interactions with anticancer agents. Among those with the fewest potential interactions are the integrase inhibitors (raltegravir, elvitegravir, dolutegravir) and the CCR5 inhibitors (such as maraviroc). HIV-positive patients undergoing treatment for lymphoma will benefit from a drug-by-drug review of interactions between drugs in the lymphoma chemotherapy regimen; those in the cART regimen; and other agents that may be used in conjunction with lymphoma treatment, such as azoles.
The recommendations we have presented here closely mirror those of the British HIV Association.[45] The National Comprehensive Cancer Network (NCCN) has long had tumor treatment guidelines that occasionally referenced HIV and that included special considerations for HIV-positive patients. The NCCN is currently drafting HIV-focused guidelines for the first time.
Results of trials in the cART era indicate that consideration should be given to the full spectrum of treatment approaches to lymphoma in patients with HIV infection. In those with DLBCL, Burkitt lymphoma, and Hodgkin lymphoma, cure is often achieved. Furthermore, in the salvage setting, whether auto-HCT or allo-HCT is used, the same appears to be true. A great deal of progress has been made in the treatment of lymphoma in patients with HIV infection, but more remains to be done before outcomes are comparable to those of the general population.
Financial Disclosure:Dr. Ambinder serves on the data and safety monitoring board for Bristol-Myers Squibb, and serves as a consultant to Celgene. Drs. Hunter and Vogt have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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