Systemic NHL

Although the risk of lymphoma has decreased significantly in patients treated with ART, this decline has been smaller than that seen with KS or various opportunistic infections, resulting in a relative increase in the occurrence of lymphoma as the initial AIDS-defining illness.

Most AIDS-related lymphomas are of high-grade B-cell type. Approximately 60% are immunoblastic lymphomas or small non-cleaved lymphomas, including Burkitt or non-Burkitt types. About 30% of patients have intermediate-grade, diffuse, large, B-cell lymphoma (DLBCL), and 10% present with more unusual form of lymphoma including low-grade B-cell lymphomas, anaplastic large-cell lymphomas, plasmablastic lymphomas, and rare T-cell lymphomas [9].

The pathogenesis of these lymphomas is not fully understood and may involve a number of different pathogenic mechanisms. Pathogenesis may involve interactions between host factors, HIV infection, chronic B-cell antigenic stimulation, and cytokine dysregulation. Between 40 and 60% of HIV-associated lymphomas are associated with the Epstein–Barr virus (EBV) [10]. EBV is more commonly associated with large-cell lymphomas and with Burkitt-type lymphomas. It is commonly believed that the excessive B-cell stimulation associated with HIV infection results in the proliferation of antigen-selected B-cell clones [9, 11], with subsequent genetic changes leading to the evolution of a transformed clonal lymphoma. The molecular pathogenesis of AIDS-NHL is characterized by distinct genetic pathways, including chromosomal rearrangements of c-MYC and BCL6 in AIDS-associated Burkitt lymphoma and AIDS-associated diffuse large B-cell lymphoma, respectively [9].

Clinical management

Most patients with HIV-associated lymphoma present with advanced-stage and extranodal disease. Two-thirds of patients have stage IV disease at the time of presentation, and 90% have extranodal lymphoma at the time of diagnosis [12]. About 80% present with B symptoms, consisting of fever, drenching night sweats, and/or weight loss. Meningeal involvement at the time of diagnosis has been observed in 3–20% of patients. Although in the pre-HAART era, the median CD4 count at the time of diagnosis had been reported to be in the range 100–180 cells/mm³, there has been a recent trend toward earlier presentation, in patients with higher CD4 counts and fewer HIV-related complications prior to diagnosis.

Decreased survival is associated with CD4 counts < 100 cells/mm³, age > 35 years, Karnofsky performance status < 70%, advanced stage IV disease, elevated lactate dehydrogenase, higher International Prognostic Index (IPI) scores (2–3), and certain subtypes of lymphoma (e.g. PCNSL, PEL, and perhaps subtypes of DLBCL, such as activated B-cell phenotype) [13–17].

In the pre-HAART era, treatment outcomes were poor regardless of treatment choice, with complete response rates of approximately 50%, and median survivals in the 5- to 8-month range [12, 18].

Since the introduction of ART in 1996, several studies have demonstrated significant improvement in clinical outcome in ART-treated patients compared to historical controls. Furthermore, patients experiencing virologic failure on ART had poorer outcomes than those being treated with suppressive ART. These findings have made ART a critical component of the management of patients with HIV-associated NHL; it is now recommended that ART be administered concurrently in patients receiving chemotherapy for HIV-NHL [19].

Infusional chemotherapy

The use of infusional combination chemotherapy regimens to increase dose intensity of chemotherapy and to reduce toxicities has been evaluated in both HIV-infected and HIV-uninfected individuals with NHL. Three different infusional regimens have been studied in the HIV-NHL population. Sparano and co-workers. were the first to study the infusional regimen CDE, in which cyclophosphamide, doxorubicin, and etoposide are infused over 96 hours every 28 days [20]. This trial included patients who were treated both in the pre- and post-HAART eras, and demonstrated a 2-year overall survival of 47% in the post-HAART group with no treatment-related mortality compared with 30% in the pre-HAART-era patients, who also had a 10% treatment-related mortality.

However, the regimen that has generated the greatest interest is EPOCH. In this regimen, doxorubicin, vincristine, and etoposide are administered as a continuous 96-hour infusion, and cyclophosphamide, dose adjusted for initial CD4 count, is administered as a bolus intravenous infusion on day 5. In a phase II National Cancer Institute trial using this regimen, the overall complete remission rate was 74%, and at 53 months of follow-up, the disease-free survival was 92%, with an overall survival rate of 60%. It should be noted that 59% fell into the intermediate-high or high of risk groups by the IPI, 41% had CD4 counts ≤ 100 cells/mm³, and none received ART until chemotherapy had been completed [21].

Use of rituximab

Rituximab is a humanized monoclonal anti-CD20 antibody currently in widespread use for treatment of a variety of B-cell non-Hodgkin’s lymphomas. Its use in combination with CHOP chemotherapy for treatment of diffuse large B-cell lymphoma in HIV-uninfected patients became standard of care after publication of a randomized study demonstrating a survival advantage for patients receiving CHOP plus rituximab versus CHOP alone [22]. Initial trials of rituximab with CHOP from other groups raised concerns about the risk of treatment-related infectious deaths that occurred in a higher proportion of rituximab-receiving versus non-receiving individuals [23]. Most of these deaths occurred in patients with baseline CD4 counts <50 cells/mm³ [23]. A larger subsequent study of EPOCH with either concurrent or sequential rituximab with use of concurrent ART, prophylactic antibiotics, and white cell growth factor conducted by the AIDS Malignancy Consortium has shown a low incidence of treatment-related infections and high response rates and disease-free survivals [24].

Hematopoietic cell transplantation for HIV-NHL

Several reports have suggested the potential value of high-dose chemotherapy with autologous stem cell transplant. In the largest of these studies, 20 (subsequently updated to 29) patients with HIV-associated lymphoma who either had relapsed or had refractory disease or high-risk first remission received high-dose chemotherapy with autologous stem cell infusion [25]. Mobilization and stem cell collection were successful in all patients. There was no engraftment failure, although one patient who was receiving zidovudine had delayed engraftment. Two patients who were not compliant with prophylaxis developed Pneumocystis pneumonia. Two developed disseminated herpes zoster, one developed cytomegalovirus (CMV) retinitis, and two developed asymptomatic CMV viremia. All of these patients responded to therapy. With a 31.8-month median follow-up time, 17 of the patients remained in remission. Progression-free survival was 85%, and overall survival was 85% for the entire group. Other small series have demonstrated similarly effective stem cell mobilization and collection, lack of unexpected toxicities, and significant long-term disease-free survival times [26–29]. A case-control study comparing 53 HIV-infected patients with lymphoma who underwent stem cell transplantation to HIV-uninfected matched controls demonstrated an overall survival of 61.5% (95% CI 47–76%) for HIV-infected patients and 70% for controls (p = NS), with a median follow-up of 30 months [30]. In view of this experience, high-dose chemotherapy with autologous stem cell transplant may be considered the best treatment option for individuals with refractory or relapsed HIV-NHL [31].

Primary CNS lymphoma

PCNSL usually occurs in severely immunocompromised patients with advanced HIV infection, the vast majority of whom have CD4 counts < 50 cells/mm³. The incidence of PCNSL has fallen significantly since the introduction of ART [32].

PCNSL in the setting of HIV infection is universally associated with Epstein–Barr virus [11], which can be useful diagnostically. EBV is rarely detected in the cerebrospinal fluid (CSF) of HIV-infected patients without PCNSL, but it is commonly detected in the CSF of patients with this tumor. In one study EBV DNA was detected by nested polymerase chain reaction (PCR) in the CSF in 7 of 8 patients with PCNSL diagnosed by brain biopsy (87.5% sensitivity), and in none of the 11 controls with non-lymphomatous mass lesions (100% specificity). A total of 21 AIDS patients with or without neurological disorders but without focal brain lesions were PCR-negative [32]. In another study, EBV DNA was detected in the CSF from 16/20 (80%) patients with PCNSL [33]. In combination with imaging studies, EBV PCR may obviate the need for brain biopsy [34].

Most HIV-PCNSLs are characterized as diffuse large B-cell lymphomas and tend to be multifocal in the brain. Confusion, memory loss, lethargy, and focal neurologic findings are the most frequent presenting symptoms and signs.

Historically, prognosis for these individuals has been poor. Palliative whole-brain radiotherapy has been used, with survival of 1–3 months. Most patients died from opportunistic infections. High-dose methotrexate with leukovorin is now used alone or in combination with radiotherapy, especially since the advent of ART, which seems to make such therapy more tolerable. A pre-ART study in PCNSL patients with a median CD4 count of 30 cells/mm³ found a 50% complete response rate and a median survival of 10 months [35]. Data suggest that immune recovery associated with ART can dramatically improve survival. A retrospective review of 111 patients with PCNSL found that the use of ART and radiotherapy were each associated with significantly improved survival [36].

Primary effusion lymphoma (PEL)

Primary effusion lymphoma (PEL) accounts for < 5% of all AIDS-related lymphomas. The disease is characterized by presentation as a body cavity effusion. Almost all of these cases are associated with Kaposi’s sarcoma-associated herpes virus (KSHV), also known as human herpesvirus-8 (HHV-8), and EBV has been identified in the vast majority of cases. These lymphomas generally lack B- or T-cell markers, although the presence of immunoglobulin gene rearrangements in most cases suggests a B-cell origin. Most patients present with advanced HIV disease and severe immunodeficiency [45]. As a result, complete response rates using CHOP-like regimens have been < 50%, and overall survival is in the 3- to 6-month range [45, 46]. More intensive chemotherapy regimens with ART may lead to better outcomes.

Plasmablastic lymphoma

Although this disorder has been observed in immunocompetent individuals, it has been reported predominately in patients with HIV disease [47]. These lymphomas are typically negative for B- and T-cell markers and generally have a phenotype more typical of mature plasma cells. Morphologically, the malignant cells appear most like plasmablasts but carry a phenotype more typical of mature plasma cells. Monoclonal gammopathy is not commonly noted, helping to distinguish this entity from solitary plasmacytoma. Historically, these lymphomas have been associated with a poor prognosis and a median survival of approximately 9 months, although use of ART has extended life expectancy [48, 49].

Multicentric Castleman’s disease

This lymphoproliferative disorder characteristically presents with polyclonal hypergammaglobulinemia, generalized lymphadenopathy, hepatosplenomegaly, constitutional symptoms, and often autoimmune hemolytic anemia [50]. Lymph node histologic findings include perifollicular vascular proliferation and germinal center angiosclerosis. Overexpression of IL-6 appears to be the hallmark of this disease [51]. The disease is associated with HHV-8 infection of the B-cells in the mantle zone of the lymph node [52]. Natural history can vary from an indolent, waxing and waning course to one that is extremely aggressive and may transform to non-Hodgkin’s lymphoma in some cases. Based on several small series, rituximab with/or without etoposide seems to give the best responses [53–55]. Although some transient responses to anti-herpesvirus agents have been reported, overall results with these agents have been disappointing [54]. Standard lymphoma chemotherapy regimens have generally been associated with relatively transient responses and poor long-term outcome [56, 57].