Epidemiology of AIDS-Related Lymphoma

Lymphoma has traditionally been considered a late manifestation of HIV infection, more likely to occur in the setting of significant immunosuppression,^[1] a CD4 cell count < 200 cells/mm³, and a prior history of an AIDS-defining illness. Thus, in HIV-infected patients who have been diagnosed with AIDS, the relative risk of immunoblastic lymphoma is increased by approximately 627-fold and that of diffuse large cell lymphoma is increased 145-fold compared with rates in the general population.^[2,3]

Recent studies have shown a definite, statistically significant decrease in the incidence of AIDS-related lymphoma since the widespread use of highly active antiretroviral therapy (HAART), although this decrease is not as dramatic as that in AIDS-related Kaposi's sarcoma (KS).^[4-6] Moreover, as a result of the very marked decline in KS and opportunistic infections in the HAART era, AIDS-related lymphoma has now become one of the most common of initial AIDS-defining illnesses.^[4] Besson and colleagues,^[7] using the French Hospital Database on HIV, have demonstrated that the incidence of AIDS-related lymphoma increases with increasing immune deficiency, as identified by decreasing CD4+ cell count. In both the pre- and post-HAART eras, the likelihood of developing AIDS-related lymphoma has been similar in patients in the same CD4+ cell count strata. Because the majority of patients respond to HAART with significant increases in CD4+ cell counts, on a population level the overall incidence of AIDS-related lymphoma is expected to fall, as has been shown in most studies to date.

Current Approaches to the Treatment of Systemic AIDS-Related Lymphoma

To provide context for the new data presented at the 6th International Conference on Malignancies in AIDS & Other Immunodeficiencies, this section briefly reviews key data on the current management of newly diagnosed AIDS-related lymphoma.

Standard-Dose vs Low-Dose Chemotherapy

The AIDS Clinical Trials Group (ACTG) evaluated the use of standard-dose vs low-dose m-BACOD chemotherapy (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone) in patients with newly diagnosed AIDS-related lymphoma.^[8,9] Although standard-dose therapy was associated with a statistically greater likelihood of severe hematologic toxicity, neither response rates nor overall disease-free survival were influenced by dose intensity. It is important to note that this study was conducted prior to the widespread use of HAART. It is certainly possible that toxicity may have been ameliorated and survival prolonged if HAART had been available, and if patients had initiated chemotherapy at higher CD4+ cell counts.

Use of Concomitant HAART With Chemotherapy

The use of standard-dose and dose-reduced CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) administered with concomitant HAART in a cohort of 65 patients with newly diagnosed AIDS-related lymphoma was studied by the National Cancer Institute (NCI)-sponsored AIDS Malignancy Consortium.^[10] HAART consisted of indinavir, stavudine, and lamivudine. Grade 3 or 4 neutropenia was more common among patients receiving full-dose CHOP (25% vs 12%). Doxorubicin clearance and indinavir concentration curves in study patients were similar to those observed in historical controls, but cyclophosphamide clearance was decreased 1.5-fold with concomitant HAART; no clinical consequence of this change was apparent. The authors concluded that CHOP could be delivered safely with HAART. However, the use of zidovudine, which may itself cause significant bone marrow compromise, should be avoided in the setting of chemotherapy.^[11]

In an important study conducted at 2 major HIV tertiary care centers in Rome, Italy, Antinori and colleagues^[12] treated all consecutive patients with newly diagnosed AIDS-related lymphoma with various regimens of chemotherapy plus concomitant HAART. Virologic and immunologic response to HAART, defined as a decline in plasma HIV-1 RNA of at least 2 log₁₀ copies/mL and an increase in absolute CD4+ cell count of at least 30% compared with its pretreatment level, was associated with a statistically greater likelihood of complete remission of the lymphoma, as well as a statistically greater prolongation in survival. On multivariate analysis, a virologic response to HAART was the only variable associated with antitumor response. Multivariate analysis of survival revealed 3 factors that independently predicted longer survival: complete response to chemotherapy, an immunologic response to HAART, and use of higher relative dose intensity of chemotherapy. These data indicate that optimal control of the underlying HIV disease must be an integral part of therapy in patients with AIDS-related lymphoma.

Infusional, Risk-Adjusted EPOCH Regimen

Wilson and his colleagues^[13] at the NCI have developed the EPOCH regimen, consisting of a 4-day infusion of etoposide, vincristine, and doxorubicin, with risk-adjusted bolus dosing of cyclophosphamide on day 5 and prednisone given orally on days 1-5 of each 22-day cycle. Granulocyte colony-stimulating factor (G-CSF) is used uniformly, beginning at day 6, and all antiretroviral therapy is withheld until day 6 of the last dose of chemotherapy. Among 33 patients reported to date, a complete remission rate of 79% was achieved, including 67% in those with CD4+ cell counts < 100 cells/mm³ and 86% among patients with CD4+ cell counts > 100 cells/mm³. Overall, 73% of the group remain alive at 33 months and, of note, no patient has yet experienced relapse of lymphoma. The plasma HIV-1 RNA level increased by 1000-fold by cycle 4 of therapy, but returned to pretreatment levels within 3 months of the resumption of antiretroviral therapy. Likewise, although CD4+ cell counts decreased during chemotherapy, they returned to baseline values by 12-24 months post-EPOCH. No increase in opportunistic infections was noted, despite the fact that antiretroviral therapy was withheld during the 6 months of chemotherapy.

Infusional CDE

Sparano and colleagues^[14] developed and tested the infusional CDE regimen (cyclophosphamide, doxorubicin, and etoposide) in patients with newly diagnosed AIDS-related lymphoma. In a large, multi-institutional European Collaborative Oncology Group (ECOG) trial, 107 patients received this 4-day infusion, of whom 48 patients received concomitant didanosine monotherapy and 59 received HAART regimens. For the group as a whole, the rate of complete remission was 44%, with partial responses in 11%. While there was no difference in the rate of complete remission among patients who received HAART compared with those treated with didanosine, the median overall survival was longer in those patients who received combination antiretroviral therapy. Viewed alongside similar data from 2 other studies of the infusional CDE regimen, these data indicate that response rates are similar to those achieved with either low-dose or standard-dose m-BACOD, while survival appears superior in patients who receive concomitant HAART.

New Data on the Treatment of AIDS-Related Lymphoma

Update on Infusional CDE

At the 6th International Conference on Malignancies in AIDS & Other Immunodeficiencies, Sparano and colleagues^[15] reviewed the long-term follow-up data on infusional CDE in the Eastern Cooperative Group Trial E1494. This study initially evaluated the infusional CDE regimen administered every 4 weeks by continuous 96-hour infusion with concomitant didanosine, as published earlier.^[14] The trial was amended in November 1996 to allow the use of antiretroviral therapy other than didanosine, and was amended once again in March 1998 to mandate the use of concurrent HAART. A total of 113 patients were enrolled, of whom 5 were considered ineligible. In the first 48 enrolled patients, didanosine was the only antiretroviral agent used, while the remainder received HAART. Data regarding toxicity were available from 112 patients, and data on efficacy from 107 patients. The median follow-up of the group was 42 months (range, 1-76 months). Specific results are shown in Table 1.

Table 1. Long-term Follow-up of Patients Receiving Infusional CDE Plus Antiretroviral Therapy

A multivariate analysis was performed to assess prognostic factors for decreased survival. The only factor statistically associated with decreased survival was a CD4+ cell count < 50 cells/mm³ or < 100 cells/mm³.

A similar regimen of infusional CDE was evaluated in a concomitant ECOG trial (E3493) for HIV-negative patients with intermediate-grade lymphoma.^[15] In 62 patients accrued between March 1995 and November 1997, the complete remission rate was 48%, the overall response rate was 76%, and the median survival was 32.4 months. Thus, although median survival is longer among the HIV-negative patients, the response rates to infusional CDE appear similar in both HIV-infected and HIV-uninfected patients with lymphoma.

This study is important, indicating that use of HAART (compared with didanosine) with the infusional CDE regimen is associated with similar rates of complete remission but statistically longer overall survival, statistically longer failure-free survival among responders, and a decreased likelihood of death due to lymphoma. Furthermore, hematologic toxicity appears to be ameliorated by the concomitant use of HAART, at least in terms of anemia and thrombocytopenia. Unfortunately, grade 4 neutropenia remained common in both HAART- and didanosine-treated patients (75%).

Liposomal Doxorubicin Plus Cyclophosphamide, Vincristine, and Prednisone

Liposome-encapsulated doxorubicin (D99; Myocet; The Liposome Company, Inc; Princeton, New Jersey) has a more favorable pharmacokinetic profile than the parent compound, with specific uptake by the reticuloendothelial system. This has resulted in an improved toxicity profile, and on this basis the drug has been licensed in the European Union for the treatment of metastatic breast cancer. With the potential for decreased toxicity and increased uptake in lymphoid organs, the compound was believed to be of potential interest in patients with newly diagnosed AIDS-related lymphoma. Accordingly, the group from University of Southern California School of Medicine^[16] undertook a phase 1/2 trial of liposome-encapsulated doxorubicin at doses of 40, 50, 60, and 80 mg/m², combined with standard doses of cyclophosphamide (750 mg/m²), vincristine (1.4 mg/m², to a maximum of 2.0 mg per cycle), and prednisone (100 mg orally for 5 days). Cycles were repeated every 21 days. All patients received G-CSF as clinically indicated, although none received G-CSF prophylactically during the first cycle of chemotherapy.

At the time of reporting, a total of 23 patients had been accrued, of whom 19 were evaluable. The complete remission rate was 79%, with partial remissions in 16%, and an overall response rate of 95%. Median duration of complete remission was in excess of 6.5 months. All 3 patients with partial responses have subsequently progressed and died. Of the 15 patients who attained complete responses, 3 have relapsed and 12 remain in continuous complete remission. The toxicity of the regimen was primarily hematologic, with dose-limiting toxicity (defined prospectively as nonhematologic toxicity) not reached at even the highest dose level of liposome-encapsulated doxorubicin. No grade 4 nonhematologic toxicity was observed among patients in the trial to date.

This study indicates that the use of this liposomal preparation to replace standard doxorubicin in the CHOP regimen results in acceptable toxicity, with outstanding response rates. It will be important to study this regimen in a larger setting to confirm these results. In addition, a trial of liposome-encapsulated doxorubicin either alone or in combination with rituximab for patients with relapsed/refractory AIDS-related lymphoma is currently being planned within the AIDS Malignancy Consortium.

Hodgkin's Disease in the Setting of HIV Infection

Incidence and Characteristics

Although it is not considered an AIDS-defining illness, the incidence of Hodgkin's disease is clearly increased among HIV-infected individuals.^[6,17] Using population-based data from the NCI's Surveillance, Epidemiology, and End Results (SEER) cancer registry from the Greater (San Francisco) Bay Area in Northern California, Glaser and colleagues^[18] studied the incidence and characteristics of Hodgkin's disease in the period July 1, 1988-December 31, 1998. All patients diagnosed with Hodgkin's disease within the 9 counties of the Greater Bay Area were included, totaling 1752 patients, of whom 56% were male and 70% were white. The median follow-up on the group was 56 months from the time of diagnosis of Hodgkin's disease, and 74% remained alive as of December 2000. Tumor tissue was requested and received from 983 cases collected between 1988 and 1997, which were then studied for presence of Epstein-Barr virus (EBV)-associated antigens EBV-encoded RNA (EBER) and latent membrane protein 1 (LMP-1). Overall, 30% were EBV-positive. Clinical and pathologic data were acquired from cancer registry data, from death certificates, and from linkage with HIV/AIDS registries. Cases were considered to be associated with HIV if there was any mention of HIV or AIDS in any of these source documents. In sum, 7% of all Hodgkin's disease cases occurred among HIV-infected individuals, and 95% of the HIV-related Hodgkin's disease cases occurred among males. Thus, a total of 124 male, HIV-infected, Hodgkin's disease patients were evaluated, and were compared with the 1492 HIV-negative males with Hodgkin's disease, diagnosed in the same time period. Results are shown in Table 2.

Table 2. Characteristics of Hodgkin's Disease in HIV-Infected vs Uninfected Patients

All of the above characteristics were significantly different among HIV-positive and HIV-negative cases. A multivariate analysis was therefore conducted to determine those factors independently associated with HIV-related Hodgkin's disease. Significant factors are shown in Table 3.

Table 3. Factors Significantly Associated With HIV-Related Hodgkin's Disease

The authors then calculated the impact of HIV on the age-adjusted incidence rates of Hodgkin's disease in males overall, and found an 11% excess of Hodgkin's disease occurring as a result of underlying HIV infection. This excess was even higher for blacks, estimated to have an excess incidence of 20% related to HIV infection. An excess of 20% was calculated for mixed-cellularity Hodgkin's disease, with an excess of 75% for lymphocyte depletion histology.

An attempt was then made to evaluate the potential effect of HAART on the epidemiologic features of Hodgkin's disease in the Greater Bay Area, using time period as a surrogate for HAART use. A total of 13% of the Hodgkin's disease cases diagnosed in the pre-HAART era (1988-1995) were associated with HIV, while 12% of the Hodgkin's disease cases diagnosed in the post-HAART era (1996-1998) occurred in HIV-infected men. Characteristics of Hodgkin's disease among HIV-infected men in the 2 time periods are shown in Table 4.

Table 4. Characteristics of HIV-Related Hodgkin's Disease in the Pre- and Post-HAART Periods

*statistically significant (P < .05)

Unusual clinical and pathologic characteristics of Hodgkin's disease have previously been described in HIV-infected patients.^[19] Thus, systemic "B" symptoms are almost always present, the predominant pathologic subtype is mixed-cellularity disease, and advanced, extranodal disease is expected in the majority. Bone marrow involvement has been documented in 40% to 60% of patients at initial diagnosis, and patients often undergo the initial diagnostic bone marrow examination for the evaluation of fever, night sweats, or weight loss in the setting of HIV infection and pancytopenia.^[19,20]

Treatment of HIV-Related Hodgkin's Disease

Although standard multiagent chemotherapy may be curative in most HIV-negative patients with stage III or IV Hodgkin's disease, the median survival for HIV-infected patients has been in the range of 1-2 years.^[19,20]

A recent prospective multi-institutional trial evaluated the use of a standard dose ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine) with hematopoietic growth factor support in a group of 21 HIV-infected patients.^[20] Antiretroviral therapy was not used. Neutropenia to levels < 500 cells/mm³ developed in almost 50%, and median survival for the group was only 18 months. It is possible that results would have improved with concomitant use of HAART, as was demonstrated with the Stanford V regimen (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, prednisone),^[21] which has been evaluated in 50 HIV-infected patients from Italy.^[22] In this study, complete remission was attained in 78%, and 68% of these (ie, 53% of all patients treated) were estimated to remain disease-free at 2 years. Grade 3 or 4 neutropenia occurred in 82%, despite use of G-CSF.

Spina and colleagues^[23] have recently determined the prognostic factors associated with worse outcome in HIV-infected patients with Hodgkin's disease treated with the Stanford V regimen. Using the International Prognostic Score (IPS) developed for patients with Hodgkin's disease,^[24] these investigators found that patients with IPS scores > 2 fared significantly worse than those with scores of ≤ 2. Thus, the complete response rate was 100% among 26 patients with low IPS scores, compared with 67% (22 of 33) in those with IPS scores > 2. In multivariate analysis, an IPS score > 2 was the only factor associated with significantly shorter survival among these patients. The overall survival of patients with IPS of ≤ 2 was 76% at 3 years, vs 33% in those with IPS scores > 2. While not statistically significant, the disease-free survival at 3 years was 83% in the low-risk vs 53% in the high-risk group. These data demonstrate that a high IPS score (> 2) is a highly significant predictor of poor prognosis in patients with HIV-related Hodgkin's disease who are treated with the Stanford V regimen.

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