Rituximab and chemotherapy is highly effective in patients with CD20-positive non-Hodgkin's lymphoma and HIV infection

HIV increases the risk of aggressive B-cell lymphoma (non-Hodgkin's lymphoma; NHL), which often presents at an advanced stage and frequently involves extranodal sites. The combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is considered to be the standard treatment for patients with diffuse large B-cell NHL, both in the general population and in the HIV setting. Recently, Coiffier et al. [1] presented the results of a phase III randomized study comparing CHOP versus CHOP plus rituximab, a chimeric monoclonal antibody against the CD20 B-cell antigen, in elderly patients (more than 60 years of age) with diffuse large B-cell NHL. The results of the study showed that the addition of rituximab to the CHOP regimen increased the complete response rate (76 versus 63%, P = 0.005) and improved the event-free survival (EFS) at 2 years (57 versus 38%, P < 0.001) and the overall survival at 2 years (70 versus 57%, P = 0.007), without a significant increase in toxic effects [1]. Infusional cyclophosphamide, doxorubicin and etoposide (CDE) is one of the most effective chemotherapeutic regimens for HIV-associated NHL, with a complete response rate of 46% and a median overall survival of 8.2 months [2]. We carried out the first prospective study testing the combination of rituximab plus chemotherapy infusional CDE in patients with CD20-positive high-grade NHL and HIV infection. In June 1998, we started a phase II study using cyclophosphamide 187.5 mg/m2 per day, doxorubicin 12.5 mg/m2 per day and etoposide 60 mg/m2 per day administered by continuous intravenous infusion for 4 days every 4 weeks for up to six cycles, and rituximab 375 mg/m2 given intravenously on day 0 before each cycle. Highly active antiretroviral therapy was given concomitantly with chemotherapy, irrespective of the CD4 cell count and HIV viral load, and was selected according to the patient's previous antiretroviral exposure. All patients received granulocyte colony-stimulating factor support (5 μg/kg from day 6 to day 11) and prophylactic treatment with trimethoprim–sulfamethoxazole double-strength by mouth once a day and fluconazole 100 mg by mouth every day. From June 1998 to October 2001, 41 patients were enrolled and 38 patients are evaluable for response and toxicity. Thirty-five patients (85%) were men and their median age was 38 years (range 29–65). The majority of our patients (13/41, 32%) were male homosexuals, 12 out of 41 (12%) were intravenous drug users, and 12 out of 41 (12%) reported heterosexual relationships as the only risk factor for HIV infection; in four out of 41 patients (10%) the risk factor was not determined. The median CD4 cell count was 120 cells/mm3 (range 3–578) and the median performance status (Eastern Cooperative Oncology Group) was 1 (range 0–2). Diffuse large B-cell NHL was diagnosed in 24 out of 41 patients (59%), Burkitt's lymphoma in 15 out of 41 (36%) and anaplastic large-cell Ki-1+ NHL in two out of 41 (5%). According to the Ann Arbor staging system, disease staging was as follows: stage I in 12 out of 41 patients (29%), stage II in four out of 41 (10%), stage III in seven out of 41 (17%) and stage IV in 18 out of 41 (44%). Twenty out of 41 patients (49%) had B symptoms. As for the distribution of the prognostic factors according to the age-adjusted international prognostic index (IPI), this turned out to be as follows: IPI = 0 in seven out of 41 patients (17%), IPI = 1 in 16 out of 41 (39%), IPI = 2 in 12 out of 41 (29%), IPI = 3 in six out of 41 (15%). Twenty-nine out of 38 evaluable patients (76%) achieved a complete response, two out of 38 (5%) had a partial remission and seven patients progressed. With a median follow-up of 12 months, only three patients out of 29 complete responders (10%) have relapsed and 32 out of 41 patients are alive. The major cause of death was NHL (8/9 patients). Grade 3–4 neutropenia, anemia and thrombocytopenia were observed in 80, 37 and 29% of patients, respectively. Twenty-nine per cent of patients developed bacterial infections during neutropenia, and two patients (5%) developed opportunistic infections (Pneumocystis carinii pneumonia and cytomegalovirus infection). Twelve per cent of patients had mucositis. No toxic deaths were observed. The actuarial overall survival and EFS at 2 years were 70 and 86%, respectively. The combination of rituximab plus CDE seems to be very active, with a complete response rate (76%) much higher than that reported so far in HIV-NHL (45–65%), also with a significant increase in overall survival (70% at 2 years in our hands versus a median 7–18 months in previous studies) [2–4]. Interestingly, comparing our data and those of Coiffier et al. [1], the complete response rates, the 2-year overall survival and EFS are superimposable, showing that the outcome of HIV-NHL in the era of highly active antiretroviral therapy seems at least comparable with that of elderly patients with high-grade NHL. In conclusion, on the basis of our results and considering the impossibility of conducting randomized studies in this setting, we think that the association of rituximab plus chemotherapy should be strongly recommended as a front line treatment also for patients with CD20-positive high-grade NHL and HIV infection.