Saquinavir enhances the mucosal toxicity of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin's lymphoma

Protease inhibitors are an important new class of agents for the treatment of human immunodeficiency virus (HIV) infection. The purpose of our trial w as to determine the feasibility of combining the protease inhibitor saquina vir with a 96-hour continuous intravenous infusion of cyclophosphamide (800 mg/M-2), doxorubicin (50 mg/M-2, and etoposide (240 mg/M-2) (CDE) plus fil grastim in patients with non-Hodgkin's lymphoma associated with HIV infecti on. The effect of saquinavir on CDE-induced myelosuppression, CD4 lymphopen ia, and non-hematologic toxicity was also sought. Twelve patients with HIV- related lymphoma received CDE every 28 or more days. Ail patients received saquinavir (600 mg PO TID), filgrastim and Pneumocystis carinii and fungal prophylaxis. Patients also received either stavudine (n = 2) or both stavud ine and didanosine (n = 10). Toxicity was analyzed using the NCI Common Tox icity Criteria for each cycle and the data were compared with the data from our prior study of CDE plus didanosine. An interim analysis was performed after accrual of the first 12 patients in order to assess toxicity. Severe (grade 3 or 4) mucositis occurred in eight of 12 patients (67%) treated wit h CDE plus saquinavir compared with three of 25 patients (12%) in our prior study treated with CDE without saquinavir (P < 0.001). In logistic regress ion analysis, saquinavir use was the only factor associated with a signific antly greater risk of severe mucositis (relative risk 7.9; P = 0.03). Saqui navir use was not associated with a significant difference in the incidence of febrile neutropenia, prolonged neutropenia, chemotherapy dose reduction , or in the degree of myelosuppression. The decrease in CD4 lymphocytes for patients treated with saquinavir (absolute decrease of 23/mu L, or a 26% d ecrease from baseline) was significantly less than for patients treated wit hout saquinavir in the prior study (absolute decrease of 91/mu L, or 42% de crease from baseline; P = 0.05). Four of 10 patients (40%) treated with saq uinavir had an increase in CD4 lymphocytes of greater than or equal to 10/m u L compared with none of 25 patients (0%) treated without saquinavir (P ( 0.001), Combination of the protease inhibitor saquinavir with infusional CD E in patients with HIV-associated lymphoma was associated with a significan t increase in the incidence of severe mucositis, This finding suggests that saquinavir may alter the metabolism of one of more of the cytotoxic agents in the CDE regimen, and underscores the need for careful investigation reg arding the use of the protease inhibitors in patients receiving chemotherap y.