Protease inhibitors are an important new class of agents for the treatment of human immunodeficiency virus (
HIV) infection. The purpose of our trial was to determine the feasibility of combining the
protease inhibitor saquinavir with a 96-hour continuous
intravenous infusion of
cyclophosphamide (800 mg/M2),
doxorubicin (50 mg/M2, and
etoposide (240 mg/M2) (CDE) plus
filgrastim in patients with
non-Hodgkin's lymphoma associated with
HIV infection. The effect of
saquinavir on CDE-induced myelosuppression, CD4
lymphopenia, and non-hematologic toxicity was also sought. Twelve patients with
HIV-related lymphoma received CDE every 28 or more days. All patients received
saquinavir (600mg PO TID),
filgrastim and Pneumocystis carinii and fungal prophylaxis. Patients also received either
stavudine (n = 2) or both
stavudine and
didanosine (n = 10). Toxicity was analyzed using the NCI Common Toxicity 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 with CDE plus
saquinavir compared with three of 25 patients (12%) in our prior study treated with CDE without
saquinavir (P < 0.001). In logistic regression analysis,
saquinavir use was the only factor associated with a significantly greater risk of severe
mucositis (relative risk 7.9; P = 0.03).
Saquinavir 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/microL, or a 26% decrease from baseline) was significantly less than for patients treated without
saquinavir in the prior study (absolute decrease of 91/microL, or 42% decrease from baseline; P = 0.05). Four of 10 patients (40%) treated with
saquinavir had an increase in CD4 lymphocytes of > or = 10/microL compared with none of 25 patients (0%) treated without
saquinavir (P < 0.001). Combination of the
protease inhibitor saquinavir with infusional CDE in patients with HIV-associated
lymphoma was associated with a significant 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 regarding the use of the
protease inhibitors in patients receiving
chemotherapy.