PILOT TRIAL OF SAQUINAVIR AND NUCLEOSIDE ANALGOGUES PLUS INFUSIONAL CYCLOPHOSPHAMIDE, DOXORUBICIN, AND ETOPOSIDE IN PATIENTS WITH HIV-ASSOCIATED NON-HODGKIN'S LYMPHOMA

Abstract

78 Background: The purpose of our trial was to determine the feasibility of combining the PI 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 and nucleoside analogue therapy in patients with HIV-associated non-Hodgkin's lymphoma (NHL). Methods: Twelve patients with HIV-NHL received CDE every 28 or more days. All patients received saquinavir (600 mg PO TID), filgrastim and Pneumocystis carinli 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 (J Clin Oncol 1997; 14: 3026). Results: The characteristics of the patient population (including baseline renal function, liver function, and proportion with lymphomatous liver involvement) were comparable to our prior report of CDE without saquinavir. The median CD4 count was 45/uL (3-310/uL). Severe (grade 3 or 4) mucositis occurred in 8/12 patients (67%) treated with CDE plus saquinavir compared with 3/25 patients (12%) treated 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), but had no effect on the incidence of febrile neutropenia, the neutrophil or platelet nadir, or the duration of severe neutropenia. The decrease in CD4 lymphocytes for patients treated with saquinavir (absolute decrease of 23/μL; 26% decrease from baseline) was significantly less than those treated without saquinavir (absolute decrease of 91/μL; 42% decrease [P = 0.05]). Four of 10 patients (40%) treated with saquinavir had an increase in CD4 count of ≥ 10/μL versus 0/25 (0%) treated without saquinavir (P < 0.001). Conclusions: Combination of the PI saquinavir with infusional CDE was associated with a significant increase in the incidence of severe mucositis, suggesting that the PIs may alter the metabolism of one of more of the cytotoxic agents in the CDE regimen. This effect may be specific for infusional therapy, and may not apply to more conventional lymphoma regimens given in as IV bolus injection. Further investigation regarding a potential pharmacokinetic interaction is warranted.