Irinotecan in relapsed or refractory non-Hodgkin's lymphomas. Indications of activity in a phase II trial.

Because irinotecan (CPT-11, Camptosar) is a topoisomerase I inhibitor with a broad spectrum of antitumor clinical activity, we investigated its activity in relapsed or refractory non-Hodgkin's lymphomas (NHLs). Irinotecan at 300 mg/m2 i.v. was administered every 21 days with intensive loperamide management of diarrhea. Responders received up to six treatment cycles. Of 44 registered patients, 32 are evaluable for response. Seventeen patients had received one previous regimen, and 15 patients had received two. Disease was refractory to the regimen preceding irinotecan in 12 patients. At baseline, serum lactate dehydrogenase levels were high in 47% (14/30), and beta-2-microglobulin levels were higher than 3.0 mg/L in 29% (8/28) of patients. Responses were seen in 12 of 32 (38%) patients (95% confidence interval [CI] = 21%-56%). Response rates were 43% for seven indolent (95% CI = 10%-82%), 0% for three mantle cell (95% CI = 0%-71%), 44% for 18 relapsed aggressive (95% CI = 22%-69%), and 20% for five refractory aggressive NHLs (95% CI = 1%-72%). Grade 3/4 toxicities included myelosuppression, neutropenic fever, and diarrhea. Irinotecan appears active and relatively well tolerated in patients with relapsed aggressive or indolent NHL. Accrual to this study is continuing for better determination of response rates in all histologic subtypes of NHL.

Clinical pharmacology of intrathecal methotrexate. II. An improved dosage regimen derived from age-related pharmacokinetics.

Cerebrospinal fluid (CSF)-antifolate concentration was analyzed in 100 specimens from 47 patients treated with intrathecal methotrexate (MTX) (12 mg/m2 of body surface area [BSA]). The drug concentrations varied 100-fold, with high levels associated with neurotoxicity and low levels with a poor response to therapy. CSF-MTX concentration was correlated directly with patient age, suggesting that a constant dose, regardless of age or BSA, should provide more consistent CSF-drug concentrations. In a subsequent study 25 patients treated with a conventional-dose schedule of 12 mg/m2 of BSA were compared with a matched group of 24 patients administered a constant dose of 12 mg. There was significantly less variability of drug levels in the CSF with the constant-dose method than with the dosage derived from BSA. It is recommended that patients between 3 and 40 years of age receive the same intrathecal dose rather than varying doses adjusted for patient BSA.