Molecular Inhibition of mTOR with Temsirolimus (TORISEL™, CCI-779) Is a Promising Strategy in Relapsed NHL: The University of Chicago Phase II Consortium.

Mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine kinase positioned at the juncture of several signal transduction pathways frequently disrupted in cancer. Downstream effectors, S6KI and 4EBP1, regulate cell cycle kinetics and cell growth via translational modulation, and this is effectively halted by rapamycin. Temsirolimus (TORISEL™, CCI-779) is a rapamycin ester derivative with cell cycle inhibitory properties. We conducted a phase II study of temsirolimus 25 mg IV over 30 minutes weekly in three cohorts of patients with relapsed/refractory NHL: Group A (diffuse large B-cell lymphoma, DLCL), Group B (follicular lymphoma, FL), Group C (small lymphocytic lymphoma/chronic lymphocytic leukemia [SLL/CLL] and other indolent B-cell lymphomas). Correlative studies in primary tumor tissue and in peripheral blood samples include phosphorylated p70S6K, total and phosphorylated 4EBP1, PTEN status, p21 status, and p27 status. Forty patients are registered, of which 21 are evaluable for response. Six patients are inevaluable and 13 too early for response evaluation; all patients were included in toxicity evaluation. There were 22 males/18 females with a median age of 59 (range, 29–83). Primary tumor samples were collected in 10 patients, with biomarker analysis pending. Histologic subtypes include 7 DLCL, 14 FL, and 13 CLL/SLL. Of 21 evaluable patients for response, there were 3 complete remissions (all FL) and 5 partial remissions (1 DLCL, 3 FL, 1 SLL), for an overall response rate of 40%. An additional 10 patients (5 FL, 6 CLL/SLL) had minor responses or stable disease; only 3 pts had progressive disease as their best response. The median follow-up is 4 months (range, 1–15 months). Grade 1–2 non-hematologic toxicities (except where noted) include increased hepatic enzymes (10 pts), skin rash (13 pts), fatigue (18 pts; grade 3 in 2 pts), hypercholesterolemia (22 pts), hyperglycemia (21 pts; grade 3 in 1 pt), hypertriglyceridemia (20 pts; grade 3 in 1 pt). Six patients were removed from study due to pneumonitis; 4 of these patients were symptomatic (cough, fevers, dyspnea) and 2 were asymptomatic but had pulmonary abnormalities on staging CT scans. Grade 3 and 4 hematologic toxicities include thrombocytopenia (5 pts), lymphopenia (5 pts), and leucopenia (2 pts). In summary, temsirolimus shows preliminary but encouraging activity across multiple B-NHL subtypes, complementing the published activity in mantle cell lymphoma. Careful attention must be paid to pulmonary toxicity. However, the early activity, including disease regression and stabilization, suggests that future combinations with cytotoxics or other biologics may be warranted, and that mTOR inhibition in NHL is a promising strategy.