Modulation of multidrug resistance by dexverapamil in EPOCH-refractory lymphomas

Abstract

We conducted a controlled trial of dexverapamil, an inhibitor of Pgp, in 45 Hodgkin's (HD) and 154 Non-Hodgkin's (NHL) lymphomas refractory to EPOCH chemotherapy. A total of 154 patients initially received EPOCH alone and (4.2%) with stable disease over two cycles or progressive disease “crossed over” to receive dexverapamil with EPOCH. Dexverapamil was escalated 8 dose levels, from 240 to 1200 mg/m² per day. When possible, serial biopsies were obtained to measureMDR-1 expression by quantitative polymerase chain reaction.

Median age was 44 years, 67% had stage IV disease, and median (range) prior regimens were 2 (1–12) in NHL and 1 (1–4) in HD. The maximum tolerated dose of dexverapamil was 900 mg/m²/day, and median plasma average concentrations of dexverapamil and nor-dexverapamil were 1.2 and 1.4 μM, respectively. There were 3 complete and 2 partial responses (12%) and 5 minor responses in NHL, and 2 of 10 HD patients achieved partial responses.MDR-1 was measured in 44 biopsies from 19 patients. Pre-therapy,MDR-1 was low (median 2.5 U) but increased (median 12.2 U) at cross-over. Among 6 patients withMDR-1>15, 3 responded to dexverapamil whereas only 1/8 patients withMDR-1<15 responded. EPOCH and dexverapamil were well tolerated. This study suggests thatMDR-1 plays a role in clinical drug resistance of lymphomas, but also suggests that non-MDR-1 mechanisms are present in such patients. Earlier intervention with dexverapamil may be more effective and warrants further study.