CONTROLLED TRIAL OF DEXVERAPAMIL, A MODULATOR OF MULTIDRUG-RESISTANCE, IN LYMPHOMAS REFRACTORY TO EPOCH CHEMOTHERAPY

Purpose: Overexpression of the multidrug resistance gene (mdr-1) is pr esent in vp to 60% of relapsed lymphomas. To study its role in lymphom as, we conducted a controlled trial of dexverapamil, an inhibitor of t he mdr-1 gene product, P-glycoprotein (Pgp), in lymphomas refractory t o etoposide, prednisone, vincristine, cyclophosphamide, and doxorubici n (EPOCH) chemotherapy. Patients and Methods: Eligible patients had re current Hodgkin's (HD) or non-Hodgkin's lymphomas (NHL) and measurable disease. Patients initially received EPOCH alone and those with stabl e tumor over two cycles or progressive disease crossed over to receive dexverapamil and EPOCH on subsequent cycles. Dexverapamil was escalat ed eight dose levels, from 240 to 1,200 mg/m(2)/d. When possible, seri al biopsies were obtained to measure mdr-1 expression by quantitative polymerase chain reaction (PCR). Results: Of 154 patients entered onto the trial, 109 had NHL and 45 had HD. The median age was 44 years, 67 % had stage IV disease, and the median number of prior regimens was tw o (range, one to 12) in NHL and one (range, one to four) in HD. Sixty- four patients (42%) crossed over, of which eight were not assessable. The maximum-tolerated dose of dexverapamil was 900 mg/m(2)/d. Among 41 NHL patients (excluding mycosis fungoides), there were three complete responses (CRs) and two partial responses (PRs) (12%) and five minor responses (MRs); two of 10 HD patients achieved PRs. The mdr-1 level w as measured in 44 biopsies from 19 patients. Pretherapy, mdr-1 was low (median, 2.5 U) but increased (median, 12.2 U) at crossover. Of six p atients with mdr-1 levels greater than 15 U, three responded to dexver apamil, while only one of eight patients with mdr-1 levels less than 1 5 U responded. EPOCH and dexverapamil were well tolerated, bur compare d with EPOCH alone, produced more hematologic toxicity. Conclusion: Th ese results suggest that Pgp plays a role in clinical drug resistance of lymphomas. However, they also suggest that mechanisms other than Pg p are prominent in heavily pretreated patients and that, although Pgp inhibition may be necessary, it is probably insufficient. Earlier inte rvention with dexverapamil may be more effective and warrants further study.