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Controlled trial of dexverapamil, a modulator of multidrug resistance, in lymphomas refractory to EPOCH chemotherapy
W H Wilson1, S E Bates, A Fojo
1Medicine Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Purpose:
Overexpression of the multidrug resistance gene (mdr-1) is present in up to 60% of relapsed lymphomas. To study its role in lymphomas, we conducted a controlled trial of dexverapamil, an inhibitor of the mdr-1 gene product, P-glycoprotein (Pgp), in lymphomas refractory to etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy.
Patients And Methods:
Eligible patients had recurrent Hodgkin's (HD) or non-Hodgkin's lymphomas (NHL) and measurable disease. Patients initially received EPOCH alone and those with stable tumor over two cycles or progressive disease crossed over to receive dexverapamil and EPOCH on subsequent cycles. Dexverapamil was escalated eight dose levels, from 240 to 1,200 mg/m2/d. When possible, serial 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 two (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/m2/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 was 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 patients with mdr-1 levels greater than 15 U, three responded to dexverapamil, while only one of eight patients with mdr-1 levels less than 15 U responded. EPOCH and dexverapamil were well tolerated, but compared with EPOCH alone, produced more hematologic toxicity.
Conclusion:
These results suggest that Pgp plays a role in clinical drug resistance of lymphomas. However, they also suggest that mechanisms other than Pgp are prominent in heavily pretreated patients and that, although Pgp inhibition may be necessary, it is probably insufficient. Earlier intervention with dexverapamil may be more effective and warrants further study.
Insights
Dexverapamil, an inhibitor of P-glycoprotein (Pgp), showed modest efficacy in treating relapsed lymphomas by increasing drug sensitivity. However, other resistance mechanisms limit its effectiveness in heavily pretreated patients, suggesting earlier intervention is needed.
Area of Science:
- Oncology
- Pharmacology
- Hematology
Background:
- Multidrug resistance gene (mdr-1) overexpression is common in relapsed lymphomas.
- P-glycoprotein (Pgp) is the mdr-1 gene product and a key mediator of drug resistance.
Purpose of the Study:
- To evaluate the efficacy of dexverapamil, a Pgp inhibitor, in lymphomas refractory to etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy.
- To investigate the role of mdr-1 expression in lymphoma drug resistance.
Main Methods:
- A controlled trial involving patients with relapsed Hodgkin's (HD) or non-Hodgkin's lymphomas (NHL).
- Patients received EPOCH chemotherapy, with crossover to dexverapamil plus EPOCH for progressive or stable disease.
- Dexverapamil dosage was escalated, and mdr-1 expression was measured via quantitative PCR.
Main Results:
- Of 154 patients, 109 had NHL and 45 had HD. The maximum-tolerated dose of dexverapamil was 900 mg/m2/d.
- In NHL patients, 12% achieved complete or partial responses, and 2 out of 10 HD patients achieved partial responses.
- mdr-1 levels increased at crossover, and higher pretherapy mdr-1 levels correlated with better response to dexverapamil.
Conclusions:
- P-glycoprotein plays a role in clinical drug resistance in lymphomas.
- Other drug resistance mechanisms are prominent in heavily pretreated patients, suggesting Pgp inhibition alone may be insufficient.
- Earlier use of dexverapamil may improve efficacy and warrants further investigation.
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