Combination of CCNU and DTIC chemotherapy for treatment of resistant lymphoma in dogs.

Background: Pleotropic-glycoprotein (P-gp)–mediated resistance is the usual cause of relapse in dogs with lymphoma. 1-(2-chloroethyl)3-cyclohexyl-1-nitrosurea (CCNU) and 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) are alkylating agents that are not affected by P-gp and lack cross-resistance to each other. A combination protocol offers the advantage of improved summation dose and synergistic activity. Hypothesis: A combination of CCNU and DTIC that is well tolerated can be used to treat dogs with lymphoma that developed resistance or failed to respond to previously administered chemotherapy. Animals: Fifty-seven dogs with lymphoma that were resistant to treatment with standard chemotherapy (l-CHOP; l-asparaginase, cyclophosphamide, doxorubicin, vincristine, prednisone). Methods: Prospective phase I and II trials were performed. CCNU was given PO immediately before a 5-h IV infusion of DTIC. Concurrent antiemetics and prophylactic antibiotics were used. Treatments were administered every 4 weeks. Results: Based on the results of 8 dogs in the phase I study, CCNU at 40 mg/m2 PO combined with DTIC at 600 mg/m2 IV was used to treat 57 dogs with resistant lymphoma. Thirteen (23%) dogs had a complete response (CR) for a median of 83 days and 7 (12%) had a partial response for a median of 25 days. The median l-CHOP CR duration of the dogs that did not respond to CCNU-DTIC was significantly longer than that of the dogs that did achieve remission with CCNU-DTIC (225 days versus 92 days, P= .02). The principal toxic event was neutropenia; the median neutrophil count 7 days after treatment was 1,275 cells/μL. Increases in alanine transaminase activity, possibly associated with hepatotoxicity, were detected in 7 dogs. Conclusions and Clinical Importance: A combination of CCNU and DTIC can be an effective option to rescue dogs with resistant lymphoma.