Primary response and saefty of 90yitrium ibritumomab tiuxetan followed by combined chemotherapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone for diffuse large B-Cell lymphoma

Abstract

To demonstrate the synergism between 90Yttrium ibritumomab tiuxetan (Y2B8) and commonly used antilymphoma drugs. The study was separated into 2 parts. First, to demonstrate the in vitro synergy in terms of direct cytotoxicity and antiproliferation to Ramos CD20-bearing lymphoma cells, 4-8 treatment arms due to drug order, different doses of 90Yttrium and 2 different incubation periods were designed. Synergy was justified by decreased IC50 and drug modification factors (DMF) greater than 1. Although 90Yttrium at 2 and 4 microCi/ml had no cytotoxic or antiproliferative effect, synergistic cytotoxicity was found when treated with doxorubicin (DMF 3.00-4.18), etoposide (DMF 1.96-2.36), and in 90Yttrium followed by fludarabine (DMF 2.99-3.52). Besides, combined 90Yttrium with cyclophosphamide, cytarabine (< 0.2 micro g/ml), and vincristine provided 60-100% antiproliferative effect. Moderately high degree of synergy was found with 0.2-200 micro g/ml fludarabine assessed after 96 hours incubation period (DMF 91.24-91.69). In the second part exploring clinical response and safety of the regimen Y2B8 followed by CHOP (Y-CHOP) for diffuse large B-cell lymphoma, 10 patients (4 male, 6 female) were enrolled during April 2006-February 2007. The increased percentage of patients with complete response or unconfirmed complete response to 80% at 3 weeks after completion of CHOP indicated the development of good response along the program. However, 4 progressive/relapse cases were noticed at 3 months-visit. Factors related to progression were disease bulkiness and the presence of extranodal sites. Non-serious drop in neutrophil and platelet counts (nadir at 5.80 +-1.69 and 4.50 +- 0.71 weeks, respectively) were common adverse events due to Y2B8. Higher percentage of good response was demonstrated among patients with Bcl-2+ than those with Bcl-2-. As summary, the regimen Y-CHOP provided more benefit in treating diffuse large B-cell lymphoma. This is related to the in vitro synergism with these drugs. In-depth investigation of rapid relapse should be performed further.