A Phase II Study of the Combination Chemotherapy Consisted of Rituximab and THP-COP Regimen as First-Line Treatment for Patients with Diffuse Large B-Cell Lymphoma

Background: A combination of rituximab and CHOP (R-CHOP) is currently the standard treatment for diffuse large B-cell lymphoma (DLBCL). We previously reported the utility of THP-COP regimen consisted of cyclophosphamide (CPA), pirarubicin (tetrahydropyranyl adriamycin: THP), vincristine (VCR), and prednisolone (PSL) in patients with DLBCL (Tsurumi H. et al. Hematol Oncol 2007). THP, a derivative of doxorubicin (DOX), is another anthracycline that has been reported to be less cardiotoxic than DOX. We conducted this phase II study to verify untreated patients with CD20 positive DLBCL.

Patients and Methods: The primary objective was to assess the efficacy of R-THP-COP with response rates. Secondary objectives were to assess the overall survival and drug safety. The study was conducted with local ethics committee approval, and all patients gave written, informed consent prior to enrollment. Adverse effects were graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. Over 18 were eligible for inclusion in the study if they had a diagnosis of untreated CD20 positive DLBCL. DLBCL was confirmed by biopsy. All patients had DLBCL at clinical stage (CS) II, III, or IV. Patients aged <70 (young patients) received 8 cycles of R-THP-COP therapy. The regimen consisted of R (375mg/m²), CPA (750mg/m²), THP (50mg/m²), VCR (1.4mg/m², maximal dose 2.0mg), and PSL (100mg daily). Patients aged ≥70 (elderly patients) received 6 cycles of R-THP-COP therapy. The R-THP-COP chemotherapy cycles were repeated at 14-day intervals in patients aged <70, and the THP-COP chemotherapy cycles were repeated at 21-day intervals in patients aged ≥70. Patients with bulky disease received radiotherapy ranging from 30 to 40 Gy. Responses to treatment were categorized as defined by Cheson et al.

Results: A total of 100 patients (55 males and 45 females) were enrolled in the study between December 2003 and December 2006. The median age was 59 years (range 24 – 69) in young patients (n = 48), and 75 years (range 70 – 83) in elderly patients (n = 52). 44 (92%) reached CR or CRu in young patients and 33 (63%) in elderly patients. Median follow-up was 29.4 months. The OS rate was 80.8 % after 3 years in young patients and 69.9% in elderly patients. The PFS rate was 74.7% after 3 years and 61.0% in elderly patients. OS rates did not differ significantly in accordance with IPI. There were 16 (35%), 35 (78%) and 7 (15%) patients who developed grade 3 or 4 anemia, neutropenia and thrombocytopenia in young patients, respectively. There were 12 (29%), 35 (85%) and 6 (14%) patients who developed grade 3 or 4 anemia, neutropenia and thrombocytopenia in elderly patients, respectively. Non-hematologic adverse effects were tolerable. Treatment regimen-related death was not observed in this study.

Discussion: In this study, the efficacy, feasibility, and toxicity of the THP-COP regimen was not inferior to those previously reported for CHOP. The CR rate was 92%, this CR rate was not inferior to our previous study and other previous reported studies. About the survival rate, the 3-year OS in our R-THP-COP regimen for patients with DLBCL was equal to or higher than that of our previous study. We concluded that R-THP-COP regimen in not inferior to R-CHOP about curative effect at least. About the safety, it is not thought that the R-THPCOP regimen has more adverse events than the R-CHOP regimen either. The results of our clinical trial prove that it is worth performing the randomized trial of the R-THP-COP regimen and the R-CHOP regimen as phase III trial. We designed this phase III trial and the trial is ongoing.