A Randomized Phase II/III Study of R-THP-Cop Vs R-CHOP for Patients Younger Than 70 Years with DLBCL

Introduction: Since the introduction of rituximab (R), a prognosis of diffuse large B cell lymphoma (DLBCL) is markedly improved. The rituximab-CHOP (R-CHOP) regimen, consisting of R, cyclophosphamide (CPA), doxorubicin (DXR), vincristine (VCR), and prednisolone (PSL), has become the current standard treatment for patients with DLBCL. On the other hand, the cardiotoxic problem due to DXR still remains. Pirarubicin (tetrahydropyranyl adriamycin: THP), a derivative of DXR, was reportedly an anthracyclin with less cardiotoxicity than DXR. Before introduction of rituximab, we reported the equivalent result between CHOP and THP-COP using THP instead of DXR regimen in aggressive non-Hodgkin’s lymphomas (74% of enrolled patients were DLBCL) (Tsurumi H et al. J Cancer Res Clin Oncol. 2004). In addition, we reported the efficacy and safety of R-THP-COP regimen for DLBCL in phase II study (Hara T et al. J Cancer Res Clin Oncol. 2010). Here, we prospectively compared the efficacy and safety of R-THP-COP and R-CHOP regimens as a clinical trial in Gifu Hematology Study Group.

Methods: In a prospective randomized phase II/III study, we assigned 80 patients (40 for R-CHOP or 40 for R-THP-COP) less than 70 years of age with previously untreated DLBCL, from July 2006 through September 2013. A diagnosis of DLBCL was histologically confirmed by 2 or 3 experts of pathology, according to the World Health Organization classification 2008. Patients who were infected with HIV or HTLV-1 were excluded. All patients provided written informed consent in accordance with the institutional guideline of Gifu University Graduate School of Medicine and the Declaration of Helsinki. The regimens consisted of R 375mg/m2 (day 1), DXR or THP 50 mg/m2 (day3), CPA 750 mg/m2 (day 3), VCR 1.4 mg/m2 (day 3) and PSL 100 mg/body for 5 days every 2 weeks for 6-8 cycles. The primary end point was the complete response rate, with the duration of overall survival (OS), safely and progression-free survival (PFS) as secondary end points.

Results: No significant differences (N.S.) in known prognostic factors (elderly patients, advanced clinical stage, poor performance status, elevated LDH and number of extranodal sites >1) were found between the both groups. At a median follow-up of 57 months (7 - 91 months), CR rate was 88.6% (87.2% for R-CHOP, 90.0% for R-THP-COP; P-value N.S.). The 2-year OS rates were 89.6% (87.1% for R-CHOP, and 92.1% for R-THP-COP; N.S.), respectively and 2-year PFS rates were 83.0% (79.0 % for R-CHOP, and 87.0 % for R-THP-COP; N.S.), respectively. In analyses of safety aspects, no cardiotoxicity of grade 3 or higher occurred in both groups. No serious adverse events were observed except for therapy-related acute myeloid leukemia in a patient with R-THP-COP group. The highest frequent adverse event was febrile neutropenia (32.5% in R-CHOP, 40% in R-THP-COP; N.S.). Therapy-related death was not observed.

Conclusions: R-THP-COP regimen produced results equivalent to those of R-CHOP regarding efficacy and safety in DLBCL patients less than 70 years of age. This regimen might be an alternative therapy instead of R-CHOP for patients with DLBCL. Further large clinical study should be considered to confirm efficacy and safety of R-THP-COP compared with R-CHOP.