Intensified 1st Cycle Rituximab (R) Plus 8^th Cycles of R-CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) Chemotherapy In Patients with Advanced or Bulky CD20⁺ Diffuse Large B-Cell Lymphoma (DLBCL); Open-Labelled, Multicenter Phase II CISL Study-Interim Analysis.

Six to Eighth cycles of R-CHOP (Rituximab + cyclophosphamide, adriamycin, vincristine and prednisolone) has been widely used as standard regimen for the advanced stage diffuse large B-cell lymphoma (DLBCL). However, the optimal dose and number of rituximab application have not been determined to date. According to the recent German DENSE-R-CHOP-14 trial, additional use of rituximab (12^th dose of rituximab) showed increased complete remission (CR) rate in high risk DLBCL patients. Based upon the promising results of DENSE-R-CHOP-14 chemotherapy in DLBCL, we have been investigated the efficacy and safety of additional 1^st cycle Rituximab + 8^th cycles of R-CHOP chemotherapy (R+8^th R-CHOP, every 3 weeks) in patients with previously untreated stage III/IV or bulky DLBCL.

92 patients with advanced stage DLBCL (Bulky stage II or Stage III or IV) from 21 institutions received 8th cycles of R-CHOP-21 with additional rituximab on days 0 of 1st cycle between January 2009 and December 2009. The primary endpoint was complete response rate after 3rd cycles of treatment. Among 92 patents who were initially enrolled this study, 14 patients had no response data after 3rd cycles of chemotherapy (3 refuse consent, 2 early death, 7 no evaluation, 1 transfer to other institution, 1 serious toxicity). The DLBCL patients who were treated with 6–8th cycles of R-CHOP-21 will be analyzed for historical control data. The trial is registered on National Cancer Institute website, number NCT01054781.

Fifty two patients (56.5%) were older than 60 years (median age; 63); 16 (17.4%) had a poor performance status (ECOG ³ 2); 64 (69.6%) had an elevated lactate dehydrogenase (LDH) and 89 (93.5%) had stage III/IV disease. According to the International Prognostic Index (IPI), 5 (5.4%) patients had low risk, 28 (30.4%) had low–intermediate risk, 43 (46.7%) had high–intermediate risk, and 16 (17.4%) had high risk disease. According to the revised IPI, 33 (35.9%) patients had good prognostic group (IPI score 1–2), and 59 (64.1%) patients had poor prognostic group (IPI score 3–5). Among the 78 evaluable DLBCL patients, complete remission (CR) rate was 42.3% (33/78) after 3^rd cycles of chemotherapy. Response rate after 3^rd cycles of chemotherapy was 96.2% (42.3% CR + 53.8% partial remission). CR were observed in 80% (4/5) of low IPI patients, 65.2% (15/23) of low intermediate IPI, 32.4% (12/37) of high intermediate IPI and 15.3% (2/13) of high IPI (P = 0.087). And CR also observed in 67.9% (19/28) of the patients with good revised IPI and 28% (14/50) of the patients with poor revised IPI (P = 0.007). Infection was one of the most frequent ³ grade 3 adverse events (17/92; 18.5%). Two (2.2%) treatment related deaths (infection) were observed. Other grade 3 and 4 adverse events were occurred as follows; neutropenia (47.8%), anemia (13.1%), thrombocytopenia (5.4%), generalized weakness (6.5%), diarrhea (3.3%), anorexia (2.2%), abdominal pain (2.2%), neuropathy (1.1%) and muscle pain (1.1%).

The addition of rituximab on days 0 of 1^st cycle of R-CHOP to the standard 8^th cycles of R-CHOP-21 for advanced DLBCL showed acceptable response rates after 3^rd cycles of chemotherapy and acceptable toxicities. We will evaluate the long-term follow up results and the comparison analysis with historical controls receiving standard R-CHOP-21.

No relevant conflicts of interest to declare.