VNCOP-B (Etoposide, Mitoxantrone, Cyclophosphamide, Vincristine, Prednisolone, Bleomycin) Plus Rituximab Therapy in Elderly Patients with Aggressive B-Cell Non-Hodgkin Lymphoma: A Phase II Study of Efficacy and Safety
Authors: Ishii Kazuyoshi , Manabe Masahiro , Yagi Toshiya , Teshima Hirofumi , Nagare Yasuaki , Kimura Hidetsugu , Urase Fumiaki , Hayashi Kunio , Shibano Masaru , Tsukaguchi Machiko , Katsurada Tatsuya , Mugitani Atsuko , Kitayama Hitoshi , Nomura Shosaku 
Published: October 2019

Abstract
[Background and Objectives] CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) plus rituximab is a standard chemotherapy used to treat patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL). However, among elderly patients, this regimen has not been completely satisfactory in its efficacy and safety because of agespecific comorbidity, increased toxicities of chemo-agents, and the more aggressive aspect of the lymphoma itself. Zinzani reported that a combination therapy including etoposide, mitoxantrone, cyclophosphamide, vincristine, prednisolone, and bleomycin (VNCOP-B) was effective in elderly aggressive NHL patients (Blood1999;94:33–38). We conducted a phase II multicenter study in 8 collaborative institutions to determine if VNCOP-B plus rituximab was effective and safe to treat elderly patients with aggressive B-NHL. The primary endpoint was to detect overall survival (OS). The second endpoint was to detect the response rate (RR) and progression-free survival (PFS).
[Patients and Treatment] Eligible patients were those aged over 60 years, with aggressive B-NHL documented as CD20 surface antigen positive, performance status (PS) 0 to 2, clinical stage over II or I with a bulky disease, measurable lesions, no prior chemotherapy nor radiation, no severe complications, no major organ dysfunction, no other active cancer, not a HBV carrier, no central nervous system involvement with lymphoma, and who gave the required written informed consent. VNCOP-B plus rituximab was administered as an induction therapy. This protocol was completed in 8 weeks and consisted of weekly doses of chemotherapy combined with rituximab every two weeks. During the 8 weeks of therapy, granulocyte colony-stimulating factor (G-CSF) was administered on a prophylactic base. Rituximab was administered weekly four times a month as a sequential therapy, following one month after the end of the induction therapy.
[Results] Between September 2004 and December 2007, 23 patients, median age 73 years, 50.0% classified as high-intermediate/high risk on the age-adjusted International Prognostic Index (IPI), entered this trial and 21 were evaluated for feasibility, toxicity, and efficacy. Twenty-two patients (95.2%) were diagnosed with diffuse large B-cell lymphoma and one (4.8%) with mediastinal large B-cell lymphoma. The nineteen patients (90.5%) completed the induction therapy and all these then received a sequential rituximab therapy. Complete remission rate was 90.5%, with a 100% overall RR at the end of induction therapy; OS rate at 3 years was 76.4% (median follow-up 744days); with an 82.6% 3-year PFS rate (median follow-up 744days). Average Relative dose intensity (RDI) in MIT was 0.61, no significant difference in survival was found regarding RDI. Although IgG level decreased during the induction therapy, it recovered to the prior level after sequential rituximab (IgG means±standard error: pre-treatment 1355.2±146.4mg/dl, post-induction therapy 785.3±107.0mg/dl, post-sequential rituximab 1010.4±60.2mg/dl). According to the IPI, there was a trend suggesting a lower probability of OS and PFS in high/high-intermediate risk than in low/low-intermediate risk cases (3-year OS: 67.5% versus 100.0%, P=0.51; 3-year PFS: 66.7% versus 100.0%, P NA). The most common grade 3/4 toxicities were hematologic, including neutropenia in 75.0% of the 21 patients despite prophylactic administration of G-CSF, febrile neutropenia in 30.0%, and thrombocytopenia in 10.0%, respectively. Regarding non-hematologic grade 3/4 toxicities, hepatitis occurred in one patient (5.0%) from HCV reactivation, intestinal perforation involving the lymphoma in one patient (5.0%). There was no treatment-related mortality. We had conducted a phase II study of VNCOP-B therapy in 16 elderly patients with aggressive B-NHL (Gan To Kagaku Ryoho2005;32:39–44, in Japanese). Against this historical comparison, the present protocol seemed better in PFS than that without rituximab (3-year PFS: 82.6% versus 56.0%, P=0.11), although OS was almost the same (3-year OS: 76.4% versus 73.4%, P=0.22).
[Conclusion] Although our enrolled patients were quite elderly with a median age of 73 years, and half of them had a poor prognosis index, VNCOP-B combined with rituximab was well tolerated and showed promise.