Clinical Trial of Rituximab Synchronized with Granulocyte Colony-Stimulating Factor in Standard CHOP Chemotherapy for Previously Untreated Patients with Follicular or Diffuse Large B-Cell Lymphomas.

Background Rituximab, a chimeric monoclonal antibody against CD20 B-cell antigen, is widely used to treat B-cell lymphomas. One of the mechanisms through which rituximab works is antibody-dependent cellular cytotoxicity (ADCC). Granulocyte colony-stimulating factor (G-CSF) enhances the cytotoxicity of neutrophils through ADCC. The issue on the optimal timing of rituximab administration during standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) to exert a maximal effect against tumor cells remains to be determined. We conducted a clinical trial in which rituximab administration was synchronized with G-CSF during standard CHOP in patients with follicular (FL) or diffuse large B-cell (DLBCL) lymphomas.

Methods We administered G-CSF for several days to treat neutropenia caused by CHOP regimen for patients with B-cell lymphoma (n=5). In these patients CD64 expressions on both neutrophils and monocytes and ADCC activity were examined at the several time points during one cycle of CHOP. Then, 9 patients with FL and 7 patients with DLBCL were enrolled to receive six to eight cycles of CHOP every three weeks. In each cycle from the second course, rituximab was given in synchronization with several daily administration of G-CSF.

Results CD64 expression was enhanced in patients given G-CSF during CHOP, whereas CD64 expression remained unchanged in patients not given G-CSF. CD64 expression levels on both neutrophils and monocytes were significantly up-regulated by the multiple daily administration of G-CSF and reached peak levels at day5 after the start of G-CSF (p=.0007). In ADCC activity, we found that rituximab-mediated cell lysis was correspondingly enhanced at day5 after starting G-CSF (p=.01). Taken together with these finding, we speculated that the administration of rituximab synchronized with multiple daily doses of G-CSF could augment the treatment efficacy of CHOP plus rituximab. First, we commenced G-CSF on day10 of each cycle from the second course of CHOP regimen and continued for at least 5 days to treat enrolled patients who developed neutropenia. Then, we administered rituximab on day5 after the start of G-CSF in the each cycle. In 9 patients with FL, the response rate was 100%, with complete remission (CR) in 8 patients and partial remission in 1 patient. With a median follow-up of 20 months (range; 8–37 months), no relapsed or flare-up patients were observed. In 7 patients with DLBCL, the CR rate was 100%. With a median follow-up of 10.2 months (range; 7–18 months), 2 of 7 patients had relapsed. There were no significant differences in clinically adverse reactions compared with CHOP alone or R-CHOP.

Conclusions The administration of rituximab synchronized with G-CSF in standard CHOP regimen may improve clinical response rate and survival without a significant increase in toxicity.