Impact of Creatinine Clearance in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP : A Real-World Long-Term Observation Analysis at a Single Institute
Authors: Nishimura Noriko , Fukuta Takanori , Nishihara Anna , Shirouchi Yuko , Uryu Hideki , Inoue Norihito , Kusano Yoshiharu , Tsuyama Naoko , Takeuchi Kengo , Mishima Yuko , Yokoyama Masahiro , Terui Yasuhito 
Published: October 2019

Abstract
Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL). Typically, the dose of rituximab is 375 mg/m2; data obtained from recent clinical trials about the pharmacokinetics of rituximab showed that elderly women have a better outcome than elderly men and a more favorable pharmacokinetics of rituximab than all other patients with DLBCL. Therefore, optimization of the dose and schedule of rituximab is required for the subpopulation of patients with DLBCL that show a fast clearance of rituximab. The metabolism of rituximab, which is mostly excreted through the kidneys, is not completely understood thus far. Renal function, which is determined using creatinine clearance (CCr), at the time of administration may affect the clearance of rituximab, and thus, the therapeutic outcomes. We examined the association between the rate of CCr and survival outcome in patients with DLBCL treated with R-CHOP.
We evaluated 653 patients with newly diagnosed de novo DLBCL, excluding those with transformed DLBCL, at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from January 2005 to December 2015. All patients were treated with R-CHOP or modified regimens. CCr was calculated using the Cockcroft-Gault formula. Tumour staging and response assessment were performed using the revised response criteria for malignant lymphoma and the International Conference on Malignant Lymphomas Imaging Working Group by using positron emission tomography-computed tomography and bone marrow biopsy. Progression-free survival (PFS) and overall survival (OS) were defined as the time from the date of initiation of R-CHOP to the date of disease progression, relapse, last follow-up, or death from lymphoma. Deaths due to reasons other than lymphoma were censored. PFS and OS were estimated using the Kaplan-Meier method, and the differences were compared using the log-rank test. The Cox proportional hazards regression models were used to identify the prognostic factors to predict the PFS and OS.
A total of 653 patients with DLBCL were met the inclusion criteria, and the median follow-up for survival was 64 months. Our results showed that 133 (20.3%) patients had a CCr rate less than 60 mL/min. Patients with a low rate of CCr were older, had an advanced stage of DLBCL, extranodal disease, high levels of lactate dehydrogenase (LDH), and high proportion of non-germinal cell (GC) subtype, which are indicators of a poor prognosis. Therefore, patients with a lower rate of CCr showed poorer PFS (5-year PFS 74.2% vs. 80.8%, p = 0.13) and OS (5-year OS 77.1% vs. 86.9%, p=0.013).
Further, we performed subgroup analysis according to CCr using the revised International Prognostic Index (R-IPI), which includes of age >60 years, stage III/IV disease, elevated LDH levels, performance status ≥ 2, more than one extranodal site of disease. Although all prognostic groups did not show a significant difference depending on the CCr, the groups with very good and good prognosis showed superior PFS in a low rate of CCr group than high rate of CCr group (Figure 1). The results of subgroup analysis for OS were similar to those observed for PFS. Thus, patients with very good and good prognosis determined using R-IPI may be affected by the subtle difference in the clearance of rituximab, whereas those with poor prognosis may not be affected by this difference. Results of multivariate analysis for PFS and OS showed that a low rate of CCr was not a significant prognostic factor. Thus, our results showed that although CCr may be a factor for clearance of rituximab, no significant association exists between the rate of CCr and survival.
Our findings suggest that modification of the dose of rituximab depending on CCr is not recommended for improving survival. Further studies are required to establish an optimal dose and schedule of rituximab in all subgroups of patients with DLBCL.

Disclosures
Nishimura: Chugai Pharmaceutical Co., Ltd.: Other: commissioned work. Mishima:Chugai pharmaceutical inc, Roche: Other: commissioned work. Yokoyama:Chugai pharmaceutical inc, Roche: Other: commissioned work. Terui:Bristol myers Squib: Honoraria; Celgene: Honoraria; Janssen Pharmaceutical KK: Honoraria; Takeda pharmaceutical: Honoraria; Novartis pharma: Honoraria.