Impact Of Dose-Density Delays In Diffuse Large B-Cell Lymphoma (DLBCL) Treated With R-CHOP21 Or R-CHOP14
Authors: Gutierrez Antonio , Bautista-Gili Antonia M , Bento Leyre , Herraez Ines , Garcia Lucia , Martinez-serra Jordi , Sampol Antonia , Ramos Rafael , Gines Jordi , Ballester Carmen , Perez Albert , Lopez-Perezagua Paloma , Daumal Jaime , Rodriguez Jose , Besalduch Juan 
Published: October 2019

Abstract

Background
DLBCL is the more common non Hodgkin lymphoma. This is an aggressive lymphoma that is treated with a standard chemotherapy regimen: R-CHOP. In the last years attempts have been done to improve the outcome both increasing dose-density (DD) (CHOP14) or intensity (CHOEP, ACVBP, frontline high dose therapy followed by autologous stem cell transplantation). Although phase 2 studies of these interventions suggested promising results, when randomized phase 3 trials have been conducted, there is no demonstrated benefit of these higher toxicity approaches when compared with R-CHOP alone. Only addition of rituximab to CHOP has proved a survival advantage. This has allowed setting R-CHOP administered every 21 days (R-CHOP21) as the standard treatment for DLBCL patients. The purpose of this study is further analyzing the prognostic impact of DD delays in two cohorts of DLBCL patients treated with R-CHOP21 or R-CHOP14.

Methods
All patients diagnosed between 1999 and 2013 of DLBCL in University Hospital Son Espases were identified from Pathology Department registry. Only patients treated with R-CHOP21 or R-CHOP14 +/- radiotherapy were included. Patients receiving other chemotherapy regimens or consolidations were excluded. DD delay was calculated as follows: DD delay = real number of days from first to last cycle of chemotherapy / expected number of days from first to last cycle in every regimen.

Results
A total of 166 cases were identified: considering inclusion and exclusion criteria finally 111 cases were selected (71 in the R-CHOP21 cohort and 40 in the R-CHOP14 cohort). Respectively for R-CHOP21 and R-CHOP14, 61% and 37% were older than 60 years (p=0.02), 26% and 35% had an ECOG PS higher than 1 (p=0.3), 49% and 62% had an Ann Arbor stage III-IV (p=0.09), 44% and 51% an a-IPI higher than 1 (p=0.47). Median DD delay was 2% versus 14% for R-CHOP21 and R-CHOP14 groups (p<0.001). Clinically significant DD delay was considered those patients with DD delay higher than the median of the R-CHOP14 group. Complete response (CR) rate in patients with or without DD delay higher than 14% was 50% versus 85% in the R-CHOP21 group (p=0.004) and 80% versus 78% for R-CHOP14 group (p=0.87). Median follow-up was 60 months (4-169). OS and PFS were not significantly different in patients treated with R-CHOP21 or R-CHOP14: respectively 5y-OS of 73% vs 82% (p=0.97) and 5y-PFS 78% vs 70% (p=0.46). However, DD delay higher than 14% influenced OS and PFS only in the R-CHOP21 group (5y-OS of 39% vs 82% with or without DD delay; p=0.002 and 5y-PFS of 61% versus 81%; p=0.024) but not in the R-CHOP14 group (5y-OS of 78% vs 84% with or without DD delay; p=0.24 and 5y-PFS of 57% versus 72%; p=0.56).

Conclusions
Overall in our series there were no differences in terms of response or survival between patients treated with R-CHOP21 or R-CHOP14. Significantly higher rates of DD delay were observed in the R-CHOP14 group. However, the impact of DD delays on response and survival was only observed in the R-CHOP21 group but not in patients treated with R-CHOP14. We can conclude that R-CHOP21 and R-CHOP14 are equivalent regimens in terms of response and survival only if DD delays are avoided. For patients receiving R-CHOP21 we recommend using clinical and support measures in order to avoid DD delays.

Disclosures:
No relevant conflicts of interest to declare.