Impact of Intended and Relative Dose Intensity of RCHOP in a Large, Consecutive Cohort of Elderly DLBCL Patients: No Difference in DFS for 70-80 Years Versus >80 Years and Idi Independently Predicts Survival
Authors: Eyre Toby A. , Martinez-Calle Nicolas , Hildyard Catherine , Eyre David W. , Plaschkes Hannah , Griffith Jonathan , Wolf Julia , Fox Chris P , McMillan Andrew , Bishton Mark , Collins Graham P. , Hatton Chris 
Published: October 2019

Abstract
Introduction
The impact of RCHOP dose attenuation in elderly patients (pts) with DLBCL is poorly understood. 1% of DLBCL 1st line pts in trials are ≥80 years (y). Attenuated R-CHOP (25mg/m2 doxorubicin (DOX); 400mg/m2 cyclophosphamide (CYCLO), 1mg vincristine) cure 50-60% in phase II trials (Peyrade et al, 2011, 2017). Full dose RCHOP compared to attenuated RCHOP does not improve outcome in ≥80y (Juul et al, 2018) or may worsen survival via toxicity (Eyre et al, 2016, Carson et al 2015).
Methods
We systematically collected data on IDI (cycle (C)1 dose) and RDI of CYCLO/DOX in consecutively treated pts ≥70ys across 6 UK centres (2009-18). Untreated de novo DLBCL and untreated transformation (HGT) of indolent NHL (iNHL) receiving ≥C1 were included. RCHOP was given at a minimum interval of 21 days. G-CSF was routine. The following were excluded: HIV+, prior solid organ transplant, isolated leg type DLBCL, pre-treated HGT, central nervous system involvement with DLBCL, and pts unfit for anthracycline. Data were collected on Cumulative Illness Rating Scale for Geriatrics (CIRS-G), CIRS-G severity index (total/no. categories), age-adjusted international prognostic index ((aa)IPI), Hb, albumin, LDH, B symptoms, bulk ≥10cm, major operation at diagnosis, and extranodal sites (ENS). Predictors of progression free (PFS), disease free (DFS), and overall survival (OS), were determined using univariable (UVA) and multivariable (MVA) Cox regression. Factors were analysed as continuous (denoted *); additionally IDI (full dose: ≥80% of weight based dose vs attenuated: <80%) and age were analysed as a categorical variables.
Results
511 pts received R-CHOP with curative intent. 49% were male and 51% were female. Median follow up was 1.67y. Median age was 77y. 32% had stage I-II and 68% stage III/IV. 14% had concurrent iNHL, 20% bulk, 33% >1 ENS, and 66% IPI 3-5. 46% had CIRS-G ≥6. When comparing age/IDI categories, in 70-80y, pts with IDI<80% had a worse ECOG (2-4; 63%) vs IDI>80% (2-4; 30%), higher IPI 3-5 (71% vs 64%), higher CIRS-G≥6 (59% vs 40%), and higher CIRS-G severity index. ≥80y receiving IDI>80% had better ECOG (0-1 67% vs IDI<80% (0-1; 52%) and a lower CIRS-G (≥6 26% vs 53%).
For all pts, median PFS was 5.4y (95% confidence interval (CI) 4.1 - 6.9), median DFS was not reached, and median OS 5.5y (95% CI 4.5 - 6.7). When analysed by 70-80 vs ≥80y: 2y PFS was 71.8% (95% CI 66.4-76.4%) vs 60.3% (95% CI 51.5-68.0%), 2y DFS 79.4% (95% CI 74.3-83.6%) vs 76.7% (95% CI 68.4-83.1%) (p = 0.23) and 2y OS 74.6% (95% CI 69.4-79.1%) vs 60.2% (95% CI 51.2-68.1%). Unlike OS and PFS, DFS was not significantly different when 70-80y vs ≥80y were compared, suggesting >80y have a worse outcome due to toxicity and/or unrelated causes of death. 15 deaths in >80y with IDI>80 were: infection (n=5), systemic progressive disease (PD) (n=7), CVA leading to stopping RCHOP post C1 (subsequent PD) (n=1), unknown (in remission) (n=1), dementia (n=1).
In 70-80y, IDI>80% had significantly improved PFS, DFS and OS. In ≥80y, there was no difference in PFS, DFS or OS according to IDI <80% vs >80% (Fig A-F).
UVA
Univariable predictors of worse PFS and OS included age*, ECOG PS*, DOX IDI*, CYCLO IDI*, combined IDI*, IPI 3-5, aaIPI 2-3, raised LDH, male gender and B symptoms (all p<0.001). Bulk, prior operation, concurrent iNHL and IDI/RDI were not predictive. DFS predictors were similar, but excluded Age*, age (70-80 vs ≥80y) and CIRS-G≥6.
MVA
IDI* remained an independent predictor of PFS, DFS and OS. Using 70-80y IDI>80 (HR 1.0) as the comparator, the following were associated with significantly increased risk of PD and / or death in PFS and OS in MVA: 70-80y IDI<80, ≥80y IDI<80 and ≥80y IDI>80. Compared to 70-80y IDI>80 (HR 1.00), the HR for DFS in ≥80y IDI>80 approached significance (p = 0.07) vs PFS and OS, suggesting that causes other than PD account in part for inferior OS and PFS (Table 1).
Conclusions
To our knowledge, this is the largest series that has systematically analysed RDI, IDI (DOX, CYCLO and combination) and co-morbidities in consecutive unselected DLBCL ≥70y. Consistent with recent literature (Juul et al, 2018), there is no clear benefit to PFS, DFS or OS in dose intensifying (IDI>80) in ≥80y. IDI is a clear independent predictor of outcome across all pts. Pts 70-80y with IDI <80 were less fit (higher ECOG and CIRS-G) which may have limited IDI and RDI. DFS did not significantly differ by 70-80y vs ≥80y suggesting systemic PD does not fully account for inferior PFS and OS in ≥80y.

Disclosures
Eyre: Janssen: Consultancy, Other: travel support; Roche: Consultancy; Abbvie: Consultancy, Other: travel support; Gilead: Consultancy, Other: travel support; Celgene: Other: travel support. Fox:Celgene: Consultancy, Other: Travel, Speakers Bureau; Sunesis: Consultancy; Abbvie: Consultancy, Other: Travel, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel, Speakers Bureau; Gilead: Consultancy, Other: Travel, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Travel, Research Funding, Speakers Bureau. McMillan:Celgene: Honoraria, Other: travel support; BMS: Honoraria; Amgen: Honoraria; Takeda: Other: travel support; Roche: Consultancy, Honoraria, Other: travel support; Pfizer: Research Funding; MSD: Honoraria. Bishton:Abbvie: Research Funding; Roche: Research Funding; Takeda: Other: travel support to ASH; Gilead: Research Funding. Collins:Celleron: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Celgene Corporation: Research Funding; MSD: Consultancy, Honoraria; Amgen: Research Funding; Pfizer: Consultancy, Honoraria.