Background: The addition of CD20 antibodies (rituximab) to CHOP(-like) chemotherapy has been the single most important progress in the treatment of diffuse large B-cell lymphoma (DLBCL) for decades. Clinical studies suggested more pronounced outcome improvements following immuno-chemotherapy in female DLBCL as compared to male patients, which was supported by pharmacokinetic studies showing faster clearance of rituximab in elderly male patients.
Aims: To explore gender-specific differences in DLBCL outcome in a population-based setting and to estimate the gender-specific improvements in relative survival seen with the introduction of immuno-chemotherapy for DLBCL.
Patients and Methods: The study was based on the nationwide Danish lymphoma registry (LYFO), which contains detailed information on lymphoma patients treated at Danish hematology departments. Patients diagnosed in the period 2000-2014 and treated upfront with CHOP or CHOP-like therapy were analyzed according to the use of rituximab or not. During the surveyed time period, rituximab was given intravenously at a dose of 375mg/m2 synchronously with CHOP(-like) chemotherapy. A relative survival approach was applied using flexible parametric survival models (1) in which the expected mortality was given by age-, sex-, and year-matched lifetables from Statistics Denmark. The overall effect of rituximab was estimated by a model with two levels (rituximab, R+ vs. no rituximab, R-) and five degrees of freedom for the baseline excess hazard; based on this model 0-5 years relative survival and excess hazard ratio (EHR) were estimated. Gender-specific outcome improvements were estimated by expanding the model with gender as an effect modification of rituximab. The life-year gain attributable to rituximab in the first five years after diagnosis was estimated by the differences in loss in expectation of life (2) for male and female DLBCL patients treated with or without rituximab. All analyses were performed using Stata (StataCorp. 2015. Stata Statistical Software: Release 14 . College Station, TX: StataCorp LP).
Results: In total, 4,368 DLBCL patients were included (3,321 in the R+ group and 1,047 in the R- group). Patient characteristics, treatment information, complete remission rates, and 5-year overall survival (OS) estimates are shown in Table 1. Men treated with rituximab were older than men without rituximab treatment suggesting a shift over time toward more intensive treatment for elderly. For both women and men the following was seen: higher Ann Arbor stage, higher R-IPI risk group, higher proportion of patients in CR, and longer 5-year OS when comparing patients with vs. without rituximab treatment. Figure 1A shows relative survival curves. Five-year relative survival of DLBCL patients was 67% (95% CI: 63% - 70%) for patients treated without rituximab and 77% (95% CI: 75% - 79%) for patients with rituximab, and the excess hazard ratio (EHR) was 1.47 (1.27 - 1.70) for patients treated without rituximab. Rituximab was also associated with substantial improvements in relative survival for male and female DLCBL patients analyzed separately (figure 1B-C). The gains of lifetime attributed to rituximab in the first 5 years after diagnosis were 0.26 years (95% CI: 0.10 - 0.43) and 0.40 years (95% CI: 0.21 - 0.61) for men and women, respectively. The effect modification of gender on rituximab was not statistically significant (p = 0.236).
Conclusions: In the present study, there was no statistically significant effect modification of gender on rituximab with respect to relative survival. There was a trend toward marginally larger gain in lifetime for women after inclusion of rituximab when compared to men, although this difference was also not statistical significant and may be explained by other factors.
1. Nelson CP, Lambert PC, Squire IB, Jones DR. Flexible parametric models for relative survival, with application in coronary heart disease. Stat Med. 2007 Dec 30;26(30):5486-98.
2. Andersson TM, Dickman PW, Eloranta S, Lambe M, Lambert PC. Estimating the loss in expectation of life due to cancer using flexible parametric survival models. 2013;(November 2012).
Jørgensen: Roche: Research Funding. Poulsen: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Starklint: Roche: Other: Travel funding. El-Galaly: Roche: Other: Travel funding.
Asterisk with author names denotes non-ASH members.