Evaluation of Participation and Recruitment Bias in a Prospective Real-Life Multicentric Cohort « Real World Data in Lymphoma and Survival in Adults » (REALYSA study) for Newly Diagnosed Lymphoma Patients over One Year in a Hematology Department of Teaching Hospital

Background: Enrollment in clinical trials is a key objective to improve the development of new treatment strategies but patients participation is less than 10%. Besides randomized and interventional studies, there is an important development of observational studies based on real-world data (RWD). Prospective real-life multicentric cohorts are set-up to overcome the limits of clinical trials in terms of population representativity and results generalizability. However, determinants that influence patient's participation to these programs are not well known. We investigated the reasons of non-inclusion in REALYSA study, over one year at a single institution to better understand participation bias in this program.

Methods: REALYSA study is a prospective real-life multicentric cohort set up in 35 hematology departments in France to study the prognostic value of epidemiological, clinical and biological factors with a prospective 9-year follow-up (NCT03869619). Adult patients with newly diagnosed diffuse large B-cell (DLBCL), follicular (FL), marginal zone (MZL), mantle cell (MCL), Burkitt, Hodgkin (HL), mature T-cell lymphoma are invited to participate by their hematologist. Exclusion criteria are: having already received anti-lymphoma treatment (except pre-phase) and having a HIV infection. We described the probability of REALYSA participation among these seven newly diagnosed lymphoma subtypes who are managed at the Department of Hematology, Lyon Sud Hospital, France between 11/01/2018 and 11/30/2019 using REALYSA and the institutional database. Generalised Additive models (GAMs) with a logit link function were used, and we modelled the continuous covariates using penalised splines. For categorical covariates, we reported the Odds Ratio (OR) of REALYSA enrollment in a forest plot, and for continuous covariates we predicted and displayed the probability of REALYSA participation. On the subpopulation of DLBCL patients we replicated the analysis using the GAM described above. We also estimated the event-free survival (EFS) according to REALYSA participation for DLBCL. For the EFS, the event was defined as either a new treatment line, a progression or death, whichever occurred first.

Results: Among the 278 patients fulfilling the eligibility criteria of REALYSA, 159 (57%) were male; median age at diagnosis was 64 years (range, 18-96); 104 (37%) patients were diagnosed with DLBCL, 56 FL (20%), 46 HL (17%), 35 MZL (13%), 19 T-cell lymphoma (7%), 16 MCL (6%), and 2 with Burkitt lymphoma. Curative treatment intent was decided for 251 (90%) patients, "watch and wait" strategy for 19 (7%) and supportive care for 8 (3%) patients. Among all patients, 151 (54%) were included in REALYSA program and 27 (10%) were included in an interventional clinical trial. The median inclusion rate by month was 55% (min: 37% - max: 74%). Among non-included patients, 39 (31%) refused to participate; for 20 patients (16%) treatment was started in emergency; for 12 patients (9%) the clinician judged inclusion not feasible; for 56 patients (44%), the reason was unknown. Figure 1A showed the OR of REALYSA enrollment with higher probability of inclusion for advanced Ann Arbor stage (OR=2.06; 95%CI, 0.98-4.31) and patients treated with curative intent (OR=4.98; 95%CI, 1.54-16.14). Interestingly, the analyses for continuous variables showed the trend for a lower probability of inclusion for older patients and patients with hypoalbuminemia and the trend for a higher probability of enrollment for patients who lived in semi-rural area (distance from residence to hospital 30-80 km) (Figure 1B). In subgroup analysis for DLBCL patients with a curative intent (n=100), we observed similar results. The event-free survival according to REALYSA participation was 50% (95%CI, 35-70) for those not included vs. 61% (95%CI, 50-76) for those included (p=0.32).

Conclusions: REALYSA program presents an enrollment rate of 54% in the studied department, higher than clinical trial inclusion rate. Clinicians tend to include more frequently lymphoma patients with advanced stage and those in curative intent (vs. palliative/surveillance). This study is the first step to better understand recruitment bias in a real-world program to ensure generalizability of findings. This type of comparative study should be extended to a larger period and to other centers to have a better comprehensive understanding of the reasons of non-participation.

Sesques:Chugai, Novartis, and Kite/Gilead: Research Funding. Karlin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial Support travel & scientific meetings; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial Support travel & scientific meetings; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Salles:Roche/Genentech, Gilead Sciences, Janssen, Celgene, Novartis, MorphoSys AG, Epizyme, Alimera Sciences, Genmab, Debiopharm Group, Velosbio, Bristol-Myers Squibb, BeiGene, Incyte, Miltenyi Biotec, Ipsen, Kite, a Gilead Company, Loxo, Rapt: Consultancy; Roche/Genentech, Janssen, Celgene, Gilead Sciences, Novartis, AbbVie, MorphoSys AG, Amgen, Bayer, Epizyme, Regeneron, Kite, a Gilead Company: Honoraria; AbbVie, BeiGene, Bristol Myers Squibb, Celgene, Debiopharm, Epizyme, Genentech/Roche, Genmab, Incyte, Kite, a Gilead Company, Miltenyi, MorphoSys, Takeda, and VelosBio: Membership on an entity's Board of Directors or advisory committees. Bachy:Roche, Gilead, ADC Therapeutics, Takeda, Novartis, Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen, BMS: Research Funding; Kite, Gilead, Novartis, Roche, Incyte, Miltenyi Biotech, Takeda, Sanofi: Honoraria; Hospices Civils de Lyon: Current Employment. Ghesquieres:Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; BMS: Honoraria; Abbvie: Honoraria.