Diagnosis-to-Treatment Interval Is an Important Clinical Factor in Newly Diagnosed Diffuse Large B-Cell Lymphoma and Has Implication for Bias in Clinical Trials

Abstract

Purpose Selection bias in clinical trials has consequences for scientific validity and applicability of study results to the general population. There is concern that patients with clinically aggressive disease may not have enrolled in recent diffuse large B-cell lymphoma (DLBCL) trials due to the consent process and the inability to delay therapy for eligibility evaluation. We have examined the diagnosis-to-treatment interval (DTI) and its association with clinical factors and outcome in a clinic-based observational cohort of patients with DLBCL from the United States. Validation of results was performed in an independent, clinical trial-based cohort from Europe. Patients and Methods Patients were prospectively enrolled in the University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource (MER; N = 986) or the Lymphoma Study Association (LYSA) LNH-2003 clinical trials program (N = 1,444). All patients received anthracycline-based immunochemotherapy at initial diagnosis. Associations of DTI with clinical factors and outcome were examined. Outcome was assessed using event-free survival at 24 months from diagnosis (EFS24). Results Median (range) DTI was 15 days (0 to 155 days in the MER and 23 days (0 to 215 days) in LYSA. Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B symptoms, and higher International Prognostic Index in both cohorts (all P < .001). Longer DTI was associated with improved EFS24 in both the MER (per-week odds ratio, 0.80; 95% CI, 0.74 to .0.87) and LYSA (per-week odds ratio, 0.90; 95% CI, 0.86 to 0.94); association with EFS24 remained significant after adjustment for International Prognostic Index. Conclusion DTI is strongly associated with prognostic clinical factors and outcome in newly diagnosed DLBCL. DTI should be reported in all clinical trials of newly diagnosed DLBCL and future trials should take steps to avoid selection bias due to treatment delay.

Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non–Germinal Center B-Cell Diffuse Large B-Cell Lymphoma

“…Therefore, the outcome in the overall population was better than anticipated, suggesting an enrollment bias toward more physically fit patients and patients with better prognosis, a common observation in clinical studies. 26 Despite the optimal outcome in the entire non-GCB DLBCL population, an improvement in younger patients was observed for ibrutinib plus R-CHOP. Ibrutinib plus R-CHOP was associated with treatment benefit in most subgroups, except for patients from the United States and Western Europe, but the event number was too small to draw any conclusions.…”

Predictive value of interim positron emission tomography in diffuse large B-cell lymphoma: a systematic review and meta-analysis

“…Some studies started their follow-up period at the time from diagnosis and others from initiation of first-line treatment. Recently some data has shown that patients who have a more aggressive disease tend to be treated earlier, so there could be selection bias between studies that have a shorter period between time of diagnosis and initiation of treatment versus studies with a longer period [ 54 ]. For future studies it seems important to have a comparable start of the follow-up period and authors should report the interval between diagnosis and start of the treatment to prevent or adjust for this risk of bias.…”

Minimal relapse risk and early normalization of survival for patients with Burkitt lymphoma treated with intensive immunochemotherapy: an international study of 264 real‐world patients

“…However, intensive multidrug chemotherapy protocols are associated with risk of life‐threatening acute toxicities and late complications (Oeffinger et al , ; Barnes et al , ; Corazzelli et al , ; Hoelzer et al , ; Ribrag et al , ). Additionally, the favourable results seen in clinical trials using such treatment protocols do not necessarily apply to the broad population of patients in the routine clinical setting, who may be older, frailer, or have urgent need for treatment excluding them from trial inclusion (Maurer et al , ).…”