Time from diagnosis to 2nd treatment is a promising surrogate for overall survival in patients with advanced stage follicular lymphoma

Introduction: It is difficult to demonstrate an overall survival (OS) benefit in trials of early therapy vs observation in asymptomatic patients (pts) with follicular lymphoma (FL) who do not meet established criteria for treatment. Time to New Treatment (TTNT) is difficult to interpret. Time from diagnosis to 2nd treatment (TD2T) is potentially a preferable endpoint that balances exposure to therapy. We hypothesize that TD2T might be a surrogate for OS. Methods: We identified 584 consecutive pts at our institution, diagnosed 1998–2007 with advanced stage FL grade 1–3A for whom intention was observation (n = 248) or therapy (n = 338). Median time to 1st treatment (TT1T), TD2T, TTNT, and OS were estimated using the subdistribution function, and modified Kendall's tau (mK) was used to assess correlation between survival endpoints. We performed landmark analyses and compared OS to the age/sex-matched US population using a standardized mortality ratio (SMR) method. Results: At a median follow-up of 10.4 years (yrs), pts who were initially observed have a median TT1T of 3.6 yrs and TD2T of 13.1 yrs, and 10-yr treatment-free survival of 25%. The 10-yr OS is 84%. The observed mortality exceeds the general population (SMR 1.56, p = 0.002). TD2T is strongly correlated with OS with initial observation (mK 0.46, p = 0.004) or therapy (mK 0.53, p < 0.0001), but TT1T is not. Among observed pts, TD2T <5 yrs is associated with inferior survival (p = 0.03) and increased mortality relative to the general population (SMR 3.91, p < 0.001). Pts who require immediate therapy have an inferior OS (HR 0.7, p = 0.047) and corresponding inferior TD2T (HR 0.6, p < 0.0001) compared with those who are observed (expected in this retrospective analysis due to confounding by indication), but a comparison of TTNT is misleading and suggests better outcomes (HR 1.5, p < 0.0001). Conclusion: The outstanding expected survival in pts with advanced stage FL grade 1–3A who are initially observed supports an active surveillance approach in appropriately selected pts, and future trials might restrict eligibility to high-risk pts expected to have inferior survival. Use of TTNT or PFS in trials of early therapy vs observation can be misleading, while TD2T is potentially a preferable endpoint that balances exposure to therapy. TD2T is strongly correlated with OS, while the duration of initial observation is not. TD2T is therefore a potential surrogate for OS, although more is needed to rigorously establish surrogacy. Keywords: follicular lymphoma (FL).