Early Complete Response as Validated Surrogate Marker in Extranodal Marginal Zone Lymphoma Systemic Therapy.

Extranodal marginal zone lymphoma (EMZL) has a very indolent course, and the validation of surrogate markers could accelerate novel therapies. Although prognostic markers do exist, no surrogate markers have been validated in EMZL. We hypothesized that time to complete response within 24 months (TTCR24) and complete response at 24 months (CR24) could be valid surrogate markers of progression-free survival (PFS). The IELSG19 phase 3 trial showed the advantage of double therapy (rituximab-chlorambucil) over single therapy (rituximab or chlorambucil) on PFS. We used two recently published single-trial approaches to assess whether TTCR24 and CR24 were good surrogate markers of 8-year PFS (8y-PFS). Among the 401 patients, 264 (66%) reached a CR in the first 24 months, of which 222 (84%) remained in CR at M24. The cumulative incidence of CR over time was significantly higher in patients under double therapy (HR = 1.75, p < 0.001). The double therapy arm was associated with a higher CR24 rate, a shorter TTCR24 and a longer 8y-PFS. The estimated proportion of treatment effect on 8y-PFS explained by TTCR24 was 95% (95%CI: 0.27,1.87). CR24 was also a strong surrogate marker as it mediated 90% (95%CI: 0.51,2.22) of the treatment effect on PFS and its natural indirect effect was significant throughout the follow-up. We found that TTCR24 predicted 95% and that CR24 mediated 90% of the treatment effect on long-term PFS. Therefore, TTCR24 and CR24 could be used in clinical trials as informative and valid early indicators of treatment effect on PFS. CT#: NCT00210353.