Clinical outcomes in patients relapsed/refractory after ≥2 prior lines of therapy for follicular lymphoma: a systematic literature review and meta-analysis.

BACKGROUND: Patients with follicular lymphoma (FL) can have high response rates to early lines of treatment. However, among FL patients relapsed/refractory (r/r) after ≥2 prior lines of therapy (LOT), remission tends to be shorter and there is limited treatment guidance. This study sought to evaluate the clinical outcomes for r/r FL after ≥2 prior LOT identified through systematic literature review. METHODS: Eligible studies included comparative or non-comparative interventional or observational studies of systemic therapies among adults with FL r/r after ≥2 prior LOT published prior to 31st May 2021. Prior LOT must have included an anti-CD20 monoclonal antibody and an alkylating agent, in combination or separately. Overall response rate (ORR) and complete response (CR) were estimated using inverse-variance weighting with Freeman-Tukey double-arcsine transformations. Kaplan-Meier (KM) curves for progression-free survival (PFS) and overall survival (OS) estimated by reconstructing digitized curves using the Guyot algorithm, and survival analyses were conducted, stratified by ≥2 prior LOT and ≥ 3 prior LOT groups (as defined in the source material). Restricting the analyses to the observational cohorts was investigated as a sensitivity analysis. RESULTS: The analysis-set included 20 studies published between 2014 and 2021. Studies were primarily US and/or European based, with the few exceptions using treatments approved in US/Europe. The estimated ORR was 58.47% (95% confidence interval [CI]: 51.13-65.62) and proportion of patients with CR was 19.63% (95% CI: 15.02-24.68). The median OS among those ≥2 prior LOT was 56.57 months (95% CI: 47.8-68.78) and median PFS was 9.78 months (95% CI: 9.01-10.63). The 24-month OS decreased from 66.50% in the ≥2 prior LOT group to 59.51% in the ≥3 prior LOT group, with a similar trend in PFS at 24-month (28.42% vs 24.13%). CONCLUSIONS: This study found that few r/r FL patients with ≥2 prior LOT achieve CR, and despite some benefit, approximately 1/3 of treated patients die within 24 months. The shorter median PFS with increasing prior LOT suggest treatment durability is suboptimal in later LOT. These findings indicate that patients are underserved by treatments currently available in the US and Europe.

Validity of event-free survival as a surrogate endpoint in haematological malignancy: Review of the literature and health technology assessments.

OBJECTIVE: Event-free survival (EFS) is increasingly used as a primary endpoint in trials of haematological malignancies (HMs). A key consideration is whether EFS can reliably predict survival. METHODS: We conducted a review of the scientific literature and health technology assessments to evaluate evidence for EFS-OS surrogacy in HMs and acceptability of EFS by payers. RESULTS: Evidence of surrogacy varies by indication and line of therapy. In first-line AML, EFS is highly correlated with OS at the trial-level supporting its use as an early endpoint for traditional approval of treatments with curative intent. Surrogacy was also demonstrated in first-line DLBCL but remains unexplored in relapsed/refractory setting where post-transplant EFS24 was not prognostic of survival. In first-line FL, PTCL, T-LBL, and MCL, EFS24 is prognostic of survival but trial-level surrogacy has not yet been evaluated. CONCLUSION: Strong EFS-OS correlation required for surrogacy may only be achievable in HMs with treatments characterised by high rates of durable remissions. Nevertheless, EFS24 is associated with favourable outcomes and remains a clinically meaningful endpoint in HMs.