S221: long-term results of the fil mcl0208 trial comparing lenalidomide maintenance (len) vs observation (obs) after autologous stem cell transplantation (asct) in mantle cell lymphoma (mcl)

Background: The FILMCL0208 (NCT02354313) international randomized, phase III study compared LEN for two years (yrs) vs OBS after an intensive Ara-c containing program (R-HDS) followed by ASCT in young (<65yrs) untreated MCL. The primary endpoint was progression free survival (PFS) with positive results at the pre-planned evaluation (Ladetto, Lancet Haem 2021). The trial included a large minimal residual disease (MRD) sub-study whose early results underscored the high prognostic value of both punctual and kinetic MRD analysis (Ferrero, Blood 2022). Aims: We here provide long-term clinical and molecular results at a median follow-up (mFU) of 84 months (M) from enrolment and 74M from randomization, including four additional late MRD time points (M18, M24, M30, M36). Methods: Pts (aged18-65yrs) with advanced MCL and without clinically significant comorbidities were enrolled. From May 2008 to Aug 2015, 300 pts were enrolled (median age 57 yrs; 235 [78%] male). 205(68%) pts were randomly assigned (104 pts to LEN and 101 pts to OBS). Additional protocol details and results have been described elsewhere (Ladetto, Lancet Haem.2021) as well as tissues, time points and experimental strategy for MRD analysis (Ferrero, Blood 2022). Results: At 84M from enrolment, 72M-PFS and overall survival (OS) for the enrolled population were 48% (42-54) and 75% (70-80), respectively. In the randomized population we observed 72M-PFS of 55% (44-65) in LEN vs 50% (39-60) in OBS with a HR of 0.76(0.50-1.13; P =0.175) (Fig 1A). Time-varying effect modelling showed a PFS advantage in favor of LEN up to 36 and 42 M (HR0.58,0.33-1.00; P=0.047 and HR 0.57,0.33-0.96; P=0.0314, respectively). However, a subsequent decrease of PFS benefit was noticed in the subsequent FU after 36 and 42M (respectively: HR1.07,0.58-1.96;P=0.83 and HR 1.21,0.62-2.35;P= 0.57). Indeed, in LEN, the monthly PFS hazard rate in the first 24M post randomization (when LEN was administered) was in the 0.5%-0.7% range, but then progressively narrowed (0.7%-0.95% from 24M to 36M), and finally became superimposable in the two arms (around 1% from 36M to 60M) (Fig 1B). No long-term 72M-OS difference was observed [77% (66-85) in LEN vs 75% (64-83) in OBS; P= 0.819]. At 60M, cumulative incidences of secondary tumors were 9.4% (3.1-15.6) in LEN vs 4.5% (0.1-8.8) in OBS, with a MIPI-adjusted HR of 1.98 (0.67-5.87; P=0.219). Subgroup analysis for PFS including gender, age, MIPI, systemic symptoms, bulky disease> 5 cm, elevated Ki67 and stratification data showed only Bone Marrow (BM) negativity as favoring LEN to OBS. 824 BM and 799 Peripheral Blood (PB) were collected during induction/consolidation phase and every 6M during FU (from M6 to M36). Our updated results showed: a) persistent increased risk of progression after a positive MRD result both in BM (HR=4.17,2.70-6.44) and PB (HR=2.64,1.69-4.12); b) persistent stability over time of kinetic models based on accumulation of MRD-negative (MRD-neg) results. With three BM MRD-neg results the HR for time to progression (TTP) compared with MRD-positive was 0.13 (0.07-0.24) while it was 0.19 (0.10-0.34) with three PB MRD-neg results. Moreover, the same parameters appeared predictive for OS with a HR 0.35 (0.16-0.73) for BM and 0.42 (0.19-0.90) for PB; c) a high prognostic value on TTP in both BM and PB by RQ-PCR during follow-up with excellent performance of previously unreported late time points (Fig 1C). Summary/Conclusion: The two-year LEN program provided an early PFS benefit, which was not maintained once LEN was interrupted with no OS advantage. Long-term MRD results stress the predictive value of this tool, particularly in the context of kinetic model.Keywords: Clinical trial, Mantle cell lymphoma, Minimal residual disease (MRD), Maintenance