SNPs as Predictive Biomarkers of Lenalidomide Efficacy Among Patients With Mantle Cell Lymphoma

Fondazione Italiana Linfomi (FIL) MCL0208 Phase 3 Trial

According to findings from the phase 3 Fondazione Italiana Linfomi (FIL) MCL0208 trial, certain genetic variations known as single nucleotide polymorphisms (SNPs) represent candidate predictive biomarkers associated with lenalidomide maintenance efficacy as well as immunochemotherapy toxicity among patients with mantle cell lymphoma (MCL) after autologous stem cell transplantation (ASCT).

Within this prospective, multicenter, randomized trial, lenalidomide maintenance after ASCT was found to improve progression-free survival (PFS) vs observation after ASCT in patients with MCL. Simone Ferrero, MD, AOU Città della Salute e della Scienza di Torino, Torino, Italy, and coauthors further analyzed these patients’ pharmacogenetic backgrounds in order to determine whether SNPs could potentially predict toxicity as well as drug efficacy among these patients. 

The trial included 300 patients, aged 18 to 65 years, without clinically significant comorbidities. 93% of these patients (n = 278) with adequate biological samples were included in the pharmacogenetic study, according to the study authors. Samples of germinal DNA were extracted for analysis through the use of commercially available kits. 

Through the analysis of these germinal DNA samples, SNPs of either ABCB1 or VEGF were found in 69% and 79% of 278 patients, respectively, and predicted favorable PFS vs homozygous wild-type in the lenalidomide arm: 3-year PFS 85% vs 70% (p < 0.05) and 85% vs 60% (p < 0.01), respectively. Patients carrying both ABCB1 and VEGF WT had the poorest 3-year PFS (46%) and overall survival ([OS] 76%). Notably, in these patients, lenalidomide did not improve PFS vs observation (3-year PFS 44% vs 60%, p = 0.62). They also found that the CRBN polymorphism (n = 28) was associated with lenalidomide dose reduction or discontinuation. Further, ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, while ABCB1 and CRBN polymorphisms predicted lower risk of grade ≥3 infections. 

Dr Ferrero and coauthors concluded, “This study demonstrates that specific SNPs represent candidate predictive biomarkers of immunochemotherapy toxicity and [lenalidomide] efficacy after ASCT in MCL.” 

Source: 

Ferrero S, Grimaldi D, Arrigoni E, et al. Candidate germline biomarkers of lenalidomide efficacy in mantle cell lymphoma: the FIL MCL0208 trial. Blood Adv. April 14, 2023; doi: 10.1182/bloodadvances.2022009504