IBRUTINIB DOSE MODIFICATION IN MANTLE CELL LYM- PHOMA: AN ITALIAN REAL-LIFE MULTICENTER EXPERIENCE. RESULTS FROM THE REDOT_MCL STUDY

BTK inhibitors (BTKi) have reshaped the therapeutic algorithm of lymphoproliferative diseases, but class-specific adverse events (AEs) such as bleeding, atrial fibrillation and cytopenia emerged. Dose modi- fication (DM) is often attempted to mitigate AEs, particularly with ibru- tinib, the first BTKi approved for relapsed/refractory (R/R) mantle cell lymphoma (MCL). The REDOT study described ibrutinib DM in R/R MCL from 14 Italian centers, evaluating DM impact on outcomes. We assessed DM rate in a real-life series of MCL patients who started ibru- tinib between 2016 and 2023. We calculated single patient’s relative cu- mulative ibrutinib dose as a percentage of expected full dose during the entire treatment period. Patients were grouped into 4 dose levels (DL1a 95-100%, DL1b 75-94%, DL2a 50-74%, DL2b <50%). We evaluated ibrutinib-related AEs, changes in response and PFS/OS/TTNT between groups. We included 226 consecutive patients with median age 73 years at ibrutinib start. Overall, 34% of patients started ibrutinib at reduced dose, in most cases (67%) due to age or comorbidities, concomitant ther- apies (16%), cytopenia (9%) or unknown reason (9%). Forty-four per- cent of patients reduced ibrutinib either at start or during treatment. Median time to first reduction was 5 months. In 73% of cases reductions were caused by AEs. Thirty-five percent of patients interrupted ibrutinib, due to AEs (65% of interruptions), surgical procedures or patient choice (35%). Sixty-five percent of patients permanently discontinued ibrutinib due to progressive disease (70%), AEs or other reasons (15% each) in- cluding allo-SCT. Overall, 54% and 15% of patients were grouped into DL1a and 1b, 22% and 9% into DL2a and 2b, respectively. No statisti- cally significant difference in response rates emerged between the 4 DLs (p=0.516; Figure 1A). We showed similar 3y-PFS (DL1a 25%, 1b 40%, 2a 30%, 2b 36%, p=0.426; Figure 1B). Accordingly, there was no statis- tically significant difference in 3y-OS (DL1a 42%, 1b 45%, 2a 37%, 2b 51%, p=0.657). Contrarily regarding TTNT, DL2b patients tended to stay in treatment longer than those who took higher doses (p=0.058). This is the first report evaluating ibrutinib DM in a real-life MCL setting. We showed higher DM rates than in clinical trials, probably due to advanced age and comorbidities. Since ibrutinib dose did not signifi- cantly impact responses and outcomes, DM is a viable strategy especially for elderly MCL patients with comorbidities or drug-related AEs.