IBRUTINIB DOSE MODIFICATION IN MANTLE CELL LYMPHOMA: AN ITALIAN REAL‐LIFE MULTICENTER EXPERIENCE. RESULTS FROM THE REDOT_MCL STUDY

Introduction: Although BTK inhibitors (BTKi) have reshaped the therapeutic algorithm of lymphoproliferative diseases, class-specific toxicities such as bleeding, atrial fibrillation and cytopenia have emerged. Dose modification (DM) is often attempted to mitigate these adverse events (AEs), particularly with ibrutinib, the first-in-class BTKi approved for relapsed/refractory (R/R) mantle cell lymphoma (MCL). The impact of ibrutinib DM has not been specifically evaluated in MCL. The REDOT study aimed to describe ibrutinib DM (reduction/interruption/discontinuation) in R/R MCL from 14 Italian centers, evaluating DM impact on AEs, responses and outcomes. Methods: We assessed DM rate in a real-life series of consecutive MCL patients who started ibrutinib between 2016 and 2023. We calculated single patient’s relative cumulative ibrutinib dose as a percentage of the 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% of expected dose). We evaluated ibrutinib-related AEs, change in responses, progression free survival (PFS), overall survival (OS) and time to next treatment (TTNT) between groups. Results: Our cohort included 226 MCL patients. Median age at ibrutinib start was 73 years, with 74% of patients receiving ibrutinib as second line. Overall, 34% of patients started ibrutinib at reduced dose, in most cases (67%) due to clinician’s choice (age, comorbidities), followed by concomitant therapies (16%), cytopenia (9%) or unknown reason (9%). Forty-four percent 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, mainly due to AEs (65% of interruptions). Thirty-five percent of interruptions were due to surgical procedures or patient choice. Sixty-five percent of patients permanently discontinued ibrutinib due to progressive disease (70%), AEs or other reasons (15% each) including allogeneic stem cell transplant. Overall, 54% and 15% of patients were grouped into DL1a and 1b, 22% and 9% into DL2a and 2b, respectively. No statistically 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 statistically 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). Conclusions: This is the first report evaluating ibrutinib DM in MCL in a real-life setting. We showed higher DM rates than in clinical trials, probably due to advanced age and number of comorbidities. Ibrutinib dose did not significantly impact responses and outcomes. Therefore, DM is a viable strategy especially for elderly MCL patients with comorbidities or drug-related AEs.