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

Ba ac ck kg gr ro ou un nd d In recent years, BTK inhibitors (BTKi) have reshaped the therapeutical algorithm of lymphoproliferative diseases. However, BTKi are characterized by class-specific toxicities such as bleeding, atrial fibrillation, and cytopenia. Dose modification (DM) is often attempted to mitigate these side effects, particularly with ibrutinib – the first-in-class BTKi approved for relapsed/refractory (R/R) MCL - due to a higher incidence of adverse events (AEs). The impact of ibrutinib DM on clinical efficacy has not yet been specifically evaluated in MCL. A Ai im ms s The REDOT_MCL study aimed to describe ibrutinib DM (reduction, interruption or permanent discontinuation) in R/R MCL patients from 14 Centers of Fondazione Italiana Linfomi (FIL). Furthermore, we evaluated DM impact on toxicity, response to treatment, and outcomes. M Me et th ho od ds s We collected clinical data from a real-life series of MCL patients who started ibrutinib between 2016 and 2023. We assessed the rate of DM, and to quantify DM regardless of the type and number, we calculated the relative cumulative ibrutinib dose for each patient as a percentage of the expected theoretical full dose during the entire treatment period. Patients were grouped into four dose levels (DL1a: 95-100%, DL1b: 75-94%, DL2a: 50-74%, DL2b: <50% of expected dose). We evaluated ibrutinib-related AEs, changes in response, and outcomes (PFS, OS, TTNT) in each group. Results Our cohort included 226 MCL (median age at diagnosis 69y, M:F 3:1, 93% advanced stage). Median age at ibrutinib start was 73y, with 74% of patients receiving ibrutinib as second line treatment. Overall, 34% of patients started ibrutinib at reduced dose, in the majority of the cases (67%) due to clinician’s choice (advanced age, comorbidities), followed by concomitant therapies (16%), cytopenia (9%) or unknown reasons (9%). Concerning dose reductions, 44% of patients reduced ibrutinib dose either at the beginning or during treatment. The 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 all interruptions). Thirty-five percent of interruptions were caused by surgical procedures or patient choice. Sixty-five percent of patients permanently discontinued ibrutinib, mainly due to progressive disease (70%), AEs or other reasons (15% each), including allo-SCT. Overall, 121 patients (54%) were grouped into DL1a, 35 (15%) into DL1b, 49 (22%) into DL2a, and only 21 (9%) into DL2b. No statistically significant differences in response rates emerged between the 4 DL groups (p=0.516) (Figure 1A). We showed similar 3-year PFS in the four DLs (DL1a 25%, DL1b 40%, DL2a 30%, DL2b 36%, p=0.426) (Figure 1B). Accordingly, there were no statistically significant differences in the 3-year OS in the 4 DLs (DL1a 42%, DL1b 45%, DL2a 37%, DL2b 51%, p=0.657). Contrarily, regarding TTNT, patients in DL2b tend to stay in treatment longer than those who take higher doses (p=0.058). Summary/Conclusion This is the first report evaluating ibrutinib DM and its consequences on outcome in MCL. We reported a higher DM rate than in clinical trials, probably due to advanced age and a high number of comorbidities of our real-life patients. In conclusion, we showed that the ibrutinib dose did not significantly impact responses to treatment and outcome. Therefore, DM is a viable strategy especially for elderly MCL patients with comorbidities or with drug-related AEs.