P019 | EFFICACY AND SAFETY OF IBRUTINIB IN RELAPSED OR REFRACTORY MARGINAL ZONE LYMPHOMAS: THE “REAL WORLD” ITALIAN EXPERIENCE

Ibrutinib was the first FDA-approved drug for patients (pts) with relapsed or refractory (R/R) marginal zone lymphomas (MZL), based on a phase 2 trial (Noy 2021). However, few real-world data on ibrutinib or other BTK inhibitors are available. From November 20 to January 24, ibrutinib was accessible in Italy to treat R/R MZL under Law 648/96. We conducted a retrospective multicenter study to evaluate the efficacy and safety of ibrutinib administered until progression or unacceptable toxicity in pts with R/R MZL of either splenic, nodal, extranodal, or disseminated subtype (SMZL, NMZL, EMZL, dissMZL). The study was approved by the IRB of the 21 participating centers, and all pts signed informed consent. The primary endpoints were ORR and PFS. Patients who switched to zanubrutinib treatment after approval were censored. We enrolled 94 pts (54 males), including 55 SMZL, 17 NMZL, 16 EMZL, and 6 dissMZL. Median age was 74 years (30-89). Median number of prior therapies was 1 (1-5). 87% received at least 1 prior immuno-chemotherapy regimen (BR in 73%). Median duration of drug exposure was 14.5 mo. ORR was 76%, including 12 pts (13%) achieving a complete response (CR) and 59 (63%) a partial response (PR). Median time to initial response was 3.8 months (mo). At a median follow-up of 23.8 mo, 49 pts progressed. Median PFS was 22.5 mo (95% CI 15.6-38.4, Fig.1), while median duration of response was 34.1 mo (95% CI, 28.0-NR). In multivariate analysis, pre-ibrutinib ECOG ≥2 (HR 2.64, p=0.01), elevated LDH (HR 3.25, p<0.01), and NMZL/dissMZL subtypes (HR 3.28, p<0.01) were associated with a worse PFS. Interestingly, pre-ibrutinib MZL-IPI (Arcaini 2024) significantly predicted distinct PFS (p<0.01). Overall, 82 pts (87%) discontinued ibrutinib, including 16 for adverse events (AEs), 32 for progressive disease (PD), and 34 for switch to zanubrutinib. Grade (Gr) 3-4 hematologic and extra-hematologic AEs were reported in 16% and 20% of pts, respectively. The most common AEs were atrial fibrillation (7%), bleeding (7%), and infections (21%), which included 8 Gr 5 events. Histologic transformation was detected in 11% of pts. A new therapy after BTKi failure was initiated in 35 pts, resulting in CR/PR in 24. Overall, 24 pts died (12 due to PD, 11 infections, 1 suicide), with a 36-mo overall survival of 74.5%. Our data confirmed that ibrutinib is associated with high ORR and durable disease control in R/R MZL in real life. Careful attention to infectious toxicity is advised.