254 | RITUXIMAB AND IBRUTINIB COMBINATION IN UNTREATED SMZL AND NMZL: LONG‐TERM OUTCOME AND THE IMPACT OF EARLY MINIMAL RESIDUAL DISEASE FROM THE IELSG47/MALIBU PHASE II STUDY

Introduction: BTK inhibitors have shown durable responses with a favorable benefit-risk profile for all MZL subtypes in the relapsed setting. The IELSG47/MALIBU phase II trial is exploring the efficacy and safety of rituximab plus ibrutinib in untreated MZL. We report here the long-term outcomes and the impact of early minimal residual disease. Methods: Treatment included 8 rituximab doses (the first 4 weekly and the subsequent 4 monthly, all but the first given subcutaneously) in combination with ibrutinib (560 mg once daily) for 2 years. Response evaluation was planned at 6, 24 weeks, and 12, 18, and 24 months after treatment start and was performed using Matutes criteria in SMZL and Lugano Classification in NMZL. The MRD analysis was investigated on a subset of SMZL centrally in a EuroMRD standardized laboratory in the bone marrow and peripheral blood samples at different time points (end of induction, 12mo, and 24mo). Results: Between October 2019 and June 2021, 45 pts (30 with SMZL and 15 with NMZL) were enrolled. Median age was 68 years (range: 44–81), 17 pts were male (38%), 41 pts had stage IV (91%), and 17 had elevated LDH (38%). All SMZL and 9 (60%) NMZL pts had bone marrow involvement. With a median follow-up at 41 months (mo), response at 12 mo was available for 35/45 patients (78%), including 25/30 SMZL (83%) and 10/15 NMZL (67%). 12-mo overall response rate was 94% including 54% in complete response (CR), including 11 SMZL (44%) and 8 NMZL (80%) and 40% in partial response (PR), including 13 (52%) SMZL and 1 NMZL (10%). Only 1 patient (3%) from the NMZL cohort had disease progression. The median time to best response was 2.38 mo (1.1–24.1). Fourteen pts relapsed (6 SMZL and 8 NMZL) with a median duration of response of 45.6 mo (22.7-NE) in the entire cohort, 45.6 (45.6-NE) for SMZL cohort and 23 (12-NE) for the NMZL cohort (HR, 3.07 (95% CI: 0.97–9.67), p = 0.0441). Median progression-free survival (PFS) was 47.2 mo (34.4-NE) in the SMZL cohort and 24.8 mo (7.34-NE) in the NMZL cohort (p = 0.020). Five patients died, none due to lymphoma progression (causes of death included SARS-CoV2 infection, ischemic stroke, car accident, suicide, and acute lymphoblastic leukemia respectively). No unexpected adverse events were observed with more follow-up than previously reported at ICML 2023. The undetectable minimal residual disease (MRD) rate in blood samples from the 13 available SMZL patients was 20% at the end of induction (D45-D56), 84.6% (11/13) at month 6, 75% (9/12) at month 12, and 42% (5/12) at month 24. MRD negativity in bone marrow samples was observed in 2/7 samples (28%) at month 12 and 0/5 samples (0%) at month 24. Clinical correlation will be presented. Conclusion: Rituximab plus ibrutinib shows promising long-term efficacy and safety in untreated MZL, with high overall response rates. Informative results come from the MRD analysis, which will be correlated with the clinical outcome. Research funding declaration: The research was supported partially by Janssen (financial and drug supply) and Roche (drug supply). Keywords: extranodal non-Hodgkin lymphoma Potential sources of conflict of interest: C. Thieblemont Honoraria: Abbvie, BMS, Novartis, Roche, Incyte M. Merli Consultant or advisory role: Regeneron Inc., Eli Lilly Educational grants: Roche, Jonhson & Jonhson L. Arcaini Consultant or advisory role: Roche, Janssen-Cilag, Verastem, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics, Novartis (Participation on a Data Safety Monitoring Board or Advisory Board) Honoraria: EUSA Pharma, Novartis, Kite, Beigene (Speaker Bureau) Educational grants: Roche E. Zucca Consultant or advisory role: AbbVie, BeiGene, BMS, Curis, Eli/Lilly, Incyte, Ipsen, Merck, Roche, Sobi Honoraria: Medical educational event AbbVie Educational grants: AstraZeneca, BeiGene, Janssen, Gilead Other remuneration: Research support (Institution) from AstraZeneca, Beigene, Celgene/BMS, Incyte, Janssen, and Roche A. Conconi Consultant or advisory role: Roche Honoraria: Janssen Educational grants: Janssen