Rituximab and ibrutinib combination is safe and effective in untreated splenic and nodal marginal zone lymphomas: planned subset analysis of the ielsg47/malibu phase ii study

Introduction: Although in a phase III trial of extranodal MZL (EMZL) patients (pts) the combination of rituximab and chlorambucil had superior progression-free and event-free survival (PFS, EFS) compared to either drug given alone (Zucca et al. JCO 2016), there is no standard front-line therapy for MZL pts requiring systemic treatment, and no randomized trial specifically addressed initial treatment for the splenic (SMZL) and nodal (NMZL) MZL subtypes. BTK inhibitors have shown durable responses with a favorable benefit-risk profile for all MZL subtypes in the relapsed setting. The ongoing IELSG47/MALIBU phase II trial is exploring efficacy and safety of rituximab plus ibrutinib in untreated MZL, with a focus on EMZL. We report here a planned preliminary analysis of the response and toxicity in the exploratory cohort of SMZL and NMZL pts. Methods: Treatment was comprised of 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. Results: Between October 2019 and June 2021, 45 pts (30 with SMZL and 15 with NMZL) were enrolled from 16 centers in France, Italy, and Switzerland. 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. The best objective response reached in the entire cohort at any time was complete response (CR) in 22 pts (49%) and partial response (PR) in 19 pts (42%). Of the 36 pts currently evaluable for response at 12 months, 18 (50%) had a CR and 15 (42%) had a PR, while 3 (8%) had disease progression. The median time to best response was 2 months (range: 1–20). At a median follow-up of 23 months, 7 pts relapsed (1 SMZL and 6 NMZL) with a median duration of response of 18 months (range: 1–28+); 3 pts died (due to SARS-CoV2 infection, ischemic stroke, and car accident, respectively). The 2-year overall survival (OS) rate was 92% (95% CI: 75–97), with no significant difference between SMZL and NMZL. Median PFS was 24 months in the NMZL subset and was not reached among SMZL pts (p = 0.0133). The 2-year PFS was 77% (95% CI: 59–88) in the whole cohort, 86% (95% CI: 62%–95%) in SMZL, and 59% (95% CI: 27–81) in NMZL. Treatment was generally well-tolerated, with the most frequent grade 3–4 adverse events being neutropenia (reported in nine pts [20%]) and cutaneous rash (reported in four pts [9%]). Grade 3 atrial fibrillation or hypertension were reported in one (2%) and two (4%) pts, respectively. Treatment was discontinued in 15 pts (33%) after a median of 8 months (range: 2–23): 3 due to progressive disease, 6 due to toxicities, 4 due to unrelated events (1 second primary tumor, 1 stroke, 1 car accident, 1 cold agglutinine disease) and 2 due to consent withdrawal. The research was funded by: The research was supported partially by Janssen (financial and drug supply) and Roche (drug supply) Keywords: extranodal non-Hodgkin lymphoma, indolent non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract C. Thieblemont Honoraria: BMS, Gilead/Kyte, Novartis, Roche, Janssen, Incyte, Abbvie, Miltenyi A. Tedeschi Consultant or advisory role: Astrazeneca, Janssen, Beigene, Abbvie A. Stathis Consultant or advisory role: Janssen, Roche Research funding: Abbvie, ADC Therapeutics, Amgen, AstraZeneca, Bayer, Cellestia, Incyte, LoxoOncology, Merck, Novartis, Pfizer, Philogen, Roche Educational grants: AstraZeneca Other remuneration: Expert testimonies from Bayer, Eli/Lilly S. Luminari Consultant or advisory role: Jannsen, Novartis, Beigene, BMS, Gilead, Regeneron, Genmab, Incyte L. Arcaini Consultant or advisory role: Roche, Janssen-Cilag, Verastem, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics Research funding: Gilead Sciences Other remuneration: Speakers’ Bureau of EUSA Pharma, Novartis O. Casasnovas Consultant or advisory role: Roche, Takeda, BMS, Merck, Gilead, Janssen, ADC therapeutics, Incyte, Astra Zeneca Honoraria: Roche, Takeda, BMS, Merck, Gilead, Janssen, ADC therapeutics, Incyte, Astra Zeneca Research funding: Roche, Takeda, Gilead, Abbvie Educational grants: Roche, Takeda, Janssen, Abbvie E. Zucca Consultant or advisory role: from BeiGene, BMS/Celgene, Celltion Healthcare, Curis, Eli/Lilly, Incyte, Ipsen, Janssen, Kyte (a Gilead Company), Merck, Roche Research funding: AstraZeneca, BMS/Celgene, Incyte, Janssen, Merck and Roche Educational grants: Abbvie, BeiGene, Janssen and Roche. A. Conconi Consultant or advisory role: Regeneron Other remuneration: speaker fees from Roche, Abbvie, Incyte, Takeda, AstraZeneca