Introduction Indolent non-Hodgkin lymphomas, such as marginal zone lymphoma (MZL), typically follow an indolent course and are associated with favorable long-term survival. Therefore, balancing efficacy and toxicity is critical when selecting front-line therapies. According to the 2023 CSCO lymphoma guidelines, there is no universally accepted standard first-line regimen for newly diagnosed MZL. For patients with indications for systemic therapy, CD20 monoclonal antibody–based regimens (± other agents) are recommended.

Phosphatidylinositide 3-kinases (PI3Ks) are intracellular enzymes that regulate multiple signaling pathways, and several PI3K inhibitors have been approved for the treatment of MZL. Linperlisib, a highly selective oral PI3Kδ inhibitor, has shown promising anti-tumor activity and manageable safety in relapsed/refractory (R/R) MZL.This study aims to evaluate the efficacy and safety of first-line Linperlisib in combination with Obinutuzumab in previously untreated MZL patients, providing new evidence for a potentially more effective front-line option.Methods We conducted a prospective, single-arm, phase Ib/II clinical trial (NCT06592170) in treatment-naïve MZL patients meeting treatment criteria per NCCN B-cell lymphoma guidelines (Version 2.2025).In the phase Ib dose-finding stage (Linperlisib 80 mg), the recommended phase II dose (RP2D) was determined to be Linperlisib 60 mg daily.The induction regimen consisted of three 28-day cycles of Linperlisib (60 mg orally, once daily) combined with Obinutuzumab (1000 mg intravenously). Subsequent therapy was response-directed: per Lugano 2014 criteria, patients achieving complete response (CR) or partial response (PR) proceeded to Linperlisib maintenance until disease progression or other discontinuation criteria, for a maximum of 24 months. Patients with stable disease (SD) or progressive disease (PD) discontinued study treatment.If patients failed to achieve CR or PR after two cycles of induction, investigators could decide whether to extend induction up to a maximum of six cycles.The primary endpoint was CR rate; secondary endpoints included overall response rate (ORR), duration of overall response (DOR), progression-free survival (PFS), overall survival (OS), and safety.Results Between November and December 2024, five patients were enrolled in the phase Ib stage. The median age was 64 years (range, 62–68); 80% had advanced-stage disease, and 40% had high tumor burden (per GELF criteria for Follicular Lymphoma).

Among four efficacy-evaluable patients, the ORR was 100%: CR in 75% and PR in 25%. A total of 21 adverse events (AEs) were reported. Two patients experienced three grade ≥3 non-hematologic AEs (rash, interstitial pneumonia, and invasive pulmonary aspergillosis) that led to treatment discontinuation.

In the ongoing phase II study (October 2024–present), eight patients have been enrolled. The median age was 68 years (range, 39–74); 87.5% had advanced-stage disease, and 37.5% had high tumor burden. Ki-67 positivity ≥10% was observed in 75% of patients; one patient had 70% p53 protein expression.

Among three efficacy-evaluable patients so far, the ORR was 100%, all achieving CR. Fifteen AEs were reported, all were laboratory abnormalities. Only one patient experienced grade ≥3 hematologic toxicity (neutropenia); no grade ≥3 non-hematologic AEs or treatment discontinuations occurred.

Conclusion Front-line treatment with Linperlisib and Obinutuzumab in MZL demonstrated encouraging early efficacy with a manageable safety profile. Further enrollment and follow-up are ongoing to confirm these preliminary findings and better define the role of this response-adapted strategy in the first-line setting for MZL.

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2025
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