Long-term outcomes of a novel initial regimen: Rituximab plus pegylated interferon α-2b in untreated advanced indolent B-cell lymphoma – 5-year follow-up of the ripple study

Abstract Background: Indolent B-cell lymphomas (iBCL), accounting for 10-15% of non-Hodgkin lymphoma (NHL) subtypes in China, exhibit clinical heterogeneity. While generally associated with favorable survival, most iBCL cases remain incurable. Rituximab monotherapy demonstrates efficacy as initial treatment, and preclinical studies suggested interferon-alpha (IFN-α) may synergistically enhance rituximab activity through immune modulation. Pegylated IFN-α2 (Peg-IFN-α2) offers improved pharmacokinetics with reduced toxicity compared to conventional IFN-α and is used in chronic hepatitis B (CHB) management. The phase II RIPPLE trial (NCT04246359) evaluates the role of rituximab biosimilar combined with Peg-IFN-α2b in treatment-naïve iBCL. Methods: Newly diagnosed iBCL (follicular lymphoma [FL] grades 1-2/3a, marginal zone lymphoma [MZL], lymphoplasmacytic lymphoma [LPL], small lymphocytic lymphoma [SLL]); ECOG ≤2; adequate organ function; measurable disease. ​Patients with chronic hepatitis B co-infection (HBsAg+, HBV DNA <3,000 IU/mL, ALT <5×ULN) were eligible. Induction therapy consisted of rituximab biosimilar (Henliritux®; 375 mg/m² IV on day 1) plus Peg-IFN-α2b (Pegberon®; 135μg SC on days 1 and 8) every 21 days for 6 cycles. Responders received maintenance (rituximab every 8 weeks; Peg-IFN-α2b monthly) for ≤2 years. CHB patients received entecavir prophylaxis. Primary endpoint: investigator-assessed ORR and CR (Lugano 2014). Secondary endpoints included TTR, DOR, PFS, OS, HBV clearance and safety (CTCAE v5.0). Results: Between September 2018 and July 2021, 57 eligible patients (median age 54 years; 56.1% female) were enrolled across six Chinese centers. 21(36.8%) pts were symptomatic. The cohort comprised 45.6% (n=26) FL grade 1-2, 36.8% (n=21) MALT lymphoma, 12.3% (n=7) FL grade 3a, 3.5% (n=2) SLL, and 1.8% (n=1) LPL, with 38.6% having FLIPI ≥3 and 10.5% being HBsAg-positive. At a median follow-up of 57.2 months (IQR 51.8-63.4), the overall response rate (ORR) was 71.9% (41/57) with 56.1% (32/57) achieving complete response (CR). Subtype-specific analyses revealed ORR/CR rates of 74.1%/48.1% in FL grade 1-2, 71.4%/71.4% in FL grade 3a, 61.9%/57.1% in MALT, 100%/50% in SLL, and 0/0 in LPL. 5-year progression-free survival (PFS) and overall survival (OS) rates were 60.5% and 91.2%, respectively. The median OS and PFS were not reached (Figure 1A and 1B). Treatment-emergent adverse events (TEAEs) were predominantly grade 1-2, including neutropenia (63.2%), anemia (36.5%), thrombocytopenia (29.8%), fever (28.1%), transaminase elevation (26.3%), fatigue (26.3%), and infusion reaction (21.7%, 10/46). No treatment-related deaths occurred. Conclusion: Rituximab biosimilar with Peg-IFN-α2b demonstrates durable efficacy and manageable toxicity in treatment-naïve iBCL, particularly in FL and MALT subtypes. ​​Absence of HBV reactivation suggests potential synergism between Peg-IFN-α2b and entecavir in HBV suppression.​​ These results support further evaluation in larger randomized trials.