Efficacy and safety of zanubrutinib in patients with non-IgM lymphoplasmacytic lymphoma

Abstract Introduction Zanubrutinib (ZANU), a second-generation BTK inhibitor, was approved in 2021 for the treatment of Waldenström macroglobulinemia (WM) based on the ASPEN study. Non-IgM-secreting lymphoplasmacytic lymphoma (LPL), a rare variant comprising 2–5% of LPL cases, is typically excluded from all WM studies, thus creating a critical knowledge gap. Although a biological rationale exists and clinical opinion supports use of ZANU in this disease entity, no published data exist for use of ZANU in treating non-IgM LPL. Thus, we sought to evaluate the efficacy and tolerability of ZANU in patients (pts) with non-IgM LPL. Methods: All LPL/WM pts treated at our center were screened. Eligible pts had confirmed serum IgG/IgA gammopathy and LPL diagnosis confirmed by pathology review at our institution. Response was assessed based on the 6th International Workshop on WM Consensus Criteria. Comparison between treatment-naïve and relapsed/refractory pts was done using Fisher's exact test. Survival was calculated with Kaplan-Meier methods starting from the time of ZANU initiation. Outcomes Of 26 total non-IgM LPL pts, we identified 14 treated with ZANU (6 treatment-naïve, 8 relapsed/refractory). At treatment initiation, the median age was 65.9 years (range, 56–81), and 8 pts (57.1%) were male. The monoclonal protein subtype was IgG in 11 pts (78.6%) with a median level of 3,379 mg/dL, and IgA in 3 pts (21.4%) with a median level of 2,628 mg/dL. All pts had bone marrow involvement; 3 (21.4%) had splenomegaly, 6 (42.9%) had nodal disease, and 1 had central nervous system involvement. The MYD88 L265P mutation was detected in 11 of 12 evaluable pts (91%), and CXCR4 mutations were found in 2 of 8 evaluable pts (25%). Relapsed/refractory pts had received a median of one prior line of therapy (range, 1–3), including rituximab (n = 4), ibrutinib (n = 3), bendamustine-rituximab (n = 1), and rituximab combined with other chemotherapy (n = 2). Pretreatment median hemoglobin was 10.9 g/dL (range, 7.5–14.3), platelets: 177×10⁹/L (range, 103–302), and beta-2 microglobulin 3.3 mg/L (range, 2.3–5.1). The median interval from diagnosis to ZANU initiation was 46.6 months overall (53.6 months for treatment-naïve and 37.6 months for relapsed/refractory pts), and the median time on ZANU was 18.2 months (range, 3.6–26.7). The overall response rate (ORR) was 57%, comprising 2 minor responses (MR), 6 partial responses (PR), and 6 pts with stable disease (SD); no pts achieved a complete response (CR) or very good partial response (VGPR). A higher PR rate (5/6, 83%) was observed in the treatment-naïve group (p = 0.026), while a higher SD rate (5/6, 83%) was observed in the relapsed/refractory group (p = 0.14). Median hemoglobin at best response assessment increased to 12.95 g/dL, with a median increase of 3.4 g/dL among pretreatment anemic pts (n = 7). Four pts required ZANU dose reductions due to adverse events (grade 1 thrombocytopenia and postsurgical bleeding; grade 2 hypertension; and grade 2 arthralgia), with improved tolerability thereafter; all had responding disease at the time of dose reduction, which continued despite dose reduction. At a median follow-up of 23 months (range, 1–42.5), 11 pts remained on therapy. Two pts discontinued due to progression (one with Bing-Neel syndrome) and one pt due to cardiovascular toxicity. The 2-year progression-free survival (PFS) and overall survival (OS) were 92% and 100%, respectively. Notably, the only pt with MYD88 wildtype and CXCR4 mutation achieved a PR with a treatment duration of 5 months. Conclusion: ZANU was well tolerated and demonstrated clinical efficacy in pts with non-IgM LPL, a population historically excluded from WM trials and without any supportive clinical data to guide management. Although the ORR was modest compared to the ASPEN study and no CR/VGPR were achieved, most pts experienced durable disease control and significant hematologic improvement, including notable hemoglobin recovery, irrespective of IgG or IgA subtype. The 2-year PFS and OS rates were favorable. Notably, the response rate was higher in the treatment-naïve pts than in the relapsed/refractory setting. This real-world cohort provides the first dedicated clinical evidence supporting the safety and efficacy of ZANU in this rare LPL subtype, warranting validation in larger studies and in pts with MYD88-wildtype disease.