Deep responses following treatment with loncastuximab tesirine (WM-NET1 trial) in patients with Relapsed/Refractory including those withhigh-risk, TP53-altered Waldenström macroglobulinemia. Free

Introduction: Waldenström macroglobulinemia (WM) is characterized by the presence of a MYD88 mutation in >90% and a CXCR4 mutation in 30-40% of cases. The impact of these mutations on treatment responses and disease outcomes is well known. TP53 alterations (TP53^ALT) have more recently been described in WM and are reported to occur in up to 25% of patients, with a higher frequency in patients with previously treated WM, especially those with prior alkylator or nucleoside analogue exposure (Tam et al Blood Adv 2024; Poulain et al CCR 2017; Tsakmaklis et al, ASH 2025). TP53 ^ALT WM is associated with a shorter time to disease progression, as well as worse overall survival (Poulain et al CCR 2017; Gustine et al, BJH 2019). Depth of response to BTK inhibitors is affected by TP53 status, with recent data reporting a very good partial response (VGPR) rate of 34% v. 25% and major response rates of 84% v. 73% in patients without or with a TP53 ^ALT (Tam et al Blood Adv 2024). No complete responses were reported and median PFS was shorter in those with a TP53^ALT compared with wild-type (TP53^WT). Loncastuximab tesirine is a humanized IgG1 anti-CD19 antibody that is conjugated to a pyrrolobenzodiazepine (PBD) dimer. Following internalization, the PBD dimer is released via proteolytic cleavage and binds to the DNA minor groove forming highly cytotoxic DNA inter-strand crosslinks. Cells deficient in DNA repair including TP53 alterations are vulnerable to the cytotoxic effects of loncastuximab tesirine (Tarantelli et al, Haematologica 2024).

Methods: In an ongoing investigator-initiated, prospective phase II study in symptomatic patients with relapsed or refractory WM (NCT05190705), patients are receiving single agent loncastuximab tesirine. Loncastuximab tesirine is administered at 150 ug/kg in cycles 1 and 2 and 75 ug/kg in cycles 3 to 6. Each cycle is 28 days. The primary outcome measure of this study is attainment of VGPR or complete (VGPR/CR) response. The accrual goal of this trial is 20 patients, based on an alternative VGPR/CR rate ≥40% versus a null of ≤10%, with a double-sided alpha of 0.037 and a power of 87%. The study would meet its endpoint if ≥6 patients attained a VGPR/CR.

Results: Of the 14 patients who have completed therapy on this trial to date, the median age is 71 years (range 53-81), 9 (64%) are male, and the median prior number of therapies is 4 (range 2-10). Median baseline hemoglobin is 9.5 g/dL (range 8.2-12.6), serum IgM is 2146 mg/dL (range 723-5955), and bone marrow involvement is 53% (range <5-90). Four patients had extramedullary disease. Twelve patients (86%) are MYD88 mutated; 8 patients (57%) are CXCR4 mutated, and 8 (57%) are TP53 altered. Nine patients completed all 6 cycles of therapy. Of the 5 other patients, treatment was stopped early due to GGT elevation (n=2), disease progression (n=1), patient decision (n=1), and skin toxicity (n=1). No IgM flare and no infusion reactions have occurred. For all patients, the median time to minor response, major response, and deepest response was 28, 55, and 172 days, respectively. The response rates include 1 (7%) CR; 9 (64%) VGPRs; 2 (14%) partial responses (PR); 1 (7%) minor response; and 1 (7%) progressive disease, for an overall response rate of 93% and a VGPR/CR rate of 71%.

For the 8 patients with TP53^ALT, the baseline characteristics were as follows: 50% male; median age of 70 years (range 53-77), median prior therapies is 4 (range 2-10); median IgM is 1877 mg/dL (range 723-5639); and median hemoglobin is 9.2 g/dL (range 8.2-11.6). All TP53^ALT patients had an MYD88 mutation, and 6 (75%) carried a CXCR4 mutation. For those with TP53 ^ALT, the median time to minor response, major response, and deepest response was 28, 49, and 235 days, respectively. All TP53^ALT patients attained a major response; 1 patient (13%) with a CR, 6 (75%) with a VGPR, and 1 (13%) with a PR, for an overall response rate of 100% and a VGPR/CR rate of 89%. One patient had splenomegaly and one had adenopathy, both of which resolved after treatment.

Conclusion: Our findings from this ongoing, prospective trial demonstrate a high VGPR/CR rate of 71% in heavily pre-treated WM. Notable, is the VGPR/CR rate of 89% in high-risk patients with TP53^ALT WM. No unexpected toxicities have been seen in this trial. Our findings identify a potentially novel time-limited therapy in relapsed or refractory WM, including patients with high-risk TP53^ALT WM.