A Phase II Trial of Loncastuximab Tesirine in Patients with Previously Treated Waldenström Macroglobulinemia

Background: Chemoimmunotherapy and covalent BTK inhibitors are standard therapies often used in first and second-line therapy for Waldenström macroglobulinemia (WM). Whereas these therapies are well tolerated, there is no standard of care for patients who progress on both of these treatments. This prospective phase II clinical trial was designed to evaluate the use of loncastuximab tesirine, a CD19 antibody drug conjugate, in patients with WM previously treated with at least two lines of therapy, including rituximab and a BTK inhibitor.

Methods: This multicenter, phase II trial is enrolling previously treated symptomatic patients with WM. Loncastuximab tesirine as a single agent is given once every 4 weeks for a total of 6 doses. Loncastuximab is administered in cycles 1-2 at 150 µg/kg and cycles 3-6 at 75 µg/kg. Baseline testing includes complete blood counts, chemistry panel, and IgM levels as well as a bone marrow biopsy/aspirate with molecular testing and PET or CT imaging of the chest/abdomen/pelvis. The primary outcome measure is overall response rate (ORR). Secondary outcomes are evaluating the depth of hematologic response, the median progression free survival, the effect of bone marrow disease burden on disease response, the impact of MYD88 and CXCR4 on disease response, the safety of loncastuximab tesirine in WM, the rate of IgM flare, the rate of tumor lysis, and patient quality of life during treatment. Assumptions included H0 ≤35%, H1 ≥65%, 2-sided alpha 0.035, and power 0.85. The trial is designed to enroll 36 patients. For purposes of this interim analysis, >2 of the first 7 participants would have to attain a response to study therapy to reject futility.

Results: To date 7 patients have been enrolled. Baseline characteristics include median age 70 years (range 53-77); median number of prior therapies 4 (range 2-5); serum IgM 2,230 mg/dL (range 723-5,955); hemoglobin 9.4 g/dL (range 8.9-12.6); bone marrow involvement 60% (range 40-90). One patient each had lymphadenopathy or splenomegaly. MYD88 mutation was found in 100% of cases, CXCR4 in 6/7 (86%) and TP53 in 4/7 (57%). To date 7 patients have started therapy, with the following outcomes: 4 patients have completed 6 cycles of therapy, 1 had progressive disease (PD) after Cycle 1, and 2 patients are receiving ongoing therapy. ORR is 86% (6/7). Three patients (43%) achieved a very good partial response (VGPR), 3 (43%) achieved a partial response (PR), and 1 had PD. One patient that achieved a VGPR at treatment completion later developed Bing-Neel syndrome. Median time to minor response was 14 days (range, 7-77), median time to PR or better was 60 days (range, 21-105). At best response, median IgM decreased to 252 mg/dL and hemoglobin improved to 13.4 g/dL. Median post-treatment marrow involvement (4 patients evaluable) was 5%. Toxicities were similar to that seen in prior loncastuximab trials, with skin toxicity or rash in all patients (all grade 1-2), 5 patients (71%) with edema (4=grade 1-2; 1=grade 3), 6 patients (86%) with cytopenias (all grade 3- 4), and 5 (71%) with asymptomatic GGT elevation (3=grade 2; 2=grade 3). Although skin toxicities and GGT elevation have persisted in some patients post-treatment, cytopenias have been transient. No patients have discontinued therapy due to toxicity.

Conclusion: Early data from this ongoing clinical trial demonstrates an overall response rate of 86% in the initial 7 patients treated with this fixed duration therapy. This ORR compares favorably to other third line agents in WM,especially in this population with high rates of CXCR4 and TP53 mutations. This treatment has a manageable side effect profile with skin toxicity, asymptomatic GGT elevation, and transient cytopenias that have not led to treatment discontinuation. Accrual will continue to enroll 36 total patients.