Comparison of Zanubrutinib and Ibrutinib As Treatments for Waldenstrom Macroglobulinemia: A Real-World Retrospective Study
Authors: Iadevaia Francesco , Hafer Ramsay , Rohan Thomas Z , Khoo Alan , Laurenti Luca , Porcu Pierluigi 
Published: December 2024

Background
The prognosis of Waldenstrom Macroglobulinemia (WM) has improved substantially since the introduction of BTK inhibitors as a continuous treatment for both naïve and relapsed disease. The safety and efficacy of these drugs have been investigated in several trials, including large multi-center randomized trials (NCT01614821, NCT02604511, iNNOVATE [NCT02165397] and ASPEN [NCT03053440]). However, to our knowledge, no retrospective study has compared ibrutinib and zanubrutinib as WM treatment in a real-world population.
Methods
This is a retrospective cohort study of BTKi treatment in patients affected by WM. Data were collected and analyzed through TrinetX, a global federated real-world data and analytics research platform. We used the diagnostic codes ICD10CM:C88.0 or ICDO3:9671/3 to search for WM and ICDO3:9671/3 to search for Lymphoplasmacytic Lymphoma (LPL) in the electronic records of affiliated Healthcare Organizations. The time window of analysis spans from the date of approval of zanubrutinib, 08/31/2021, to 07/31/2024. The two cohorts compared were composed of patients with both treatment naïve and relapsed/refractory WM treated with either ibrutinib or zanubrutinib; those with a concomitant or previous diagnosis of Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL) were excluded from analysis. The primary objective was to evaluate the real-world clinical effectiveness and safety outcomes of patients with Waldenstrom Macroglobulinemia receiving zanubrutinib or ibrutinib, including mortality risk, rate of progression to next treatment, and cumulative incidence rates of adverse events of special interest, notably atrial fibrillation, hypertension, and infections. Propensity Score Matching was performed on several characteristics: age at treatment beginning, sex, ethnicity, race and past medical history of atrial fibrillation.
Results
At the cutoff date (July 31st, 2024) 441 and 453 patients were followed in 54 HCOs across 17 countries. After propensity score matching, 378 patients were considered for 1:1 comparison. Median follow-up time was 652 days and 299 days for the ibrutinib and zanubrutinib treated cohort, respectively. Median age at treatment beginning was 72.8 and 73.2 years. Male patients were 58.85% and 60.49% respectively. Due to lack of data, it was not possible to stratify the analysis for 17p deletion or CXCR4 mutations. Myd88 status of patients is unknown. A higher all-cause mortality risk was observed in the ibrutinib cohort (RR 1.67, 95% C.I. of 1.03-2.71) with mortality rates of 10.5% in the ibrutinib cohort and 6.3% in the zanubrutinib cohort. There was no statistically significant difference in the rate of initiation of a subsequent line of treatment. Hospital admission or emergency department usage cumulative incidence rate was higher with ibrutinib (36.2% against 26.5%) with a RR of 1.37 (95% C.I. 1.10-1.69). Patients in the ibrutinib cohort were found to have a greater risk of pneumonia (RR 1.89, 95% C.I. 1.23-2.93), UTI (RR 1.81, 95% C.I. 1.14-2.86), hypertension (RR 1.26, 95% C.I. 1.11-1.42), diarrhea (RR 2.06, 95% C.I. 1.19-3.55), musculoskeletal pain (RR 1.50, 95% C.I. 1.10-2.39), back pain (RR 1.74, 95% C.I. 1.27-2.39), rash (RR 1.8, 95% C.I. 1.13-2.87) and peripheral edema (RR 1.64, 95% C.I. 1.15-2.34). Risk ratios of developing atrial fibrillation, sepsis, upper respiratory tract infection, acute myocardial infarction, bleeding, neutropenia, thrombocytopenia, anemia, fatigue, non-melanoma skin cancer, syncope, contusion, cough, headache, muscle spasms or nausea were not statistically different between the two cohorts.
Conclusions
We report the first real-world, multicenter retrospective study comparing ibrutinib and zanubrutinib as treatment for WM implementing PSM to minimize bias. Mortality rate of ibrutinib treated patients was higher than that of zanubrutinib treated patients during almost three years of follow-up. Patients treated with ibrutinib were more likely to experience pneumonia, UTI, hospital admission and emergency medical services utilization along with several other minor adverse events. Our findings are largely consistent with the results of ASPEN trial. We did not observe a significant difference in atrial fibrillation and flutter cumulative incidence rate. These data suggest that zanubrutinib is a safer therapeutic option for WM than ibrutinib and equally effective.