Risk of second primary malignancies in patients with chronic lymphocytic leukemia treated with zanubrutinib and acalabrutinib: A real-world data analysis

Abstract Background: Second primary malignancies (SPMs) are one of the complications in patients with chronic lymphocytic leukemia (CLL). Zanubrutinib and acalabrutinib, as newer generation of Bruton tyrosine kinase inhibitors (BTKi), have been developed to improve selectivity and safety profiles for CLL. However, there is limited real-world data on the incidence of SPMs associated with these agents. Both agents carry FDA-approved labeling that states SPMs, including non-melanoma skin cancers, solid tumors, and hematologic malignancies. This study aims to evaluate and compare the risk of SPMs in CLL patients treated with zanubrutinib and acalabrutinib in real-world conditions. Method: Using the TriNetX global health research network, we identified adult CLL patients (aged ≥18 years) who received zanubrutinib or acalabrutinib. A propensity score matching was applied to control for age, sex, and race, creating two balanced cohorts for comparison. Outcomes of interest were incidence of second primary malignancies listed on the drug labels and were assessed three years after the treatment, including non-melanoma skin cancers, solid tumors, and hematologic malignancies. To compare against expected background rates, we compared them with general population cancer incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program, adjusted to a 3-year timeframe to align with this study, but it should be noted that SEER data do not report incidence rates for basal cell carcinoma and squamous cell carcinoma.. Result: After propensity score matching, each treatment arm included 1,964 patients. The average age at treatment initiation was 72.1 years. Males comprised 63.3% of the zanubrutinib group and 62.1% of the acalabrutinib group. The racial distribution was similar, with the majority of patients identifying as White (79.9% vs. 79.0%), followed by African American (7.7% in both groups), Asian (1.5% vs. 1.7%), and Native Hawaiian or other Pacific Islander (0.5% in both). The mean follow-up duration was 408.5 days for the zanubrutinib group and 625.7 days for the acalabrutinib group. Zanubrutinib was associated with a significantly lower incidence of basal cell carcinoma (1.73% vs. 2.97%, p = 0.0015), diffuse large B-cell lymphoma (1.77% vs. 3.38%, p = 0.0019), and lung cancer (0.52% vs. 2.03%, p < 0.0001; 0.143% in general population (GP)). DLBCL and follicular lymphoma were reported separately in this study. By comparison, the non-Hodgkin lymphoma (without differentiation of subtypes reported in SEER) incidence of 0.057% in SEER. No statistically significant differences were observed in rates of follicular lymphoma (0.52% in both groups, p = 0.9935) squamous cell carcinoma (2.12% vs. 2.76%, p = 0.2137), melanoma (0.52% vs. 0.74%, p = 0.4091; GP: 0.066%), bladder cancer (0.67% vs. 0.52%, p = 0.540; GP: 0.058%), renal cancer (0.52% in both groups, p = 0.9935; GP: 0.053%), breast cancer (0.53% vs. 0.95%, p = 0.1270; GP: 0.392%), prostate cancer (1.31% vs. 1.30%, p = 0.9879; GP: 0.361%), or Hodgkin lymphoma (0.52% vs. 0.62%, p = 0.6707; GP: 0.008%). Conclusion: This study showed that zanubrutinib had a lower risk of some SPM, including basal cell carcinoma, diffuse large B-cell lymphoma, and lung cancer, than compared to acalabrutinib. For other malignancies, the incidence rate was relatively comparable between both groups, although both groups experienced higher SPM than incidence rate in the general population. However, the shorter follow-up for the zanubrutinib cohort and the retrospective nature of the analysis are the limitations of this study. Prospective studies with longer follow-up are warranted to confirm these findings and to further explore the long-term oncologic safety of BTK inhibitors.