Comparison of infections in patients with chronic lymphocytic leukemia (CLL) treated with BTKi versus venetoclax obinutuzumab in first line therapy Free

Chronic lymphocytic leukemia (CLL) is a lymphoid neoplasm with increased number of mature but immunologically dysfunctional B lymphocytes. Higher risk of infections in CLL is due to immune suppression caused by both the disease and therapy. Two commonly used regimens in first line (1L) are either bruton tyrosine kinase inhibitors (BTKi) or venetoclax & obinutuzumab (VenObin). We aim to compare rates of various infections and overall survival between two groups, BTKi and VenObin.

We performed a retrospective analysis on TriNteX database Global Collaborative Network with data from 148 healthcare organizations. Patients with diagnosis of CLL/SLL were divided into 2 groups based on 1L therapy, BTKi (ibrutinib, zanubrutinib, or acalabrutinib) and VenObin. Infection rates were compared using risk ratio and survival was calculated by Kaplan-Meier analysis. Outcomes were calculated with and without propensity score matching.

A total of 16888 patients were treated with BTKi and 1490 with VenObin. Most were male (62% in both groups) and white, 78.4% in BTKi and 76.2% in VenObin. Mean age at index event was 70.9 years in BTKi and 66.6 years in VenObin group.

Bacterial pneumonia was the most common infection, 18.9% (n=2647) in BTKi and 14.2% (n=173) in VenObin group. Similar percentage developed sinusitis 8.5% in BTKi and 7.4% in VenObin. Skin and subcutaneous tissue infections (SSTI) were also higher in BTKi, 13% versus 6.5% in VenObin group. In BTKi, 1547 (10.4%) patients developed urinary tract infections (UTI), and 72 (5.5%) in VenObin. More patients developed diverticulitis in BTKi 8.2% than in VenObin group 5.7%. Bacteremia was also higher in BTKi 8.1% (n=297) than in VenObin group 4.8% (n=68).

More patients developed fungal pneumonia in BTKi 2.2% (n=366) than in VenObin group 0.9% (n=13). Invasive Aspergillosis cases in BTKi were 0.9% (n=155) and in VenObin group were 0.7% (n ≤ 10). Rate of infection with Pneumocystis jirovecii was 0.6% in BTKi and 0.7% in VenObin group.

COVID-19 cases were higher in BTKi group 14.5% (n=2288) than 16.6% (n=216) in VenObin. More patients had HZV in BTKi 3.7% (n=581) than in VenObin 2% (n=28). More HSV cases were in BTKi 2.3% (n=373) than in VenObin 1.3% (n=19). Influenza cases in BTKi group were 2.7% (n=444) and in VenObin group were 2.4% (n=34). There were 3.5% (n=558) RSV cases in BTKi group and 2.7% (n=36) in VenObin group. CMV and Hep B cases were similar 0.7% in both groups.

The instance of arrhythmias/atrial fibrillation was higher in BTKi 20.1% (n=2593) versus 10.3% (n=113) in VenObin group. Other CVS complications were similar in BTKi 11.6% and 10.6% VenObin group.

After propensity score matching, infection rates were compared again (n=1490 in both groups). Bacterial pneumonia had the highest number 18.2% (n = 224) in BTKi and 14.2% (n=173) in VenObin group (RR 1.3, 95% CI: 1.2 - 1.5, p<0.0001). SSTI were higher in BTKi, 12.3% (n=157) versus 6.5% (n=81) in VenObin group (RR 2, 95% CI: 1.6 - 2.5, p<0.0001). In BTKi group 1547 (10.4%) patients developed UTI, and 72 (5.5%) in VenObin (RR 1.9, 95% CI: 1.5 - 2.3, p<0.0001). More diverticulitis cases were seen in BTKi group 18.2% (n=224) than in VenObin 5.7% (n=69), RR 1.4, 95% CI: 1.1 - 1.8, p=0.002. Incidence of Bacteremia was also higher in BTKi group 8.1% (n=115) than in VenObin group 4.8% (n=68), RR 1.7, 95% CI: 1.3 - 2.1, p<0.0001. More patients had fungal pneumonia in BTKi 2.3% (n=34) than in VenObin group 0.9% (n=13) with Risk Ratio of 2.5, 95% CI: 1.4 - 4.3, p=0.0008. HZV infection was higher in BTKi group 3.5% (n=48) than in VenObin group 2% (n=28), RR 1.8, 95% CI: 1.3 - 2.7, p=0.0014. There were more HSV cases in BTKi group 2.4% (n=34) than in VenObin 1.3% (n=19), RR 1.7, 95% CI: 1.1 - 2.7, p=0.02.

Overall survival was compared using Kaplan Meier analysis. The median OS was 9.5 years in BTKi group while it was not reached in VenObin group. The survival probability at the end of the time window was 24.7% in BTKi group vs 79.1% in VenObin group, Hazard Ratio = 1.81 (95% CI: 1.5 to 2.2), p<0.0001.

CLL patients treated with BTKi developed significantly higher rate of bacterial, fungal and viral infections compared to VenObin. Possible causes include partial response, continuous therapy and immune suppressive effects with BTKi versus deeper response and fixed duration of treatment with VenObin. Further studies are needed to explore the underlying mechanisms.