Tolerability and Outcomes of Bruton Tyrosine Kinase Inhibitors for Chronic Lymphocytic Leukemia in Patients with Severe Renal Dysfunction
Authors: Lin Chenyu , Anderson Clare E , Scobie Micaela R , Rodgers Thomas D , Kelley Michael J , Friedman Daphne R 
Published: December 2023

Introduction:
There is limited data on the outcomes and tolerability of Bruton Tyrosine Kinase (BTK) inhibitors for chronic lymphocytic leukemia (CLL) in patients with severe renal dysfunction, particularly older adults. The most commonly prescribed BTK inhibitor, ibrutinib, is believed to be safe for mild to moderate renal dysfunction. However, severe renal failure has been excluded from prospective studies, and there is no guidance on dosing under the FDA label. Furthermore, ibrutinib itself can cause kidney injury and worsen existing renal dysfunction. This national Veterans Affairs (VA) analysis aims to review the safety and tolerability of BTK inhibitors in severe renal impairment.
Methods:
An electronic query of the VA Corporate Data Warehouse and retrospective chart review were performed to identify patients with CLL treated with a BTK inhibitor between 2013-2022 and who had severe chronic kidney disease defined as an estimated glomerular filtration rate (eGFR) &lt; 30 ml/min/1.73 m 2 overlapping with their treatment period. Isolated acute kidney injuries lasting &lt; 1 month were excluded. Fisher's exact test was utilized to evaluate categorical variables, logistic regression for binary outcomes, and log-rank and Cox regression for time-to-event analyses.
Results:
A total of 115 patients across 68 VA medical centers received 124 lines of BTK inhibitors with an eGFR &lt; 30 (Table 1). The median duration of follow-up from the start of therapy was 26 months (range, 0.5 - 94). The median age was 74, and 98% were male, reflecting the U.S. veteran population. 64% had an eGFR &lt; 30 at the start of therapy, with 18% requiring dialysis, while the remaining 36% experienced progressive renal dysfunction during treatment. The oral BTK agents prescribed were ibrutinib ( n = 103), acalabrutinib ( n = 18), and zanubrutinib ( n = 3). Most BTK inhibitors (n = 94 of 124 lines, 76%) were initiated at the FDA-label dose. 46 (37%) later required dose reduction, primarily due to drug toxicity ( n = 37). The most common reasons for dose reduction were cytopenia ( n = 10), failure to thrive ( n = 6), bleeding ( n = 5), and worsening renal function ( n = 5). Discontinuation of therapy for toxicity occurred in 50% (ibrutinib), 39% (acalabrutinib), and 33% (zanubrutinib). The most common reasons for discontinuation were infection ( n = 15), bleeding ( n = 10), arrhythmia ( n = 9), and disease progression ( n = 9).
Among patients who received ibrutinib ( n = 103), the median progression-free survival (PFS) and overall survival (OS) were 45 and 49 months, respectively. In multivariate Cox regression, covariates associated with shorter PFS included the baseline severity of renal failure (HR 1.85, 95% CI 1.21 - 2.88), cirrhosis (HR 6.36, 95% CI 1.45 - 19.76), and heart failure (HR 4.20, 95% CI 1.82 - 9.47). Younger age, dialysis, and absence of atrial fibrillation at the start of therapy were protective in univariate but not multivariate models. Heart failure and cirrhosis retained their prognostic impact on OS in multivariate modeling. Factors including race, rural residence, obesity, IGHV status, and TP53 deletion were not significantly associated with survival in this cohort. The median duration of therapy of ibrutinib was 33 months. Ibrutinib dose reductions at initiation or during treatment were associated with a longer duration of therapy (Figure 1). Of note, dose reductions did not significantly reduce the response rate to ibrutinib or worsen survival.
Interestingly, 11 patients had CLL-related kidney dysfunction. However, kidney function did not improve after treatment with a BTK inhibitor in any of the 115 patients. Progression of renal impairment was observed in 51 patients (50%) on ibrutinib, 8 (44%) on acalabrutinib, and none on zanubrutinib. The etiology of worsening renal function was uncertain for the majority of patients.
Conclusion:
The clinical outcomes of BTK inhibitors in patients with CLL and severe renal dysfunction have not been well-described. In our real-world data analysis, these agents appear to be a reasonable therapeutic option in severe renal impairment, including in older adults and those on dialysis. Lab monitoring is needed, given the risk of worsening renal function. Dose modifications may help improve tolerability without reducing efficacy. Unfortunately, severe renal dysfunction is unlikely to improve with CLL treatment, even in CLL-related kidney failure.