Outcomes of Bruton Tyrosine Kinase Inhibitors for Chronic Lymphocytic Leukemia in U.S. Veterans with Severe Renal Dysfunction

To the Editor,

There is limited data to guide the use of Bruton Tyrosine Kinase inhibitors (BTKi) in patients who have renal dysfunction. Severe kidney disease was excluded from pivotal trials, and manufacturer labels of approved BTKi provide little guidance on the safety of their use in this population (1, 2, 3). Ibrutinib has low levels of renal excretion, but is associated with kidney injury and may worsen existing renal dysfunction (1, 4, 5). This U.S. Veterans Health Administration (VHA) retrospective cohort study aims to evaluate the real-world outcomes of BTK inhibition in patients with chronic lymphocytic leukemia (CLL) and concurrent severe renal impairment.

We performed an electronic query of the VHA Corporate Data Warehouse to identify veterans with CLL and an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m² while receiving treatment with a BTKi. Only patients with kidney dysfunction that persisted beyond 1 month were included. Retrospective chart review was conducted to collect data on patient characteristics, CLL therapies, and clinical outcomes. Fisher’s exact and Chi Square testing were utilized to evaluate categorical variables, logistic regression for binary outcomes, and log-rank testing and Cox Proportional-Hazards regression for time-to-event analyses.

Our query identified 115 eligible patients who were treated with a BTKi between January 1, 2013 and December 1, 2022 (Table 1), with 8 receiving more than one BTKi. These 115 veterans received their care across 68 VHA medical centers. The median duration of follow-up from the start of therapy was 26 months (range, 0.5 – 94). The cohort demographics were representative of the VHA population: median age was 74 years, 98% male, and 68% non-Hispanic white. Thirty-nine patients (34%) progressed from none or mild to severe renal (eGFR < 30) at a median of 12.3 months from initiation of the BTK inhibitor (range, 0.3-72.6). The cause of worsening renal failure was unknown in 59% of patients, with only 7% attributed to the BTK inhibitor. Progressive renal dysfunction led to dose reduction in 5 patients (4%), and drug discontinuation in 5 patients (4%). Twenty-one patients (18%) were on dialysis at the initiation of therapy, while an additional 16 (14%) became dialysis-dependent during therapy.

Table 1. Baseline Characteristics.

Baseline clinical characteristics of the U.S. veterans with concurrent severe renal dysfunction and chronic lymphocytic leukemia (CLL) receiving Bruton Tyrosine Kinase (BTK) inhibitors. Rurality is defined in the U.S. Veterans Health Administration in a 3-tiered classification system based on Rural Urban Commuting Area (RUCA) codes. Urban residence is defined as census tract records with a RUCA code of 1.0 or 1.1, while rural and highly rural residence have a RUCA score above 1.1. *7 patients received 2 BTK inhibitors, and 1 patient received 3 BTK inhibitors. eGFR: estimated glomerular filtration rate, ATN: acute tubular necrosis.

	BTK (N = 115)
Median age, years (range)	74 (54 – 97)
Male sex, N (%)	113 (98%)
Median body mass index, kg/m2 (range)	26.3 (16.1 – 47.2)
Race/Ethnicity, N (%)
Non-Hispanic White	78 (68%)
Non-Hispanic African American	30 (26%)
Hispanic	1 (1%)
Asian	1 (1%)
Unknown	5 (4%)
Rurality, N (%)
Urban Residence	85 (74%)
Rural / Highly Rural Residence	30 (26%)
Use of Oral Targeted Agents*, N (%)
Ibrutinib	103 (90%)
Acalabrutinib	18 (16%)
Zanubrutinib	3 (3%)
Deletion 17p, N (%)
Deletion	17 (15%)
Wildtype	71 (62%)
Unknown	27 (23%)
Renal Dysfunction at start of therapy, N (%)
eGFR 30-59 ml/min/1.73 m2	39 (34%)
eGFR 15-29 ml/min/1.73 m2	51 (44%)
eGFR < 15 ml/min/1.73 m2	23 (20%)
Unknown eGFR	2 (2%)
Renal Dysfunction during therapy, N (%)
eGFR 15-29 ml/min/1.73 m2	68 (59%)
eGFR < 15 ml/min/1.73 m2	47 (41%)
Etiologies of Chronic Kidney Disease, N (%)
Hypertension and/or diabetes	60 (52%)
Obstructive	12 (10%)
CLL-related	9 (8%)
Ischemic ATN	6 (5%)
Other	18 (16%)
Unknown	10 (9%)
Comorbidities, N (%)
Cirrhosis	5 (4%)
Heart Failure	27 (23%)
Atrial Fibrillation	16 (14%)

The BTKi prescribed were ibrutinib (n=103), acalabrutinib (n=18), and zanubrutinib (n=3). Of the 124 BTKi prescribed, 64 (52%) were treated with a BTKi as initial therapy, 42 (34%) as second line, and 18 (14%) as third or later line. BTKi were started at the FDA label dose in 94 patients (76%), with the rest initiated at a reduced dose. Forty-six (37%) required a dose reduction during treatment, primarily due to drug toxicity (n=37). Specifically, the most common reasons cited for dose reduction were cytopenias (n=10) and failure to thrive (n=6). Toxicity was the cause of discontinuation for 50% of the ibrutinib courses, 39% of acalabrutinib, and 33% of zanubrutinib. The most common specific causes for discontinuation were infection (n=15), bleeding (n=10), arrhythmia (n=9), and disease progression (n=9). Ibrutinib had higher rates of new symptomatic tachyarrhythmias or stroke compared to acalabrutinib and zanubrutinib (16.5% vs. 0%, p=0.045), while use of hemodialysis was not associated with increased rates of these cardiovascular events. Neither the BTK inhibitor choice nor hemodialysis were associated with an increased incidence of severe infections requiring hospitalization or intravenous antimicrobials.

Among the 103 patients who received ibrutinib, the median duration of therapy (DoT) was 33.4 months, and the median overall survival (OS) was 49 months. The most common attributed causes of death were infection (n=19), disease progression (n=10), and renal failure (n=10). In multivariable regression, factors that impacted DoT included subsequent dose reduction (HR 0.45, 95% CI 0.24-0.82), eGFR at initiation at BTK initiation (HR 0.98, 95% CI 0.96-0.998), history of cirrhosis (HR 6.06, 95% CI 1.34-19.9), and history of heart failure (HR 3.90, 95% CI 1.73-8.50). Covariates including age, use of dialysis, racial-ethnic group, rural residence, body mass index, history of atrial fibrillation, and deletion 17p were not significantly associated with DoT in this cohort. 81 of 103 patients who received ibrutinib were evaluable for a hematologic response. The overall hematologic response rate for ibrutinib was 81.5% (95% CI, 71.7 – 88.4). Dose reductions of ibrutinib did not significantly reduce the response rate to ibrutinib or worsen progression-free survival in this cohort.

Compared to a separate cohort of veterans with eGFR ≥ 30 ml/min/1.73m² and CLL treated with ibrutinib during the same time period (n=2,328), this cohort of veterans with more severe renal dysfunction (n=115) had worse overall survival (median OS 49.0 vs. 66.9 months; HR 1.35, p = 0.03) (Fig 1A). While veterans with more severe renal dysfunction had numerically shorter DoT with a BTKi, this was not a statistically significant difference (median DoT 21.6 vs. 31.8 months; HR 1.16, p = 0.14) (Fig 1B). Patients receiving a lower initial dose of ibrutinib had a numerically longer DoT than full dose (median DoT 26.0 vs. 19.6 mo; HR 0.67, p = 0.23) (Fig 1C). Subsequent dose reductions of ibrutinib were associated with a longer DoT (median DoT 55.9 vs. 19.6 months; HR 0.45, p = 0.002) (Fig 1C).

Figure 1.

(A) Kaplan-Meier analysis of overall survival using log-rank testing to compare between patients receiving ibrutinib with an eGFR ≥ 30 ml/min/1.73m2 vs. those with an eGFR < 30 ml/min/1.73m2. Survival from initiation of BTK inhibitor was worse in those with more severe renal dysfunction. (B) Time-to-event analysis of the duration of ibrutinib therapy by severity of renal dysfunction, demonstrating a numerically shorter duration of therapy in severe renal failure, but without statistical significance. (C) Time-to-event analysis of different dosing strategies for ibrutinib vs. maintaining the full dose. In pairwise comparisons to full dose, there was a significant difference in favor of subsequent dose reduction for prolonging the duration of ibrutinib therapy. eGFR: estimated glomerular filtration rate, CI: confidence interval, BTK: Bruton Tyrosine Kinase, mo: months.

Nine of 115 patients (8%) had CLL-related kidney dysfunction and confirmed to have associated findings on kidney biopsy. The relevant findings on pathology were interstitial infiltration by CLL (n=6), membranoproliferative glomerulonephritis (n=2), and light chain cast nephropathy (n=1). While prior studies have shown improvements in mild-moderate renal dysfunction after CLL therapy, severe renal dysfunction did not improve with BTK inhibition in any of the 115 patients in this cohort (6).

Given the limitations of retrospective chart review in assessing symptomatic improvement, and the infrequency of real-world use of subsequent imaging to assess lymph node and spleen size response, all responses were graded to a maximum of partial response primarily for hematologic improvements in circulating lymphocyte counts and peripheral cytopenias. Furthermore, the majority of patients in this cohort were on ibrutinib and primarily in the first line. Therefore, extrapolation of these results to later generations of BTK inhibitors and subsequent lines of therapy should be performed with caution.

The clinical outcomes of BTKi use in CLL patients with significant renal dysfunction (eGFR < 30 ml/min/1.73m²) have not been well-described. Our real-world VHA study of U.S. veterans, which featured a high proportion of African American and elderly patients, demonstrated that BTKi are a reasonable therapeutic option even in the setting of severe renal impairment, including patients on hemodialysis. Using BTK inhibition during hemodialysis was not associated with increased cardiovascular or infectious complications. The poorer survival in patients with severe renal failure on BTK inhibitors may be more related to renal failure as an adverse risk rather than suboptimal response to BTK inhibition. Nonetheless, dose reductions of the BTKi may help to improve tolerability in this population without significantly reducing efficacy.

Data availability statement

Please contact the corresponding author for inquiries regarding data availability.