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Real-World Study Supports Ibrutinib Dose Reduction for Managing Adverse Events in CLL
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Reducing the dose of ibrutinib following adverse events improved tolerability without compromising clinical efficacy in chronic lymphocytic leukemia (CLL).
Real-world data showed that ibrutinib (Imbruvica; Janssen Biotech, Inc) dose reduction (DR) is an effective method of adverse event (AE) management in patients with chronic lymphocytic leukemia (CLL), according to study results published in Leukemia & Lymphoma. The authors found that DR improved tolerability without compromising clinical efficacy.1
Pharmacist holding package of ibrutinib |Image Credit: © CLShebley - stock.adobe.com
In 2025 alone, more than 23,000 people in the US are anticipated to receive a diagnosis of CLL, the most prevalent form of leukemia in adults. The gradual growth of clonal mature B lymphocytes is its defining feature. Bruton tyrosine kinase (BTK) inhibitors, which help control the B-cell receptor signaling pathway to stop cancer cell development, are one type of targeted therapy that has significantly improved CLL outcomes and prognoses.2
As the first BTK inhibitor approved by the FDA, ibrutinib has demonstrated a substantial improvement in overall survival and progression-free survival in multiple randomized phase 3 trials involving patients with relapsed/refractory CLL or small lymphocytic lymphoma (SLL) who had not previously received treatment. Despite the evident efficacy of BTK inhibitors, including ibrutinib, many patients discontinue treatment due to complications with tolerability and AEs.1
About the Study
Various formulations of ibrutinib offer DR strategies, leading investigators to describe in this trial the dosing patterns, time to next treatment (TTNT), health care resource use (HRU), and costs in patients with CLL who had or had not received ibrutinib DR following an AE. The retrospective real-world study utilized data across 3 databases—Optum Clinformatics Data Mart (CDM), ConcertAI, and Medicare Fee-for-Service (FFS). They focused on enrollment and claims data, which included inpatient and outpatient medical claims, pharmacy claims, and estimated costs of medical services from recipients of commercial health insurance and Medicare Advantage.1
Eligible patients were 18 years or older diagnosed with CLL/SLL who initiated first-line (1L) ibrutinib at a starting dose of 420 mg per day, had an incident AE following the initiation of 1L ibrutinib, had a 12-month or longer baseline period prior to starting 1L ibrutinib, and had 30 to 90 days or more of continuous eligibility following initiation of 1L ibrutinib. Patients with and without DRs after an AE occurred were documented in terms of demographics, clinical features, treatment patterns, and TTNT across the 3 databases.1
First-incident AEs were divided into groups related and unrelated to the heart, according to the United States prescribing instructions for ibrutinib. ICD-9-CM/ICD-10-CM codes were used to identify cardiac AEs, including ventricular tachyarrhythmia (cardiac arrhythmias), hypertension, cardiomyopathy, ischemic heart disease, heart failure, congestive heart failure (cardiac failure), and atrial fibrillation (cardiac arrhythmias). ICD-9-CM/ICD-10-CM codes were used to identify noncardiac AEs, which included feverish neutropenia, anemia, neutropenia, pancytopenia, thrombocytopenia, diarrhea, abdominal discomfort, musculoskeletal pain, rash, respiratory infection (pneumonia), lymphopenia, and leukopenia.1
Optum CDM Dataset
There were 658 CLL/SLL patients treated with 1L ibrutinib who had an AE in the Optum CDM dataset. Following the first episode of AEs, 563 patients (86%) in this sample did not have a DR, whereas 95 individuals (14%) did.1
The TTNT in patients with a DR was 32.9 months compared with 27 months in patients with a DR following first-incidence AE at the median follow-up of 32.9 months. The median TTNT was 59.5 and 30.6 months, respectively (adjusted hazard ratio [HR] 0.62; 95% CI 0.42–0.92; P = .017). Patients who experienced cardiac AEs, with and without DR, had a median TTNT or death of 44.4 and 22.9 months (adjusted HR 0.74; 95% CI, 0.38–1.44; P = .374), respectively. Those with noncardiac AEs with DR had a median TTNT of 59.5 months and in those without DR, TTNT not reached (adjusted HR 0.45; 95% CI, 0.24–0.85; P = .013).1
Patients with a DR had significantly lower mean per-patient-per-month (PPPM) all-cause inpatient hospital admissions compared with those without a DR (0.05 vs 0.14, P < .001). The mean number of all-cause outpatient visits was similar between groups (2.71 vs 2.87, P = .457), while the mean number of all-cause emergency department visits was significantly lower in patients with a DR (0.10 vs 0.22, P = .043). For CLL/SLL-related health care utilization, inpatient hospital admissions were lower in patients with a DR (0.04 vs. 0.09, P < .001), and outpatient visits showed no significant difference (1.14 vs 1.33, P = .237). Patients with a DR had significantly lower CLL/SLL-related medical costs PPPM throughout the follow-up period, averaging $2,335 compared to $6,884 for those without a DR.1
Medical illustration of chronic lymphocytic leukemia | Image Credit: © AI Photo Stock - stock.adobe.com
ConcertAI Dataset
In the ConcertAI database, 95 patients (18%) and 427 patients (82%) of the 522 patients experienced a DR after their first occurrence of AE. After the first incident AE, patients with a DR had a median follow-up of 20.5 months, whereas those without a DR had a median TTNT of 18.0 months. The adjusted HR for patients with a DR was 0.71 (95% CI, 0.53–0.96; P = .027), matching the adjusted HR for patients without a DR (0.71; 95% CI, 0.53–0.96; P = .027).1
In patients with cardiac AEs, with and without DR, the median TTNT or death was 29.9 and 18.3 months (adjusted HR 0.69; 95% CI, 0.45–1.04; P = .077), respectively. Those with noncardiac AEs had a median TTNT of 24.9 and 18.0 months (adjusted HR 0.73; 95% CI, 0.46–1.17; P = .190).1
The mean PPPM all-cause inpatient hospital admissions were similar between patients with and without a DR (0.52 vs 0.54, P = .893). However, the mean number of all-cause outpatient visits was significantly lower in patients with a DR (0.31 vs 0.45, P = .027), while all-cause emergency department visit rates did not differ significantly (0.03 vs 0.05, P = .298). For CLL/SLL-related health care utilization, inpatient hospital admissions were comparable between groups (0.16 vs 0.15, P = .752), as were outpatient visits (0.06 vs 0.07, P = .627).1
Medicare FFS Dataset
A total of 3575 patients treated with 1L ibrutinib for CLL/SLL were identified in the Medicare FFS dataset. Among them, 459 patients (13%) underwent a DR following the first incident AE, whereas 3116 patients (87%) did not.1
In terms of treatment outcomes, the median follow-up was 31.7 months for patients with a DR and 24.0 months for those without a DR. The median TTNT was longer for patients with a DR at 49.8 months, compared with 22.0 months for those without a DR. However, the adjusted HR for TTNT in patients with a DR versus those without a DR was 0.89 (95% CI 0.71–1.12; P = .330), indicating no statistically significant difference between the groups.1
For patients who experienced cardiac AEs, the median TTNT or death was 49.6 months in those with a DR compared with 14.0 months in those without a DR (adjusted HR 0.90; 95% CI 0.71–1.13; P = .36). Among patients with noncardiac AEs, the median TTNT was 53.0 months for those with a DR and 24.7 months for those without a DR (adjusted HR 0.91; 95% CI 0.73–1.15; P = .45).1
The mean PPPM all-cause inpatient hospital admissions were identical in both groups (0.04 vs 0.04, P < .001). The mean number of all-cause outpatient visits was slightly higher in patients with a DR (0.81 vs 0.80, P < .001), while emergency department visit rates remained the same (0.07 vs 0.07, P < .001). Regarding CLL/SLL-related health care utilization, inpatient hospital admissions were also identical (0.03 vs 0.03, P < .001), while outpatient visits were slightly lower in patients with a DR (0.37 vs 0.40, P < .001). Patients with a DR incurred significantly lower CLL/SLL-related medical costs PPPM compared with those without a DR ($1127 vs $1303, P < .001).1
The findings from this real-world study highlight that DR of ibrutinib following an AE can be an effective strategy for improving treatment tolerability without significantly impacting clinical outcomes. These insights underscore the importance of personalized treatment approaches in managing CLL/SLL, optimizing both patient outcomes and health care resources.
