Characteristics and Clinical Outcomes of Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Receiving Ibrutinib for ≥5 Years in the RESONATE-2 Study

Simple Summary Ibrutinib is an established standard of care in the first-line treatment of chronic lymphocytic leukemia. Since ibrutinib is given continuously, data on long-term treatment, outcomes, and safety are essential to inform clinical decision making. Here, we describe characteristics and outcomes of patients who received long-term treatment with ibrutinib for ≥5 years in the phase 3 RESONATE-2 study. More than half (58%) of the patients randomly assigned to receive ibrutinib in the RESONATE-2 study continued to benefit from ibrutinib treatment for ≥5 years, regardless of baseline characteristics. Among patients who were on ibrutinib treatment for ≥5 years, complete response rates improved over time through the 5 years. The safety profile of ibrutinib treatment for ≥5 years was consistent with previous reports and no new safety signals were identified. For patients who experienced adverse events, dose modification was effective in resolving adverse events, thereby facilitating continued treatment. Abstract Primary results from the phase 3 RESONATE-2 study demonstrated superior efficacy and tolerability with ibrutinib versus chlorambucil in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Here, we describe characteristics and outcomes of patients who received ibrutinib treatment for ≥5 years in RESONATE-2. Patients aged ≥65 years with previously untreated CLL/SLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n = 136) or chlorambucil 0.5–0.8 mg/kg for ≤12 cycles (n = 133). Baseline characteristics in ibrutinib-randomized patients (n = 136) were generally similar between patients on ibrutinib treatment for ≥5 years (n = 79) versus those on treatment for <5 years (n = 57). In patients on ibrutinib treatment for ≥5 years, complete response rates improved over time, reaching 42% by 5 years. Estimated 7-year progression-free survival and overall survival rates were 82% and 94%, respectively. Adverse events (AEs) led to dose reductions in 16/79 patients (20%); these AEs were resolved for 13/16 patients (81%). AEs led to dose holds (≥7 days) in 45/79 patients (57%); these AEs were resolved for 43/45 patients (96%). More than half (58%) of ibrutinib-randomized patients benefitted from ibrutinib treatment for ≥5 years regardless of baseline characteristics. Dose modification resolved AEs for most patients, thereby facilitating continued treatment.


Introduction
Ibrutinib is a once-daily oral Bruton tyrosine kinase (BTK) inhibitor that is approved as first-line treatment for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the United States, Europe, and other countries. Ibrutinib has the longest follow-up of any targeted therapy across multiple randomized phase 3 studies and is the only therapy to date that has demonstrated a significant overall survival (OS) benefit compared with chemotherapy/chemoimmunotherapy in patients with previously untreated CLL/SLL [1][2][3][4]. Initial approval of ibrutinib in the first-line setting was supported by results from the primary analysis of the phase 3 RESONATE-2 study, which demonstrated that ibrutinib was superior to chlorambucil with respect to both efficacy and tolerability [5]. With up to 8 years of follow-up (median: 82.7 months; range, 0.1-96.6 months) in the RESONATE-2 study, the majority of ibrutinib-randomized patients remained progression-free; median progression-free survival (PFS) was not yet reached at the latest data cut [1].
Previous studies suggest that patients who continue treatment with single-agent ibrutinib experience better survival outcomes than patients who discontinue treatment within the first few years [6][7][8][9]. Additionally, real-world evidence suggests that dose management (dose reduction or temporary dose holds for up to 1-2 weeks) results in improvement in or resolution of adverse events (AEs) [10] without impacting disease outcomes [6,[10][11][12][13][14][15][16][17][18]. Therefore, active management of AEs by dose modification might facilitate continued ibrutinib treatment and maximize clinical outcomes [12]. As of May 2022, the US prescribing information for ibrutinib includes updates to recommended dose modifications for AEs [19].
As it is the only BTK inhibitor with long-term follow-up for up to 8 years, we have the opportunity to examine efficacy and safety outcomes in patients with longer-term experience on ibrutinib treatment. Here, we describe characteristics and outcomes of patients who received treatment with ibrutinib for ≥5 years in the RESONATE-2 study.

RESONATE-2 (PCYC-1115 [NCT01722487]/PCYC-1116 [NCT01724346]
) is a multicenter, international, randomized, open-label, phase 3 study designed to compare the efficacy and safety of first-line treatment with ibrutinib versus chlorambucil in patients aged ≥65 years with previously untreated CLL/SLL who required therapy per the 2008 International Workshop on CLL (iwCLL) criteria [20]. Patients with del(17p) were excluded. Detailed methods were previously reported [5]. Briefly, eligible patients were randomly assigned in a 1:1 ratio to receive oral ibrutinib 420 mg once daily until occurrence of progressive disease or unacceptable toxicity, or chlorambucil 0.5 mg/kg, escalated to a maximum of 0.8 mg/kg as tolerated, on days 1 and 15 of each 28-day cycle for up to 12 cycles. After confirmation of progressive disease per iwCLL criteria [20,21], patients who were randomly assigned to the chlorambucil arm could cross over to second-line treatment with ibrutinib. Per protocol, ibrutinib was temporarily held for any unmanageable grade ≥ 3 AE that was considered by the investigator to be potentially related to the study's treatment. Other AEs, including AEs of grade 2 in severity, could be managed with a one-level dose reduction of ibrutinib if the AE was considered to be potentially manageable by dose reduction as judged by the investigator.
This study was performed in accordance with International Conference on Harmonisation Guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. The study protocol was approved by institutional review boards of each participating institution, and all patients provided written informed consent before participation in the study. This study was registered with ClinicalTrials.gov, numbers NCT01722487 and NCT01724346.

Analysis
The current exploratory analysis evaluated baseline demographics and clinical characteristics, overall response rates (per iwCLL criteria [20,21]), PFS, OS, prevalence of AEs over time, and AEs leading to dose modifications (per protocol) for ibrutinib-randomized patients who were on ibrutinib treatment for ≥5 years. Since the study protocol provided flexibility for dose reductions based on an investigator's judgment, additional analyses were performed to retrospectively determine the incidence of dose reductions due to AEs for which dose reductions are recommended in the recently updated US prescribing information (grade 2 cardiac failure, grade 3 cardiac arrhythmia, grade 3 or 4 nonhematologic AEs [excluding cardiac failure and cardiac arrhythmia], grade 3 or 4 neutropenia with infection or fever, and grade 4 hematologic AEs) [19].
Baseline characteristics were also evaluated as potential predictors for remaining on treatment for ≥5 years using a multivariate logistic regression model including the following baseline characteristics: age group, sex, Eastern Cooperative Oncology Group performance status, Cumulative Illness Rating Scale score, creatinine clearance, TP53 mutation status, IGHV mutation status, del(11q) status, disease histology, bulky disease, β-2 microglobulin, Rai stage, any history of cytopenia, lactate dehydrogenase level, and geographic region. Additionally, PFS and OS were analyzed in subgroups of patients with and without dose reductions in the overall population of all ibrutinib-treated patients; these exploratory post hoc analyses were not powered for significance, and comparative statistics are provided for descriptive purposes only. PFS and OS were estimated using the Kaplan-Meier method.

Baseline Characteristics
Within ibrutinib-randomized patients in the intention-to-treat population (n = 136), baseline characteristics in the subset of patients who were on ibrutinib treatment for ≥5 years (n = 79) were generally similar to those in the subset of patients who were on ibrutinib treatment for <5 years (n = 57) ( Table 1). Compared with the subset of patients who were on ibrutinib treatment for <5 years, the subset of patients who were on ibrutinib treatment for ≥5 years were more likely to be in the youngest age group (65-69 years; 37% vs. 19% of patients) and had a longer interval between initial diagnosis and initiation of study treatment (median 35 vs. 26 months).

Prevalence of AEs over Time
In patients who were on ibrutinib treatment for ≥5 years, the median duration of ibrutinib treatment was 89.2 months (range: 60.4-96.6). Median relative dose intensity of ibrutinib for these patients was 98% (range: 47-100). The most frequent AEs of any grade across the entire study period were diarrhea (42/79 patients; 53%), cough (34/79; 43%), and upper respiratory tract infection (33/79; 42%). Prevalence of the most frequent AEs of any grade and of grade ≥ 3 were generally highest in years 0-1 and decreased over time thereafter (Figure 3a  AEs of any grade (occurring in ≥25% of patients overall) by yearly interval; (b) Most frequent grade ≥ 3 AEs (occurring in ≥5% of patients overall) by yearly interval. Prevalence was determined by the proportion of patients with a given AE (existing event or new onset of an event) during each yearly interval. Multiple onsets of the same AE term within a specific yearly interval were counted once, and the same AE term continuing across several yearly intervals was counted in each of the intervals. Abbreviations: AE, adverse event; UTI, urinary tract infection; URTI, upper respiratory tract infection.

Dose Management with Ibrutinib Treatment
AEs led to dose reductions in 16/79 patients (20%) who were on ibrutinib treatment for ≥5 years and in 31/135 patients (23%) in the overall population of all ibrutinib-treated patients ( Table 2). Most patients (12/16; 75%) experienced only one AE leading to dose reduction. Among patients who were on ibrutinib treatment for ≥5 years, the lowest ibrutinib dose for most patients with dose reductions was 280 mg once daily (10/16 patients). At data cutoff, 3/16 patients were receiving ibrutinib 420 mg once daily, 10/16 were receiving 280 mg once daily, and 3/16 were receiving 140 mg once daily. The median duration of treatment with ibrutinib at a reduced dose was not reached (range: 8.4-84.0+ months) for patients who were on ibrutinib treatment for ≥5 years compared with 36.1 months (range: 0.0-84.0+) in all ibrutinib-treated patients with dose reductions (n = 31).
Following dose reduction, 13/16 patients (81%) had a resolution of the initial AE. Three patients had AEs that were not resolved at data cutoff (grade 3 malignant lung neoplasm, grade 2 fatigue, and grade 1 contusion in 1 patient each). When considering the subset of AEs for which dose reductions are recommended in the updated ibrutinib US prescribing information (as of May 2022), such AEs led to dose reductions in 4/79 patients (5%) ( Table 3). Among these patients, AEs did not recur or recurred at a lower grade in 3/4 patients; 1 patient had recurrence at the same grade AE 3 years after initial resolution (grade 3 atrial fibrillation), that resolved without further dose reduction. Patients who were on ibrutinib treatment for <5 years (n = 56) experienced similar rates of AEs leading to dose reduction (15/56; 27%). Most common reasons for dose reduction by system organ class in this subgroup were hematologic (n = 3), cardiac (n = 3), and dermatologic (n = 3). Dose reductions were more common in response to grade 3 AEs (n = 8); however, 100% of AEs (15/15) were initially resolved. Six patients (40%) experienced a recurrence of their AE at the same or higher grade.
AEs led to dose holds of ≥7 days in 45/79 patients (57%) who were on ibrutinib treatment for ≥5 years and in 79/135 patients (59%) in the overall population of all ibrutinibtreated patients (Table 4).
Among patients who were on ibrutinib treatment for ≥5 years, ibrutinib was restarted at 420 mg once daily after dose holds of ≥7 days for most patients (42/45 patients). Following a dose hold of ≥7 days, 43/45 patients (96%) had resolution of the initial AE.
Among patients who were on ibrutinib for ≥5 years, the frequency of AEs leading to dose reductions was highest in years 0-2 and lower in subsequent years, whereas the frequency of AEs leading to dose holds of ≥7 days remained relatively consistent across the first 6 years of treatment (Supplementary Figure S2).  (15) a The same patient may be counted in more than one category because of multiple AE events leading to dose holds; b Denominator is patients with dose holds ≥7 days because of any AE. Abbreviations: AE, adverse event; SOC, system organ class.

Concomitant Medications
Concomitant medications of clinical interest in patients who were on ibrutinib treatment for ≥5 years are shown in Supplementary Table S1. Anticoagulants and antiplatelet agents were frequently used during the treatment period (33% and 65%, respectively), as were antihypertensive medications, including agents acting on the renin-angiotensin system (61%), beta-blocking agents (46%), calcium channel blockers (35%), and other antihypertensives (10%). Overall, 67% of patients received medications to treat acid-related disorders, including proton pump inhibitors in 58% of patients.

Discussion
Results of the current analysis demonstrate that more than half of patients with previously untreated CLL/SLL were able to receive treatment with single-agent ibrutinib for ≥5 years. While real-world studies have suggested an increased risk of discontinuation of targeted therapies in patients with older age, higher comorbidity burden, higher tumor burden, and/or worse performance status at baseline [13,22,23], no individual baseline characteristics were identified as significant predictors for continuation of long-term ibrutinib treatment in the current study.
Among patients who were on ibrutinib treatment for ≥5 years, responses deepened over time. This subgroup of patients had a higher CR rate over the course of the study (46%) relative to the overall population of ibrutinib-randomized patients (34%) [1], suggesting that patients with favorable responses may be more likely to continue on ibrutinib treatment. In line with this, a higher PFS rate at 7 years was seen in patients who remained on long-term ibrutinib treatment for ≥5 years (82%) relative to the overall ibrutinib-randomized population (59%) [1]. These findings are consistent with those of previous studies, suggesting that continuation of ibrutinib treatment is associated with improved efficacy outcomes [6][7][8].
Safety results in patients who were on ibrutinib treatment for ≥5 years were consistent with those seen in the overall population of ibrutinib-treated patients, including incidences of AEs of clinical interest (hypertension, atrial fibrillation, and major hemorrhage) [1]. AEs generally decreased over time with continued ibrutinib treatment, and no new safety signals emerged in patients who received ibrutinib treatment for ≥5 years. Treatment with ibrutinib was well tolerated irrespective of the frequent use of concomitant antithrombotics, antihypertensives, and acid-reducing agents. Since AEs are the most common reason for discontinuation of ibrutinib in the first-line setting [1,[23][24][25][26][27][28], optimization of AE management is crucial to enabling patients to remain on long-term therapy. In the subgroup of patients who were on ibrutinib treatment for ≥5 years, active management of AEs with dose reductions or dose holds was associated with AE resolution in the majority (>80%) of patients. Additionally, dose reductions helped to prevent recurrence or worsening of AEs for most patients, facilitating continued benefit from ibrutinib treatment.
In the current study, disease assessments were performed at regularly scheduled intervals based on iwCLL criteria [20,21]. With up to 8 years of follow-up in the RESONATE-2 study, PFS and OS were similar between patients with and without dose reductions in the overall population of ibrutinib-randomized patients. Patients who had dose reductions received reduced doses of ibrutinib for extended periods of time (median of 3 years in all ibrutinib-treated patients with dose reductions). Together, these results suggest that patients experiencing AEs leading to dose reduction continue to benefit from ibrutinib at the reduced dose. While two real-world studies found significantly worse PFS in patients receiving ibrutinib at reduced doses (<420 mg once daily), this finding from RESONATE-2 is consistent with several other studies that have found no significant difference in efficacy outcomes between patients with dose reductions due to AEs compared to patients without dose reductions [10,[12][13][14][15][16]29,30].

Conclusions
Regardless of demographic and disease characteristics at baseline, more than half (58%) of the patients randomly assigned to the ibrutinib arm in the RESONATE-2 study continued to benefit from ibrutinib treatment for ≥5 years. With up to 8 years of follow-up, the subset of patients who received ibrutinib treatment for ≥5 years experienced sustained efficacy benefits as evidenced by improved depth of response over time and high PFS rates.
For patients who received ibrutinib treatment for ≥5 years, the safety profile was consistent with previous reports of long-term ibrutinib treatment and no new or unexpected AEs were observed. Dose modification (dose reduction or dose hold) was effective in resolving AEs for most patients, likely facilitating continuation of ibrutinib treatment.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/ 10.3390/cancers15020507/s1: Figure S1, Adverse events of clinical interest of any grade by yearly interval; Figure S2, AEs leading to dose modifications over time in patients on long-term ibrutinib treatment for ≥5 years; Table S1, Concomitant medications of clinical interest in patients on long-term ibrutinib treatment for ≥5 years.  honoraria from Gilead, Janssen, Novartis, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company; consulting/advisory role and speakers bureau for BeiGene, Gilead, Janssen, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company; research funding from AstraZeneca, BeiGene, and Pharmacyclics LLC; an AbbVie Company; travel/accommodations/expenses from Gilead, Janssen, Novartis, TG Therapeutics, and Pharmacyclics LLC; an AbbVie Company. This study was sponsored by Pharmacyclics LLC, an AbbVie Company. The sponsor was involved in study design, data analysis, data interpretation, writing/review of the manuscript, and the decision to publish the results. The sponsor had no role in data collection.