Dose Reductions in Ibrutinib Therapy Are Not Associated with Inferior Outcomes in Patients with Chronic Lymphocytic Leukemia (CLL)
Authors: Akhtar Othman S. , Attwood Kris , Lund Ian , Hare Ryan , Hernandez-Ilizaliturri Francisco J. , Torka Pallawi 
Published: October 2019

Abstract
Introduction: Ibrutinib is a first-in-class small molecule inhibitor that binds irreversibly to Bruton's Tyrosine Kinase (BTK) and has shown remarkable efficacy in the treatment of CLL. Current guidelines recommend life-long therapy with administration at a fixed daily dose of 420 mg. However, lower doses of ibrutinib have been demonstrated to adequately abrogate kinase function. Limited clinical data suggests that dose reductions are not associated with inferior outcomes. Hypothetically, judicious dose reductions to manage toxicities could result in improved tolerance and decreased discontinuation rates. Our objective was to study the impact of dose reductions on outcomes in CLL patients treated with ibrutinib in a real-world setting. Methods: We conducted a retrospective chart review of all CLL patients treated with ibrutinib at Roswell Park Comprehensive Cancer Center between January 2014 and June 2017. Patients who underwent ibrutinib dose reduction were identified. Baseline characteristics and outcomes were compared between patients who underwent dose reductions vs those who did not. Reason and timing of dose reduction was also elucidated. Mann-Whitney U and Fisher's Chi Square test were used to compare groups, Kaplan Meier methods were used for time to event analysis, and Cox regression was used to obtain hazard ratios (HR). Overall survival (OS) was calculated as time from start of ibrutinib until death or last follow-up, freedom from progression (PFS) was taken as time from start of ibrutinib until progression or last follow-up. All analyses were performed in SAS v9.4 (Cary, NC). Results: A total of 70 CLL patients treated with ibrutinib were followed for a median period of 21.9 months. Most patients had RR disease (n = 63) and 7 received ibrutinib as frontline therapy. All patients received a fixed dose regimen with the standard dose of 420 mg once daily. Twenty-three (31.3%) patients required dose reductions and received ibrutinib at a median dose of 140 mg . Eleven (47.8%) of these had dose reductions within 3 months of treatment initiation. There was no statistically significant difference in baseline characteristics including age, number of prior lines of treatment, WBC count, hemoglobin or LDH level in the dose reduced group (DRG) and standard dose group (SDG). Patients in the DRG had a lower median platelet count at initiation of ibrutinib than patients in the SDG (86 x 103/mm3 vs 145 x 103/mm3, p<0.05). The most frequent reasons for dose reductions included cytopenia (n=8), fatigue (n=5), infections (n=4) and atrial fibrillation (n=3) with 2 patients requiring dose reduction due to simultaneous CYP inhibitor administration. There was no statistically significant difference in the overall response rate (ORR) (p=0.25) and clinical benefit rate (CBR) (p=1.00) between the DRG (ORR- 65.2%, CBR- 91.4%) and SDG (ORR 78.7%, CBR 91.5%). Median PFS and OS was not reached in both groups. PFS at 12 months was 86% (95% CI 63-95%) and 87% (95% CI 71- 94%) in the DRG and SDG respectively (p=0.92). OS at 12 months was 83% (95% CI 60-93%) and 84% (95% CI 69-92%) in the DRG and SDG respectively (p=0.53). We noticed no statistically significant difference in the median PFS and OS between the two groups (Figure 1). In a subgroup analysis, we compared outcomes in patients in the SDG with those who had dose modifications within 3 months of initiating therapy or later and found no statistically significant differences in OS and PFS between the groups (p=0.15 and p=0.46 respectively). Of the 23 patients requiring dose modifications, 11 (47.8%) had to eventually discontinue therapy as compared to 17 (36.2%) patients in the SDG and we noticed similar 1-year discontinuation rates in the DRG and SDG groups (22% vs 21% respectively, p=0.91). Conclusion: In CLL patients treated with ibrutinib, reductions in the dose of ibrutinib were not associated with worse outcomes. These results extended to all patients with dose modifications, irrespective of whether the modification was made within 3 months of treatment initiation, or later in the course of treatment.

Disclosures
No relevant conflicts of interest to declare.