Disease Progression on Ibrutinib Therapy Is Associated with a Poor Clinical Outcome in Chronic Lymphocytic Leukemia (CLL) Patients Managed in Standard Clinical Practice

Abstract Introduction: Ibrutinib is an irreversible Bruton Tyrosine Kinase (BTK) inhibitor that has shown efficacy in the treatment of CLL as a front-line therapy or in patients with relapse/refractory (RR) disease. Anecdotally, accelerated disease progression and refractoriness to subsequent therapies in CLL or other B-cell malignancies patients treated with ibrutinib has been observed. In our present contribution, we studied in a real-world patient population the clinical outcome of CLL patients treated with ibrutinib who discontinued therapy. Methods: We conducted a comprehensive retrospective analysis on CLL patients receiving ibrutinib at our Institute. Demographic characteristics, response to subsequent therapies, and results of FISH analysis were obtained. Correlation between clinical outcomes and status on ibrutinib therapy (responding, progressing, or discontinuing due to toxicity) was performed. Statistical analysis was carried out in SPSS v20. Chi Square, Fisher's exact test were used to compare categorical data, Kaplan Meier and Log rank tests for time to event analysis and Cox regression for univariate analysis. Results: A total of 70 CLL patients treated with ibrutinib were followed for a median period of 19.4 mo [ range 0.3 - 41.3]. Sixty-three patients had RR CLL and 7 received ibrutinib as frontline therapy. Our patients had a median age of 67.9 years (46 - 92), a majority had advanced stage disease (Rai stage 3 - 31.4%, Rai stage 4 - 41.4%). Median number of prior treatments was 2 (range 0-7). Overall response rate (ORR) to ibrutinib was 52.8% (complete response [CR] - 11.4%, partial response [PR] - 41.4%]. Additionally, stable disease [SD] was present in 25.7% leading to a Clinical Benefit Rate (CBR) of 78.5%. A total of 25 (38%) patients discontinued therapy. Reasons for discontinuation included progressive disease (PD) in 13 (52%) (5 with Richter's transformation [RT]), drug toxicity (DT) in 7 (28%), and other reasons in 5 (20%) patients. DTs included atrial fibrillation (n=2), sepsis (n=2), pneumonia (n=1), congestive heart failure (n=1) and fatigue (n=1). Other reasons for discontinuation were other terminal cancer (n=2), patient preference, alcoholism and insurance issues. Univariate analysis showed an increased risk of discontinuation associated with del(13q) (HR 1.56, 95%CI 0.7-3.7, p=0 .32), ATM deletion (HR 1.32, 95%CI 0.5-3.4, p=0 .57), Unmutated IgH (HR 3.5, 0.5-27.3, p=0 .23) though none reached statistical significance. We did not observe an increased risk of discontinuation in patients with del(17p) (HR 0.80, 95%CI 0.3-2.7, p=0 .72). Cytogenetic data after ibrutinib discontinuation was available in 12 patients and showed new onset del(13q) (n= 3), del(17p) (n= 4) and ATM deletion (n= 1) including 1 patient who had complex cytogenetics (≥3 cytogenetic abnormalities). In patients who discontinued therapy, we observed a mortality rate of 72% (18/25) with a median overall survival (OS) of 17.8 mo (95% CI, 7.4-28.2); in comparison, median OS was not reached in patients who remained on therapy (p Disclosures No relevant conflicts of interest to declare.