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

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 <0.05). A lower median OS was observed in patients who discontinued due to DT (5.9 mo, 95% CI, 3.9-8), compared to those with RT (11.5 mo, 95% CI 3.1-20), PD (18.2 mo, 95%CI 3.8-32.6) though this was not statistically significant (p= 0.117). Despite trends towards lower median OS in patients who discontinue ibrutinib, univariate analysis did not show a statistically significant association with del(13q) (HR 1.8, 95%CI 0.7-5, p=0 .248), ATM deletion (HR 1.32, 95%CI 0.5-3.9, p=0 .61), Unmutated IGH (HR 1.08, 95%CI 0.13-9, p=0 .94), and ZAP70+ (HR 1.15, 95%CI 0.36-3.64, p=0 .81). Two patients had complex cytogenetics with a median OS of 1.5 mo (HR 4.5, 95%CI 0 .9-22.4, p <0.05). Thirteen patients received subsequent therapy after ibrutinib discontinuation with idelalisib (n=3), lenalidomide (n=3), rituximab with bendamustine (n=2), R-CHOP (n=2), or other treatments (n=3). ORR to post ibrutinib therapy was 23.1% with CR in 3/13 patients (reason for discontinuation- RT - 1, other reasons- 2). Two patients had SD (both discontinued Ibrutinib for PD) leading to a CBR of 38.5%. Eight of 13 patients had PD and died during follow up period. Conclusion: Ibrutinib has good efficacy in the treatment of CLL as front-line therapy and in relapse refractory disease in a real-world setting. However, patients who discontinue therapy have poor survival outcomes and poor response to salvage therapy.