Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib

Abstract

Ibrutinib is associated with bleeding-related adverse events of grade ≤ 2 in severity, and infrequently with grade ≥ 3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤ 2 bleeding-related adverse events in 55% of 85 patients. No grade ≥ 3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100™) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade ≤ 2 can be identified by clinical laboratory tests and counseled to avoid aspirin, non-steroidal anti-inflammatory drugs and fish oils. ClinicalTrials.gov identifier NCT01500733.

Figure 1.

Cumulative incidence of bleeding-related adverse events and platelet counts in patients receiving ibrutinib. (A) Incidence of bleeding-related adverse events on ibrutinib. The dashed lines represent the 95% confidence interval. 26% of patients experienced an event within the first 4 weeks. The cumulative event rate plateaued beyond 24 weeks, with 55% of patients reporting a first bleeding event at a median follow-up time of 24 months. (B) Mean platelet counts in all 85 patients for the first 6 months on ibrutinib are depicted. One-sided error bar shows SEM. (C) Comparison of platelet counts (box and whisker plot 10–90 percentile) in patients with and without bleeding. There was no statistically significant difference.

Figure 2.

Analysis of vWF activity, vWF antigen and Factor VIII levels in patients on ibrutinib. (A–C) Change in vWF activity, vWF antigen, and Factor VIII levels on day 28 compared to baseline. Dashed lines indicate normal reference range. Comparison by Paired Student’s t-test.

Figure 3.

Baseline predictors of an increased risk of developing a bleeding-related adverse event on ibrutinib. (A–C) Cumulative incidence of bleeding stratified by dichotomized cut-offs for EPI closure time, Factor VIII level, and vWF activity. P values were calculated via univariate Cox regression analyses.

Figure 4.

Collagen-induced platelet aggregation and dense granule release. Platelet aggregation and dense granule release in response to collagen in normal controls (n=12), treatment-naïve CLL patients (n=14), CLL patients on ibrutinib (n=30), and XLA patients (n=3). All graphs show means +/− SEM. (A) Maximum 5 mμ/mL collagen-induced aggregation at 6 minutes was significantly inhibited in treatment-naïve CLL patients and ibrutinib-treated CLL patients, compared to healthy controls. Results in XLA patients are shown for comparison. Ibrutinib-treated patients exhibited impaired aggregation compared to treatment-naïve CLL patients (mean reduction 19%, P=0.041 at high dose). XLA patients demonstrated aggregation in a similar range to patients on ibrutinib at high dose. (B) Dense granule release was decreased by >80% in treatment-naïve CLL patients and by >60% in CLL patients on ibrutinib, but was in the normal range for XLA patients. (P<0.0001 between control and CLL patients or ibrutinib patients). (C) Untreated CLL patients exhibited impaired ADP-induced platelet aggregation compared to untreated controls. Platelets from ibrutinib-treated patients exhibited an intermediate level of ADP aggregation that was greater than platelets of untreated CLL patients, yet less robust than healthy controls. (D) Measurement of dense granule release after ADP stimulation demonstrated a marked defect in untreated CLL patients, with platelets from ibrutinib-treated patients also exhibiting a defect compared to healthy controls, but superior ATP release than in untreated CLL patients.