Dynamics of Hemorragic Events and Primary Hemostasis Deffects during Treatment with Ibrutinib. Real-Life Experience

INTRODUCTION: Ibrutinib is a first-in-class Bruton kinase inhibitor (BTK) registered for the treatment of Chronic Lymphocytic Leukemia (CLL), mantle cell linphoma (MCL) and Waldenström Macroglobulinemia (WM).

Increased risk of bleeding events is asociated with ibrutinib, mostly grade ≤2. Alleged mechanism for this risk could be the role of BTK in platelet activation via GPIb, GPVI and FVW.

We here present our experience regarding hemorragic events and hemostasis tests alterations in CLL patients (pts) treated with ibrutinib.

PATIENTS AND METHODS: 15 pts with relapsed CLL were started on ibrutinib between december/2012 and july/2016. Median age was 69 years (range: 42-83 years). 12 of them were male. Median exposure to the drug was 17 month (range 1- 38).

After 9 to 36 months from initiation of treatment (median 22 months) 6/15 were thouroughly interviewed about personal history of bleeding events and the following laboratory work was performed: factor VIII level, FVW antigen and activity, platelet function analysis (PFA-100^TM) with ADP and epinephrine, and aggregation studies with colagen, ADP and arachidonic acid. Along these tests all patients had blood counts with platelets more than 100 x 10e9/L.

RESULTS: 3 out of 15 pts had bleeding events (grade 1 or 2), 2 consisting in spontaneus bruising and 1 in upper grastrointestinal bleeding, in the first weeks of treatment. 4 pts underwent minor invasive procedures with no complications, witholding the drug at least 3 days before and after. 2 pts were on concomitant antiplatelet (1) or anticoagulant (1, LMWH, due to AF) and had no bleeding events.

All pts tested (6/6) had normal or slightly elevated leves of F VIII, FVW:Ag and FVW:Ac. 2 pts had abnormal PFA-100^TM and abnormal aggregations with any agonist. One case had normal PFA-100 ^TM while aggregations with colagen and AA were mildly altered.

COMMENTS: Our limited experience shows a moderate risk of minor bleedings consisting with a platelet disfunction drug-driven effect. Despite the fact that we have no baseline tests done, alterations in primary hemostasis test, including PFA-100^TM and specially aggregometry could be expected early on after exposure to ibrutinib.