Analysis of Primary Hemostasis Alterations Induced By Ibrutinib Assessed By Shutter Speed and Aggregometry Impedance

Introduction:

Ibrutinib is a covalent inhibitor of Bruton Tyrosine Kinase (BTK), approved for the treatment of Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL) and Waldenstrom's Macroglobulinemia (WM). BTK is expressed in platelets and is believed to have a central role in platelet activation through GPIb and GPIV pathway. However, the clinical significance of inhibition of BTK is unclear in terms of bleeding and it is known that patients with congenitally deficient BTK do not exhibit increased risk of bleeding.

Objectives:

The main objectives were: (1) identify possible alterations in hemostasis induced by Ibrutinib in patients who start taking the drug, and (2) to monitor the development of hemorrhagic adverse effects in patients who start taking Ibrutinib.

Methods:

From August 31, 2015 and January 31, 2016 we conducted a prospective study including all consecutive patients with the diagnosis of MCL, CLL or WM treated in 2nd line or more, with Ibrutinib as single-drug therapy. The following parameters were analyzed on day 0 (baseline), 10 and 28 after starting treatment with Ibrutinib: APTT, PT, platelet count, PFA-100 Collagen/Epinephrine and Collagen/ADP, aggregometry impedance in whole blood by multiplate assay with AA, ADP, Ristocetin and TRAP as agonists. Von Willebrand factor antigen (vWF:Ag), Ristocetin cofactor (vWF:RCo) and coagulant factor VIII were also analyzed. We collected prospectively bleeding adverse events.

Results:

In the period of study, we enrolled 11 patients, 7 were males and 4 females, with a median age of 63 years old (range, 53-88). Five patients had the diagnosis of CLL, 5 patients had MCL and 1 patient had WM. After a median follow-up of 6 months, 3 out of 11 (27.3%) developed grade 1 bleeding adverse events. Of these, 1 patient was under anticoagulant treatment with intermediate dose of enoxaparin, and another patient had low levels of vWF:Ag and vWF:RCo, suggesting a possible acquired von Willebrand disease. Five out of 11 (45.5%) of patients had a prolonged shutter speed Collagen/Epinephrine at baseline, with a median of 175 sec (range, 94-270). After Ibrutinib exposure, median shutter speed Collagen/epinephrine at 10 days was 231 sec (range, 108-287), p=0.02; and at 30 days was 142 sec (range, 79-300), p=n.s. Four out of 11 patients (36.4%) had a prolonged shutter speed Collagen/ADP at base line, with a median of 105 sec (range, 63-190). After Ibrutinib exposure, median shutter speed Collagen/ADP at 10 days was 107 sec (range, 66-192), p=n.s; and at 30 days was 78 sec (range, 75-149), p=n.s. Regarding platelet aggregometry impedance, 2 patients had abnormal platelet aggregation baseline at TRAP assay, 6 at ADP assay, 3 at AA assay and 4 at Ristocetin assay. After Ibrutinib exposure, there was a worsening of platelet aggregation in ADP analysis at 10 days of treatment but became normal after 30 days of treatment. There was an improvement with TRAP at both 10 and 30 days of treatment. Of notice, all 3 patients with minor bleeding had abnormal hemostasis studies baseline before starting with Ibrutinib.

Conclusions:

Almost half of patients showed an altered haemostasis baseline studies before starting with Ibrutinib. The biology of the disease appears to cause in subjects primary hemostasis changes that result in a basal bleeding risk regardless of the treatment used. Only minor bleeding complications were observed under Ibrutinib treatment, all with baseline altered platelet function; 2 of the three patients who developed bleeding complications had other bleeding risk factors associated. PFA-100 Collagen/Epinephrine is prolonged in almost 50% of patients after Ibrutinib is started compared with baseline study. Aggregometry impedance only worsened with ADP at 10 days, but went into normal level at 30 days. There is an interindividual variability in alterations of haemostasis and hemorrhagic clinical signs.