CLINICAL AND LABORATORY CHARACTERIZATION OF PLATELET DYSFUNCTION DURING IBRUTINIB TREATMENT IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA. MONOCENTRIC EXPERIENCE.
(Abstract release date: 05/18/17)
EHA Library. Innocenti I. 05/18/17; 182494; PB1780
Dr. Idanna Innocenti
Contributions
Contributions
Abstract
Abstract: PB1780
Type: Publication Only
Background
Ibrutinib (IBR) is a potent and irreversible inhibitor of Bruton's tyrosine kinase (Btk) approved by FDA for the treatment of patients (pts) affected by chronic lymphocytic leukemia (CLL) with del 17p or TP53 mutation or for pts with relapsed/refractory (R/R) CLL. IBR is associated with bleeding events usually mild (Common Toxicity Criteria (CTC) grades 1-2), rarely severe (grade 3-4). A defect of platelet function, namely an inhibition of Btk-mediated signaling by platelet glycoproteins (GP) GPVI and GPIb, has been hypothesized to cause these bleedings. IBR associated bleedings and platelet dysfunction may be relevant in CLL pts who are usually elderly and with comorbidities requiring antithombotic therapies.
Aims
To investigate and characterize the effect of IBR on platelet function in pts with CLL.
Methods
We enrolled from May 2014 to December 2016 twenty pts with CLL treated with orally administered 420 mg daily of IBR; 18 R/R CLL pts received IBR in monotherapy and 2 pts with previously untreated CLL received IBR in association with anti-CD20 MoAb. Median age was 68 years (57-84); 13 pts had unmutated IgVH and 2 had 17p deletion. The median number of prior therapies in R/R CLL pts was 3 (2-7). Five pts discontinued IBR therapy: 2 for Richter's transformation, 1 for progressive CLL, 1 underwent allogeneic HSCT, 1 for heart disease. The platelet function was studied before and during IBR by light transmission aggregometry (LTA) using platelet-rich plasma and the following agonists: ADP 2-4 uM, PAR1-AP 25 uM, Collagen 10-3.3-2 ug /mL, arachidonic acid 1 mM, ristocetin 0.6-1.2 mg/mL. Also measurements of von Willebrand factor antigen (vWF:Ag) and ristocetin cofactor activities (RiCo) by chemiluminescent immunoassay were performed. All pts had measurements of the platelet function at the baseline and after 1, 3, 6 months initiation of IBR and then every 3 months up to 24 months. Median observation period was 9 months. No patient received concomitant antiplatelet or anticoagulation therapy.
Results
Nineteen pts achieved a partial response and an increase of hemoglobin and platelet count. We recorded CTC grade 1 or 2 bleedings (bruising, petechiae, conjunctival and retinal hemorrhage, rectal bleeding) in 15 pts; no patient needed IBR interruption or dose reduction. All pts displayed severe impairment of collagen induced aggregation upon IBR. Reduction of maximal aggregation (35.6+/- 32% vs 70.6+/- 21% baseline) and prolongation of the lag phase (261+/- 54 sec vs 72+/- 26.8 sec baseline) by 2 ug/mL collagen was measured in all pts during IBR. In 10 pts a significant improvement of the aggregation by 2 uM ADP (71+/- 31.8% vs basal 48.6+/- 31%) and 4 uM ADP (84+/- 11% vs basal 64+/- 25%) was found during IBR. The aggregation by 25 uM PAR1-AP, 1.2 mg/ml ristocetin and 1 mM arachidonic acid was unchanged before and under IBR. Finally, in 9 pts the vWF:Ag and RiCo were high at the onset of the disease (163+/- 59.8% and 181.6+/- 82.5%) and reduced up to normal values under IBR (118+/- 71% and 145+/- 65%).
Conclusion
Our study showed minor bleedings in pts treated with IBR. A severe impairment of collagen-induced aggregation was caused by IBR, which was counteracted by amelioration of ADP-induced aggregation, that could explain, at least partially, the mild clinical phenotype in treated pts. The assessment of platelet function in IBR treated CLL pts could help to predict and monitor the bleeding risk, and to guide pts through invasive procedures. In addition, pts under anticoagulant or antiplatelet treatment might need be carefully monitored by clinical and laboratory evaluation.
Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical
Keyword(s): Platelet aggregation, Inhibitor, Bleeding, B cell chronic lymphocytic leukemia
Abstract: PB1780
Type: Publication Only
Background
Ibrutinib (IBR) is a potent and irreversible inhibitor of Bruton's tyrosine kinase (Btk) approved by FDA for the treatment of patients (pts) affected by chronic lymphocytic leukemia (CLL) with del 17p or TP53 mutation or for pts with relapsed/refractory (R/R) CLL. IBR is associated with bleeding events usually mild (Common Toxicity Criteria (CTC) grades 1-2), rarely severe (grade 3-4). A defect of platelet function, namely an inhibition of Btk-mediated signaling by platelet glycoproteins (GP) GPVI and GPIb, has been hypothesized to cause these bleedings. IBR associated bleedings and platelet dysfunction may be relevant in CLL pts who are usually elderly and with comorbidities requiring antithombotic therapies.
Aims
To investigate and characterize the effect of IBR on platelet function in pts with CLL.
Methods
We enrolled from May 2014 to December 2016 twenty pts with CLL treated with orally administered 420 mg daily of IBR; 18 R/R CLL pts received IBR in monotherapy and 2 pts with previously untreated CLL received IBR in association with anti-CD20 MoAb. Median age was 68 years (57-84); 13 pts had unmutated IgVH and 2 had 17p deletion. The median number of prior therapies in R/R CLL pts was 3 (2-7). Five pts discontinued IBR therapy: 2 for Richter's transformation, 1 for progressive CLL, 1 underwent allogeneic HSCT, 1 for heart disease. The platelet function was studied before and during IBR by light transmission aggregometry (LTA) using platelet-rich plasma and the following agonists: ADP 2-4 uM, PAR1-AP 25 uM, Collagen 10-3.3-2 ug /mL, arachidonic acid 1 mM, ristocetin 0.6-1.2 mg/mL. Also measurements of von Willebrand factor antigen (vWF:Ag) and ristocetin cofactor activities (RiCo) by chemiluminescent immunoassay were performed. All pts had measurements of the platelet function at the baseline and after 1, 3, 6 months initiation of IBR and then every 3 months up to 24 months. Median observation period was 9 months. No patient received concomitant antiplatelet or anticoagulation therapy.
Results
Nineteen pts achieved a partial response and an increase of hemoglobin and platelet count. We recorded CTC grade 1 or 2 bleedings (bruising, petechiae, conjunctival and retinal hemorrhage, rectal bleeding) in 15 pts; no patient needed IBR interruption or dose reduction. All pts displayed severe impairment of collagen induced aggregation upon IBR. Reduction of maximal aggregation (35.6+/- 32% vs 70.6+/- 21% baseline) and prolongation of the lag phase (261+/- 54 sec vs 72+/- 26.8 sec baseline) by 2 ug/mL collagen was measured in all pts during IBR. In 10 pts a significant improvement of the aggregation by 2 uM ADP (71+/- 31.8% vs basal 48.6+/- 31%) and 4 uM ADP (84+/- 11% vs basal 64+/- 25%) was found during IBR. The aggregation by 25 uM PAR1-AP, 1.2 mg/ml ristocetin and 1 mM arachidonic acid was unchanged before and under IBR. Finally, in 9 pts the vWF:Ag and RiCo were high at the onset of the disease (163+/- 59.8% and 181.6+/- 82.5%) and reduced up to normal values under IBR (118+/- 71% and 145+/- 65%).
Conclusion
Our study showed minor bleedings in pts treated with IBR. A severe impairment of collagen-induced aggregation was caused by IBR, which was counteracted by amelioration of ADP-induced aggregation, that could explain, at least partially, the mild clinical phenotype in treated pts. The assessment of platelet function in IBR treated CLL pts could help to predict and monitor the bleeding risk, and to guide pts through invasive procedures. In addition, pts under anticoagulant or antiplatelet treatment might need be carefully monitored by clinical and laboratory evaluation.
Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical
Keyword(s): Platelet aggregation, Inhibitor, Bleeding, B cell chronic lymphocytic leukemia
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