PLATELET DYSFUNCTION CAUSED BY IBRUTINIB TREATMENT IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA. MONOCENTRIC EXPERIENCE: CLINICAL AND LABORATORY CHARACTERIZATION.
(Abstract release date: 05/19/16)
EHA Library. Innocenti I. 06/09/16; 134698; PB1798
Dr. Idanna Innocenti
Contributions
Contributions
Abstract
Abstract: PB1798
Type: Publication Only
Background
Ibrutinib (IBR) is a potent and irreversible inhibitor of Bruton's tyrosine kinase (Btk), approved for treatment naïve of chronic lymphocytic leukemia (CLL) with del 17p or TP 53 mutation or for patients (pts) with relapsed/refractory (R/R) disease. IBR treatment is associated with bleeding events, mostly mild to moderate (I-II grade of severity), rarely severe (III-IV grade of severity). The mechanism causing these bleeding events remains unknown. A defect of platelet function has been hypothesized and inhibition of signaling by glycoprotein VI (GP-VI) has been previously described. IBR associated bleedings and platelet dysfunction may be relevant in CLL pts who are elderly and with comorbidities.
Aims
To investigate and characterize the effect of IBR on platelet function in vitro and in vivo in pts with CLL.
Methods
Nine pts with CLL were treated with oral IBR at dose of 420 mg/day; 7 received IBR in monotherapy for relapsed/refractory CLL and 2 in association with monoclonal antibody anti-CD20 for treatment-naïve CLL. Median age was 68 years (57-75); 5 pts had unmutated IgVH and 2 had 17p deletion on FISH. The median number of prior therapies in R/R CLL pts was 3 (range 2-7). After a median follow up of 14 months (range 6-20) all pts achieved a partial response. Thereafter 2 pts discontinued IBR therapy: 1 for Richter's transformation, 1 underwent allogeneic HSCT. All pts before and after initiation of treatment with IBR were studied with light transmission aggregometry (LTA) using platelet-rich-plasma and the following agonists : ADP 2-4 uM, PAR1-AP 25 uM, Collagen 10 ug /mL, arachidonic acid 1 mM, ristocetin 0.6-1.2 mg/mL; measurement of von Willebrand factor(vWF) antigen and ristocetin cofactor activities by chemiluminescent immunoassay.
Results
We recorded only grade I or II bleeding events (bruising, petechiae, conjunctival hemorrhage, rectal bleeding) in 7 pts at a median time of 3 months after IBR treatment (range 1-9); no patient needed treatment interruption or dose reduction. Eight pts displayed abnormalities of the aggregation induced by 10 ug/ml collagen after initiation of IBR treatment. At these collagen concentration, only significant prolongation of the lag phase was measured (74.6 +/- 23.7 sec vs basal 40.4 +/- 17.2 sec), whereas the maximal aggregation was not impaired (67.9 +/- 21.4% vs basal 85.5+/-5.8%). Interestingly, in 5 pts a significant improvement of the aggregation by 2 uM ADP (91.2 +/- 5.1% vs basal 39.3 +/- 24.6%) and 4 uM ADP (91.6 +/- 2.9% vs basal 65.4 +/- 19.4%) during IBR treatment was reported. On the contrary the aggregation by PAR1-AP, ristocetin and arachidonic acid was not affected under IBR. Finally, in 3/3 pts the vWF antigen and ristocetin cofactor activity were higher at the onset of the disease (169 +/- 38%) and returned to normal values under IBR treatment (111.4 +/- 47%).
Conclusion
Our study showed that collagen induced platelet aggregation resulted impaired while ADP induced aggregation improved upon IBR treatment. Finally the levels of vWF were significantly higher in CLL pts before treatment and normalized during IBR. In conclusion, IBR treatment in CLL pts causes a mild bleeding phenotype most probably due to platelet dysfunction. The bleeding risk was unrelated to platelets count. The assessment of platelet aggregation in IBR treated CLL pts could help to predict and monitor bleeding risk, and to guide pts through invasive procedures.
Session topic: E-poster
Keyword(s): B cell chronic lymphocytic leukemia, Bleeding, Inhibitor, Platelet aggregation
Type: Publication Only
Background
Ibrutinib (IBR) is a potent and irreversible inhibitor of Bruton's tyrosine kinase (Btk), approved for treatment naïve of chronic lymphocytic leukemia (CLL) with del 17p or TP 53 mutation or for patients (pts) with relapsed/refractory (R/R) disease. IBR treatment is associated with bleeding events, mostly mild to moderate (I-II grade of severity), rarely severe (III-IV grade of severity). The mechanism causing these bleeding events remains unknown. A defect of platelet function has been hypothesized and inhibition of signaling by glycoprotein VI (GP-VI) has been previously described. IBR associated bleedings and platelet dysfunction may be relevant in CLL pts who are elderly and with comorbidities.
Aims
To investigate and characterize the effect of IBR on platelet function in vitro and in vivo in pts with CLL.
Methods
Nine pts with CLL were treated with oral IBR at dose of 420 mg/day; 7 received IBR in monotherapy for relapsed/refractory CLL and 2 in association with monoclonal antibody anti-CD20 for treatment-naïve CLL. Median age was 68 years (57-75); 5 pts had unmutated IgVH and 2 had 17p deletion on FISH. The median number of prior therapies in R/R CLL pts was 3 (range 2-7). After a median follow up of 14 months (range 6-20) all pts achieved a partial response. Thereafter 2 pts discontinued IBR therapy: 1 for Richter's transformation, 1 underwent allogeneic HSCT. All pts before and after initiation of treatment with IBR were studied with light transmission aggregometry (LTA) using platelet-rich-plasma and the following agonists : ADP 2-4 uM, PAR1-AP 25 uM, Collagen 10 ug /mL, arachidonic acid 1 mM, ristocetin 0.6-1.2 mg/mL; measurement of von Willebrand factor(vWF) antigen and ristocetin cofactor activities by chemiluminescent immunoassay.
Results
We recorded only grade I or II bleeding events (bruising, petechiae, conjunctival hemorrhage, rectal bleeding) in 7 pts at a median time of 3 months after IBR treatment (range 1-9); no patient needed treatment interruption or dose reduction. Eight pts displayed abnormalities of the aggregation induced by 10 ug/ml collagen after initiation of IBR treatment. At these collagen concentration, only significant prolongation of the lag phase was measured (74.6 +/- 23.7 sec vs basal 40.4 +/- 17.2 sec), whereas the maximal aggregation was not impaired (67.9 +/- 21.4% vs basal 85.5+/-5.8%). Interestingly, in 5 pts a significant improvement of the aggregation by 2 uM ADP (91.2 +/- 5.1% vs basal 39.3 +/- 24.6%) and 4 uM ADP (91.6 +/- 2.9% vs basal 65.4 +/- 19.4%) during IBR treatment was reported. On the contrary the aggregation by PAR1-AP, ristocetin and arachidonic acid was not affected under IBR. Finally, in 3/3 pts the vWF antigen and ristocetin cofactor activity were higher at the onset of the disease (169 +/- 38%) and returned to normal values under IBR treatment (111.4 +/- 47%).
Conclusion
Our study showed that collagen induced platelet aggregation resulted impaired while ADP induced aggregation improved upon IBR treatment. Finally the levels of vWF were significantly higher in CLL pts before treatment and normalized during IBR. In conclusion, IBR treatment in CLL pts causes a mild bleeding phenotype most probably due to platelet dysfunction. The bleeding risk was unrelated to platelets count. The assessment of platelet aggregation in IBR treated CLL pts could help to predict and monitor bleeding risk, and to guide pts through invasive procedures.
Session topic: E-poster
Keyword(s): B cell chronic lymphocytic leukemia, Bleeding, Inhibitor, Platelet aggregation
Abstract: PB1798
Type: Publication Only
Background
Ibrutinib (IBR) is a potent and irreversible inhibitor of Bruton's tyrosine kinase (Btk), approved for treatment naïve of chronic lymphocytic leukemia (CLL) with del 17p or TP 53 mutation or for patients (pts) with relapsed/refractory (R/R) disease. IBR treatment is associated with bleeding events, mostly mild to moderate (I-II grade of severity), rarely severe (III-IV grade of severity). The mechanism causing these bleeding events remains unknown. A defect of platelet function has been hypothesized and inhibition of signaling by glycoprotein VI (GP-VI) has been previously described. IBR associated bleedings and platelet dysfunction may be relevant in CLL pts who are elderly and with comorbidities.
Aims
To investigate and characterize the effect of IBR on platelet function in vitro and in vivo in pts with CLL.
Methods
Nine pts with CLL were treated with oral IBR at dose of 420 mg/day; 7 received IBR in monotherapy for relapsed/refractory CLL and 2 in association with monoclonal antibody anti-CD20 for treatment-naïve CLL. Median age was 68 years (57-75); 5 pts had unmutated IgVH and 2 had 17p deletion on FISH. The median number of prior therapies in R/R CLL pts was 3 (range 2-7). After a median follow up of 14 months (range 6-20) all pts achieved a partial response. Thereafter 2 pts discontinued IBR therapy: 1 for Richter's transformation, 1 underwent allogeneic HSCT. All pts before and after initiation of treatment with IBR were studied with light transmission aggregometry (LTA) using platelet-rich-plasma and the following agonists : ADP 2-4 uM, PAR1-AP 25 uM, Collagen 10 ug /mL, arachidonic acid 1 mM, ristocetin 0.6-1.2 mg/mL; measurement of von Willebrand factor(vWF) antigen and ristocetin cofactor activities by chemiluminescent immunoassay.
Results
We recorded only grade I or II bleeding events (bruising, petechiae, conjunctival hemorrhage, rectal bleeding) in 7 pts at a median time of 3 months after IBR treatment (range 1-9); no patient needed treatment interruption or dose reduction. Eight pts displayed abnormalities of the aggregation induced by 10 ug/ml collagen after initiation of IBR treatment. At these collagen concentration, only significant prolongation of the lag phase was measured (74.6 +/- 23.7 sec vs basal 40.4 +/- 17.2 sec), whereas the maximal aggregation was not impaired (67.9 +/- 21.4% vs basal 85.5+/-5.8%). Interestingly, in 5 pts a significant improvement of the aggregation by 2 uM ADP (91.2 +/- 5.1% vs basal 39.3 +/- 24.6%) and 4 uM ADP (91.6 +/- 2.9% vs basal 65.4 +/- 19.4%) during IBR treatment was reported. On the contrary the aggregation by PAR1-AP, ristocetin and arachidonic acid was not affected under IBR. Finally, in 3/3 pts the vWF antigen and ristocetin cofactor activity were higher at the onset of the disease (169 +/- 38%) and returned to normal values under IBR treatment (111.4 +/- 47%).
Conclusion
Our study showed that collagen induced platelet aggregation resulted impaired while ADP induced aggregation improved upon IBR treatment. Finally the levels of vWF were significantly higher in CLL pts before treatment and normalized during IBR. In conclusion, IBR treatment in CLL pts causes a mild bleeding phenotype most probably due to platelet dysfunction. The bleeding risk was unrelated to platelets count. The assessment of platelet aggregation in IBR treated CLL pts could help to predict and monitor bleeding risk, and to guide pts through invasive procedures.
Session topic: E-poster
Keyword(s): B cell chronic lymphocytic leukemia, Bleeding, Inhibitor, Platelet aggregation
Type: Publication Only
Background
Ibrutinib (IBR) is a potent and irreversible inhibitor of Bruton's tyrosine kinase (Btk), approved for treatment naïve of chronic lymphocytic leukemia (CLL) with del 17p or TP 53 mutation or for patients (pts) with relapsed/refractory (R/R) disease. IBR treatment is associated with bleeding events, mostly mild to moderate (I-II grade of severity), rarely severe (III-IV grade of severity). The mechanism causing these bleeding events remains unknown. A defect of platelet function has been hypothesized and inhibition of signaling by glycoprotein VI (GP-VI) has been previously described. IBR associated bleedings and platelet dysfunction may be relevant in CLL pts who are elderly and with comorbidities.
Aims
To investigate and characterize the effect of IBR on platelet function in vitro and in vivo in pts with CLL.
Methods
Nine pts with CLL were treated with oral IBR at dose of 420 mg/day; 7 received IBR in monotherapy for relapsed/refractory CLL and 2 in association with monoclonal antibody anti-CD20 for treatment-naïve CLL. Median age was 68 years (57-75); 5 pts had unmutated IgVH and 2 had 17p deletion on FISH. The median number of prior therapies in R/R CLL pts was 3 (range 2-7). After a median follow up of 14 months (range 6-20) all pts achieved a partial response. Thereafter 2 pts discontinued IBR therapy: 1 for Richter's transformation, 1 underwent allogeneic HSCT. All pts before and after initiation of treatment with IBR were studied with light transmission aggregometry (LTA) using platelet-rich-plasma and the following agonists : ADP 2-4 uM, PAR1-AP 25 uM, Collagen 10 ug /mL, arachidonic acid 1 mM, ristocetin 0.6-1.2 mg/mL; measurement of von Willebrand factor(vWF) antigen and ristocetin cofactor activities by chemiluminescent immunoassay.
Results
We recorded only grade I or II bleeding events (bruising, petechiae, conjunctival hemorrhage, rectal bleeding) in 7 pts at a median time of 3 months after IBR treatment (range 1-9); no patient needed treatment interruption or dose reduction. Eight pts displayed abnormalities of the aggregation induced by 10 ug/ml collagen after initiation of IBR treatment. At these collagen concentration, only significant prolongation of the lag phase was measured (74.6 +/- 23.7 sec vs basal 40.4 +/- 17.2 sec), whereas the maximal aggregation was not impaired (67.9 +/- 21.4% vs basal 85.5+/-5.8%). Interestingly, in 5 pts a significant improvement of the aggregation by 2 uM ADP (91.2 +/- 5.1% vs basal 39.3 +/- 24.6%) and 4 uM ADP (91.6 +/- 2.9% vs basal 65.4 +/- 19.4%) during IBR treatment was reported. On the contrary the aggregation by PAR1-AP, ristocetin and arachidonic acid was not affected under IBR. Finally, in 3/3 pts the vWF antigen and ristocetin cofactor activity were higher at the onset of the disease (169 +/- 38%) and returned to normal values under IBR treatment (111.4 +/- 47%).
Conclusion
Our study showed that collagen induced platelet aggregation resulted impaired while ADP induced aggregation improved upon IBR treatment. Finally the levels of vWF were significantly higher in CLL pts before treatment and normalized during IBR. In conclusion, IBR treatment in CLL pts causes a mild bleeding phenotype most probably due to platelet dysfunction. The bleeding risk was unrelated to platelets count. The assessment of platelet aggregation in IBR treated CLL pts could help to predict and monitor bleeding risk, and to guide pts through invasive procedures.
Session topic: E-poster
Keyword(s): B cell chronic lymphocytic leukemia, Bleeding, Inhibitor, Platelet aggregation
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