Abstract

Background: Ibrutinib is a first-in-class, oral covalent inhibitor of Bruton’s tyrosine kinase (BTK) that has shown single-agent efficacy and an acceptable safety profile in patients (pts) with CLL. While BTK is expressed in platelets, bleeding diathesis has not been reported in pts with hereditary BTK deficiency (e.g., X-linked agammaglobulinemia). Pts with CLL often have comorbidities requiring anticoagulants and/or antiplatelet agents, which can increase bleeding risk. We sought to characterize the pattern of use of these agents and describe bleeding adverse events (AEs) observed in 2 trials of single-agent ibrutinib in pts with CLL.

Methods: Event-based analysis of data from the ibrutinib phase 2 PCYC-1102 trial and interim analysis of the phase 3 RESONATETM(PCYC-1112 trial) of ibrutinib vs. ofatumumab were analyzed to determine the use of concomitant anticoagulants and/or antiplatelet therapy. Precautionary language on the use of anticoagulant or antiplatelet agents, particularly regarding restrictions on the use of vitamin K antagonists (e.g., warfarin), and recommendations for perioperative holding of ibrutinib, were added late during the 1102 trial. Major bleeding was defined as any grade ≥ 3 bleeding event, or hemorrhage of any grade resulting in one of the following: intraocular bleeding causing loss of vision, need for ≥ 2 units of RBC transfusion, hospitalization, prolonged hospitalization, or any intracranial hemorrhage.

Results: In the 2 trials, 327 pts with CLL/SLL were treated; 132 in 1102 trial and 195 in the ibrutinib arm of 1112. Median age was 68 and 67 years, respectively, and median number of prior therapies was 3 in both trials. Overall, 65 pts (20%) received concomitant anticoagulation across the 2 trials, 70 (21%) received ASA, and 7 (2%) received clopidogrel (Table). The most common bleeding AEs were grade 1 petechiae and contusion. In the 1102 trial, grade 1 bleeding AEs occurred in 52%, grade 2 in 5%, and grade 3 in 3%. In the ibrutinib arm of 1112, grade 1 bleeding AEs occurred in 41%, grade 2 in 4%, and grade 3 in 1%. Overall, major bleeding occurred in 8 of 327 pts (2.4%): 5% in 1102 (6 of 132) and 1% in the ibrutinib arm of 1112 (2 of 195). For comparison, in the ofatumumab arm of 1112, major bleeding occurred in 1.6% of pts (3 of 191). Among the 8 ibrutinib-treated pts with major bleeding, 5 were reported to have concomitant use of either an anticoagulant alone (LMWH, n=1), an antiplatelet agent alone (ASA, n=1; NSAID, n=1), or both an anticoagulant and an antiplatelet agent (ASA and warfarin, n=1; NSAID, heparin and LMWH, n=1). The case of major bleeding on warfarin occurred on the 1102 trial before a protocol amendment restricted its use. Bleeding AEs led to discontinuation of ibrutinib in 4 pts (1.2%) from the 2 studies (3 on 1102 and 1 on 1112), all due to major bleeding.

Conclusions: In summary, the concomitant use of anticoagulant or antiplatelet agent was common in 2 clinical trials of single-agent ibrutinib in 327 pts with CLL/SLL. Bleeding AEs in these trials were primarily grade 1 and associated with low rates of treatment discontinuation. Major bleeding events were uncommon and most cases occurred in pts taking one or more concomitant anticoagulant and/or antiplatelet agents. Importantly, there was no difference in the incidence of major bleeding between the 2 arms of the randomized 1112 trial while many of these pts were receiving concomitant anticoagulants or antiplatelet agents. Adherence to appropriate drug-withholding guidelines perioperatively and precautions surrounding the use of antiplatelet agents and anticoagulants, as applied in the 1112 trial, resulted in few major bleeding complications.

Table.

Concomitant anticoagulants or antiplatelet agents used in single-agent trials


n (%) 
1102
(n=132) 
1112
ibrutinib arm
(n=195) 
Total
(N=327) 
Any anticoagulant 23 (17) 42 (22) 65 (20) 
Vitamin K antagonist*
Heparin
LMWH
Dabigatran
Rivaroxaban
Apixaban
Alteplase 
6 (5)
3 (2)
14 (11)
0
0
0
1 (1) 
4 (2)
5 (3)
34 (17)
3 (2)
1 (1)
1 (1)
10 (3)
8 (2)
48 (15)
3 (1)
1 (<1)
1 (<1)
1 (<1) 
Any antiplatelet 67 (51) 73 (37) 140 (43) 
ASA
Clopidogrel
NSAIDs
Dipyridamole/ASA 
33 (25)
0
46 (35)
1 (1) 
37 (19)
7 (4)
45 (23)
1 (1) 
70 (21)
7 (2)
91 (28)
2 (1) 
*Included warfarin (n=8), acenocoumarol (n=1) and fluindione (n=1). 

n (%) 
1102
(n=132) 
1112
ibrutinib arm
(n=195) 
Total
(N=327) 
Any anticoagulant 23 (17) 42 (22) 65 (20) 
Vitamin K antagonist*
Heparin
LMWH
Dabigatran
Rivaroxaban
Apixaban
Alteplase 
6 (5)
3 (2)
14 (11)
0
0
0
1 (1) 
4 (2)
5 (3)
34 (17)
3 (2)
1 (1)
1 (1)
10 (3)
8 (2)
48 (15)
3 (1)
1 (<1)
1 (<1)
1 (<1) 
Any antiplatelet 67 (51) 73 (37) 140 (43) 
ASA
Clopidogrel
NSAIDs
Dipyridamole/ASA 
33 (25)
0
46 (35)
1 (1) 
37 (19)
7 (4)
45 (23)
1 (1) 
70 (21)
7 (2)
91 (28)
2 (1) 
*Included warfarin (n=8), acenocoumarol (n=1) and fluindione (n=1). 

Disclosures

Jones:Pharmacyclics: Consultancy, Research Funding. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Barr:Pharmacyclics: Research Funding. Kipps:Pharmacyclics: Research Funding. Flinn:Pharmacyclics: Research Funding. Jaeger:Janssen Cilag: Honoraria. Burger:Pharmacyclics: Consultancy, Honoraria, Research Funding. Cheng:Pharmacyclics: Employment. Lee:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Byrd:Pharmacyclics: Research Funding. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.