title: Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib.
abstract: Ibrutinib is associated with bleeding-related adverse events of grade ≤ 2 in severity, and infrequently with grade ≥ 3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤ 2 bleeding-related adverse events in 55% of 85 patients. No grade ≥ 3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100™) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade ≤ 2 can be identified by clinical laboratory tests and counseled to avoid aspirin, non-steroidal anti-inflammatory drugs and fish oils. ClinicalTrials.gov identifier NCT01500733.
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA Department of Internal Medicine, Montefiore Medical Center, Bronx, New York, NY, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Lipsky
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Mohammed Z H
authors.initials: MZ
authors.lastname: Farooqui
authors.affiliation: Office of Biostatistics Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Martyr
authors.affiliation: Department of Laboratory Medicine, NIH Clinical Center, Bethesda, MD, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Cullinane
authors.affiliation: Department of Laboratory Medicine, NIH Clinical Center, Bethesda, MD, USA.
authors.forename: Khanh
authors.initials: K
authors.lastname: Nghiem
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Clare
authors.initials: C
authors.lastname: Sun
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Valdez
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Carsten U
authors.initials: CU
authors.lastname: Niemann
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Herman
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Nakhle
authors.initials: N
authors.lastname: Saba
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Soto
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Marti
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Steve M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Department of Laboratory Medicine, NIH Clinical Center, Bethesda, MD, USA wiestnera@mail.nih.gov lozierjn@cc.nih.gov.
authors.forename: Jay N
authors.initials: JN
authors.lastname: Lozier
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA wiestnera@mail.nih.gov lozierjn@cc.nih.gov.
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005169:Factor VIII / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D010974:Platelet Aggregation / Q000187:drug effects*; D010979:Platelet Function Tests; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects; D012307:Risk Factors; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D014841:von Willebrand Factor; C551803:ibrutinib; C078147:F8 protein, human; D005169:Factor VIII; D000225:Adenine