Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib
Andrew H. Lipsky,
Mohammed Z.H. Farooqui,
Xin Tian,
Sabrina Martyr,
Ann M. Cullinane,
Khanh Nghiem,
Clare Sun,
Janet Valdez,
Carsten U. Niemann,
Sarah E. M. Herman,
Nakhle Saba,
Susan Soto,
Gerald Marti,
Gulbu Uzel,
Steve M. Holland,
Jay N. Lozier,
Adrian Wiestner
Affiliations
Andrew H. Lipsky
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
Mohammed Z.H. Farooqui
Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Xin Tian
Office of Biostatistics Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Sabrina Martyr
Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Ann M. Cullinane
Department of Laboratory Medicine, NIH Clinical Center, Bethesda, MD, USA
Khanh Nghiem
Department of Laboratory Medicine, NIH Clinical Center, Bethesda, MD, USA
Clare Sun
Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Janet Valdez
Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Carsten U. Niemann
Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Sarah E. M. Herman
Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Nakhle Saba
Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Susan Soto
Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Gerald Marti
Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Gulbu Uzel
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Steve M. Holland
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Jay N. Lozier
Department of Laboratory Medicine, NIH Clinical Center, Bethesda, MD, USA
Adrian Wiestner
Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
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
