Oncology

Chronic Lymphocytic Leukemia

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Managing Bleeding Risk in Patients With Chronic Lymphocytic Leukemia

clinical study insights by Jennifer R. Brown, MD, PhD

Overview

Chronic lymphocytic leukemia (CLL) typically occurs in older patients with an elevated risk for cardiovascular comorbidities, and the use of anticoagulants/antiplatelet agents is relatively common. Additionally, the incidence of major hemorrhage has been reported to be higher among patients with CLL than that of the age‐ and gender‐matched general population. To address bleeding risk in patients with CLL and concomitant anticoagulation or antiplatelet use, several strategies have been proposed, including close monitoring for the risk of bleeding, careful re-assessment of the continued need for anticoagulation, and use of novel oral anticoagulants (NOACs) when anticoagulation is needed.

Expert Commentary

Jennifer R. Brown, MD, PhD

Director, Center for Chronic Lymphocytic Leukemia
Institute Physician
Dana-Farber Cancer Institute
Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology
Harvard Medical School
Boston, MA

Ibrutinib is a first-in-class, once-daily Bruton’s tyrosine kinase inhibitor that is approved by the US Food and Drug Administration for the treatment of various B-cell malignancies, including CLL, and has a favorable risk-benefit profile in patients with CLL. Early clinical studies with ibrutinib reported increased rates of low-grade hemorrhage and, infrequently, serious hemorrhage. This led to the inclusion of hemorrhage risk in the Warnings and Precautions section of the drug’s prescribing information. Anticoagulants/antiplatelet therapy may be used with ibrutinib; however, the use of vitamin K antagonists was excluded in ibrutinib clinical trials following early clinical experience and data review from early studies. Additionally, patients with CLL have an increased risk of major hemorrhage compared with the age- and sex-matched general population, and there is concern about the risks of anticoagulation/antiplatelet therapy in many patients with CLL in general—and not just with the use of warfarin, for example.

“Patients with CLL have an increased risk of major hemorrhage compared with the age- and sex-matched general population, and there is concern about the risks of anticoagulation/antiplatelet therapy in many patients with CLL in general—and not just with the use of warfarin, for example.”

Jennifer R. Brown, MD, PhD

My practice has been to try to avoid anticoagulation, if possible, but then, if necessary, to use NOACs. We recently examined the experience across approximately 1800 patients on ibrutinib at risk for major hemorrhage. Among those on anticoagulation, the highest risk was reported in patients exposed to warfarin or low-molecular-weight heparin, and the lowest risk was reported in patients who were on NOACs. Available data on the risk of bleeding do not alter the risk‐benefit balance supporting ibrutinib treatment for patients with CLL with average bleeding risks, but they do suggest that patients and physicians should be informed of the potential risk for bleeding.

“My practice has been to try to avoid anticoagulation, if possible, but then, if necessary,
 to use NOACs.”

Jennifer R. Brown, MD, PhD

In practice, I avoid the use of ibrutinib in patients who have a history of major or potentially life-threatening hemorrhage owing to an irreversible cause. If a reasonable alternative therapy is available for a patient requiring long-term anticoagulation or dual antiplatelet therapy, I favor the alternative CLL therapy. However, if ibrutinib is uniquely the best option, then I evaluate the true necessity of the anticoagulation or dual antiplatelet therapy. I also suggest that all patients stop vitamin E, fish oils, and nonsteroidal anti-inflammatory drugs, as in the ibrutinib clinical trials. Further, in patients on aspirin, I consider stopping or reducing to the lowest available dose.

References

Brown JR. How I treat CLL patients with ibrutinib. Blood. 2018;131(4):379-386.

Brown JR, Moslehi J, Ewer MS, et al. Incidence of and risk factors for major hemorrhage in patients treated with ibrutinib: results from an integrated analysis. Blood. 2017;130:1743.

Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437.

Gifkins DM, Matcho A, Yang H, Xu Y, Gooden MA, Wildgust M. Incidence of major hemorrhage among CLL and MCL patients compared to the general elderly population: an analysis of the US SEER‐Medicare linked database. Blood. 2015;126(23):3268.

Gribben JG, Bosch F, Cymbalista F, et al. Optimising outcomes for patients with chronic lymphocytic leukaemia on ibrutinib therapy: European recommendations for clinical practice. Br J Haematol. 2018;180(5):666-679.

Imbruvica [package insert]. Sunnyvale, CA: Pharmacyclics LLC; 2018.

Jones JA, Hillmen P, Coutre S, et al. Use of anticoagulants and antiplatelet in patients with chronic lymphocytic leukaemia treated with single‐agent ibrutinib. Br J Haematol. 2017;178(2):286-291.

Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the Management of Atrial Fibrillation Developed in Collaboration With EACTS. Eur J Cardiothorac Surg. 2016;50(5):e1-e88.

Makris M, Van Veen JJ, Tait CR, Mumford AD, Laffan M; British Committee for Standards in Haematology. Guideline on the Management of Bleeding in Patients on Antithrombotic Agents. Br J Haematol. 2013;160(1):35-46.

Jennifer R. Brown, MD, PhD

Director, Center for Chronic Lymphocytic Leukemia
Institute Physician
Dana-Farber Cancer Institute
Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology
Harvard Medical School
Boston, MA

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