Ibrutinib and Novel Oral Anticoagulants: Three Case Reports from a Single Center Real Life Experience
Authors: Sapienza Giuseppe 
Published: November 2020

Background: Chronic Lymphocytic Leukemia (CLL) represents 7% of Non Hodgkin Lymphoma being the most common leukemia. Efficacy and safety data on Ibrutinib used as a single agent for treatment of previously treated CLL comes from RESONATE trial, which showed 6% of Overall incidence of grade 3 atrial fibrillation (AF).Another side effect of Ibrutinib is increased rate of bleeding. The 2019 long term follow-up of RESONATE 2 trial of Ibrutinib in previously untreated CLL reported major hemorrhage and grade 3 AF in 11% and 5% of patients on Ibrutinib arm, respectively; notably, 67% of patients who experienced Grade 3 Major hemorrhage were taking concomitant anticoagulation therapy. The use of Ibrutinib in patients with AF requiring anticoagulation therapy could be challenging, given that both the optimal starting dose of Novel Anti Coagulants (NOACs) and the specific NOAC to be used in patients taking ibrutinib have not been established yet. Here we describe the clinical history of three CLL patients affected by AF treated with ibrutinib associated with NOACs.
Cases :
1.
The first patient was a 72-year-old male affected by IGHV unmutaded CLL with no TP53 disruption relapsed five years after the achievement of first complete remission through 6 courses R-Bendamustine. He started full dose Ibrutinib on august 2019. When he started ibrutinib there were no bulky lesions, the biggest node diameter was 2.7 cm, spleen longest diameter was 18 cm, Hb was 9.3 g/dL, platelets were 166,000/µL, neutrophils 4,000/µL and ALC 129,000/ µL, b symptoms were absent. Since 2018 he suffered from chronic AF treated with Apixaban at the dose of 5 mg BID. He achieved partial response with no evidence of lymphadenopathy and lymphocytosis after 6 months of treatment with no occurrence of major bleeding. On April 2020 he came to our attention with minor bleeding consisting of small petechial macules. Neither epistaxis nor bruising were reported. Petechiae resolved on May 2020, at last follow-up clinical visit (July 2020) Ibrutinib and Apixaban are still well tolerated and signs and symptoms of both CLL and bleeding are absent.
2.
The second patient was a 65-year-old male affected by IGHV unmutated CLL with no TP53 disruption, relapsed three years after a complete response achieved with first line treatment with 6 courses of R-Bendamustine. When he started full dose Ibrutinib (420 mg OD), Hb was 11.8 g/dL, neutrophils 5,100/ µL, lymphocyte 145,000/ µL and platelets 51,000/ µL. He achieved partial remission on May 2020. On April 2020, high rate AF was diagnosed, heart rate was 162 beats per min, systolic and diastolic blood pressure were 125 and 80 mmHg, respectively. The cardiologist prescribed bisoprolole 1.25 mg OD and after 24h heart rate became normal (60 beats per min). An Echocardiography was performed showing ejection fraction of 60% with all other parameters being normal. CHADS-VASc score was 3 and HAS-BLED score was 2, so he started Edoxaban at the dose of 30 mg OD, while Ibrutinib was never stopped. The patient now has neither signs and symptoms of CLL, nor those of AF and bleeding.
3.
The last patient was a 81-year-old male affected by previously untreated IGHV mutated CLL with TP53 mutation and absence of del 17p. High rate AF was diagnosed on may 2020 and edoxaban 30 mg OD was started. He started reduced dose Ibrutinib (280 mg OD) on the first days of July 2020 due to risk of bleeding. Hb, neutrophils, lymphocyte and platelets were 10.8 g/dL, neutrophils 2,730/ µL, lymphocyte 195,000/µL and platelets were 116,000/µL. RAI and Binet where 3 and B, respectively. CLL-IPI was 8 (very high risk), neither bulky nodes nor B symptoms were present. After 1 month-follow-up there is no evidence of bleeding and AF is still asymptomatic.
Conclusions: In our limited experience and according with literature, Ibrutinib could be safely used in patients with pre-existing or de novo AF in association with NOACs with no or minimal bleeding signs. Therefore, patients affected by AF might completely benefit from this highly effective therapy for CLL.

Disclosures
No relevant conflicts of interest to declare.