BCR SIGNALING INHIBITORS: AN OVERVIEW OF TOXICITIES ASSOCIATED WITH IBRUTINIB AND IDELALISIB IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA
Main Article Content
Keywords
Chronic lymphocytic leukemia, ibrutinib, idelalisib, toxicity, safety
Abstract
The B-cell receptor signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment landscape of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in treatment-naïve CLL patients. Both ibrutinib and idelalisib are well tolerated by most patients, including older, frailer individuals. Toxicities are usually mild and self-resolving. Clinicians must, however, be aware of a number of peculiar adverse events, the effects of which can be severe enough to limit the clinical use of these agents. In this review, we survey the salient aspects of the pharmacology of these agents, as well as clinical experience regarding their use for the treatment of patients with CLL. Our foci will be both the most common and the most clinically significant toxicities associated with these drugs.
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References
1. Rozman C, Montserrat E. Chronic lymphocytic leukemia. N. Engl. J. Med. 1995;333(16):1052-1057.
2. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2012, based on November 2014 SEER data submission, posted to the SEER web site. Bethesda, MD: National Cancer Institute;2015.
3. Tam CS, Keating MJ. Chemoimmunotherapy of chronic lymphocytic leukemia. Nature Reviews Clinical Oncology. 2010;7(9):521-532.
4. Dighiero G, Maloum K, Desabilens B, et al. Chlorambucil in Indolent Chronic Lymphocytic Leukemia. The New England Journal of Medicine. 1998;338:1506-1514.
5. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N. Engl. J. Med. 2000;343(24):1750-1757.
6. Robak T, Dmoszynska A, Solal-Celigny P, et al. Rituximab Plus Fludarabine and Cyclophosphamide Prolongs Progression-Free Survival Compared With Fludarabine and Cyclophosphamide Alone in Previously Treated Chronic Lymphocytic Leukemia. J. Clin. Oncol. 2010;28(10):1756-1765.
7. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fl udarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. the Lancet. 2010;376:1164–1174.
8. Byrd JC, Jones JJ, Woyach JA, Johnson AJ, Flynn JM. Entering the era of targeted therapy for chronic lymphocytic leukemia: impact on the practicing clinician. J. Clin. Oncol. 2014;32(27):3039-3047.
9. Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. ChemMedChem. 2007;2(1):58-61.
10. Ibrutinib [package insert]. . In: Inc. P, ed. Sunnyvale, CA2015.
11. Kurosaki T. Regulation of BCR signaling. Mol. Immunol. 2011;48(11):1287-1291.
12. Woyach JA, Bojnik E, Ruppert AS, et al. Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood. 2014;123(8):1207-1213.
13. Herman SEM, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117(23):6287-6296.
14. Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119(5):1182-1189.
15. de Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590-2594.
16. Herishanu Y, Perez-Galan P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117(2):563-574.
17. de Jong J, Sukbuntherng J, Skee D, et al. The effect of food on the pharmacokinetics of oral ibrutinib in healthy participants and patients with chronic lymphocytic leukemia. Cancer Chemother. Pharmacol. 2015;75(5):907-916.
18. Bernard S, Goldwirt L, Amorim S, et al. Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. Blood. 2015;126(14):1695-1698.
19. Marostica E, Sukbuntherng J, Loury D, et al. Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies. Cancer Chemother. Pharmacol. 2015;75(1):111-121.
20. Idelalisib [package insert]. In: Inc. GS, ed. Foster City, CA2014.
21. Saito K, Scharenberg AM, Kinet JP. Interaction between the Btk PH domain and phosphatidylinositol-3,4,5-trisphosphate directly regulates Btk. J. Biol. Chem. 2001;276(19):16201-16206.
22. Franke TF, Kaplan DR, Cantley LC, Toker A. Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science. 1997;275(5300):665-668.
23. Hoellenriegel J, Meadows SA, Sivina M, et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011;118(13):3603-3612.
24. Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117(2):591-594.
25. Flinn IW, Kahl BS, Leonard JP, et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-delta, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood. 2014;123(22):3406-3413.
26. Webb HK, Chen H, Yu AS, et al. Clinical Pharmacokinetics of CAL-101, a p110? Isoform-Selective PI3K Inhibitor, Following Single- and Multiple-Dose Administration In Healthy Volunteers and Patients with Hematological Malignancies. Blood. 2015;116(21):1774-1774.
27. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 2013;369(1):32-42.
28. O'Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. The Lancet Oncology. 2014;15(1):48-58.
29. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497-2506.
30. Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N. Engl. J. Med. 2014;371(3):213-223.
31. Farooqui MZH, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. The Lancet Oncology. 2015;16(2):169-176.
32. Stilgenbauer S, Jones JA, Coutre S, et al. Outcome of Ibrutinib Treatment by Baseline Genetic Features in Patients with Relapsed or Refractory CLL/SLL with del17p in the Resonate-17 Study. 57th American Society of Hematology Annual Meeting and Exposition; 2015; Orlando, FL.
33. Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. The Lancet Oncology. 2014;15(10):1090-1099.
34. Jaglowski SM, Jones JA, Nagar V, et al. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood. 2015;126(7):842-850.
35. Brown JR, Barrientos JC, Barr PM, et al. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015;125(19):2915-2922.
36. Akmal Chanan-Khan AA, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): First results from a randomized, double-blind, placebo-controlled, phase III study. J. Clin. Oncol. 2015;33:LBA7005.
37. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390-3397.
38. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 2014;370(11):997-1007.
39. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncol. 2015;1(1):80-87.
40. Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc. Natl. Acad. Sci. U. S. A. 2010;107(29):13075-13080.
41. Son AI, Park JE, Zhou R. The role of Eph receptors in lens function and disease. Sci China Life Sci. 2012;55(5):434-443.
42. Park JE, Son AI, Hua R, Wang L, Zhang X, Zhou R. Human cataract mutations in EPHA2 SAM domain alter receptor stability and function. PLoS One. 2012;7(5):e36564.
43. Klein BE, Klein R, Lee KE. Incidence of age-related cataract over a 10-year interval: the Beaver Dam Eye Study. Ophthalmology. 2002;109(11):2052-2057.
44. Liu J, Fitzgerald ME, Berndt MC, Jackson CW, Gartner TK. Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo. Blood. 2006;108(8):2596-2603.
45. Quek LS, Bolen J, Watson SP. A role for Bruton's tyrosine kinase (Btk) in platelet activation by collagen. Curr. Biol. 1998;8(20):1137-1140.
46. Bye AP, Unsworth AJ, Vaiyapuri S, Stainer AR, Fry MJ, Gibbins JM. Ibrutinib Inhibits Platelet Integrin alphaIIbbeta3 Outside-In Signaling and Thrombus Stability But Not Adhesion to Collagen. Arterioscler. Thromb. Vasc. Biol. 2015;35(11):2326-2335.
47. Levade M, David E, Garcia C, et al. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions. Blood. 2014;124(26):3991-3995.
48. Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia. 2015;29(4):783-787.
49. Mcmullen JR, Boey EJH. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2015;124(25):3829-3830.
50. McMullen JR, Amirahmadi F, Woodcock EA, et al. Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy. Proc. Natl. Acad. Sci. U. S. A. 2007;104(2):612-617.
51. Pretorius L, Du XJ, Woodcock EA, et al. Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation. Am. J. Pathol. 2009;175(3):998-1009.
52. Byrd JC, Hillmen P, James DF. Response: Additional data needed for a better understanding of the potential relationship between atrial fibrillation and ibrutinib. Blood. 2015;125(10):1673.
53. Schnabel RB, Yin X, Gona P, et al. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study. Lancet. 2015;386(9989):154-162.
54. Farooqui M, Valdez J, Soto S, Bray A, Tian X, Wiestner A. Atrial Fibrillation in CLL/SLL Patients on Ibrutinib. 57th American Society of Hematology Annual Meeting and Exposition; 2015; Orlando, FL.
55. Okkenhaug K, Bilancio A, Farjot G, et al. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science. 2002;297(5583):1031-1034.
56. Coutre SE, Barrientos JC, Brown JR, et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk. Lymphoma. 2015:1-8.
57. O'Brien SM, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia. Blood. 2015.
58. Lampson BL, Matos T, Kim HT, et al. Idelalisib Given Front-Line for the Treatment of Chronic Lymphocytic Leukemia Results in Frequent and Severe Immune-Mediated Toxicities. 57th American Society of Hematology Annual Meeting and Exposition; 2015; Orlando, FL.
59. O'Brien S, Davies AJ, Flinn IW, et al. Idelalisib Treatment Is Associated with Improved Cytopenias in Patients with Relapsed/Refractory iNHL and CLL. 57th American Society of Hematology Annual Meeting and Exposition; 2015; Orlando, FL.
2. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2012, based on November 2014 SEER data submission, posted to the SEER web site. Bethesda, MD: National Cancer Institute;2015.
3. Tam CS, Keating MJ. Chemoimmunotherapy of chronic lymphocytic leukemia. Nature Reviews Clinical Oncology. 2010;7(9):521-532.
4. Dighiero G, Maloum K, Desabilens B, et al. Chlorambucil in Indolent Chronic Lymphocytic Leukemia. The New England Journal of Medicine. 1998;338:1506-1514.
5. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N. Engl. J. Med. 2000;343(24):1750-1757.
6. Robak T, Dmoszynska A, Solal-Celigny P, et al. Rituximab Plus Fludarabine and Cyclophosphamide Prolongs Progression-Free Survival Compared With Fludarabine and Cyclophosphamide Alone in Previously Treated Chronic Lymphocytic Leukemia. J. Clin. Oncol. 2010;28(10):1756-1765.
7. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fl udarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. the Lancet. 2010;376:1164–1174.
8. Byrd JC, Jones JJ, Woyach JA, Johnson AJ, Flynn JM. Entering the era of targeted therapy for chronic lymphocytic leukemia: impact on the practicing clinician. J. Clin. Oncol. 2014;32(27):3039-3047.
9. Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. ChemMedChem. 2007;2(1):58-61.
10. Ibrutinib [package insert]. . In: Inc. P, ed. Sunnyvale, CA2015.
11. Kurosaki T. Regulation of BCR signaling. Mol. Immunol. 2011;48(11):1287-1291.
12. Woyach JA, Bojnik E, Ruppert AS, et al. Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood. 2014;123(8):1207-1213.
13. Herman SEM, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117(23):6287-6296.
14. Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119(5):1182-1189.
15. de Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590-2594.
16. Herishanu Y, Perez-Galan P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117(2):563-574.
17. de Jong J, Sukbuntherng J, Skee D, et al. The effect of food on the pharmacokinetics of oral ibrutinib in healthy participants and patients with chronic lymphocytic leukemia. Cancer Chemother. Pharmacol. 2015;75(5):907-916.
18. Bernard S, Goldwirt L, Amorim S, et al. Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. Blood. 2015;126(14):1695-1698.
19. Marostica E, Sukbuntherng J, Loury D, et al. Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies. Cancer Chemother. Pharmacol. 2015;75(1):111-121.
20. Idelalisib [package insert]. In: Inc. GS, ed. Foster City, CA2014.
21. Saito K, Scharenberg AM, Kinet JP. Interaction between the Btk PH domain and phosphatidylinositol-3,4,5-trisphosphate directly regulates Btk. J. Biol. Chem. 2001;276(19):16201-16206.
22. Franke TF, Kaplan DR, Cantley LC, Toker A. Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science. 1997;275(5300):665-668.
23. Hoellenriegel J, Meadows SA, Sivina M, et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011;118(13):3603-3612.
24. Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117(2):591-594.
25. Flinn IW, Kahl BS, Leonard JP, et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-delta, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood. 2014;123(22):3406-3413.
26. Webb HK, Chen H, Yu AS, et al. Clinical Pharmacokinetics of CAL-101, a p110? Isoform-Selective PI3K Inhibitor, Following Single- and Multiple-Dose Administration In Healthy Volunteers and Patients with Hematological Malignancies. Blood. 2015;116(21):1774-1774.
27. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 2013;369(1):32-42.
28. O'Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. The Lancet Oncology. 2014;15(1):48-58.
29. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497-2506.
30. Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N. Engl. J. Med. 2014;371(3):213-223.
31. Farooqui MZH, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. The Lancet Oncology. 2015;16(2):169-176.
32. Stilgenbauer S, Jones JA, Coutre S, et al. Outcome of Ibrutinib Treatment by Baseline Genetic Features in Patients with Relapsed or Refractory CLL/SLL with del17p in the Resonate-17 Study. 57th American Society of Hematology Annual Meeting and Exposition; 2015; Orlando, FL.
33. Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. The Lancet Oncology. 2014;15(10):1090-1099.
34. Jaglowski SM, Jones JA, Nagar V, et al. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood. 2015;126(7):842-850.
35. Brown JR, Barrientos JC, Barr PM, et al. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015;125(19):2915-2922.
36. Akmal Chanan-Khan AA, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): First results from a randomized, double-blind, placebo-controlled, phase III study. J. Clin. Oncol. 2015;33:LBA7005.
37. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390-3397.
38. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 2014;370(11):997-1007.
39. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncol. 2015;1(1):80-87.
40. Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc. Natl. Acad. Sci. U. S. A. 2010;107(29):13075-13080.
41. Son AI, Park JE, Zhou R. The role of Eph receptors in lens function and disease. Sci China Life Sci. 2012;55(5):434-443.
42. Park JE, Son AI, Hua R, Wang L, Zhang X, Zhou R. Human cataract mutations in EPHA2 SAM domain alter receptor stability and function. PLoS One. 2012;7(5):e36564.
43. Klein BE, Klein R, Lee KE. Incidence of age-related cataract over a 10-year interval: the Beaver Dam Eye Study. Ophthalmology. 2002;109(11):2052-2057.
44. Liu J, Fitzgerald ME, Berndt MC, Jackson CW, Gartner TK. Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo. Blood. 2006;108(8):2596-2603.
45. Quek LS, Bolen J, Watson SP. A role for Bruton's tyrosine kinase (Btk) in platelet activation by collagen. Curr. Biol. 1998;8(20):1137-1140.
46. Bye AP, Unsworth AJ, Vaiyapuri S, Stainer AR, Fry MJ, Gibbins JM. Ibrutinib Inhibits Platelet Integrin alphaIIbbeta3 Outside-In Signaling and Thrombus Stability But Not Adhesion to Collagen. Arterioscler. Thromb. Vasc. Biol. 2015;35(11):2326-2335.
47. Levade M, David E, Garcia C, et al. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions. Blood. 2014;124(26):3991-3995.
48. Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia. 2015;29(4):783-787.
49. Mcmullen JR, Boey EJH. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2015;124(25):3829-3830.
50. McMullen JR, Amirahmadi F, Woodcock EA, et al. Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy. Proc. Natl. Acad. Sci. U. S. A. 2007;104(2):612-617.
51. Pretorius L, Du XJ, Woodcock EA, et al. Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation. Am. J. Pathol. 2009;175(3):998-1009.
52. Byrd JC, Hillmen P, James DF. Response: Additional data needed for a better understanding of the potential relationship between atrial fibrillation and ibrutinib. Blood. 2015;125(10):1673.
53. Schnabel RB, Yin X, Gona P, et al. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study. Lancet. 2015;386(9989):154-162.
54. Farooqui M, Valdez J, Soto S, Bray A, Tian X, Wiestner A. Atrial Fibrillation in CLL/SLL Patients on Ibrutinib. 57th American Society of Hematology Annual Meeting and Exposition; 2015; Orlando, FL.
55. Okkenhaug K, Bilancio A, Farjot G, et al. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science. 2002;297(5583):1031-1034.
56. Coutre SE, Barrientos JC, Brown JR, et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk. Lymphoma. 2015:1-8.
57. O'Brien SM, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia. Blood. 2015.
58. Lampson BL, Matos T, Kim HT, et al. Idelalisib Given Front-Line for the Treatment of Chronic Lymphocytic Leukemia Results in Frequent and Severe Immune-Mediated Toxicities. 57th American Society of Hematology Annual Meeting and Exposition; 2015; Orlando, FL.
59. O'Brien S, Davies AJ, Flinn IW, et al. Idelalisib Treatment Is Associated with Improved Cytopenias in Patients with Relapsed/Refractory iNHL and CLL. 57th American Society of Hematology Annual Meeting and Exposition; 2015; Orlando, FL.