Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma

Wang, Michael L.; Rule, Simon; Martin, Peter; Goy, André; Auer, Rebecca; Kahl, Brad S.; Jurczak, Wojciech; Advani, Ranjana H.; Romaguera, Jorge; Williams, Michael E.; Barrientos, Jacqueline C.; Chmielowska, Ewa; Radford, John; Stilgenbauer, Stephan; Dreyling, Martin; Jędrzejczak, Wiesław Wiktor; Johnson, Peter; Spurgeon, Stephen E.; Li, Lei; Zhang, Liang; Newberry, Kate J.; Ou, Zhishuo; Cheng, Ni; Fang, Bingliang; McGreivy, Jesse; Clow, Fong; Buggy, Joseph J.; Chang, Betty; Beaupre, Darrin M.; Kunkel, Lori; Blum, Kristie A.

doi:10.1056/nejmoa1306220

Cited by 1,488 publications

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“…The U.S. Food and Drug Administration declared ibrutinib as a breakthrough therapy in February 2013 for the treatment of relapsed/ refractory mantle cell lymphoma and gave approval for this indication in November 2013 (Wang et al, 2013). Recently, in February 2014 the Food and Drug Administration provided accelerated approval for ibrutinib for chronic lymphocytic leukemia in patients who had received at least one previous therapy (Byrd et al, 2013;O'Brien et al, 2014).…”

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confidence: 99%

Absorption, Metabolism, and Excretion of Oral ¹⁴C Radiolabeled Ibrutinib: An Open-Label, Phase I, Single-Dose Study in Healthy Men

et al. 2014

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The absorption, metabolism, and excretion of ibrutinib were investigated in healthy men after administration of a single oral dose of 140 mg of 14 C-labeled ibrutinib. The mean (S.D.) cumulative excretion of radioactivity of the dose was 7.8% (1.4%) in urine and 80.6% (3.1%) in feces with <1% excreted as parent ibrutinib. Only oxidative metabolites and very limited parent compound were detected in feces, and this indicated that ibrutinib was completely absorbed from the gastrointestinal tract. Metabolism occurred via three major pathways (hydroxylation of the phenyl (M35), opening of the piperidine (M25 and M34), and epoxidation of the ethylene on the acryloyl moiety with further hydrolysis to dihydrodiol (PCI-45227, and M37). Additional metabolites were formed by combinations of the primary metabolic pathways or by further metabolism. In blood and plasma, a rapid initial decline in radioactivity was observed along with long terminal elimination half-life for total radioactivity. The maximum concentration (C max ) and area under the concentration-time curve (AUC) for total radioactivity were higher in plasma compared with blood. The main circulating entities in blood and plasma were M21 (sulfate conjugate of a monooxidized metabolite on phenoxyphenyl), M25, M34, M37 (PCI-45227), and ibrutinib. At C max of radioactivity, 12% of total radioactivity was accounted for by covalent binding in human plasma. More than 50% of total plasma radioactivity was attributed to covalently bound material from 8 hours onward; as a result, covalent binding accounted for 38% and 51% of total radioactivity AUC 0-24 h and AUC 0-72 h , respectively. No effect of CYP2D6 genotype was observed on ibrutinib metabolism. Ibrutinib was well-tolerated by healthy participants.

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Section: Introductionmentioning

confidence: 99%

Absorption, Metabolism, and Excretion of Oral ¹⁴C Radiolabeled Ibrutinib: An Open-Label, Phase I, Single-Dose Study in Healthy Men

et al. 2014

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“…Most events were grade 1 to 2 (spontaneous bruising or petechiae), but in 5% of patients, they were of grade 3 or higher after trauma. [4][5][6] Platelets are the most important blood cells to prevent bleeding after vascular injury. Two Tec family kinases, Btk and Tec, are involved in platelet activation downstream of the collagen receptor glycoprotein VI (GPVI) via phospholipase Cg2 (PLCg2) phosphorylation and activation.…”

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Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions

Levade

David

Garcia

et al. 2014

Blood

282

260

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Key Points• Ibrutinib affects collagen and VWF-mediated platelet activation.• The bleeding diathesis correlates with defects in collagen-induced platelet aggregation and firm adhesion on VWF at arterial shear rate.The oral Bruton's tyrosine kinase inhibitor, ibrutinib, has recently demonstrated high efficiency in patients with relapsed B-cell malignancies. Occurrence of bleeding events has been reported in a subgroup of ibrutinib-treated patients. We demonstrate that ibrutinib selectively inhibits platelet signaling and functions downstream of the collagen receptor glycoprotein VI and strongly affects firm platelet adhesion on von Willebrand factor (VWF) under arterial flow. A longitudinal study of 14 patients indicated a correlation between occurrence of bleeding events and decreased platelet aggregation in response to collagen in platelet-rich plasma and firm adhesion on VWF under arterial flow. The addition of 50% untreated platelets was sufficient to efficiently reverse the effects of ibrutinib, and platelet functions recovered after treatment interruption as physiological platelet renewal occurred. These data have important clinical implications and provide a basis for hemostasis management during ibrutinib treatment. (Blood. 2014;124(26):3991-3995) IntroductionThe Bruton tyrosine kinase (Btk) is an essential actor downstream of the B-cell receptor, and its covalent inhibitor, ibrutinib, has recently been approved for therapies of relapsed chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). [1][2][3][4][5][6][7][8] Bleeding has been reported in up to 50% of ibrutinib-treated patients. Most events were grade 1 to 2 (spontaneous bruising or petechiae), but in 5% of patients, they were of grade 3 or higher after trauma. [4][5][6] Platelets are the most important blood cells to prevent bleeding after vascular injury. Two Tec family kinases, Btk and Tec, are involved in platelet activation downstream of the collagen receptor glycoprotein VI (GPVI) via phospholipase Cg2 (PLCg2) phosphorylation and activation.9,10 Under arterial shear rate, interaction of platelets with the damaged vessel wall is largely mediated by binding of von Willebrand factor (VWF) to its receptor, the GPIb-IX-V complex. In a mouse model, Btk has been shown to play a role in VWF/GPIb-IX-V-induced platelet activation.11 To further characterize the bleeding events in ibrutinib-treated patients, we investigated the effect of this drug on platelet functions in vitro and ex vivo in 14 patients. Study designFor in vitro experiments, whole blood, platelet-rich plasma (PRP), or washed platelets from healthy donors free of antiplatelet medication were preincubated with ibrutinib (PCI-32765; Selleckchem) or dimethylsulfoxide for 10 or 30 minutes as indicated. For ex vivo experiments, blood samples were obtained before and 2 to 4 weeks after starting ibrutinib treatment (Imbruvica; Janssen-Cilaq Laboratories) in patients with CLL (420 mg daily) or MCL (560 mg daily) [4][5][6] (French compassionate use program) after informed consent, in ...

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“…Ibrutinib (previously called PCI-32765) is a potent (IC 50 , 0.5 nM) BTK inhibitor that inactivates BTK through irreversible covalent bonding to Cys-481 in the ATP-binding domain of BTK (3)(4)(5). Early-stage clinical trials found ibrutinib to be particularly active in patients with CLL (6, 7) and mantle cell lymphoma (8), and the drug recently has been Food and Drug Administration-approved for patients with relapsed CLL and mantle cell lymphoma.…”

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Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)

Komarova

Burger

Wodarz

2014

Proc. Natl. Acad. Sci. U.S.A.

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The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib is a new targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib is given orally on a continuous schedule and induces durable remissions in the majority of CLL patients. However, a small proportion of patients initially responds to the BTKi and then develops resistance. Estimating the frequency, timing, and individual risk of developing resistance to ibrutinib, therefore, would be valuable for long-term management of patients. Computational evolutionary models, based on measured kinetic parameters of patients, allow us to approach these questions and to develop a roadmap for personalized prognosis and treatment management. Our kinetic models predict that BTKi-resistant mutants exist before initiation of ibrutinib therapy, although they only comprise a minority of the overall tumor burden. Furthermore, we can estimate the time required for resistant cells to grow to detectable levels. We predict that this can be highly variable, depending mostly on growth and death rates of the individual CLL cell clone. For a specific patient, this time can be predicted with a high degree of certainty. Our model can thus be used to predict for how long ibrutinib can suppress the disease in individual patients. Furthermore, the model can suggest whether prior debulking of the tumor with chemo-immunotherapy can prolong progression-free survival under ibrutinib. Finally, by applying the models to data that document progression during ibrutinib therapy, we estimated that resistant mutants might have a small (<2%) mean fitness advantage in the absence of treatment, compared with sensitive cells.evolutionary dynamics | drug resistance | personalized medicine | mathematical models | stochastic dynamics

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Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma

Cited by 1,488 publications

References 30 publications

Absorption, Metabolism, and Excretion of Oral ¹⁴C Radiolabeled Ibrutinib: An Open-Label, Phase I, Single-Dose Study in Healthy Men

Absorption, Metabolism, and Excretion of Oral ¹⁴C Radiolabeled Ibrutinib: An Open-Label, Phase I, Single-Dose Study in Healthy Men

Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions

Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)

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Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma

Cited by 1,488 publications

References 30 publications

Absorption, Metabolism, and Excretion of Oral 14C Radiolabeled Ibrutinib: An Open-Label, Phase I, Single-Dose Study in Healthy Men

Absorption, Metabolism, and Excretion of Oral 14C Radiolabeled Ibrutinib: An Open-Label, Phase I, Single-Dose Study in Healthy Men

Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions

Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)

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Product

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Absorption, Metabolism, and Excretion of Oral ¹⁴C Radiolabeled Ibrutinib: An Open-Label, Phase I, Single-Dose Study in Healthy Men

Absorption, Metabolism, and Excretion of Oral ¹⁴C Radiolabeled Ibrutinib: An Open-Label, Phase I, Single-Dose Study in Healthy Men