If you are a consumer or patient please visit this version. Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML. Tablets : 15 mg, 30 mg and 45 mg 3. Lactation : Advise women not to breastfeed.
Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML [see Warnings and Precautions 5. The optimal dose of Iclusig has not been identified. In clinical trials, the starting dose of Iclusig was 45 mg administered orally once daily.GIST Day of Learning Miami 2016- Dr. Jonathan Trent
Start dosing with 45 mg once daily. If a serious non-hematologic adverse reaction occurs, modify the dose, interrupt treatment, or consider discontinuation. Do not restart Iclusig in patients with arterial or venous occlusive reactions unless the potential benefit outweighs the risk of recurrent arterial or venous occlusions and the patient has no other treatment options.
For serious reactions other than arterial or venous occlusion, do not restart Iclusig until the serious event has resolved or the potential benefit of resuming therapy is judged to outweigh the risk. The recommended dose should be reduced to 30 mg once daily when administering Iclusig with strong CYP3A inhibitors [see Drug Interactions 7.
Iclusig can cause fatal and life-threatening arterial occlusion within 2 weeks of starting treatment, and at dose levels as low as 15 mg per day.
Iclusig can also cause recurrent or multisite vascular occlusion. Patients have required revascularization procedures coronary, cerebrovascular, and peripheral arterial. In the Phase 2 trial, the median time to onset of the first cardiac vascular, cerebrovascular, and peripheral vascular arterial occlusive events was range: 1 torange: 5 toand range: 3 to days, respectively. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events.
Arterial occlusion adverse events were more frequent with increasing age and in patients with history of ischemia, hypertension, diabetes, or hyperlipidemia see Table 4. Patients have developed heart failure concurrent or subsequent to the myocardial ischemic event [see Warnings and Precautions 5.
Iclusig can cause stenosis over multiple segments in major arterial vessels that supply the brain e. Patients have developed digital or distal extremity necrosis and have required amputations. Renal artery stenosis, associated with worsening, labile or treatment-resistant hypertension, has occurred in some Iclusig-treated patients [see Warnings and Precautions 5.
Clinicians should consider whether the benefits of Iclusig treatment are expected to exceed the risks of therapy. In patients suspected of developing arterial occlusive events, interrupt or stop Iclusig.
A benefit-risk consideration should guide a decision to restart Iclusig therapy [see Dosage and Administration 2.Alona Merkulova, Steven C.
Mitchell, Evi X. Stavrou, Gabriel L. Forbes, Alvin H. Schmaier; Ponatinib treatment promotes arterial thrombosis and hyperactive platelets. Blood Adv ; 3 15 : — Ponatinib therapy heightens arterial thrombosis and platelet reactivity. Concurrent pioglitazone treatment reverses heightened thrombosis risk and platelet reactivity induced by ponatinib. Ponatinib has the widest inhibitory spectrum of CML tyrosine kinases. Our investigations reveal that ponatinib increases in vivo arterial thrombosis risk and platelet hyperreactivity, but concurrent pioglitazone administration reverses both.
Ponatinib and imatinib were provided by Ariad Pharmaceuticals, which assayed in vivo drug level by liquid chromatography with tandem mass spectrometry. Pioglitazone hydrochloride and ponatinib were purchased from Tocris Bioscience. Immunoperoxidase staining reactions were developed with reagents from Cell Signaling and Thermo Fisher All TKIs to mice were administered by gavage twice daily for 14 days.
Murine carotid artery thrombosis studies were performed using Rose Bengal as previously reported. Alexa Fluor fibrinogen F was obtained from Molecular Probes. Immunoblot band density was determined with ImageJ. To examine global thrombosis risk after TKI therapy, an in vivo murine arterial thrombosis model was established. Influence of ponatinib on thrombosis propensity, vessel wall, and platelets.
A Aged mice were untreated UT or treated with the indicated TKI at the concentration shown for 14 days by oral gavage twice daily. Each symbol in the graph represents the investigation of a single mouse.
Ponatinib: Accelerated Disapproval
The insets in the right lower part of each histologic panel are a fourfold increase in the size of the section of each tissue shown.
The brown intracellular material seen is the presence of antibodies to nitrotyrosine or caspase 3, respectively, in the tissue of mice treated with Poni.
Each symbol on the graph represents analysis from 1 complete slide. G Aged mice were UT or treated with the indicated agent for 14 days by oral gavage. P values were determined by Student t test.
Preparation of slides and analysis were performed as described in panel B. Concentrations of TKI levels in murine plasma at steady-state condition a fter 4 days of t reatment and 2 and 24 hours a fter oral administration.
Groups of treated mice were given the agent twice daily for 4 d before sample collection. Vessel apoptosis of the adventitia is associated with increased nicotinamide adenine dinucleotide phosphate oxidase—derived ROS.
Platelet glycoprotein VI activation after CRP treatment revealed that in vivo ponatinib-treated platelets were hyperreactive. In previous in vitro investigations, CRP-induced, but not thrombin-induced, platelet activation was inhibited by treating washed platelets with nM of ponatinib. In contrast, imatinib treatment inhibited murine platelets, because the CRP threshold dose was higher supplemental Figure 5.
Next, we investigated if concurrent pioglitazone and ponatinib treatment in mice ameliorated vessel wall ROS and apoptosis and corrected platelet hyperreactivity.Medically reviewed by Drugs. Last updated on May 11, Excipient information presented when available limited, particularly for generics ; consult specific product labeling. Chronic myeloid leukemia: Treatment of chronic myeloid leukemia CML in chronic, accelerated, or blast phase in patients for whom no other tyrosine kinase inhibitor therapy is indicated or who are TI-positive.
Limitations of use: Ponatinib is not indicated and not recommended for treatment of newly diagnosed chronic phase CML. Canadian labeling: Hypersensitivity to ponatinib or any component of the formulation; unmanaged cardiovascular risk factors, including uncontrolled hypertension; patients not adequately hydrated and with uncorrected hyperuricemia. Note: The optimal ponatinib dose has not been identified. Consider discontinuing therapy if no response has occurred by 3 months 90 days of therapy.
Chronic myeloid leukemia CML; chronic, accelerated, or blast phaseTI-positive or in patients for whom no other tyrosine kinase inhibitor therapy is indicated: Oral: Initial: 45 mg once daily; consider reducing the dose for patients in chronic or accelerated phase who have achieved a major cytogenetic response.
Note: Ponatinib is not recommended for treatment of newly diagnosed chronic phase CML. Consult drug interactions database for more information. Arterial or venous occlusive reactions: Interrupt therapy; do not resume ponatinib in the event of serious occlusive events unless the potential benefit of therapy outweighs the risk of recurrent occlusions and other treatment options are not available.
Asymptomatic grade 1 or 2 serum lipase elevation: Consider interrupting therapy or dose reduction. If toxicity occurs at a dose of 15 mg daily, discontinue therapy. Other nonhematologic toxicities: For serious reactions other than arterial or venous occlusionmodify the dose or interrupt treatment; do not restart therapy until symptom resolution or unless the benefit of therapy outweighs the risk of recurrent toxicity. Avoid combination. Monitor therapy.
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Specifically, the risk for neutropenia may be increased. Management: Per ponatinib U. Consider therapy modification. Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone.
Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination. Management: Reduce ponatinib starting dose to 30 mg daily when patients consume grapefruit consistently or in large amounts. Since grapefruit effects on CYP3A mediated metabolism are variable and poorly predictable, consider advising patients to avoid.
Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents.
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Cardiovascular: Atrial flutter, atrial tachycardia, complete atrioventricular block, prolonged QT interval on ECG, sinus node dysfunction, superficial thrombophlebitis, supraventricular tachycardia, tachycardia, ventricular tachycardia. Ophthalmic: Blepharitis, cataract, corneal ulcer, eyelid edema, glaucoma, iridocyclitis, iritis, ocular hyperemia, periorbital edema.
Cardiovascular: Aneurysm includes aortic aneurysm, aortic dissection, aortic rupture, arterial dissection, arterial rupture.Specific activation of Notch signaling in CML cells by ponatinib can be considered as the "on-target effect" on the tumor and represents a therapeutic approach for CML. Nevertheless, ponatinib-induced vascular toxicity remains a serious concern, with underlying mechanisms being poorly understood. We aimed to determine the mechanisms of ponatinib-induced vascular toxicity, defining associated signaling pathways and identifying potential rescue strategies.
We exposed human umbilical endothelial cells HUVECs to ponatinib or vehicle in the presence or absence of the neutralizing factor anti-Notch-1 antibody for exposure times of h. Label-free proteomics and network analysis showed that protein cargo of HUVECs treated with ponatinib triggered apoptosis and inhibited vasculature development.
We validated the proteomic data showing the inhibition of matrigel tube formation, an up-regulation of cleaved caspase-3 and a downregulation of phosphorylated AKT and phosphorylated eNOS. We delineated the signaling of ponatinib-induced vascular toxicity, demonstrating that ponatinib inhibits endothelial survival, reduces angiogenesis and induces endothelial senescence and apoptosis via the Notch-1 pathway.
Ponatinib induced endothelial toxicity in vitro. Hyperactivation of Notch-1 in the vessels can lead to abnormal vascular development and vascular dysfunction. By hyperactivating Notch-1 in the vessels, ponatinib exerts an "on-target off tumor effect", which leads to deleterious effects and may explain the drug's vasculotoxicity.
Selective blockade of Notch-1 prevented ponatinib-induced vascular toxicity. Keywords: Notch-1; ponatinib; tyrosine kinase inhibitors; vascular toxicity.Advances in Pulmonary Hypertension 1 August ; 17 2 : 69— The treatment of the malignant hematological diseases has been revolutionized by the use of tyrosine kinase inhibitors TKI : for example, imatinib in patients with chronic myeloid leukemia.
The mechanism of PAH development is presumed to be endothelial cell toxicity through the production of mitochondrial reactive oxygen species. A third of the patients who develop PAH can have persistent symptoms of dyspnea and right heart failure even after the interruption of the TKIs. For these patients, use of specific PAH treatment is indicated along with close follow-up. Thus, early screening for PAH diagnosis and proper management is required.
Imatinib was the first generation of designer therapies developed at the beginning of the s to target the BCR-ABL1 tyrosine kinase and was a monumental success in the treatment of CML patients. Lapatinib is a TKI used in the treatment of human epidermal growth factor receptor 2-positive breast cancer. Investigating TKI toxicity is very important, as patients with CML may require lifelong treatment with a TKI and because some complications can be fatal if not diagnosed and treated expediently.
Interestingly, imatinib showed encouraging results in animal studies as a treatment for PAH, having properties such as blocking platelet-derived growth factor and c-KIT signaling, which are involved in PAH pathogenesis. It was proposed that imatinib could prevent abnormal vascular proliferation and be used as PAH treatment. Although imatinib showed clinical efficacy and met the clinical trial's primary endpoint, severe side effects of edema, anemia, and an increased risk of subdural hematoma were seen.
For dasatinib-induced PAH, an incidence of at least 0. Eight patients required second-line therapy with dasatinib because of resistance to or intolerance of first-line imatinib. The median delay between dasatinib initiation and the PAH diagnosis was 34 months and the median dose of dasatinib used was mg per day.
The median 6-minute walk test distance was meters. Following PAH diagnosis, additional evaluation found that 6 patients had bilateral pleural effusions on computed tomography and 3 patients had mild pericardial effusions on echocardiography. While most patients had moderate or severe PAH at diagnosis, by the time of 4-month follow-up after dasatinib discontinuation, 8 patients were significantly improved.
Two patients died at follow-up 1 unexplained sudden death and 1 cardiac failure, 8 and 12 months respectively after dasatinib cessation. Inas a continuation of the previous study, the long-term follow-up of 21 cases of dasatinib-induced PAH from France were reported. Fifteen patients were female, and the median age was 52 years. PAH diagnosis occurred after median dasatinib treatment duration of 42 months. The median dose of dasatinib was mg per day. The right heart catheterization confirmed precapillary PH in 19 patients, and combined pre- and postcapillary PH in 2 patients.
Median mPAP was 45 mm Hg; cardiac index 3. Dasatinib was discontinued in all patients; in addition, 9 patients received specific PAH treatment and 2 patients received calcium channel blockers alone. After a median follow-up of 24 months, 19 patients improved NYHA functional class, and the median 6-minute walking distance increased to meters.
One patient presented hemodynamic deterioration after withdrawal of PAH-specific treatment, and 2 patients had normal hemodynamic parameters, but demonstrated exercise PH.Blood ; 14 : — In this issue of BloodLafiti et al address the critical question of vascular and cardiac toxicity of ponatinib, using a mouse model. Although ponatinib has a powerful effect on TI-mutated cells, cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, have occurred in ponatinib-treated patients.
To explore the vascular toxicity due to endothelial alterations from ponatinib, Lafiti et al used in vivo ultrasound molecular imaging and intravital microscopy. They compared ponatinib to dasatinib treatment in these 2 mice strains. Dasatinib was selected as a control because this TKI was known to induce very few thrombotic events. A large panel of in vivo imaging methods was employed to investigate the endothelial angiopathy.
Mice were the unfortunate actors in movies performed with contrast-enhanced ultrasound molecular imaging, intravital microscopy, echocardiography, or computed tomography coronary angiography. I really encourage the readers to look at the impressive videos provided in the supplemental data. The treatment-related mortality was significantly higher in ponatinib-treated mice. This supports the previous observation of the activity of ponatinib on vascular endothelial growth factor receptor In both large arteries and the peripheral microcirculation, ponatinib caused a prothrombotic angiopathy.
More precisely, ponatinib increased endothelial VWF with exposure of the A1 binding domain, and platelet adhesion several fold within days of the onset of treatment. Thus, ponatinib caused an acquired resistance to VWF.
Of interest, there was no coronary artery occlusion or stenosis but rather wall motion abnormalities as revealed by left ventricular coronary microvascular anatomy. In the aggregate, these data provided evidence of a thrombotic microangiopathy due to ponatinib.
This is consistent with postmortem findings in patients of coronary microvascular thrombosis and histologic evidence of platelets adhesion. Ponatinib also increased surface expression of VWF on human umbilical vein endothelial cells HUVECs cultured in a microfluidic system, indicating that increased surface mobilization and decreased proteolytic cleavage played a role in the angiopathy. Ponatinib inhibited HUVEC tube formation, indicating a possible suppressive effect on neoangiogenesis of vascular endothelial cells.
The activity of ponatinib on coagulation has also been studied. Gene expression and pathway analysis demonstrated that ponatinib enhanced the messenger RNA expression of coagulation factors of both the contact activation intrinsic and the tissue factor extrinsic pathways.
In line with this, ponatinib enhanced plasma levels of factor VII and increased cardiovascular risk through induction of a prothrombotic state. In the initial ARIAD brochure, it was stated that no remarkable adverse effects of ponatinib were identified in single-dose mouse and rat studies designed to assess central nervous system, renal, pulmonary, and gastrointestinal system functioning.
Ponatinib was extensively tested in 2 multicenter trials for drug registration. Thus, what shall we do now for our patients? Physicians should optimize control of cardiovascular risk factors and carefully select patients when ponatinib therapy is considered.
Patients with the highly resistant TI mutated clone are the most likely to benefit from treatment. Sign In or Create an Account.By: Dana A. New research has shown that the third-generation tyrosine kinase inhibitor ponatinib significantly increased endothelial toxicity in vitro. Their findings were published in the Journal of Clinical Medicine. The researchers exposed human umbilical endothelial cells to ponatinib, or a vehicle, in the presence or absence of the anti—Notch-1 antibody for exposure times of 0 to 72 hours.
Analysis showed that the protein cargo of human umbilical endothelial cells treated with ponatinib triggered apoptosis and inhibited vasculature development. The data showed the inhibition of tube formation using a branded complex protein mixture—based assay, upregulation of cleaved caspase-3, as well as downregulation of phosphorylated AKT and phosphorylated endothelial NOS.
The signaling of ponatinib-induced vascular toxicity was identified, and it was found that ponatinib inhibited endothelial survival, reduced angiogenesis, and induced endothelial senescence and apoptosis via the Notch-1 pathway. Ponatinib induced endothelial toxicity in vitro. Hyperactivation of Notch-1 in the vessels led to abnormal vascular development and dysfunction. Selective blockade of Notch-1 prevented ponatinib-induced vascular toxicity, they noted.
Journal of Clinical Medicine.
Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway
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