Refractory Philadelphia Chromosome-Positive CML Regimen: Ponatinib (ICLUSIG)
Cortes JE et al. N Engl J Med 2012;367:2075–2088
Ponatinib hydrochloride 45 mg/day; administer orally with or without food, continually for 28 consecutive days, on days 1–28, every 4 weeks (total dose/28-day cycle = 1260 mg)
Notes:
On the basis of safety, pharmacokinetic, and pharmacodynamic data, 45 mg of ponatinib was determined to be the maximum tolerated dose
The optimal dose of ponatinib has not been identified. In clinical trials, the starting dose of ponatinib was 45 mg administered orally once daily. However, 59% of the patients required dose reductions to 30 mg or 15 mg once daily during the course of therapy
More safety information will become available with additional analysis and follow-up
Start dosing with 45 mg once daily. Consider reducing the dose of ponatinib for CP CML and AP CML patients who have achieved a major cytogenetic response
The recommended dose should be reduced to 30 mg once daily when administering ponatinib with strong CYP3A subfamily inhibitors
Supportive Care
Antiemetic prophylaxis
Emetogenic potential is MINIMAL
See Chapter 39 for antiemetic recommendations
Hematopoietic growth factor (CSF) prophylaxis
Primary prophylaxis is NOT indicated
See Chapter 43 for more information
Antimicrobial prophylaxis
Risk of fever and neutropenia is LOW
Antimicrobial primary prophylaxis to be considered:
See Chapter 47 for more information
United States Food and Drug Administration (US FDA): Safety Announcement, 12-20-2013
The U.S. Food and Drug Administration (FDA) is requiring several new safety measures for the leukemia drug Iclusig (ponatinib) to address the risk of life-threatening blood clots and severe narrowing of blood vessels. Once these new safety measures are in place, the manufacturer of Iclusig is expected to resume marketing to appropriate patients. Healthcare professionals should review these additional safety measures and carefully consider them when evaluating the risks and benefits of Iclusig for each patient
The required safety measures involve label changes to narrow the indication, provide additional warnings and precautions about the risk of blood clots and severe narrowing of blood vessels, revise recommendations about dosage and administration of Iclusig, and update the patient Medication Guide. We are also requiring a risk evaluation and mitigation strategy (REMS). In addition, the manufacturer of Iclusig, ARIAD Pharmaceuticals, must conduct postmarket investigations to further characterize the drug's safety and dosing
On October 31, 2013, FDA requested and ARIAD agreed to voluntarily suspend marketing of Iclusig. FDA's request resulted from FDA's investigation, which revealed a steady increase in the number of serious vascular occlusion events identified through continued safety monitoring of the drug. This observation represented a significant change in the safety profile of Iclusig as the proportion of patients on the drug experiencing vascular occlusion events such as blood clots and severe narrowing of blood vessels was significantly greater than the proportion reported at the time of its approval in December 2012
During the marketing suspension, Iclusig treatment has been available through single patient or emergency investigational new drug applications (INDs). Patients should continue to receive Iclusig under their authorized IND until marketing of Iclusig is resumed. FDA is working closely with ARIAD on the new safety measures and anticipates these will be in place by the end of January 2014. Once that process is complete, patients being treated under these INDs can be transitioned back to receiving the marketed Iclusig product. In more detail, the new safety measures for Iclusig include the following:
The indications for use are limited to:
Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)
Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated
The Warnings and Precautions in the label are revised to describe the vascular occlusion events. This includes a description of the observed arterial and venous thrombosis and occlusions that have occurred in at least 27%—more than 1 in every 4—of patients treated with Iclusig
The Dosage and Administration recommendations are revised to state that the optimal dose of Iclusig has not been identified. The recommended starting dose remains 45 mg administered orally once daily with or without food; however, additional information is included regarding dose decreases and discontinuations
The patient Medication Guide is revised to include additional safety information consistent with the safety information in the revised drug label
The Iclusig REMS will inform prescribers about the approved indications for use and the serious risk of vascular occlusion and thromboembolism associated with the drug
We urge healthcare professionals and patients to report side effects involving Iclusig to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of this page
European Medicines Agency Recommendations: November 22, 2013
Following a review of the data on the risk of occlusive vascular events with Iclusig, the European Medicines Agency has concluded that healthcare professionals may continue to use ponatinib in its authorized indication with increased caution. The Agency has made the following recommendations:
Iclusig should not be used in patients with a history of heart attack or stroke, unless the potential benefits of treatment outweigh the risks
The cardiovascular status of patients should be assessed and cardiovascular risk factors actively managed before starting treatment with Iclusig. Cardiovascular status should continue to be monitored and optimized during treatment
Hypertension should be controlled during treatment with Iclusig and healthcare professionals should consider interrupting treatment if hypertension is not controlled
Patients should be monitored for evidence of vascular occlusion or thromboembolism, and treatment should be interrupted immediately if this occurs
The recommendations are based on a review of data from clinical studies, including 2 ongoing studies (a phase I dose-finding study and a pivotal phase II study), which showed a higher incidence of arterial and venous thrombotic events in patients treated with Iclusig than was observed at the time of marketing authorization. In the phase I study, preliminary analysis of follow-up data from September 2013 showed a rate of serious occlusive vascular events of 22% (18 out of 81 patients) while in a preliminary analysis of data from the phase II study the rate was 13.8% (62 out of 449 patients). Median treatment duration was 2.7 years in the phase I study and 1.3 years in the phase II study
In addition, in a recently discontinued phase III study that compared Iclusig with imatinib with a median treatment duration of 3 months, there was a higher number of occlusive vascular events reported in the Iclusig arm, although the data from this study are still preliminary
The reported events from the studies include cardiovascular, cerebrovascular, peripheral vascular and venous thrombotic events. These events were seen in patients with and without risk factors but were seen more frequently in older patients and patients with a history of ischaemia (such as heart attacks) and strokes, high blood pressure, diabetes or blood fat disorders
Changes in Prescribing Information for Iclusig (Ponatinib) as of 12/2013 in Accordance with Fda Guidelines:
Boxed Warning
WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY
Vascular Occlusion:
Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig-treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events
Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit–risk consideration should guide a decision to restart Iclusig therapy
Heart Failure:
Hepatotoxicity:
Indications and Usage
Iclusig (ponatinib) is a kinase inhibitor indicated for the:
Treatment of adult patients with T315I-positive chronic myeloid leukemia (CML) (chronic phase, accelerated phase, or blast phase) and T315I-positive Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)
Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated
These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig
Dosage and Administration
2.1. Recommended Dosing
The optimal dose of Iclusig has not been identified. In clinical trials, the starting dose of Iclusig was 45 mg administered orally once daily. However, 59% of the patients required dose reductions to 30 mg or 15 mg once daily during the course of therapy
Start dosing with 45 mg once daily. Consider reducing the dose of Iclusig for CP CML and AP CML patients who have achieved a major cytogenetic response
Consider discontinuing Iclusig if response has not occurred by 3 months (90 days)
Iclusig may be taken with or without food. Tablets should be swallowed whole
Warnings and Precautions
3.1. Vascular Occlusion
Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can cause fatal and life-threatening vascular occlusion within 2 weeks of starting treatment. Iclusig can also cause recurrent or multisite vascular occlusion
In the dose-escalation (phase 1) clinical trial, 48% (31/65) of patients with CML or Ph+ ALL developed vascular occlusive events. The median time to onset of the first vascular occlusion event was 5 months. Iclusig can cause fatal and life-threatening vascular occlusion in patients treated at dose levels as low as 15 mg per day
Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Vascular occlusion adverse events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia (see Table)
Arterial Occlusion and Thrombosis
Arterial occlusion and thrombosis occurred in at least 20% (91/449) of Iclusig-treated patients with some patients experiencing events of more than 1 type. Patients have required revascularization procedures (cerebrovascular, coronary, and peripheral arterial) because of vascular occlusion from Iclusig
Cardiac vascular occlusion, including fatal and life-threatening myocardial infarction and coronary artery occlusion has occurred in 12% (55/449) of Iclusig-treated patients, Patients have developed heart failure concurrent or subsequent to themyocardial ischemic event
Cerebrovascular occlusion, including fatal stroke has occurred in 6% (27/449) of Iclusig-treated patients. Iclusig can cause stenosis over multiple segments in major arterial vessels that supply the brain (eg, carotid, vertebral, middle cerebralartery)
Peripheral arterial occlusive events, including fatal mesenteric artery occlusion and life-threatening peripheral arterial disease have occurred in 8% (36/449) of Iclusig-treated patients. Patients have developed digital or distal extremity necrosis and have required amputations
Clinicians should consider whether the benefits of Iclusig treatment are expected to exceed the risks of therapy. In patients suspected of developing arterial thrombotic events, interrupt or stop Iclusig. A benefit–risk consideration should guide a decision to restart Iclusig therapy
Venous Thromboembolism
Venous thromboembolic events occurred in 5% (23/449) of Iclusig-treated patients, including deep venous thrombosis (8 patients), pulmonary embolism (6 patients), superficial thrombophlebitis (3 patients), and retinal vein thrombosis (2 patients). Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism
3.2. Heart Failure
Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusig-treated patients (N = 22). Eight percent of patients (N = 35) experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure
3.3. Hypertension
Treatment-emergent hypertension occurred in 67% of patients (300/449). Eight patients (2%) treated with Iclusig in clinical trials experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensivecrisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In patients with baseline systolic BP <140 mm Hg and baseline diastolic BP <90 mm Hg, 78% (220/282) experienced treatment-emergent hypertension; 49% (139/282) developed Stage 1 hypertension (defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg) while 29% developed Stage 2 hypertension (defined as systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled
3.4. Neuropathy
Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients (<1% grade 3/4)
Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected
3.5. Ocular Toxicity
Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients
Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of the patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment
Patient Population Studied
Patients with a diagnosis of CML whose disease had relapsed or was resistant to standard care, or for which no standard care was available or acceptable. Ph-positive disease was classified and characterized as relapsed or refractory disease on the basis of standard criteria. In addition, patients were required to have an Eastern Cooperative Oncology Group performance status of 2 or lower