Ponatinib (Iclusig)

A kinase inhibitor indicated for the treatment of chronic phase, accelerated phase or blast phase CML that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia that is resistant or intolerant to prior kinase inhibitor therapy.

A third line tyrosine kinase inhibitor.

Ponatinib approved for the treatment of patients with chronic-phase chronic myeloid leukemia that is resistant or intolerant to at least 2 prior kinase inhibitors.


Daily starting dose of 45 mg. 


When achieving at least 1% BCR-ABL the dose is then reduced to 15 mg. 


The decision for approval is based on data from the phase 2 OPTIC and PACE trials.


A third-generation TKI.


Effective for many patients with resistant disease.


In the OPTIC trial, investigators enrolled patients with CP-CML whose disease was highly-resistant to the latest TKI they had received; 65% of these patients had not experienced a better response than that of a complete hematological response (CHR) on their immediate prior therapy.


Forty-two percent of 88 patients who received the response-based dosing regimen achieved at least a 1%BCR-ABL1IS at 12 months, meeting the primary end point of the trial. 


Moreover, at a median follow-up of 28.5 months, 73% of these patients were noted to have maintained that response.

Capable of inhibiting old single BCR-ABL1 mutatants reported in patients with resistance to first generation and second-generation tyrosine kinase inhibitors.

Ponatinib management result in durable responses after 4 years in heavily pretreated patients with CML

Ponatinib is an approved tyrosine kinase inhibitor with potent activity against native and resistant BCR-ABL, including T3151 mutation.

Not recommended for newly diagnosed chronic phase CML.

A potent oral tyrosine kinase inhibitor that blocks native and mutated BCR – ABL, including the gatekeeper mutant T3151, which is uniformly resistant to tyrosine kinase inhibitors.

Dose limiting effects are elevated lipase, amylase , and pancreatitis.

Common adverse events are rash, myelosuppression, and constitutional symptoms.

6% of treated patients experience venous occlusive events, and venothromboembolism.

Associated with arterial occlusive events and hepatic toxicity.

Late cerebro5252777revascular and peripheral vascular events can occur more than one year after the start of treatment.

PACE trial, a multicenter, international, single-arm clinical trial of 449 patients with disease that was resistant or intolerant to prior tyrosine kinase inhibitor therapy;The efficacy results demonstrated a 54% major cytogenetic response (MCyR) rate in patients with Chronic- phase (CP) CML.

In the above study 70% of patients with CP-CML with T315I mutation achieved MCyR.

In the above study patients with accelerated (AP) CML, Blast phase CML and Ph+ ALL, the MaHR rates were 52%, 31% and 41%, respectively, with a median duration of MaHR in patients with AP-CML, BP-CML and Ph+ ALL was 9.5 months, 4.7 months and 3.2 months respectively.

In the above study patients with accelerated (AP) CML, Blast phase CML and Ph+ ALL, the MaHR rates were 52%, 31% and 41%, respectively, with a median duration of MaHR in patients with AP-CML, BP-CML and Ph+ ALL was 9.5 months, 4.7 months and 3.2 months respectively.

Major hematologic responses by six months is achieved by 55% and 31% of patients with accelerated and blast phase CML, respectively

Arterial thrombosis and liver toxicity have occurred.

The most common side effects reported in the clinical trial include hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and nausea.

Ocular toxicity, fluid retention, hypertension, pancreatitis, arrhythmias, tumor lysis syndrome, reversible posterior leukoencephalopathy, compromise wound healing and G.I. perforation may occur.

Recommended dose and schedule for ponatinib is 45 mg taken orally once daily with or without food.

Reducing the dose to 30-15 mg a day decreases adverse events significantly.

Among the Philadelphia chromosome positive patients heavily pretreated with tyrosine kinase inhibitors, 43 patients with chronic phase CML, 98% had complete hematologic response, 72% had a major cytogenetic response and 44% had a major molecular response.

Of 22 patients with accelerated phase disease or PH positive ALL 36% a major hematologic response and 32% had a major cytogenetic response.

Of 12 patients with chronic phase CML with the T3151 mutation one hundred percent had a complete hematologic response, 92% had a major cytogenetic response.

Highly active in heavily treated patients with Philadelphia chromosome positive leukemias with resistance to tyrosine kinase inhibitors including those with BCR-ABL T3151 mutations, other unique mutations, or no mutations (Cortes JE et al).

New data indicate that approximately 24% of patients in the phase 2 clinical trial with a median treatment duration, 1.3 years and approximately 48% of patients in the phase 1 clinical trial, median treatment duration, 2.7 years, experienced serious adverse vascular events.

The events include fatal and life-threatening heart attack, stroke, loss of blood flow to the extremities resulting in tissue death, and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow.

In the phase 2 trial, heart failure, including fatalities, occurred in 8% of patients treated.

Serious adverse reactions involving the eyes, which led to blindness or blurred vision, also occurred.

In some patients, fatal and serious adverse events have occurred as early as 2 weeks after starting ponatinib therapy.

Currently, the FDA has pulled the drug from the market Oct 2013 due to vascular complications-the drug has been reintroduced 1/14 for patients for whom no other TKI is indicated.

Can be associated with life threatening thromboses.

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