Ponatinib in Chronic Myeloid Leukemia and Philadelphia Chromosome–positive Acute Lymphoblastic Leukemia 

Get Permission

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.


On December 14, 2012, ponatinib (Iclusig) was granted accelerated approval for the treatment of adult patients with chronic-phase, accelerated-phase, or blast-phase chronic myeloid leukemia (CML) with resistance or intolerance to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior tyrosine kinase inhibitor therapy.1

Approval was based on rates of major cytogenetic response in patients with chronic-phase CML and major hematologic response in patients with accelerated-phase CML, blast-phase CML, or Philadelphia chromosome–positive ALL in a single-arm trial (PACE) in patients with intolerance of or disease resistant to prior tyrosine kinase inhibitor treatment, including patients with the BCR-ABL T315I mutation.2 Currently, there are no data verifying an improvement in disease-related symptoms or increased survival with ponatinib. Submission of 24-month follow up data was a condition for accelerated approval.

In the trial,2 449 patients received a ponatinib starting dose of 45 mg daily. Patients had a median age of 59 years, 53% were male, 79% were white, 92% had ECOG performance status 0 or 1, 88% had resistance to prior tyrosine kinase inhibitor therapy, and 56% had received three or more prior approved tyrosine kinase inhibitors. At the time of analysis, the median durations of ponatinib treatment were 281 days in patients with chronic-phase CML, 286 days in those with accelerated-phase CML, 89 days in those with blast-phase CML, and 81 days in those with Philadelphia chromosome–positive ALL. The median dose was 37 mg.

Major cytogenetic response occurred in 54% of 267 chronic-phase CML patients, including 49% of 203 with resistance/intolerance and 70% of 64 with the T315I mutation. Major hematologic response occurred in 52% of 83 patients with accelerated-phase CML (complete hematologic response in 47%), 31% of 62 patients with blast-phase CML (complete hematologic response in 21%), and 41% of 32 patients with Philadelphia chromosome–positive ALL (complete hematologic response in 34%).

Median time to major cytogenetic response in chronic-phase CML patients was 84 days, and median duration of major cytogenetic response had not been reached at the time of analysis. Median times to major hematologic response were 21, 29, and 20 days in patients with accelerated-phase CML, blast-phase CML, and Philadelphia chromosome–positive ALL, respectively, and median durations of response were 9.5, 4.7, and 3.2 months.

How It Works

Ponatinib is a kinase inhibitor that blocks activity of ABL and T315I-mutant ABL kinases, members of the VEGFR, PDGFR, FGFR, EPH receptor, and SRC families of kinases, and KIT, RET, TIE2, and FLT3 kinases. In preclinical studies, ponatinib inhibited the viability of cells expressing native or mutant BCR-ABL, including T315I and reduced the size of tumors expressing native or T315I-mutant BCR-ABL.

How It Is Given

The recommended dose of ponatinib is 45 mg orally once daily with or without food. Treatment is continued until evidence of disease progression or unacceptable toxicity.

Treatment interruption and sequential dose reduction to 30 mg and 15 mg are recommended for neutropenia and thrombocytopenia, grade 2 or higher liver transaminase elevations, grade 3 lipase elevations, and grade 2 or 3 pancreatitis. Discontinuation is recommended for elevation of AST or ALT to greater than or equal to three times the upper limit of normal concurrent with an elevation of bilirubin to greater than two times the upper limit of normal and alkaline phosphatase to greater than two times the upper limit of normal, grade 4 pancreatitis, and for liver abnormalities and lower-grade pancreatitis persisting at the lowest ponatinib dose (15 mg).

The ponatinib dose should be reduced to 30 mg daily in patients receiving strong CYP3A inhibitors (for example, protease inhibitors [ritonavir, idinavir], some macrolide antibiotics [clarithromycin], and
some antifungals [ketoconazole, itraconazole]).

Safety Profile

The most common grade 3 or 4 nonhematologic adverse events by patient group were: hypertension (39%), abdominal pain (10%), and rash (5%) in patients with chronic-phase CML; hypertension (36%), pneumonia (9%), abdominal pain (8%), and rash (8%) in accelerated-phase CML patients; hypertension (26%), cardiac failure (11%), febrile neutropenia (11%), and pneumonia (11%) in blast-phase CML patients; and hypertension (31%), febrile neutropenia (25%), and sepsis (22%) in Philadelphia chromosome–positive ALL patients. Among all patients, the most common serious adverse events were arterial ischemic events (8%, including myocardial infarction or worsening coronary artery disease in 5%) and pancreatitis (5%).

Grade 3 or 4 hematologic abnormalities by treatment group included thrombocytopenia, neutropenia, and anemia in 36%, 24%, and 14% of chronic-phase CML patients; 47%, 51%, and 26% of accelerated-phase CML patients; 57%, 55%, and 55% of blast-phase CML patients; and 47%, 63%, and 34% of Philadelphia chromosome–positive ALL patients. Among all patients, the most common grade 3 or 4 nonhematologic abnormalities were increased lipase (15%), increased ALT (8%), and decreased phosphorus (8%).

Adverse events resulted in discontinuation of treatment in 13% of chronic-phase CML patients, 11% of accelerated-phase CML patients, 15% of blast-phase CML patients, and 9% of Philadelphia chromosome–positive ALL patients, with the most common causes consisting of thrombocytopenia (4%) and infections (1%). Overall, adverse events caused dose delays or reductions in 74% of patients, with the most common causes consisting of thrombocytopenia (30%), neutropenia (13%), increased lipase (12%), rash (11%), abdominal pain (11%), pancreatitis (6%), and increased ALT, AST, or GGT (6%).

Ponatinib carries boxed warnings for arterial thrombosis (cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke) and hepatotoxicity (including liver failure and death). Ponatinib also carries warnings/precautions for congestive heart failure, hypertension, pancreatitis, hemorrhage, fluid retention, cardiac arrhythmias, myelosuppression, tumor lysis syndrome, compromised wound healing and gastrointestinal perforation, and embryo-fetal toxicity.

Patients should be monitored monthly for serum lipase and every 2 weeks for 3 months and then monthly as clinically indicated for complete blood counts. Adequate hydration should be ensured and high uric acid levels corrected before starting ponatinib treatment.


The estimated wholesale cost of ponatinib is $115,000 per year. ■


1. U.S. Food and Drug Administration: Ponatinib. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm332368.htm. Accessed January 21, 2013.

2. ICLUSIG® (ponatinib) tablets prescribing information, ARIAD Pharmaceuticals, Inc, December 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf. Accessed January 21, 2013.