The tyrosine kinase inhibitor ponatinib produced a high degree of complete cytogenetic responses when used in first-line treatment of patients with chronic myeloid leukemia in chronic phase. But the drug’s toxicities, especially its propensity for causing thromboembolic events, mitigate against its upfront use, investigators say.
In a small phase II study, 90% of evaluable patients with chronic-phase chronic myeloid leukemia (CML) treated with the tyrosine kinase inhibitor (TKI) had a complete cytogenetic response (CCyR) after 3 months, and 94% had a CCyR after 6 months, but that efficacy came at the cost of significant adverse events requiring dose reductions, treatment interruptions, and early termination of the trial for safety reasons at the recommendation of the Food and Drug Administration, reported Dr. Preetesh Jain of MD Anderson Cancer Center in Houston, Tex., and colleagues.
“[O]ur study shows that ponatinib is a very potent TKI with high clinical activity in the first-line treatment of patients with chronic-phase CML. However, at the doses currently used in other settings, the safety profile might not be appropriate for treatment of this patient population who have other treatment options with high efficacy,” the investigators wrote (Lancet Haematol. 2015;2[9]:e376-e383).
Ponatinib (Iclusig) is a third-generation TKI with action against malignancies with mutations in the ABL kinase domain that make the cancers resistant to first- and second-generation TKIs such as imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna).
Ponatinib is approved in the United States for treatment of adult patients with CML positive for the T3151 mutation in chronic phase, accelerated phase, or blast phase, or T3151-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL). It is also approved for treatment of adults with chronic phase, accelerated phase, or blast phase CML or Ph+ALL for whom no other TKI is indicated.
The drug labeling carries a boxed warning about increased risk for vascular occlusion, heart failure, and hepatotoxicity. The warning notes that “[a]rterial 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.”
In a single-arm, open label trial, the investigators enrolled 51 patients with recently diagnosed CML in chronic phase, starting them on doses of oral ponatinib 45 mg daily. The protocol was later amended to a starting dose of 30 mg daily because of the high frequency of dose reductions required among patients started at 45 mg. Following a warning from the FDA about vascular complications with the drug, patients were started on daily low-dose aspirin (81 mg), and all drug doses were reduced to either 30 mg or 15 mg daily.
One of the patients discontinued therapy prior to assessment because of the FDA warning, leaving 50 for assessment at 6 months.
Of 46 patients evaluable for the primary outcome of CCyR by 6 months, 43 (94%) achieved it. Major molecular responses, defined as a BCR-ABL to ABL transcript ratio of 0.1% or lower, occurred in 40 of 50 patients (80%) evaluable for this secondary endpoint, and deep molecular response (MR4.5), defined as a ratio less than 0.0032% or lower, occurred in 28 of 50 (55%).
Cardiovascular events, primarily hypertension, occurred in 25 patients (49%), 15 (29%) had grade 3-4 myelosuppression, and 5 patients (10%) developed cerebrovascular or vaso-occlusive disease.
In all, 43 patients (85%) needed treatment interruptions at some time and 45 (88%) needed dose reductions. The study was terminated in June 2014, a little more than a year after recruitment began.
The study was sponsored by MD Anderson Cancer Center with partial support from Ariad Pharmaceuticals. Coauthors Hagop Kantarjian, Elias Jabbour, and Jorge Cortes report receiving grants, research support, or serving as consultants to Ariad.