Ponatinib acts against refractory Philadelphia chromosome–positive leukaemias
Ponatinib highly active in phase I study in heavily pretreated patients with resistance to TKIs, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations
- Date : 29 Nov 2012
- Topic : Haematologic malignancies
A previously invincible mutation in chronic myeloid leukemia (CML) has been thwarted by an investigational drug in a phase I clinical trial reported in The New England Journal of Medicine. All 12 patients in the trial with chronic phase CML and the T315I mutation had a complete haematologic response after treatment with ponatinib. Eleven had a major reduction in CML cells in the bone marrow and nine achieved a complete cytogenetic response.
T315I is present in up to 20% of patients. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor (TKI) that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to TKIs.
According to trial principal investigator Dr Jorge Cortes, professor in The University of Texas MD Anderson Department of Leukemia, ponatinib is a promising new treatment for patients who have run out of options and its activity against other resistant mutations and in patients with no known mutations suggests a broad range of efficacy.
Dr Cortes will report the results of a pivotal phase II clinical trial of ponatinib at the 54th ASH Annual Meeting and Exposition in December 2012.
The USA Food and Drug Administration in October accepted a new drug application by ARIAD Pharmaceuticals for accelerated review of ponatinib for patients with resistant or intolerant CML or Philadelphia chromosome-positive ALL.
Targeted therapy success story
CML is caused by the abnormal gene BCR-ABL, which occurs when two chromosomes swap portions of their DNA from the BCR and ABL genes during cell division. This abnormality is called the Philadelphia chromosome and the resultant BCR-ABL fusion protein drives the overproduction of white blood cells that characterizes CML. BCR-ABL is a tyrosine kinase.
Discovery of the drug imatinib revolutionized treatment of CML. Now approximately 90% of patients survive for at least five years, up from about 50% before imatinib. Two second-generation drugs, nilotinib and dasatinib are more potent than imatinib. Each can be used in front-line therapy.
Preclinical experiments indicated ponatinib acts against BCR-ABL and all known mutant forms of the protein.
Ponatinib active against known mutations and no mutations
The phase I trial enrolled 81 patients at five centres, 60 with CML and five with Philadelphia chromosome-positive ALL. Among Philadelphia chromosome-positive patients, 91% had received two or more approved TKIs, and 51% had received all three approved TKIs. Median follow-up was 56 weeks.
Of 43 patients with chronic-phase CML, 98% had a complete haematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response.
Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete haematologic response and 92% had a major cytogenetic response.
Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete haematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable.
Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major haematologic response and 32% had a major cytogenetic response.
The dose escalation trial started at a daily oral dose of ponatinib of 2 mg ranging up to 60 mg. The investigators settled on a 45mg dose. Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis.
The most common non-haematologic side effects were skin disorders, fatigue and nausea (grade 1 or 2). Pancreatitis occurred in 11 patients and was a serious adverse event in eight. Nine of the 11 experienced one episode of pancreatitis, only two discontinued treatment.
Twelve patients with acute myeloid leukaemia also participated in the trial. A separate paper will address those results.
The study was supported by ARIAD Pharmaceuticals and by a grant (CA016672) to MD Anderson Cancer Center from the National Institutes of Health (USA). Two co-authors are Scholars in Clinical Research of the Leukaemia and Lymphoma Society. Dr Cortes has received research support from and consulted for ARIAD.
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