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Scientists Claim New Substance Overcomes Treatment Resistance in Leukemia
Hematologists at Goethe University Frankfurt, working with a Russian pharmaceutical company, claim to have developed a new substance that effectively combats the most aggressive forms of Philadelphia chromosome-positive (Ph+) leukemia, both in vitro and in vivo.
The chances of patients with Ph+ leukemia being cured have greatly increased in recent years, according to the researchers. Nevertheless, a high percentage of patients still develop resistance to available medications.
Patients with the Philadelphia chromosome develop chronic myelogenous leukemia (CML) or acute lymphatic leukemia (ALL). These are the first types of leukemia that became amenable to treatment, thanks to the development of targeted molecular therapy, the authors say. Selective tyrosine kinase inhibitors (TKIs) directly affect the cancer-inducing gene BCR/ABL. However, this therapy gradually loses its effectiveness in many patients because of either BCR/ABL mutations or non-mutational mechanisms that have yet to be discovered.
Currently, only one TKI –– ponatinib (Iclusig, Ariad Pharmaceuticals) –– is useful in overcoming clinical resistance in patients with Ph+ leukemia. Ponatinib is the only TKI that can inhibit the “gatekeeper” mutation T315I. Unfortunately, this drug must be used with extreme caution because of its potential to cause vascular occlusion, heart failure, or hepatotoxicity.
The Moscow-based company Fusion Pharma has developed a new TKI, PF-114, with the aim of achieving the same clinical effects on Ph+ leukemia that are seen with ponatinib, but with a reduced incidence of adverse events. PF-114 was designed 1) to target T315I and other resistance mutations in BCR/ABL; 2) to achieve high selectivity to improve safety; and 3) to overcome non-mutational resistance in Ph+ leukemias.
In the current edition of Leukemia, the team reports that PF-114 is as effective as ponatinib against treatment-resistant Ph+ disease. International phase I clinical studies are scheduled to begin in the first half of 2015.
Sources: Medical Xpress; December 1, 2014; Leukemia; November 14, 2014; Iclusig Prescribing Information; September 2014.