Chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) are leukemias that develop when pieces of DNA from chromosome 9 and chromosome 22 break and switch places during cell division. A portion of chromosome 9's ABL gene fuses with a portion of chromosome 22's BCR gene, resulting in the BCR-ABL oncogene. This abnormal gene produces bcr-abl tyrosine kinase, a protein that triggers signals in the development of malignant white blood cells. In CML and Ph+ALL, these malignant cells crowd out healthy cells.
Tyrosine kinase inhibitors (TKIs), such as Gleevec (imatinib), Sprycel (dasatinib), Tasigna (nilotinib) and Bosulif (bosutinib) bind to these rogue proteins and "turn off" their activation signal. But in some patients, a mutant gene, T315I, prevents TKIs from reaching their target. Iclusig (ponatinib), a newly approved TKI, not only works to circumvent T315I but also thwarts other mutations. The FDA approved the drug more than three months ahead of schedule.
In the PACE trial, 449 CML or Ph+ALL patients who were intolerant or resistant to previous TKI treatments or had the T315I mutation received ponatinib. More than half (54 percent) of patients with chronic-phase CML experienced a major cytogenetic response, meaning more than 65 percent of their blood cells were cleared of the Philadelphia mutation, within 12 months, with nearly half (46 percent) experiencing a complete cytogenetic response. More than one-third (34 percent) of patients with advanced-phase CML or Ph+ALL experienced a major hematologic response, meaning their blood counts returned to normal, within six months of treatment. Like the approved TKIs, ponatinib works by preventing certain proteins (tyrosine kinases) from signaling cancer cell growth.Side effects include blood clots and liver toxicity.