Beth Galliart and her horse Austin{credit}Michelle Arani{/credit}
In June 2008, Beth Galliart was diagnosed with chronic myeloid leukemia. At the time, her doctors put her on Gleevec (imatinib), a small-molecule drug available since 2001 that is often touted as the poster child of personalized medicine. Marketed by Switzerland’s Novartis, Gleevec specifically targets the tyrosine kinase enzyme that is overactive in the white blood cells of people with leukemia. For close to nine months, the drug worked wonders for Galliart, and her blood counts returned to normal levels. But she soon started to feel tired again. A blood test confirmed that her cancer had returned.
Galliart’s doctors made a decision in March 2009 to switch her to Sprycel (dasatinib), a comparable tyrosine kinase inhibitor (TKI) from New York’s Bristol-Myers Squibb. She ended up taking that drug for only three days, though: her doctors took her off the drug when they received the results of a genetic test revealing that her cancer cells had evolved the T315I mutation in the tyrosine kinase BCR-ABL, making it impervious to all approved TKIs for the disease, including Gleevec and Sprycel. Galliart, an executive assistant at an investment firm in Silicon Valley, California, prepared herself for a risky bone marrow transplant. Her family prepared for the possibility that she might die.
Distant cousins from Kansas came to visit and say their final goodbyes. They and Galliart were picking strawberries one day in May 2009 when her phone rang. It was a clinical study coordinator from the University of California–San Francisco (UCSF) on the line. A managing partner from Galliart’s firm knew a UCSF doctor who was running a phase 1 clinical trial with an experimental agent called ponatinib. On the basis of preclinical work, this drug was thought to inhibit the mutated forms of the BCR-ABL protein that are responsible for people’s resistance to most TKIs—including the T315I mutation.
Galliart quickly enrolled in the study. A month later, she received her first dose of the drug.
Although she did suffer intense bone pain for three days after first receiving ponatinib—“It was sort of like a bomb was going off in my whole body,” recalls Galliart, 47—her cancerous blood cells have not come back since. She is now training for a half-marathon and regularly rides and jumps horses.
Fortunately, Galliart’s positive experience with ponatinib is not unique. In a phase 2 trial of 449 people with CML or the similar acute lymphoblastic leukemia (ALL) who were intolerant to other TKIs or who had a confirmed T315I mutation, around half responded favorably to the drug. The results were presented earlier this month at the American Society for Hematology meeting in Atlanta. Phase 1 trial results involving 81 participants, including Galliart, were published in late November in the New England Journal of Medicine (367, 2075–2088, 2012). Ponatinib was approved by the US Food and Drug Administration (FDA) today. It will be marketed by Ariad Pharmaceuticals of Cambridge, Massachusetts, as Iclusig.
“This drug has the potential to be a best-in-class agent that may be completely invulnerable to single-kinase-domain mutations,” says Neil Shah, the UCSF hematologist who treated Galliart. “I’m hopeful that it really will remove single-kinase-mutation–mediated resistance out of the picture.”