Leukemia pill tested
at VICC
The so-called “leukemia pill” is being offered to eligible Vanderbilt-Ingram Cancer Center patients on a first-come, first-serve basis through an expansion in clinical trials to provide greater access while the drug undergoes fast-track review by the Food and Drug Administration.
The drug, STI-571 (to be marketed under the trade name Glivec), has generated excitement among cancer scientists, physicians and consumers since promising results from early clinical trials in patients with chronic myeloid leukemia (CML) were first announced nearly a year and a half ago.
The drug is now under “expedited review” by the Food and Drug Administration. Meanwhile, long waiting lists have developed at the handful of centers worldwide where the drug was initially being tested.
“This drug is generating so much excitement because it is specifically directed at the molecular abnormality that causes this disease,” said Dr. John Greer, associate professor of Medicine and Pediatrics and principal investigator in Vanderbilt-Ingram’s studies. “It has a relatively safe toxicity profile, and we’re all stunned by the fact that it’s a pill.”
CML is a common form of leukemia, representing 15-20 percent of the blood cancer in adults. Standard therapies include a bone marrow transplant from a donor, which is risky, and interferon, an injected drug that can cause severe flu-like symptoms that make it difficult for some patients to tolerate. Overtime, some patients’ leukemia becomes resistant to the effects of interferon.
By contrast, STI-571 generates a quicker response than interferon and causes only mild side effects, including headache and weight gain, studies have shown thus far. It has only been studied in patients for about three years, so long-term results are not yet known.
CML is caused by a genetic abnormality (called the Philadelphia chromosome) that fuses two proteins into one that then allows the proliferation of abnormal cells. STI-571 blocks the signal that tells the cells to proliferate.
This abnormality is found to a lesser extent in other forms of leukemia. The studies that Vanderbilt-Ingram Cancer Center opened last month are being conducted in adult patients with CML that is resistant to the effects of interferon, as well as adults with acute myeloid or acute lymphocytic leukemia that are Philadelphia chromosome-positive. Dr. James Whitlock, Craig-Weaver Professor of Pediatrics and director of the division of Pediatric Hematology-Oncology, is also testing STI-571 in children with Philadelphia chromosome-positive leukemia.
The most recent studies, reported in March in the New England Journal of Medicine, have seen responses to the drug in almost all CML patients who received it. Blood counts, one measurement of disease, returned to normal in 53 of the 54 patients who were treated with STI-571. In 29 patients, a reduction was seen in the proportion of cells that have the genetic mutation as measured by standard cytogenetic tests. Seven patients had a complete cytogenetic response.
STI-571 is likely to be the first of a new class of anti-cancer drugs to receive FDA approval. These drugs block enzymes called tyrosine kinases, which are critical links in the message chain to the cell’s control center, the nucleus. Inhibiting these enzymes can block the runaway cell growth that characterizes cancer. Because these inhibitors are small, they often can be given orally; because they are so specific, their side effects are often minimal.
STI-571 also has been shown to inhibit other tyrosine kinases. These include the c-kit tyrosine kinase, which is mutated in some cases of a rare cancer, gastrointestinal stromal tumor. Dr. Jordan Berlin, assistant professor of Medicine, is an investigator in a national study of STI-571 in patients with this tumor. Studies of STI-571 have also begun in patients with lung, prostate and brain cancer.
Other tyrosine kinase inhibitors are being developed and tested, including one called Iressa, which blocks an overactive signal of the epidermal growth factor, implicated in several types of cancer. Vanderbilt-Ingram is a national leader in the study of this drug in patients with lung cancer.
“This is one of many anti-cancer agents being studied that are based on molecular biology and genetics,” Berlin said. “It is more rationally designed than older, standard chemotherapy, and it has shown some effects. It proves we are probably starting to bark up some very interesting trees.”
In CML, Greer said he doubts STI-571 will completely replace transplantation but that it will “probably” replace interferon.
Greer is also skeptical that the pill will totally eliminate the Philadelphia chromosome abnormality as detected by the most sensitive tests available. Therefore, it may be unlikely to “cure” patients by itself and may instead become a therapy taken on a chronic basis to keep the leukemia in check or combined with other therapies.
“It opens up all kinds of opportunities to explore,” Greer said. “Maybe we can do better by adding it to interferon or use it to push a patient into a phase of disease where a less risky autologous transplant will be effective.” (In an autologous transplant, a patient’s own bone marrow is removed and transplanted after high-dose treatment to wipe out the leukemia.)
Greer echoed Berlin about the broader implications of the drug’s rapid development and approval. “It’s the tip of the iceberg,” Greer said. “The speed of moving exciting discoveries from the bench to the bedside is becoming faster and faster.”
FDA approval of STI-571 is widely anticipated within the next several months, possibly as soon as late spring or early summer. Once it is approved and commercially available, the studies will end and therapy will be available to patients through prescription from their treating physician.
Because there is a waiting list for these studies, all inquiries from referring physicians and potential participants should be directed to the Vanderbilt-Ingram Cancer Center’s Cancer Information Program. The number is 1-800-811-8480.