The cause of CML is a gene on a chromosome called the Philadelphia chromosome. The gene makes a poisonous protein that causes cancer in white blood cells. Gleevec is a drug that inhibits the actions of the gene on the Philadelphia chromosome.
There's only one cure for CML. It's a drastic bone marrow transplant. Only people with marrow-matching brothers or sisters -- or those who can find an acceptable unrelated donor -- can get it. It doesn't always work. And it's a drastic operation that too often kills the patient.
Gleevec doesn't cure CML. But the new study shows it can prevent the white-blood-cell changes that signal worsening disease and death. And it does so much better than what used to be the best treatment, interferon alpha plus low-dose cytarabine chemotherapy. Stephen O'Brien, MD, PhD, of the University of Newcastle, England, and an international research team report the findings in the March 13 issue of The New England Journal of Medicine.
"[Gleevec] was significantly superior to interferon alpha plus low-dose cytarabine," they write. "We believe that [Gleevec] therapy may significantly improve long-term survival."
Nearly all of the patients who got Gleevec -- 87% -- had a "major" response after 18 months. This was seen in only 34.7% of patients getting interferon alpha plus cytarabine. There was a "complete" response (defined as the absence of cells with the abnormal gene) in 76% of Gleevec patients vs. only 14.5% of the interferon/cytarabine patients. Moreover, there were far fewer side effects in the Gleevec group.
The study doesn't prove that patients who get Gleevec will live longer. That's because the study was stopped early when it became clear that patients not getting the drug were doing much worse. The researchers will continue to follow patients for another five years to see whether, as expected, the drug will improve CML survival.
Now that Gleevec is clearly the best first-line treatment for CML, there's a new question. Given the danger of trying to cure the disease with BMT, should patients wait to see if Gleevec can indefinitely postpone disease and death?
An editorial accompanying the study report offers some guidance. Karl Peggs and Stephen Mackinnon, MD, of Royal Free and University College London Medical School, note that fewer than half of CML patients are younger than 60 -- the usual cut-off age for transplants. As not everybody has a suitable donor, only 40% of CML patients have the bone marrow transplant option.
If Gleevec doesn't work, Peggs and Mackinnon suggest, patients under 60 who have a suitable donor should get a transplant. For others, it's a tough question.
"One approach would be to continue [Gleevec] therapy in all such patients except the 10% to 15% with a low risk of death from transplantation -- the youngest patients with sibling donors," they write. "Transplantation could be considered in the higher-risk patients only when signs of disease progression appeared."
SOURCE: The New England Journal of Medicine, March 13, 2003.