Best choice for chronic leukemia treatment may change

NEW ORLEANS — People fighting chronic myeloid leukemia got a double dose of good news at the meeting of the American Society of Hematology.

The drug nilotinib, marketed as Tasigna, proved better than the reigning frontline drug used against CML, a new study finds. “Based on these results, we strongly believe that nilotinib may become the new standard of care in newly diagnosed CML patients,“ says Giuseppe Saglio, a hematologist at the University of Turin in Italy.

Meanwhile, in those CML patients who fail to improve on either of these medications, an old drug abandoned in the last decade now shows promise as a rescue therapy, researchers reported.

Based on the first study, nilotinib may now supersede imatinib, sold as Gleevec, a drug that has led to a sea change in treatment for CML over the past decade (SN: 12/14/02, p. 371).

Before imatinib, the typical CML patient had roughly three years to live, barring a bone marrow transplant. Now, more than four-fifths of patients who have started on imatinib are still alive after seven years, according to Novartis, the company that makes the drug. The availability of imatinib has also lessened the need for bone marrow transplant, an operation that carries risks, particularly for elderly people.

But imatinib isn’t foolproof, and nilotinib was developed to improve upon it. To test the drugs head to head, Saglio and a team of collaborators in 35 countries identified 846 recently diagnosed CML patients and randomly assigned two-thirds to receive nilotinib and one-third to get imatinib. After one year, 80 percent of those on nilotinib no longer had signs of an incriminating genetic marker of CML on their white blood cells. Of those getting imatinib, 65 percent were clear of this marker.

A closer examination of the patients’ white blood cells, down to the molecular level, found that 44 percent of those getting nilotinib but only 22 percent of the imatinib group had apparently cleared the cancer, says Saglio, who presented the findings on December 8.

Nilotinib and a similar drug called dasatinib, marketed as,Sprycel, gained regulatory approval in recent years as backup drugs for imatinib in CML patients who could not tolerate imatinib’s side effects or whose cancer had worsened in spite of it. All three drugs disable a rogue enzyme called BCR-ABL that removes the brakes on leukemia cells’ growth (SN: 1/1/05, p. 14). A genetic mutation, called Philadelphia chromosome, results in the production of this abnormal enzyme, which is responsible for nearly all cases of CML.

“Fifteen years ago, the standard of care [for CML] was a bone marrow transplant, a very, very toxic therapy — curative to some patients but toxic,” says Peter Emanuel, a physician at the University of Arkansas for Medical Sciences in Little Rock. “Now the standard of care is comparing one pill against another. Things have changed.”

Although neutralizing BCR-ABL has been a life-saver in the true sense, the drugs aren’t universally curative, notes Richard Larson, a hematologist at the University of Chicago, who coauthored the nilotinib study and worked on an earlier trial testing imatinib.

In particular, another mutation has surfaced in some CML patients that makes their leukemia cells resistant to all three of these drugs. In the other study providing welcome news for CML patients, researchers reported that an older drug called omacetaxine stopped the cancer in many of these high-risk patients. 

Omacetaxine is an injectable drug that had been tested against leukemia in past decades but was shelved when imatinib came along. “It was displaced because imatinib was so spectacular,” says Jorge Cortes, an internist at the University of Texas M.D. Anderson Cancer Center in Houston.

Cortes and his colleagues gave omacetaxine to 81 patients who had ceased to benefit from the other CML drugs. The median survival time for such patients is about 20 months. In this study, 80 percent of the patients getting omacetaxine were still alive at the 24-month point, said Cortes, who presented the data on December 5.

Although it remains unclear how omacetaxine works, leukemia researchers are heartened that it can provide at least some benefit in this group of patients with the troublesome mutation. “There is reason to believe that omacetaxine may also be effective against other subsets of CML where the exact mechanism of resistance is unclear,” says Larson.

About 5,000 people are diagnosed with CML each year in the United States and about 22,000 are currently living with it. Although these people have benefited greatly, the story of CML may also have broader ramifications, Emanuel says.

Scientists have argued for decades that knowing the genetics that underlie a cancer or other disease could lead to better treatments. “CML is a fairly simple cancer,” he says. “The story of imatinib, nilotinib and dasatinib shows us that what scientists have been saying is correct — if we understand the genetic basis of a disease we can make more rational drugs to cure it.”

Saglio reports the he has done consulting for Novartis and BMS, which make nilotinib and dasatinib, respectively. Larson reports consulting for Novartis.