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Best choice for chronic leukemia treatment may change

Newer drug outperforms Gleevec in trial

By <http://sciencenews.org/view/authored/id/57/name/_Seppa>

Seppa

January

<http://sciencenews.org/view/issue/id/51064/title/January_2nd%2C_2010%3B_Vol

..177_%231> 2nd, 2010; Vol.177 #1 (p. 15)

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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 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 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 Cortes, an internist at the

University of Texas M.D. 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.

Zavie (age 71)

67 Shoreham Avenue

Ottawa, Canada, K2G 3X3

dxd AUG/99

INF OCT/99 to FEB/00, CHF

No meds FEB/00 to JAN/01

Gleevec since MAR/27/01 (400 mg)

CCR SEP/01. #102 in Zero Club

2.8 log reduction Sep/05

3.0 log reduction Jan/06

2.9 log reduction Feb/07

3.6 log reduction Apr/08

3.6 log reduction Sep/08

3.7 log reduction Jan/09

3.8 log reduction May/09

3.8 log reduction Aug/09

4.0 log reduction Dec/09

e-mail: zmiller@...

Tel: 613-726-1117

Fax: 613-482-4801

Cell: 613-282-0204

ID: zaviem