Dasatinib and Nilotinib Both Effective for CML When Imatinib Won't Work
Chronic myelogenous leukemia (CML), dasatinib (Sprycel®), nilotinib (Tasigna®), imatinib (Gleevec®). (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Two new targeted drugs - dasatinib (Sprycel®) and nilotinib (Tasigna®) - are effective in most patients with chronic myelogenous leukemia who cannot take or who have become resistant to imatinib (Gleevec®), according to results from two separate phase II clinical trials.
Blood, published online ahead of print, August 22, 2007 (see the journal abstract).
(Blood. 2007 Aug 22; [Epub ahead of print])
Blood, March 15, 2007 (see the journal abstract).
(Blood. 2007 Mar 15;109(6):2303-9. Epub 2006 Nov 30)
Chronic myelogenous leukemia (CML) is a slowly progressing cancer of the blood. An estimated 4,570 Americans will be diagnosed with CML in 2007. The disease most commonly affects people in their 60s.
Almost all cases of CML can be linked to a mutated chromosome in the blood-forming cells of the bone marrow. Called the Philadelphia (Ph) chromosome, it produces an abnormal protein that leads to the overproduction of immature, poorly functioning white blood cells.
The drug imatinib (Gleevec) has revolutionized the treatment of CML. Imatinib is a targeted therapy - it acts on the abnormal protein produced by the Philadelphia chromosome and has limited effects on normal cells. However, CML can become resistant to imatinib and some patients experience intolerable side effects on the drug.
Dasatinib (Sprycel) and nilotinib (Tasigna) are new targeted drugs developed to treat imatinib-resistant CML. They work against the same abnormal protein targeted by imatinib, but in slightly different ways. In phase I studies, patients with imatinib-resistant CML responded well to treatment with either dasatinib or nilotinib.
The two separate phase II studies described here tested dasatinib and nilotinib. Phase II clinical trials assess how well a drug works against a specific cancer in the body and also identify side effects that patients may experience when they take the drug.
CML has several phases that are distinguished by the number of abnormal white blood cells in the bone marrow and blood and the effects of the leukemia on the normal elements of the blood. The patients enrolled in these studies all had CML that was in the chronic phase, an early stage of the disease when the number of abnormal white blood cells is higher than normal, but lower than in more advanced phases of the disease.
Study 1 (Dasatinib)
Patients in this phase II dasatinib study had all been previously treated with imatinib. Either their disease had become resistant to imatinib or they could no longer take it because of side effects.
The study reports initial results for 186 patients, all of whom took dasatinib twice daily. The patients, from 20 countries including the United States, were enrolled in the study between February and May 2005 and followed for at least eight months. The study’s principal investigator was Andreas Hochhaus, M.D., of Heidelberg University in Mannheim, Germany.
Patients had blood and bone marrow samples drawn to evaluate their response to the drug. The response signals that researchers looked for were the elimination or reduction of the abnormal white blood cells characteristic of CML (known as a hematologic response) and the elimination or reduction of the Ph chromosome in the bone marrow (known as a cytogenetic, or cellular, response).
Results of Study 1 (Dasatinib)
In 90 percent of patients the abnormal white blood cells characteristic of CML either disappeared or were reduced to very low levels. In 52 percent the Ph chromosome either disappeared from the bone marrow or was reduced to very low levels. After at least eight months of follow-up, 92 percent of patients were free of disease progression.
Patients for whom imatinib had stopped being effective and those who had stopped taking imatinib because of side effects responded equally well to treatment with dasatinib.
The most common side effects of dasatinib treatment were low white blood cell counts, headaches, diarrhea, fatigue, shortness of breath, and a skin rash. Six patients (three percent) experienced a potentially serious side effect in which fluid collects in the lungs.
Study 2 (Nilotinib)
The 280 patients in this phase II study of nilotinib had also all been previously treated with imatinib. Either that drug had stopped being effective against their disease or they could no longer take it because of side effects. All patients took nilotinib twice a day.
Patients were enrolled in the study in the United States and 14 other countries between April 2005 and August 2006 and followed up for at least six months. The principal investigator was Hagop M. Kantarian, M.D., of the M.D. Anderson Cancer Center in Houston, Texas.
As in the dasatinib study, patients had blood and bone marrow samples drawn to evaluate their response to the drug and the response signals that researchers looked for were the same.
Results of Study 2 (Nilotinib)
After at least six months of follow-up, nearly half of the patients responded to nilotinib treatment. In 31 percent the Ph chromosome was eliminated from the bone marrow and in 16 percent it was reduced to low levels. Patients whose disease had become resistant to imatinib and those no longer able to take imatinib because of side effects responded equally well to treatment with nilotinib.
The most common side effects of nilotinib treatment were a mild skin rash, nausea, fatigue, and headaches. About 30 percent of patients had moderate to severe drops in their white blood cell count or in their platelets, another component of the blood.
Common side effects of imatinib such as cramps and weight gain were uncommon with nilotinib. Fluid collection in the lungs and swelling of the legs, ankles, and feet - side effects seen with both imatinib and dasatinib in other studies - were rare with nilotinib.
Usually, randomized phase III clinical trials are needed to establish that a drug truly works and is better than other available treatments (see Which Study Results Are the Most Helpful in Making Cancer Care Decisions?). In the case of dasatinib and nilotinib, however, a phase III trial (which would require several hundred patients and take several years to complete) may be impractical, says John Janik, M.D., of the National Cancer Institute’s Center for Cancer Research.
“The results of these phase II studies corroborate in a much larger number of patients the high response rates seen with these agents in phase I trials,” he says. “We now have two drugs that are effective for most, although not all, patients with chronic-phase CML who are resistant to imatinib.”
Based on the nilotinib results, on October 29, 2007, the U.S. Food and Drug Administration granted accelerated approval to nilotinib for use in the treatment of chronic phase and accelerated phase Philadelphia chromosome positive CML in adult patients resistant or intolerant to prior therapy that included imatinib. For more information, see FDA Approval for Nilotinib.
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