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Nilotinib and Dasatinib Are Safe, Potentially Effective Treatment for Ph-Positive Leukemias

Summary

Two new targeted drugs - nilotinib and dasatinib - can be safely given to patients with chronic myelogenous leukemia and Ph-positive acute lymphocytic leukemia who cannot take imatinib (Gleevec®) or who have become resistant to the older drug, according to results from early clinical trials. The two new drugs also showed encouraging anticancer activity in these diseases.

Background

Almost all cases of chronic myelogenous leukemia (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 Philadelphia chromosome can also be found in some patients with acute lymphocytic leukemia (ALL). These patients are said to have Ph-positive ALL.

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. Two new targeted drugs, nilotinib and dasatinib, have been developed to treat imatinib-resistant CML. They work against the same abnormal protein targeted by imatinib, but in slightly different ways.

The two studies described here tested nilotinib and dasatinib in phase I clinical trials. Phase I trials are performed to find the highest dose of a new drug that does not cause overly harmful side effects when given to people. Investigators with these trials also look for preliminary evidence that a new drug may be effective against disease in humans. Researchers don’t often see high rates of tumor response in phase I trials, though they have with certain targeted therapies for the treatment of CML.

Study 1 (Nilotinib)

This phase I trial, which enrolled patients between May 2004 and May 2005, was performed to find the maximum amount of nilotinib that could be safely given (called the maximum tolerated dose). The investigators also looked at whether imatinib-resistant CML and Ph-positive ALL responded to treatment with nilotinib, to get a preliminary idea of the drug’s effectiveness.

Of 116 patients who enrolled in the trial, 17 had chronic-phase CML, 56 had accelerated-phase CML, 33 had blastic-phase CML, and 10 had Ph-positive ALL.

Patients were successively assigned to one of nine groups, each receiving an increased dose of the drug. Doses ranged from 50 to 1200 mg once daily and from 400 to 600 mg twice daily. Patients whose disease did not respond to a lower dose and who did not experience significant toxic effects were allowed to receive higher doses.

A cycle of therapy consisted of 28 days. Blood and bone marrow samples were drawn to evaluate responses to the drug. A hematologic (blood) response was the reduction or elimination of excess immature white blood cells circulating in the blood. A cytogenetic (cellular) response was the reduction or elimination of the Philadelphia chromosome in the bone marrow.

Results of Study 1

The maximum tolerated dose of nilotinib was determined to be 600 mg given twice daily. For the phase II trials that come next, the investigators recommend a starting dose of 400 mg twice daily.

Responses to nilotinib were seen in all phases of CML, especially the chronic phase:

• Out of 17 patients with chronic phase CML, 12 had active disease (a measurable amount of abnormal white blood cells) whereas five others had normal peripheral blood counts but cytogenetic abnormalities. Ninety-two percent of patients with active disease had a complete hematologic response, and 53 percent of all patients with chronic CML had a cytogenetic response.

• Out of 56 patients with accelerated-phase CML, 51 had active disease. Seventy-four percent of patients with active disease had a hematologic response, and 55 percent of all patients with accelerated-phase CML had a cytogenetic response.

• Out of 33 patients with blastic-phase CML, 13 (39 percent) had a hematologic response and 9 (27 percent) had a cytogenetic response.

By contrast, one out of 10 patients with hematologically relapsed ALL had a partial hematologic response and one in three patients with minimal residual disease (no evidence of abnormal cells in the blood but cytogenetic abnormalities) had a complete cytogenetic response. (See the journal abstract.)

Study 2 (Dasatinib)

This phase I trial, performed to find the maximum tolerated dose of dasatinib, enrolled 84 patients between November 2003 and April 2005. Patients with CML or Ph-positive ALL who were resistant to or intolerant of imatinib were eligible to enroll.

Forty patients had chronic-phase CML, 11 had accelerated-phase CML, and 33 had blast-crisis CML or Philadelphia-chromosome positive ALL. Seventy-two patients were resistant to imatinib, and 12 were intolerant (they had unacceptable reactions to the drug).

Patients were successively assigned to one of 16 groups, each receiving an increased dose of the drug. Doses for patients with chronic disease ranged from 15 to 180 mg once daily and from 25 to 70 mg twice daily. Doses for patients with more advanced CML or with Ph-positive ALL ranged from 35 to 120 mg twice daily.

As in the nilotinib study, blood and bone marrow samples were used to evaluate hematologic and cytogenetic responses to the drug.

Results of Study 2

A maximum tolerated dose for dasatinib was not determined during the study, though hematologic responses were seen at 50 mg or more per day while cytogenetic responses required larger doses. No patients withdrew from the study because of toxicity.

Responses to dasatinib were seen in Ph-positive ALL and in all phases of CML, especially the chronic phase.

• Out of 40 patients with chronic-phase CML, 92 percent had a complete hematologic response and 45 percent had a major cytogenetic response.

• Of patients with accelerated-phase CML, blast-phase CML, or Ph-positive ALL, 70 percent had a major hematologic response. Twenty-five patients also had a cytogenetic response.

Notably, dasatinib was cytogenetically active in those patients who had become resistant to imatinib.

A large number of patients developed high-grade side effects, most often a drop in blood cell production. However, these effects generally went away with an interruption of treatment or dose reduction. Patients who were intolerant to imatinib found the side effects of dasatinib to be manageable. (See the journal abstract.)

Comments

Usually, larger phase II and phase III clinical trials are needed before it can be known whether a drug truly works and is better than other available treatments. In the case of nilotinib and dasatinib, however, additional studies may not be necessary. In fact, dasatinib has already received approval from the U.S. Food and Drug Administration for the treatment of CML and Ph-positive ALL.

“I think the big news is that we now have drugs for patients who have mutations that make them resistant to imatinib,” says John Janik, M.D., of the National Cancer Institute’s Center for Cancer Research. “The down side is that these drugs aren’t the answer for the vast majority of patients with blast crisis or accelerated-phase disease.”

“These drugs really work best in patients who have CML that’s still in chronic phase,” he explains. With Ph-positive ALL, and when CML patients progress to the accelerated or blast-crisis phase of the disease, he says, “the efficacy decreases.”

This point is reinforced by Brian J. Druker, M.D., from the Oregon Health and Science University Cancer Institute, in an editorial that accompanied the trial results: "Response rates in patients with chronic-phase CML were impressive…but responses in accelerated-phase and blast-phase disease were lower, and relapses have been common. For this reason, other strategies are required for the advanced phases of CML” and for patients whose CML carries mutations that make the cancer resistant to the new drugs.
Limitations

Additional trials are also needed to clarify the side effects of nilotinib and dasatinib, says Drucker: “The question as to whether additional side effects will be observed over time will require larger studies and longer follow-up.

Source

New England Journal of Medicine, June 15 2006.
(N Engl J Med. 2006 Jun 15;354(24):2542-51)
(N Engl J Med. 2006 Jun 15;354(24):2531-41)

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