Higher Dosing Doesn't Mean Better Health

Chronic myeloid leukemia patients who have received other drugs respond best to standard imatinib dosing

/ Author:  / Reviewed by: Robert Carlson, M.D

(RxWiki News) It's a common concept. If one dose works well, then two doses may work even better. This theory was tested recently in patients being treated for chronic myeloid leukemia (CML), and it didn't work.

CML patients who have been previously treated with other medications, do not respond well to higher doses of Gleevec (imatinib).

While initial results seemed to indicate that this so-called "dose intensification" would be helpful, there were other dangers.

"Take all of your medications precisely as prescribed."

Andreas L. Petzer, of the Central European Leukemia Study Group (CELSG) at the Medical University Innsbruck in Innsbruck, Austria, led the  open-label phase III study performed in 13 centers in seven different countries

Participants included 227 pre-treated CML patients in chronic phase who were randomly assigned to receive either the Gleevec standard dose (400 mg/day) continuously, or  six months of a higher dose (800 mg/day) followed by a standard dose of the drug as maintenance.

CML is a disease in which the bone marrow makes too many white blood cells. People with the disease have an abnormal chromosome called the Philadelphia chromosome, which creates an abnormal gene called BCR/ABL.

Treatment effectiveness is measured in various ways. A so-called cytogenetic (cellular) response indicates there are fewer cells with the Philadelphia chromosome. A major cytogenetic response (MCR) means at least 65 percent of cells are normal, and a complete cytogenetic response (CCR) means all cells tested normal. A major molecular response (MMR)

For this study, the people who received higher doses had significantly higher major and complete cytogenetic responses at 3 and 6 months than did people receiving the standard dose: 

  • Major cytogenetic responses: 36.8 vs. 21.2 percent
  • Complete cytogenetic responses: 22.8 vs. 6.2 percent

At 12 months, CCR was still significantly different between the two groups - 40.4 vs. 24.8 percent, but not major cytogenic responses - 49.1 vs. 44.2 percent

That's the good news. In terms of progression or worsening of the disease, the news wasn't so good.

In the higher dose group, there was no improvement in progression free or overall survival. Surprisingly, though, event free (without a negative event such as a fracture, for example) survival was significantly worse in the group receiving intensified dosing of Gleevec. 

As a result of these findings, the authors conclude that standard dose Gleevec should be used in CML patients who have received previous therapies.

This study, published in the journal Hematologica, was supported by an unrestricted research grant from Novartis to the Central European Leukemia Study Group.

Several authors disclosed financial relationships with Novartis, the manufacturer of Gleevec and/or Bristol Myers Squibb, which manufactures Sprycel (dasatinib), another CML drug. One of the authors was an employee of Novartis and another is currently employed by the company.

Reviewed by: 
Review Date: 
April 25, 2012
Last Updated:
May 14, 2012