What is the most common reason for treatment failure?

FAQ Library  published on May 6, 2015
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Karen P. Seiter, MD
Professor of Medicine
New York Medical College
Division of Oncology/Hematology
Hawthorne, New York
What is the most common reason for treatment failure?
Welcome to Managing CML. My name is Karen Seiter, and I am professor of medicine at New York Medical College and director of the Leukemia Service at Westchester Medical Center. I am often asked, “What is the most common reason for treatment failure?” There are actually several important mechanisms of treatment failure. They can be divided into 1) patient factors and 2) factors directly related to the leukemic cell. In terms of patient factors, one of the most important factors is compliance. Most of the medications used for the treatment of CML are oral. We rely on patients to take every dose of medication to get the optimal response. Sometimes patients forget to take a dose. This can be prevented by trying to associate taking the medication with another routine activity that the patient does on a daily basis such as brushing their teeth. Setting an alarm can also be helpful. Some patients have poor compliance due to side effects. It is important for the physician to both recognize these side effects and optimize supportive care to prevent this type of noncompliance. Other patients are compliant with medication but have a confounding reason that their drug level is too low. For example, patients who have undergone gastrectomy or who are taking proton pump inhibitors, both of which can reduce drug absorption, can have a low serum level of drug. Other medications such as CYP3A4 inhibitors can increase the metabolism of CML drugs and result in a subtherapeutic level. The most important mechanism of resistance directly related to the leukemic cell is the acquisition of mutations in the BCR-ABL kinase that make CML drugs unable to bind their target. There have been many such mutations described with some mutations favoring a change of therapy to one drug or another. Other mechanisms include amplification of BCR-ABL resulting in insufficient drug to find target, decreased ALK-1 which results in decreased entry of drug into the cell, increased ABC which results in increased efflux of drug out of the cell, activation of non-BCR-ABL pathways such as the Src kinase pathway, and microenvironment effects. Additionally, quiescent cells such as the CML leukemic stem cells are intrinsically resistant to many of the drugs that we use. Thank you for viewing this activity. For additional resources, please view the other additional educational activities on ManagingCML.com.
Last modified: April 1, 2015
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