Inconsistent thiopurine dose for pediatric leukemia may raise relapse risk

By David Douglas

NEW YORK (Reuters Health) - Children with acute lymphoblastic leukemia (ALL) who do not adhere to prescribed doses of 6-mercaptopurine (6MP) may have increased risk of relapse, according to researchers.

"Among adherers, fluctuations in red blood cell levels of the 6MP metabolite (thioguanine) increase the risk of relapse. These fluctuations are primarily caused by drug interruptions," Dr. Smita Bhatia, of the University of Alabama at Birmingham, told Reuters Health by email.

In a March 26 online paper in JAMA Oncology, Dr. Bhatia and colleagues note that drug interruptions may result in emergence of resistance and relapse. This may also be true of intra-individual variability of 6MP systemic exposure.

The team monitored 6MP and disease relapse in 742 children with ALL in ambulatory care settings between May 30, 2005 and September 9, 2011. They measured daily 6MP regimen adherence over 68,716 person-days via an electronic system that recorded the date and time when each 6MP container was opened. They measured average monthly 6MP dose intensity over 120,439 person-days.

After adjusting for clinical prognosticators, after a median follow-up of 6.7 years from diagnosis, the researchers found that a mean adherence rate of <95% led to a 2.7-fold increased risk of relapse (p=0.01).

Among adherers, high intra-individual variability in thioguanine nucleotide levels contributed to increased relapse risk (hazard ratio 4.4, p=0.02). Adherers with varying thioguanine levels had varying 6MP dose intensity (odds ratio 4.5, p=0.01) and 6MP drug interruptions (OR 10.2, p=0.003).

Taken together, the researchers say the findings "emphasize the need to maximize adherence to 6MP maintenance therapy regimens and to maintain steady thiopurine exposure to minimize relapse in children with ALL."

In an accompanying editorial, Drs. Franklin O. Smith and Maureen M. O'Brien of the University of Cincinnati College of Medicine, Ohio, note that in children with ALL, "improvements in outcome have started to slow after six decades of almost continuous progress."

However, optimizing known effective therapy is of great value, Dr. Smith told Reuters Health by email, and this paper "is a beautiful example of precision medicine at its best. This study encompasses the power of biology, the study of human behavior and the need to work together in cooperative groups to better understand how to better use even old drugs."

The National Institutes of Health and the American Lebanese Syrian Associated Charities supported this research. Two authors reported receiving partial royalties from genetic testing patents through St. Jude Children's Research Hospital; no other authors made any disclosures.

SOURCE: http://bit.ly/1DkZGkp and http://bit.ly/1HhbBin

JAMA Oncol 2015.

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